text
stringlengths 3.48k
29.8k
|
|---|
Front Neurol Front Neurol Front. Neurol. Frontiers in Neurology 1664-2295 Frontiers Media S.A. 10.3389/fneur.2023.1333474 Neurology Editorial Editorial: Application of noninvasive neuromodulation in cognitive rehabilitation Wei Pengxu 1 * Li Le 2 Lanza Giuseppe 3 4 Cantone Mariagiovanna 5 Gu Ping 6 1Alzheimer's Disease and Cognitive Rehabilitation Committee, Chinese Association of Rehabilitative Medicine, Beijing, China 2Institute of Medical Research, Northwestern Polytechnical University, Xi'an, China 3Department of Surgery and Medical-Surgical Specialties, University of Catania, Catania, Italy 4Clinical Neurophysiology Research Unit, Oasi Research Institute-IRCCS, Troina, Italy 5Neurology Unit, Policlinico University Hospital "G. Rodolico-San Marco", Catania, Italy 6Department of Neurology, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei, China Edited and reviewed by: Andrea Martinuzzi, Eugenio Medea (IRCCS), Italy *Correspondence: Pengxu Wei [email protected] 07 12 2023 2023 14 133347405 11 2023 27 11 2023 Copyright (c) 2023 Wei, Li, Lanza, Cantone and Gu. 2023 Wei, Li, Lanza, Cantone and Gu This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Editorial on the Research Topic Application of noninvasive neuromodulation in cognitive rehabilitationcognitive impairment cognitive training rehabilitation noninvasive neuromodulation neurological diseases National Natural Science Foundation of China 10.13039/501100001809 The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study was supported by the National Natural Science Foundation of China (Grant Number 81972160) and the Science and technology development project of Chinese Association of Rehabilitation Medicine. section-at-acceptanceNeurorehabilitation pmcAlzheimer's disease (AD), Parkinson's disease (PD), cerebrovascular diseases, and many other neurological diseases are common causes of cognitive dysfunction. Mild cognitive impairment (MCI) may progress into dementia, which imposes a severe burden upon patients and their caregivers. Currently, given the lack of disease-modifying treatments, this Research Topic aimed at widening the knowledge on cognitive training and noninvasive neuromodulation therapies including transcranial magnetic stimulation (TMS), transcranial alternating current stimulation (tACS), and focused ultrasound-mediated blood-brain barrier (BBB) opening, which may improve cognitive function and/or reduce deposition of pathologic substances, such as amyloid b (Ab) protein. Sargenius et al. found that for children with acquired brain injury, a 8-week cognitive rehabilitation program resulted in a sustained improvement of executive function lasting for two years. This finding indicates that the 8-weeks training might shape some factors, which facilitated the improvement of cognition in a 2-year period. Similarly, a 4-week video game training in the elderly enhanced cognitive abilities and the training-induced boost in sustained attention and preservation of cognitive improvement could be observed 6 months later (1). Also, a short duration (ten 60-75 min sessions over 5-6 weeks + four 75-min sessions at 11 and 35 months) of specific types of cognitive training for the elderly led to improved cognitive abilities, even at 10 years after intervention (2). These long-term cognitive protection effects suggest that a short-term cognitive training may be a cost-effect intervention for treating or preventing cognitive impairments, although the reason why a short-period training resulted in such long-lasting effects is not fully understood. Additionally, more studies on the long-term effects of cognitive intervention are expected. TMS or tACS can transiently modulate brain activity and improve cognitive function. Chen et al. found that high-definition theta tACS resulted in weakened connections between some brain regions during both resting state and a memory task in health subjects. Yan et al. performed a systematic review and meta-analysis, which demonstrated the effects of TMS on cognitive improvement in patients with MCI and AD. The applied stimulation sites (i.e., the dorsolateral prefrontal cortex and the cerebellum), parameters (e.g., frequency of 5 Hz and 10 Hz), and protocols (such as the intermittent theta-burst stimulation) influenced the effects of TMS interventions. Low-intensity ultrasound (LIUS) beams oscillate intravenous microbubbles to generate acoustic cavitation that, transiently and reversibly, is able to open tight junctions in capillaries and the BBB in the superficial dorsolateral prefrontal cortex as well as deeply located hippocampus and entorhinal cortex (3). This method can be used also for targeted noninvasive delivery of genetic vectors and cells. Zhou et al. reviewed the effects of LIUS combined with microbubble-mediated BBB opening on reducing Ab and tau pathologies, stimulating neurogenesis, and improving cognitive performance in both AD mice and patients with and without delivering any drugs. Interestingly, LIUS combined with intravenous microbubbles resulted in reduction in amyloid burden and cognitive improvement in PD-related dementia (4), led to decreased amyloid accumulation, and slowed down the reduction of glucose metabolism in mild AD patients (5). Taken together, the improvement in cognitive function found in the above studies may stem from a variety of factors, including reduction in amyloid burden, improvement of glucose metabolism status, increases of the activity of local brain regions, and strengthening of functional connectivity between brain areas. Concluding, cognitive training and noninvasive neuromodulation therapies are both safe and effective when rationally applied and in selected cases (6). One of possible applications is to use these methods to decelerate the exacerbation of cognitive impairment (e.g., due to AD) or to improve cognitive function in patients with secondary dementia, such as vascular-related cognitive disorders (7); the other main application can be the disease prevention and differential diagnosis with other, non-degenerative, conditions (8) (more evidence is needed to substantiate these possible applications). For instance, pathologic changes and cognitive decline of AD occur continuously over a long period. Based on different genetic backgrounds, the burden of Ab/tau pathology, neurodegeneration, and cognitive symptoms, three variants of AD are proposed, namely the autosomal dominant AD, the apolipoprotein-E (APOE) e4-related sporadic AD, and the APOE e4-unrelated sporadic AD. What these three variants have in common is that the brain pathological process may occur at the age of around 20, i.e., several decades before the typical dementia onset (9). These low-cost, safe, and effective strategies can be applied during such a long period to enhance brain resilience (e.g., via cognitive training) that may prevent or delay cognitive impairment due to AD and/or to reduce deposition of pathologic substances (e.g., the Ab protein), eventually modifying the progression of AD. Moreover, the parameters of interest of each therapy can be optimized to improve efficacy and feasibility. Additionally, the application of these approaches as a combined therapy is also worth of investigation, considering that they may improve cognitive function through a variety of mechanisms. For instance, LIUS combined with microbubble-mediated BBB opening is applied to reduce Ab pathology in its very early stage, TMS and/or tACS are applied to modulate brain connectivity, and cognitive training is used to increase the so-called "cognitive reserve" for subjects at the early stage of AD pathology (MCI or even earlier). Future studies on larger samples are needed, based on careful sample selection, rigorous methodology, and follow-up. In the meantime, the high-quality translational studies included in this Research Topic may help to disentangle the multifaceted aspects of this complex scenario. Author contributions PW: Conceptualization, Writing - original draft. LL: Conceptualization, Writing - original draft. GL: Conceptualization, Writing - original draft. MC: Conceptualization, Writing - original draft. PG: Conceptualization, Writing - original draft. We deeply thank all the authors and reviewers who have contributed to this Research Topic. Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Publisher's note All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. References 1. Anguera JA Boccanfuso J Rintoul JL Al-Hashimi O Faraji F Janowich J . Video game training enhances cognitive control in older adults. Nature. (2013) 501 :97-101. 10.1038/nature12486 24005416 2. Rebok GW Ball K Guey LT Jones RN Kim H-Y King JW . Ten-year effects of the advanced cognitive training for independent and vital elderly cognitive training trial on cognition and everyday functioning in older adults. J Am Geriatr Soc. (2014) 62 :16-24. 10.1111/jgs.12607 24417410 3. Rezai AR Ranjan M D'Haese PF Haut MW Carpenter J Najib U . Noninvasive hippocampal blood-brain barrier opening in Alzheimer's disease with focused ultrasound. Proc Natl Acad Sci U S A. (2020) 117 :9180-2. 10.1073/pnas.2002571117 32284421 4. Gasca-Salas C Fernandez-Rodriguez B Pineda-Pardo JA Rodriguez-Rojas R Obeso I Hernandez-Fernandez F . Blood-brain barrier opening with focused ultrasound in Parkinson's disease dementia. Nat Commun. (2021) 12 :779. 10.1038/s41467-021-21022-9 33536430 5. Epelbaum S Burgos N Canney M Matthews D Houot M Santin MD . Pilot study of repeated blood-brain barrier disruption in patients with mild Alzheimer's disease with an implantable ultrasound device. Alzheimers Res Ther. (2022) 14 :40. 10.1186/s13195-022-00981-1 35260178 6. Sarica C Nankoo JF Fomenko A Grippe TC Yamamoto K Samuel N . Human studies of transcranial ultrasound neuromodulation: a systematic review of effectiveness and safety. Brain Stimul. (2022) 15 :737-46. 10.1016/j.brs.2022.05.002 35533835 7. Cantone M Lanza G Fisicaro F Pennisi M Bella R Di Lazzaro V . Evaluation and treatment of vascular cognitive impairment by transcranial magnetic stimulation. Neural Plast. (2020) 2020 :8820881. 10.1155/2020/8820881 33193753 8. Lanza G Bella R Giuffrida S Cantone M Pennisi G Spampinato C . Preserved transcallosal inhibition to transcranial magnetic stimulation in nondemented elderly patients with leukoaraiosis. Biomed Res Int. (2013) 2013 :351680. 10.1155/2013/351680 23984349 9. Frisoni GB Altomare D Thal DR Ribaldi F van der Kant R Ossenkoppele R . The probabilistic model of Alzheimer disease: the amyloid hypothesis revised. Nat Rev Neurosci. (2022) 23 :53-66. 10.1038/s41583-021-00533-w 34815562 |
Background Failing bioprosthesis is an emerging issue due to (i) a shift towards liberal bioprosthesis implantation instead of mechanical prosthesis and (ii) an ageing population. Management of high-risk patients with bioprosthesis degeneration remains challenging. Case summary An 82-year-old patient with history of aortic and mitral valve replacement six years before presents with severe dyspnoea. Echocardiograpic assessment reveals (i) structural valve degeneration of the mitral prosthesis (severe stenosis and regurgitation) with concomitant major annular calcifications and (ii) structural valve degeneration of the aortic prosthesis with low-flow, low-gradient restenosis. Due to mitral annular calcifications, the risk of double valve re-replacement and the age of the patient conventional reoperation was deemed very high. The patient is evaluated for transapical double valve implantation. This option is rejected due to the high risk of left ventricular outflow obstruction. The patient is treated with an open transcatheter double valve-in-valve procedure at the following sequence: leaflet resection of the mitral bioprosthesis, mitral valve implantation and fixation under direct view, leaflet resection of the aortic bioprosthesis, and valve frame cracking and aortic valve implantation under direct view. Post-bypass echocardiography shows neither left ventricular outflow tract obstruction nor paravalvular leak or prosthesis dysfunction. The patient is extubated on the first post-operative day and transferred to normal care unit. Discussion Open transcatheter double valve-in-valve replacement for degenerated bioprostheses on the arrested heart might be a valuable alternative to treat selected high-risk patients with bioprosthetic valve degeneration. Valve-in-valve Transcatheter double valve replacement Bioprosthesis degeneration pmcLearning points Evaluation for double valve reoperation Open transcatheter valve implantation Techniques to avoid left ventricular outflow tract obstruction in mitral valve-in-valve implantation Introduction Over 200 000 heart valves are implanted annually worldwide. Improved durability and the evolution of transcatheter techniques have caused a shift towards a more liberal use of bioprosthetic heart valves (BHV) instead of mechanical valves.1 Despite excellent haemodynamic performance and no need for oral anticoagulation (OAC), BHV are prone to structural valve deterioration (SVD). The glutaraldehyde-fixed xenografts evoke a host immune response resulting in progressive valve destruction with pannus growth, leaflet fibrosis, and micro-calcifications causing haemodynamic deterioration and prosthesis failure.2 Predictors for SVD include the size of the used valve prosthesis, patient-prosthesis mismatch (PPM), diabetes, smoking, dyslipidaemia, renal function, the oral anticoagulation regime, and the patient's age at implantation.3 Structural valve deterioration is defined according to the European Association of Cardiovascular Imaging Guidelines as (i) an increase in mean gradient >= 5 mmHg for mitral prosthetic valves and >20 mmHg for aortic prosthetic valves (possible SVD) or >=10 mmHg for mitral prosthetic valves and >=35 mmHg for aortic prosthetic valves (significant SVD) during follow-up, with a concomitant decrease in valve orifice area and abnormal morphology of the prosthetic leaflets and (ii) presence of new transprosthetic regurgitation.4,5 Management of patients with SVD remains challenging, as perioperative mortality after reoperation is significantly increased, especially in elder multimorbid patients, and is as high as 13.8% hospital mortality.6 Although there are only a few case reports, transcatheter valve-in-valve replacement might be a feasible option for selected high-risk patients.7 Summary figure Case presentation An 82-year-old patient presents with shortness of breath and weakness during exertion and rest. His symptoms have been progressive over the last six months. He was previously active, going for regular walks and hikes but is now home bound, significantly affecting his wellbeing. Physical examination reveals a patient with reduced general condition, i.e. NYHA III-IV. There are no signs of congestion, with normal respiratory sounds. A hemi-sternotomy scar is visible on the patient's chest. Cardiac auscultation reveals a systolic aortic murmur. The patient has a history of aortic valve (AV) replacement with a 21 mm Carpentier Edwards Magna Ease bioprosthesis and mitral valve (MV) replacement using a 27 mm St. Jude Medical bioprosthesis six years before. By then, he had severe aortic stenosis with concomitant mitral stenosis and massive mitral annular calcifications . Transthoracic echocardiographic assessment reveals an excentric severe transvalvular mitral regurgitation with a vena contracta of 6 mm and concomitant severe stenosis (diastolic mean pressure gradient 10 mmHg). The aortic valve shows obvious signs of degeneration (calcifications) and a severe low-flow/low-gradient aortic stenosis with a mean pressure gradient of 17 mmHg, an aortic valve orifice area of 0.8 cm2, and an indexed stroke volume of 24 mL/m2. The left atrium (LA) is dilated (56 mm), while other cardiac dimensions and ejection fraction (EF) are normal. The patient has signs of right ventricular strain with mild pulmonary hypertension (sPAP 45 mmHg). Additional transoesophageal echocardiography is performed to dissect the underlying valve pathologies. It reveals a moderately degenerated AV prosthesis with a non-mobile non-coronary cusp due to calcifications. After a planimetrical assessment, AV stenosis is confirmed with an orifice area of 0.8 cm2. Assessment of the MV confirms a distinct, excentric transvalvular mitral regurgitation (EROA 0.54 cm2) with concomitant stenosis. For further patient assessment, left-heart catheterizations are performed. Mean pulmonary capillary wedge pressure is 9 mmHg, mean right atrial pressure is 2 mmHg, mean right ventricular pressure is 2 mmHg, and mean pulmonary artery pressure of 20 mmHg, respectively. The invasive stroke volume index is 21.77 mL/m2, and the invasive cardiac output is 3.39 L/min. There are no signs of coronary artery disease. Carotid ultrasound reveals intima-media thickening on both sides with plaques but no haemodynamically relevant stenosis. Spirometry shows regular pulmonary function. The patient is evaluated for a possible double-valve transcatheter procedure. Cardiac CT reveals no kinking, aneurysms, or relevant stenosis in the femoral and iliac arteries. The patient has increased LDH (388 U/L), hs-TropT (18.6 ng/L), NT-proBNP (835 ng/L), and kidney function is normal (glomerular filtration rate > 60 mL/min/1.73 m2). Moreover, the patient has permanent atrial fibrillation (CHADS2VASC-Score 5, OAC: rivaroxaban) and a stroke history after conversion. Current ECG confirms atrial fibrillation (109 b.p.m.), with no abnormalities in QRS or QTc. The patient is discussed intensively with the heart team. Due to mitral annular calcifications, the risk of double valve re-replacement, and the patient's age, conventional reoperation risk is deemed very high. This is also reflected by Society of Thoracic Surgeons and EuroScoreII risk assessments, with 6.9% and 6.3%, respectively. Therefore, a transapical double valve implantation is taken into account. This option is rejected due to the high left ventricular outflow obstruction risk. Cardiac CT shows an angle of 112deg between LV inflow and outflow. Septal thickness is 7 mm (basal) and 14 mm (midventricular). Left ventricular outflow tract (LVOT) diameter is 20 mm by 27 mm . Figure 1 post-operative transthoracic echocardiography findings. aFib, atrial fibrillation; AOA, aortic valve area; EDVI, end-diastolic volume index; EF, ejection fraction; ESV, end-systolic volume; ESVI, end-systolic volume index; EVD, end-diastolic volume; FS, fractional shortening; HWDD, posterior wall end-diastolic diameter; IVSDD, interventricular septal end-diastolic diameter; LA, left atrium; LVEDD, left ventricular end-diastolic diameter; LVDDI, left ventricular diastolic diameter index; LVDSI, left ventricular systolic diameter index; LVESD, left ventricular end-systolic diameter; RA, right atrium; RV, right ventricle; SVI, stroke volume index; TAPSE, tricuspid annular plane systolic excursion. Figure 2 Pre-operative CT evaluation reveals high risk for LVOT obstruction. Cardiac CT shows an angle 112deg between LV inflow and outflow. Septal thickness is 7 mm (basal) and 14 mm (midventricular). LVOT diameter is 20 x 27 mm. Moreover, the possibility of a PPM further complicates the decision. Finally, the decision is made to treat the patient with an open transcatheter double valve-in-valve procedure. After median re-sternotomy and installation of cardiopulmonary bypass, the MV is exposed via a left atrial roof incision, and the superior vena cava is disconnected from the heart . The high risk of conventional re-replacement of the mitral valve prosthesis due to the massive mitral annular calcification (MAC) can be confirmed after situs inspection. To avoid obstruction of the left ventricular outflow, the leaflets of the mitral bioprosthesis are resected. Subsequently, three sutures are placed at the ring of the degenerated mitral bioprosthesis corresponding to the three commissures. Finally, a 26 mm Edwards Sapien 3 valve is implanted under controlled expansion and direct view. The three sutures are used to stabilize the annulus of the implanted valve and to ensure circular expansion. Next, the AV is exposed via a conventional aortotomy. Severe calcification of the left coronary cusp is identified as the culprit for the gradient and the bioprosthetic dysfunction. Conventional replacement of the bioprosthesis seems to be risky due to the severe calcifications in the aortomitral curtain. The bioprosthetic leaflets are resected to avoid obstruction of the coronary ostia . To fit in a larger aortic valve and to avoid PPM, the remaining bioprosthetic ring is cracked using a 22 mm ATLAS Gold Non-compliant balloon . Subsequently, a 23 mm Edwards Sapien 3 valve is implanted under direct vision . The total cross-clamp time is 76 min. Post-bypass echocardiography shows neither LVOT obstruction nor paravalvular leak or prosthesis dysfunction. The patient is extubated on the first post-operative day and transferred to the normal care unit. Transthoracic echocardiography before discharge reveals an adequate function of both prostheses. Systolic aortic valve mean gradient: 8 mmHg; aortic valve area: 2.35 cm2; systolic mitral valve mean gradient: 6 mmHg; indexed end-diastolic left ventricular volume: 31.14 mL/m2; indexed end-systolic left ventricular volume: 18.48 mL/m2; EF: 40.80%. There are no signs of paravalvular leak (PVL) or haemolysis. Long-term follow-up is needed to evaluate the clinical significance of the initial decline in EF after MV surgery.8 Figure 3 Intraoperative imaging. (A) Exposure of the MV prosthesis, (B) excision of AV prosthesis leaflets, (C) cracking of the prosthesis frame, (D) open transcatheter aortic valve implantation (TAVI) implantation in AV position, (E) deployed transcatheter valve in AV position. The post-operative course is uneventful. The patient can be transferred to the post-operative IMCU on Day 1 and subsequently to the regular ward on Day 3. Post-operative CT confirms the adequate post-operative result . The patient is discharged one week after the intervention. The patient can do long walks and small hiking tours three months after the intervention without symptoms. Follow-up transthoracic echocardiography (TTE) reveals adequate prosthetic function, with an aortic effective orifice area of 2.35 cm2 and no signs of PVL. Figure 4 Post-operative CT scan. Discussion We report an 82-year-old patient with double prosthesis degeneration six years AV and MV replacement. Different treatment strategies were discussed inter-disciplinary in the heart team with the patient and his family. Transcatheter double valve-in-valve replacement is a minimal-invasive treatment option for selected patients with double prosthesis regeneration but seemed unfeasible here due to LVOT and mitral annular calcifications. Therefore, the patient was evaluated for a transapical double valve implantation. However, due to the massive calcifications and an LV-inflow-outflow angle of >60deg, the risk of LVOT obstruction seemed too high. Obstruction of neo-LVOT after transcatheter mitral valve replacement remains a major challenge,9 as it is associated with significantly higher procedural mortality. Estimated neo-LVOT area and aortomitral angulation are predictors for LVOT obstruction. An estimated neo-LVOT area <= 1.7 cm2 is considered high risk. Aortomitral angulation, usually measured in end-systole, describes the angle between the annular planes of the aortic and mitral valves. A near perpendicular orientation, where the mitral valve trajectory runs towards the septum, increases LVOT obstruction risk.10 Surgical re-double valve replacement was considered intensively. However, calcifications of the LVOT refrained us from exchanging the aortic valve. Moreover, extensive mitral annular calcification discouraged us from conventional MV re-replacement. Due to his surgical high-risk profile regarding age and concomitant severe mitral annular calcification, we decided to treat the patient with an open transcatheter double valve-in-valve replacement. Mitral valve was exposed via the LA roof to optimize the trajectory path of implantation. Transatrial access for open transcatheter MV replacement has been suggested as a useful approach in patients with severe MAC.11 To avoid LVOT obstruction in our patient, we chose resection of the MV prosthesis leaflets with subsequent open implantation of the transcatheter valve. This is not feasible in a conventional transcatheter approach, where the displacement of the anterior MV (prosthesis) leaflet through the transcatheter valve can cause LVOT obstruction. One transcatheter option would have been the intentional laceration of the anterior mitral leaflet, called LAMPOON procedure (Intentional Laceration of the Anterior Mitral Leaflet to Prevent Left Ventricular Outflow Tract Obstruction During Transcatheter Mitral Valve Implantation). The results from a small cohort of patients are promising. This procedure is challenging, and patients have to be selected carefully, i.e. leaflets have to be free of calcification.12 Here, three sutures were placed at the ring of the degenerated mitral bioprosthesis corresponding to the three commissures to guarantee circularity of expansion and to avoid a post-operative paravalvular leak. Prior to the implantation of the aortic prosthesis, the leaflets of the aortic valve prosthesis were excised to avoid coronary obstruction. The remaining ring of the aortic valve was cracked to enable the implantation of a larger (23 mm) prosthesis to avoid PPM a technique that has proven useful in using larger valve-in-valve prosthesis.12 This case adds valuable insights into outstanding issues in treating patients with valvular heart disease from a lifetime perspective. Ever-increasing survival rates after valvular procedures scale up the need for secondary procedures. The choice of the first intervention should be driven, amongst commonly known factors, by the options for re-intervention. We herein conclude that open transcatheter double valve-in-valve replacement for degenerated bioprostheses on the arrested heart might be a valuable choice to treat selected high-risk patients with bioprosthetic valve degeneration. Lead author biography Can Gollmann-Tepekoylu obtained a PhD in Molecular Cell Biology focusing on heart failure and valve disease. He has done research fellowships in the USA, Switzerland, and Taiwan and is part of a translational research group based in Innsbruck, Austria. The group was awarded numerous national and international research awards for their work on cardiac regeneration and valvular heart disease. Currently, he is a staff surgeon at the Department of Cardiac Surgery at the Medical University of Innsbruck. His areas of interest are mitral valve surgery, coronary revascularization, and heart failure surgery. Consent: Informed consent was obtained from the patient following COPE guidelines. Funding: None declared. Data availability The data associated with this case report are available upon reasonable request. |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.49194 Family/General Practice Geriatrics Infectious Disease Salmonella Bacteremia in an Older Patient With No Specific Entry: A Case Report Muacevic Alexander Adler John R Kudo Koki 1 Ohara Junya 2 Sano Chiaki 3 Ohta Ryuichi 4 1 Family Medicine, International University of Health and Welfare Graduate School of Health Sciences, Tokyo, JPN 2 Family Medicine, Matsue Seikyo Hospital, Matsue, JPN 3 Community Medicine Management, Shimane University Faculty of Medicine, Izumo, JPN 4 Community Care, Unnan City Hospital, Unnan, JPN Ryuichi Ohta [email protected] 21 11 2023 11 2023 15 11 e4919421 11 2023 Copyright (c) 2023, Kudo et al. 2023 Kudo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License CC-BY 4.0., which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from In this case report, we describe a rare case of non-typhoidal Salmonella bacteremia in an 87-year-old woman with no apparent history of daily Salmonella exposure. The patient presented with fever, body discomfort, and diarrhea. Medical examinations ruled out usual sources of Salmonella, including raw food consumption and pet contact. Her medical history included postoperative sigmoid colon cancer, left breast cancer, and other ailments. Although Salmonella infection typically stems from oral intake, this case suggests that bacterial translocation from the gastrointestinal tract could be the primary cause, potentially exacerbated by the patient's age and medical history. Another hypothesis is an ascending infection from diarrhea to the urinary tract, which might have led to pyelonephritis and subsequent bacteremia. This case highlights the importance of recognizing the potential for severe infections such as sepsis in older individuals presenting with diverse symptoms. Therefore, this case further underscores the need for heightened clinical vigilance, especially in community hospitals, to ensure timely and appropriate management of such severe conditions in the older population. gastrointestinal tract urinary tract infection family medicine general medicine rural hospital older bacteremia salmonella pmcIntroduction Salmonella is a gram-negative, facultatively anaerobic, rod-shaped bacterium belonging to the Enterobacteriaceae family. It is an enterobacterium that lives mainly in the digestive tracts of humans and animals . Salmonella is classified into two groups: those that cause typhoid fever and paratyphoid fever (Salmonella Typhi and Salmonella Paratyphi A), which are classified as class III infectious diseases, and non-typhoidal Salmonella (NTS), which cause infectious food poisoning . Typhimurium is a serotype of NTS, and its official scientific name is Salmonella enterica subsp. enterica serovar Typhimurium . The former is a systemic infection that causes bacteremia, whereas the latter mainly causes infectious enteritis and food poisoning and rarely causes bacteremia . Conservative treatment is often selected, and the disease rarely becomes severe. However, Salmonella infections in the blood can be severe. The entry of Salmonella during infections varies widely, and the immune status of older individuals may be a factor . The primary route of Salmonella infection is oral . It is generally believed that an average of approximately 106-109 or more organisms is required for disease onset . However, according to a survey on actual outbreaks, the number of bacteria required for disease onset was calculated to be approximately 10-104 . Symptoms of Salmonella infection include fever, headache, abdominal pain, diarrhea, and vomiting . In healthy adults, symptoms are limited to gastroenteritis; however, in children and older individuals, the disease can become severe and can result in death from sepsis . In this case report, we describe a case of NTS bacteremia in an older patient. There were no history of consumption of raw eggs or raw meat and no history of pet ownership. We believe that this case provides essential insights into the treatment of future cases of Salmonella bacteremia in older individuals and search for new entries. Case presentation An 87-year-old woman visited the emergency department of a rural community hospital with a chief complaint of fever and difficulty moving her body. Until the day before admission, she was able to lead her daily life without any significant changes. On the morning of admission, she developed a fever of 38degC and diarrhea at a day service. She had not consumed any food that might pose a risk of infection until one week prior and had not consumed raw chicken eggs, raw meat, eels, or soft-shelled turtles. She also did not keep pets or reptiles such as green turtles and had no international travel history. She had a history of postoperative sigmoid colon cancer, postoperative left breast cancer, hypothyroidism, type 2 diabetes mellitus, hypertension, Alzheimer's disease, and a humeral fracture. Her medical history included administration of donepezil (5 mg). The vital signs at the visit were as follows: blood pressure, 136/80 mmHg; pulse rate, 96 beats/min; body temperature, 37.8degC; respiratory rate, 22 breaths/min; and oxygen saturation, 96% on room air. The patient was alert to time, place, and person. A physical examination revealed no lymphadenopathy. No abnormal heart or respiratory sounds were observed. The abdomen was flat and soft, with no spontaneous pain, tenderness over the entire abdomen, or hyperintestinal peristaltic sounds. There were no costovertebral angle tenderness. No edema or skin rash was observed on the extremities. Blood counts showed a normal white blood cell count but a predominance of neutrophils. Biochemical examinations revealed elevated C-reactive protein levels (Table 1). Table 1 Initial laboratory test data of the patient eGFR: estimated glomerular filtration rate; Na: sodium; K: potassium; Cl: chlorine Parameter Value Reference White blood cell count 8.20 3.5-9.1 x 103/mL Neutrophil differential count 90.5% 44.0-72.0% Lymphocyte differential count 7.1% 18.0-59.0% Monocyte differential count 2.0% 0.0-12.0% Eosinophil differential count 0.0% 0.0-10.0% Basophil differential count 0.4% 0.0-3.0% Red blood cell count 4.04 3.76-5.50 x 106/mL Hemoglobin level 11.0 11.3-15.2 g/dL Hematocrit volume 33.5% 33.4-44.9% Mean corpuscular volume 82.9 79.0-100.0 fl Platelet count 15.8 13.0-36.9 x 104/mL Total protein level 6.0 6.5-8.3 g/dL Albumin level 3.7 3.8-5.3 g/dL Total bilirubin level 0.9 0.2-1.2 mg/dL Aspartate aminotransferase level 35 8-38 IU/L Alanine aminotransferase level 18 4-43 IU/L Alkaline phosphatase level 96 106-322 U/L g-Glutamyl transpeptidase level 20 <48 IU/L Lactate dehydrogenase level 287 121-245 U/L Blood urea nitrogen level 17.2 8-20 mg/dL Creatinine level 0.60 0.40-1.10 mg/dL eGFR 69.5 >60.0 mL/min/L Serum Na level 137 135-150 mEq/L Serum K level 3.5 3.5-5.3 mEq/L Serum Cl level 100 98-110 mEq/L Creatine kinase level 104 56-244 U/L C-reactive protein level 7.21 <0.30 mg/dL A simple computed tomography (CT) scan of the abdomen revealed no fluid accumulation in the small or large intestines. Two sets of blood and urine cultures were performed upon admission. On the first day of admission, the fever increased to 39.1degC. Based on diarrheal symptoms and imaging findings, infectious enteritis was diagnosed, and the patient was treated with fluid replacement and symptomatic therapy. On the second day, a blood culture revealed the presence of gram-negative bacilli . Figure 1 Gram stain of blood culture showing gram-negative rods dispersed throughout the field (x400) Cefmetazole (4 g/day) was administered, considering infectious enteritis led to bacteremia. On the seventh day, Salmonella sp. was identified in two sets of blood, urine, and stool cultures. Drug susceptibility testing showed that the patient was sensitive to ampicillin at a dose of 4 g/day, and a change in administration was made. On the seventh day, cardiac ultrasonography was performed for a detailed examination of infective endocarditis caused by Salmonella bacteremia without any abnormalities. Contrast-enhanced CT was performed on the eighth day, investigating any inflammation and abscess formations for the detection of entry of the bacteria. However, no abscess formation or apparent lesions were observed in the skull, lungs, pleura, liver, kidneys, iliopsoas muscle, or large blood vessels. The patient's abdominal pain improved after the second day of illness, and diarrhea persisted until the ninth day. Thereafter, there was no diarrhea or abdominal pain, and the patient recovered to the point where she could consume all her food. On the 29th day, a fecal occult blood test was performed as part of searching for colon cancer; however, the results were negative. On the 31st day, the patient was transferred to a rehabilitation ward and discharged. Discussion In this case report, we present the case of an older patient with Salmonella bacteremia of unknown etiology. Salmonella bacteremia in older patients with no history of Salmonella exposure is rare, and its entry is most likely due to contact infection or bacterial translocation from endemic Salmonella in the intestinal tract . However, there have been no reports of its progression to Salmonella bacteremia. Our case highlights the importance of considering the possibility of Salmonella colonization in the intestinal tract of older patients and the possibility of bacterial translocation, including Salmonella, in older patients who become severely ill due to diarrheal symptoms. Bacterial translocation from the gastrointestinal tract should be considered first as an entry point for Salmonella bacteremia, which includes typhoidal salmonellosis caused by Salmonella Typhi and Salmonella Paratyphi A and non-typhoidal salmonellosis caused by other species of bacteria. Salmonellosis can be classified into typhoidal Salmonella, caused by Salmonella Typhi and Salmonella Paratyphi A, and NTS, caused by other species . NTS is found in the intestinal tract of domestic animals such as chickens, pigs, and cows, as well as in reptiles and rodents . NTS bacteremia is transmitted by the oral ingestion of Salmonella entering the intestinal tract, where macrophages phagocytose them, and they reach the mesenteric lymph nodes via macrophages to avoid bactericidal mechanisms, leading to proliferation in the lymph nodes and bacteremia . In addition, older individuals are at a risk of developing NTS bacteremia. The patient had a history of postoperative sigmoid colon and left breast cancer, and that she was of older age and had a malignant tumor were predisposing factors. Although there have been reports of Salmonella bacteremia in patients with cancer, there have been few reports of Salmonella bacteremia in older patients in Japan, and this novel case suggests the possibility of such cases . No infection sites were observed in this case, and Salmonella was detected in the blood, urine, and stool. The main factors that cause bacterial translocation include changes in the intestinal microbiota, weakening of the intestinal mucosa, and host immunity . The modes of occurrence have been reported to include direct breakthroughs of the intestinal epithelium, intercellular breakthroughs, and phagocytosis by macrophages . In the present case, changes in the intestinal microbiota, intestinal immunity, fragile intestinal mucosa, and host immunity were all associated with the patient's advanced age and postoperative sigmoid colon cancer, and bacterial translocation was likely the cause of the disease . Another possibility for Salmonella bacteremia is that Salmonella migration from the gastrointestinal tract to the urinary tract may have led to pyelonephritis and bacteremia . In Salmonella infection, diarrhea is watery and sometimes contains mucous membranes or blood, which are quickly transmitted to the urinary tract . In this case, the patient presented with fever, abdominal tenderness, and watery diarrhea in large quantities when brought to the emergency room. The details of when the diarrhea began may not be clear because of patient's age and cognitive functions, and we cannot rule out the possibility that the diarrhea preceded the onset of the disease before the patient's arrival. Gram staining of the urine also revealed gram-negative bacilli. Although urinalysis and physical examination findings were not suggestive of pyelonephritis, the urine and blood cultures were positive for Salmonella, suggesting that the patient may have had pyelonephritis and that diarrhea may have caused an ascending infection through the urethra, leading to a blood infection from pyelonephritis, which could have led to bacteremia. The patient's condition may have been caused by the diarrhea. This case highlights the importance of suspecting sepsis and bacteremia in older patients presenting with various symptoms. We believe that medical professionals working in community hospitals, including general physicians, should always be aware of the possibility of fatal sepsis due to various symptoms and respond appropriately to these symptoms to improve the prognosis of older patients in community hospitals . Conclusions In this case report, an 87-year-old woman with no apparent exposure to familiar sources of Salmonella developed NTS bacteremia. Despite having no known risk factors, such as consumption of raw eggs or raw meat or contact with pets, she exhibited severe symptoms, prompting a search for the source of infection. The report concluded that bacterial translocation from the gastrointestinal tract, possibly exacerbated by the patient's age and medical history, may have been a key factor in the bacteremia, underscoring the need for clinicians in community hospitals to be vigilant of signs of sepsis in older patients with diverse symptoms. Author Contributions Human Ethics Concept and design: Ryuichi Ohta, Junya Ohara, Chiaki Sano, Koki Kudo Acquisition, analysis, or interpretation of data: Ryuichi Ohta, Junya Ohara, Chiaki Sano, Koki Kudo Drafting of the manuscript: Ryuichi Ohta, Junya Ohara, Chiaki Sano, Koki Kudo Critical review of the manuscript for important intellectual content: Ryuichi Ohta, Junya Ohara, Chiaki Sano, Koki Kudo Supervision: Ryuichi Ohta Consent was obtained or waived by all participants in this study The authors have declared that no competing interests exist. References 1 Humoral immunity vs. Salmonella Front Immunol Takaya A Yamamoto T Tokoyoda K 3155 10 2019 32038650 2 Antimicrobial drug resistance in Salmonella: problems and perspectives in water-borne infections FEMS Microbiol Rev Threlfall EJ 141 148 26 2002 12069879 3 Virulence factors in Salmonella Typhimurium: the sagacity of a bacterium Curr Microbiol Dos Santos AM Ferrari RG Conte-Junior CA 762 773 76 2019 29785632 4 The global burden and epidemiology of invasive non-typhoidal Salmonella infections Hum Vaccin Immunother Balasubramanian R Im J Lee JS 1421 1426 15 2019 30081708 5 Burden of bacterial bloodstream infection-a brief update on epidemiology and significance of multidrug-resistant pathogens Clin Microbiol Infect Kern WV Rieg S 151 157 26 2020 31712069 6 Invasive non-typhoidal Salmonella (iNTS) infections Clin Infect Dis Fierer J 732 738 75 2022 35041743 7 High incidence of intravascular focus in nontyphoid Salmonella bacteremia in the age group above 50 years: a population-based study APMIS Nielsen H Gradel KO Schonheyder HC 641 645 114 2006 16948817 8 Bacteremia caused by Salmonella Poona in a healthy adult in Tokyo, Japan Intern Med Fukushima K Yanagisawa N Sekiya N Izumiya H 289 292 59 2020 31534082 9 Non-typhoidal Salmonella bacteremia in adults J Microbiol Immunol Infect Yen YF Lin YC Chen TL Chen YY Lin ML Wang FD Liu CY 227 233 40 2007 17639163 10 Salmonella type III secretion effectors: pulling the host cell's strings Curr Opin Microbiol Schlumberger MC Hardt WD 46 54 9 2006 16406778 11 Risk factors for recurrent bacteremia in adult patients with nontyphoid salmonellosis Am J Med Sci Hsu RB Chen RJ Chu SH 315 318 328 2004 15599326 12 Non-typhoidal Salmonella bacteremia among adults: an adverse prognosis in patients with malignancy J Microbiol Immunol Infect Li CW Chen PL Lee NY Lee HC Chang CM Lee CC Ko WC 343 349 45 2012 22209686 13 Nontyphoidal cardiac salmonellosis: two case reports and a review of the literature Tex Heart Inst J Ortiz D Siegal EM Kramer C Khandheria BK Brauer E 401 406 41 2014 25120393 14 Salmonella urinary tract infection and bacteremia following non-typhoidal Salmonella gastroenteritis: an unusual presentation Cureus Altaf A Tunio N Tunio S Zafar MR Bajwa N 0 12 2020 15 Non-typhi Salmonella enterica urinary tract infections Med Mal Infect Mellon G Delanoe C Roux AL 389 393 47 2017 28600113 16 The effectiveness of family medicine-driven interprofessional collaboration on the readmission rate of older patients Healthcare (Basel) Ohta R Sano C 269 11 2023 36673637 17 Family physicians as system-specific specialists in Japan's aging society Cureus Ohta R Sano C 0 14 2022 |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.49140 Pediatrics Pediatric Surgery Oncology Ewing's Sarcoma of the Hand: An Unusual Presentation in a Young Hispanic Male Muacevic Alexander Adler John R McBee Dylan B 1 Bentley Hope A 2 Toledanes Giancarlo 3 1 School of Medicine, Baylor College of Medicine, Houston, USA 2 School of Medicine, McGovern Medical School, Houston, USA 3 Department of Pediatrics, Division of Pediatric Hospital Medicine, Texas Children's Hospital, Houston, USA Dylan B. McBee [email protected] 20 11 2023 11 2023 15 11 e4914020 11 2023 Copyright (c) 2023, McBee et al. 2023 McBee et al. This is an open access article distributed under the terms of the Creative Commons Attribution License CC-BY 4.0., which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from Ewing's sarcoma is a neuroectodermal malignancy classically associated with innocuous and chronic symptomatology. Although tumors typically involve the axial skeleton, some malignancies may be confined to extraosseous tissue only. This report presents the case of a 15-year-old Hispanic male with a tender, slow-growing mass of seven months in the subcutaneous tissue of the right hand. Core needle biopsy and fine needle aspiration confirmed the diagnosis of high-grade extraosseous Ewing's sarcoma and the patient was treated via surgical resection and chemotherapy. Nonspecific findings of Ewing's sarcoma may mimic infection or trauma and contribute to a delay in diagnosis. However, social and economic influences including limited English proficiency and insurance status also critically affect the timing of presentation. upper extremity reconstruction pediatrics chemotherapy sarcoma soft tissue limited english proficiency extraosseous ewing's sarcoma pmcIntroduction Ewing's sarcoma is the second most common bone cancer found in the pediatric population and classically involves bones of the axial and distal skeleton . Despite this, a minority of primary tumors will reliably arise in the extraosseous space . Up to 20% of these cancers may present in soft tissues with reports detailing involvement of almost every major organ . Ewing's sarcoma of the hand is extremely rare with less than 25 cases reported to date [3-12]. A small review suggests that Ewing's sarcoma of the hand most commonly involves the proximal phalanx of either the thumb or third digit . Fatty tissue involvement at the exclusion of bone or muscle is even less likely . Case presentation A 15-year-old Spanish-speaking, Hispanic male with no relevant past medical history presented to the emergency department with one day of acute onset right-hand pain. He reported noticing a small lump on his right hand that grew slowly over the last seven months. The lump was occasionally tender but became significantly more painful in the previous 24 hours. He described the pain as a sharp, stabbing 10/10 pain around the mass, which worsened with manipulation of his fingers. The pain was accompanied by numbness and tingling along his right arm that extended to his thumb and second and third digits. Tylenol taken at home provided little relief, prompting his visit to the emergency department. Physical examination revealed a tense, non-mobile mass involving the dorsal webspace between the first and second fingers. Overlying the mass was a pink-purple discoloration with underlying visible vasculature . The mass was exquisitely tender to palpation but sensation and motor function to the thumb and other digits remained intact. Figure 1 Clinical photograph of the right-hand mass Ultrasound revealed an oval-shaped circumscribed mass measuring 3.2 x 1.8 x 3 cm, arising from the subcutaneous fat with large lobular margins . There was a complex mixed echo architecture consisting of hypoechoic and hyperechoic areas including scattered tiny hyperechoic foci. The mass also demonstrated moderate internal vascularity . Figure 2 Right-hand dorsal ultrasound demonstrating heterogeneous internal echogenicity The patient was ultimately admitted for pain control and further evaluation of the hand mass. MRI of the right hand confirmed a well-defined mass involving only the subcutaneous fat. The mass demonstrated a heterogeneously increased T2 signal that lacked high-flow vasculature . Figure 3 T2-weighted MRI of the right hand without contrast demonstrating heterogeneously increased T2 signal without high-flow vasculature A core needle biopsy and a fine needle aspiration taken the following day confirmed the diagnosis. Smears demonstrated densely clustered small round blue cells with frequent mitoses, apoptosis, and focal necrosis consistent with high-grade features. The cells showed weak, patchy cytoplasmic reactivity for the cluster of differentiation 99 (CD99), and NKX2 nuclear staining was appreciated in 20-30% of the tumor cells. Fluorescence in-situ hybridization (FISH) demonstrated an Ewing's sarcoma breakpoint region 1 (EWSR1) gene rearrangement; however, poor specimen preservation prevented the identification of the exact fusion partner. Ultimately, a diagnosis of extra-skeletal Ewing's sarcoma of the hand was made. The patient underwent complete resection of the tumor with negative margins and subsequent reconstruction using a full-thickness skin graft. Metastatic evaluation for distant disease with full body positron emission tomography (PET) and CT of the chest was negative, and the patient promptly began a standard chemotherapy regimen for non-metastatic Ewing's sarcoma. Alternating cycles of vincristine, doxorubicin, and cyclophosphamide with high-dose ifosfamide and etoposide were administered every two weeks. To date, the patient has completed six cycles of induction chemotherapy with no significant adverse effects. Screenings for lung metastasis using chest CT continue to show no evidence of metastatic disease. Discussion Although Ewing's sarcoma is considered a pediatric cancer, it is primarily a disease of adolescence. The incidence of Ewing's sarcoma climbs gradually with age and peaks at around 15 to 19 years of age . Ewing's sarcoma also varies according to race and ethnicity with an overwhelming majority of diagnoses made in patients of European descent . Despite this, Hispanic patients have a higher proportion of tumors involving soft tissue only, an earlier age of onset, and ultimately inferior survival outcomes compared to white, non-Hispanic patients . The setting and timing of the presentation may also vary according to race. One study found that Hispanic patients were more likely to present to the emergency department rather than to primary care physicians at the onset of their symptoms . Hispanic patients in this study were less likely to have insurance and demonstrated a lower socioeconomic status (SES) on average compared to non-Hispanic patients . Limited English proficiency (LEP) may also significantly delay the time to initial presentation among cancer patients . Thus, barriers to care including lower SES and LEP play into the discrepancy seen in the presentation, prognosis, and outcomes of Hispanic patients. Ewing's sarcoma frequently presents to nononcologic providers with nonspecific or subtle findings. Most patients primarily report point tenderness and persistent pain upon presentation and may or may not have evidence of local erythema or swelling . Clinically, Ewing's sarcoma may mimic a localized infection or minor sports-related trauma; yet, persistent pain noticeable even at night should raise concern for an underlying malignant etiology . As with our patient, the rather indolent and nonspecific findings of Ewing's sarcoma commonly delay definitive diagnosis by several months . Furthermore, a delay in care may be magnified by lower SES, which independently contributes to more advanced presentations with poorer prognosis among childhood cancers . While radiographic and laboratory findings may support a diagnosis, histological and molecular analysis ultimately confirm the presence of Ewing's sarcoma. For tumors involving the skeleton, alkaline phosphatase and lactate dehydrogenase may be elevated . However, these findings are nonspecific and even less useful for extraosseous manifestations of the disease. Radiographic imaging of the affected bone may provide greater diagnostic value. Tumors involving bone have a cluster of cardinal features including the Codman triangle, representing new subperiosteal bone growing over the tumor, as well as a moth-eaten and onion peel appearance . However, these findings are limited once again to skeletal disease. Histologically, Ewing's sarcoma appears as densely clustered small, round, blue cells with prominent nuclei . Our patient demonstrated moderate expression of CD99 on immunohistochemical staining. While not specific to Ewing's Sarcoma, the absence of CD99 expression likely rules out this diagnosis . NKX2.2 provides greater specificity and has gained prominence over the past decade as another standard immunohistochemical marker of this disease . Genetically, Ewing's sarcoma possesses an incredibly low mutational burden compared to other high-grade malignancies . This is because the defining chromosomal abnormality, a translocation of EWSR1 to friend leukemia virus integration 1 (FLI1), results in a fusion protein that alone can drive malignant transformation . The combination of cytotoxic chemotherapy and local reduction through either surgery or radiotherapy remains the mainstay of treatment with a five-year survival rate of 70% for non-metastatic, completely resected disease . The primary prognostic factor is the presence of distant metastasis, most commonly to the lungs, bone, or bone marrow at presentation . Thus, CT of the chest and bilateral bone marrow biopsies are typically performed at diagnosis . Several studies now demonstrate that primary tumors involving the distal extremities reliably favor a better prognosis . This advantage is likely a consequence of their relative isolation and smaller tumor size at presentation . Local control with either radiotherapy or surgery is critical for successful treatment . While not performed for our patient, neoadjuvant chemotherapy also provides the distinct advantage of early response assessment. As demonstrated in the Euro EWING 2012 clinical trial, patients should undergo a standard chemotherapy regimen involving alternating cycles of vincristine, doxorubicin, and cyclophosphamide with high-dose ifosfamide and etoposide every two weeks . Conclusions Ewing's sarcoma most commonly involves the axial skeleton but extraosseous presentation involving any soft tissue is possible. An indolent course defined by nonspecific findings that mimic localized infection or sports-related trauma can significantly delay diagnosis. Barriers to preventative care including lower SES and LEP may further delay early recognition of disease. Radiographic and laboratory findings offer limited value in the context of extraosseous disease while histologic and genetic studies provide true diagnostic value. Ultimately, multimodal treatment involving surgical resection and chemotherapy remains the most effective treatment for Ewing's sarcoma localized to the distal extremities. Author Contributions Human Ethics Concept and design: Dylan B. McBee, Giancarlo Toledanes Acquisition, analysis, or interpretation of data: Dylan B. McBee, Hope A. Bentley Drafting of the manuscript: Dylan B. McBee, Giancarlo Toledanes, Hope A. Bentley Critical review of the manuscript for important intellectual content: Dylan B. McBee, Hope A. Bentley Supervision: Giancarlo Toledanes Consent was obtained or waived by all participants in this study The authors have declared that no competing interests exist. References 1 Ewing's sarcoma N Engl J Med Riggi N Suva ML Stamenkovic I 154 164 384 2021 33497548 2 Extraskeletal versus skeletal Ewing sarcoma in the adult population: controversies in care Surg Oncol Lynch AD Gani F Meyer CF Morris CD Ahuja N Johnston FM 373 379 27 2018 30217290 3 Ewing's sarcoma of the finger: report of two cases and literature review Orthop Traumatol Surg Res Baccari S Hamdi MF Mabrouki Z Daghfous M Tarhouni L 233 237 98 2012 22424955 4 Ewing's sarcoma of the hand BMJ Case Rep Bouzaidi K Sbai MA Daghfous A Marhoul LR 14 2014 2014 5 Ewing's sarcoma of proximal phalanx of the hand with skip metastases to metacarpals Indian J Orthop Shekhar A Korlhalli S Murgod G 365 368 49 2015 26015641 6 Ewing's sarcoma of the finger J Clin Imaging Sci Gokalp MA Kaplanoglu V Unsal SS Erten R 57 4 2014 25379350 7 Ewing sarcoma in an infant metacarpal J Hand Surg Am Skinner S Conant S Lansinger Y 701 705 44 2019 8 Saving the hand: role of multimodality therapy for Ewing's sarcoma family tumor of the palm Adv Radiat Oncol Joseph SA Bhandari R Albert A 205 208 3 2018 29904746 9 Large extraskeletal ewing sarcoma of the hand: a rare entity Ann Afr Med Saran S Kharbanda A Malik S 177 179 18 2019 31417021 10 An extraosseous ewing sarcoma of the index finger masquerading as a benign tumor J Hand Surg Am Wolthuizen R Nieken J Overbosch J Pool SM 366 364 45 2020 11 Ewing sarcoma of the proximal phalanx: case report J Plast Surg Hand Surg Fujii H Honoki K Kobata Y Yajima H Kido A Takakura Y 441 443 48 2014 23822186 12 Ewing sarcoma in the fifth metacarpal of an adult woman: a case report JBJS Case Connect Mahan MC Frisch N Durrant B Parsons T 3rd Woods T Mott M 0 6 2016 13 Osteosarcoma/Ewing sarcoma Pediatr Rev Self C MacQuarrie KL Cost CR 256 265 43 2022 35490205 14 Comparison of Latino and non-Latino patients with Ewing sarcoma Pediatr Blood Cancer Sharib J Horvai A Gray Hazard FK Daldrup-Link H Goldsby R Marina N DuBois SG 233 237 61 2014 23970433 15 Ewing sarcoma demonstrates racial disparities in incidence-related and sex-related differences in outcome: an analysis of 1631 cases from the SEER database, 1973-2005 Cancer Jawad MU Cheung MC Min ES Schneiderbauer MM Koniaris LG Scully SP 3526 3536 115 2009 19548262 16 Limited English proficiency and head and neck cancer outcomes Am J Otolaryngol Duraiswamy S Rubin SJ Kim Y Mur T Edwards HA 103470 43 2022 35427938 17 Survival variability by race and ethnicity in childhood acute lymphoblastic leukemia JAMA Kadan-Lottick NS Ness KK Bhatia S Gurney JG 2008 2014 290 2003 14559954 18 The biology of Ewing sarcoma Cancer Lett Riggi N Stamenkovic I 1 10 254 2007 17250957 19 NKX2.2 is a useful immunohistochemical marker for Ewing sarcoma Am J Surg Pathol Yoshida A Sekine S Tsuta K Fukayama M Furuta K Tsuda H 993 999 36 2012 22446943 20 Comparison of two chemotherapy regimens in patients with newly diagnosed Ewing sarcoma (EE2012): an open-label, randomised, phase 3 trial Lancet Brennan B Kirton L Marec-Berard P 1513 1521 400 2022 36522207 |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.49191 Gastroenterology Internal Medicine Emergency Medicine Complex Diagnostic Dilemma of Viral Hepatitis vs. Drug-Induced Hepatitis: A Case Report Muacevic Alexander Adler John R Sharma Nava R 1 Siriya Pranay 1 Sandhu Samar Pal Singh 1 Pokhrel Madalasa 2 Ching Diana 3 1 Internal Medicine, Maimonides Medical Center, New York, USA 2 Internal Medicine, Montefiore New Rochelle Hospital, New Rochelle, USA 3 Gastroenterology, Maimonides Medical Center, New York, USA Nava R. Sharma [email protected] 21 11 2023 11 2023 15 11 e4919120 11 2023 Copyright (c) 2023, Sharma et al. 2023 Sharma et al. This is an open access article distributed under the terms of the Creative Commons Attribution License CC-BY 4.0., which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from This case report explores the intricate diagnostic challenges encountered in a 30-year-old male patient with abdominal pain, jaundice, and a history of acetaminophen use. Initially presenting as a potential case of drug-induced hepatitis due to acetaminophen overdose, the diagnosis took an unexpected turn when the patient tested positive for hepatitis B surface antigen. The case highlights the complexity of diagnosing acute hepatitis, considering multiple potential etiologies, including viral and drug-induced factors. Differential diagnoses for this case involve considering drug-induced hepatitis, autoimmune hepatitis, various viral hepatitis types, and the potential contribution of cocaine-induced hepatitis as individual possibilities or in combination. This case emphasizes the need for a comprehensive evaluation, the consideration of multiple potential causes, and the importance of ongoing monitoring and follow-up to ensure optimal patient care in cases of acute hepatitis. ebv serology ebv hepatic failure cocaine induced liver injury drug-induced liver injury (dili) viral hepatitis b pmcIntroduction Acetaminophen overdose has emerged as a significant contributor to overdose-related acute liver failure (ALF) and fatalities in the United States, constituting a substantial portion of ALF cases. It is noteworthy that in the United States, overdoses involving acetaminophen are the primary cause of calls made to Poison Control Centers, with an annual incidence exceeding 100,000 . These overdoses lead to more than 56,000 emergency room visits, resulting in approximately 2,600 hospitalizations and, tragically, around 450 deaths attributed to ALF each year . Such cases of ALF attributed to acetaminophen may stem from intentional overdoses or unintentional ingestions, often influenced by various factors, including the concurrent use of alcohol and specific medications known to promote the formation of reactive and harmful metabolites . Simultaneously, hepatitis B presents a global public health challenge with diverse modes of transmission. It can manifest in various forms, further complicated by concurrent infections and clinical factors, making diagnosis a complex task. This case explores the presentation of a previously healthy 30-year-old male with symptoms initially suggestive of acetaminophen-induced hepatotoxicity. However, the subsequent discovery of a positive hepatitis B surface antigen (HBsAg) raised questions about the role of viral hepatitis in his condition. Case presentation We present the case of a 30-year-old male with no significant past medical history who presented to the emergency department with a three-day history of persistent abdominal pain, nausea, and vomiting. He mentioned experiencing flu-like symptoms a week before seeking medical attention. During that period, the patient took oral acetaminophen regularly, around five to eight times a day, with each dose containing 500mg of acetaminophen. This regimen continued for five days. The patient did not measure his temperature but reported feeling feverish without experiencing chills or rigor. The abdominal pain, graded at 10/10 in severity, was diffuse and lasted for approximately one to two hours, exacerbated after meals but spontaneously relieved. Accompanying the pain were episodes of non-projectile, non-bilious vomiting, occurring postprandially and during transit to the hospital. No history of diarrhea, constipation, chest pain, or similar abdominal pain episodes in the past was reported. The patient denied any prior blood transfusions, recent travel, or sick contacts within his family. He acknowledged one female sexual partner and denied any symptoms in his partner. Although he admitted to occasional alcohol consumption and previous cocaine use via snorting, he denied any other illicit drug intake or herbal medications. On further examination, the patient presented with pallor and icterus, indicating a potential underlying hepatic involvement. There were no signs of acute distress, and the patient appeared conscious and oriented. The respiratory examination revealed normal breath sounds without any adventitious sounds. Cardiovascular examination demonstrated a pulse rate of 60 beats per minute, with no murmurs or abnormal heart sounds. The blood pressure was 110/60 mmHg, and the patient exhibited adequate perfusion. The abdomen was soft but tender on palpation, especially in the right upper quadrant, with no palpable organomegaly. Bowel sounds were present and normal. Peripheral edema and clubbing were absent. The neurological examination revealed no focal deficits, and the patient was alert and cooperative throughout the evaluation. Given the patient's history of consuming acetaminophen (paracetamol) at higher than recommended doses for five days and the presentation with abdominal pain, nausea, vomiting, and jaundice, a suspicion of paracetamol toxicity was raised. As a result, the patient was immediately started on N-acetylcysteine (NAC) therapy in the emergency room as per the gastroenterology team's recommendation. Supportive measures, such as intravenous fluids and antiemetics, were provided to alleviate symptoms and maintain hydration. Additionally, investigations were performed to rule out other potential causes of hepatitis, such as viral or autoimmune etiologies, considering the initial uncertainty between viral hepatitis and drug-induced hepatitis. Initial laboratory reports revealed abnormal liver function tests, including significantly elevated levels of alanine aminotransferase at 1631 U/L and aspartate aminotransferase at 800 U/L, well above the normal range. Alkaline phosphatase and total bilirubin levels were also elevated. The initial lab value has been tabulated in Table 1. Furthermore, the patient tested positive for HBsAg, suggesting a concurrent hepatitis B infection. The international normalized ratio was slightly elevated, indicating potential liver dysfunction. Table 1 Initial laboratory value Lab test Normal range Patient's result Hemoglobin (Hb) 13.5-17.5 g/dL 14 g/dL White blood cells (WBC) 4.5-11.0 x 10^3/mL 8 x 10^3/mL Platelet count (PLT) 150-450 x 10^3/mL 200 x 10^3/mL Alanine aminotransferase (ALT) 5-40 U/L 1700 U/L Aspartate aminotransferase (AST) 5-35 U/L 800 U/L Alkaline phosphatase (ALP) 30-120 U/L 200 U/L Total bilirubin (TBIL) 0.2-1.2 mg/dL 8 mg/dL Direct bilirubin (DBIL) 0-0.3 mg/dL 4.9 mg/dL Total protein 6.0-8.3 g/dL 7 g/dL International normalized ratio (INR) 0.8-1.2 1.2 Blood urea nitrogen (BUN) 7-20 mg/dL 14 mg/dL Serum creatinine (Cr) 0.6-1.2 mg/dL 0.8 mg/dL Random blood glucose (RBS) 70-99 mg/dL 90 mg/dL Sodium (Na) 135-145 mmol/L 136 mmol/L Potassium (K) 3.5-5.0 mmol/L 4 mmol/L Ethanol (alcohol) level <10 mg/dL <10 mg/dL Salicylate level <2.5 mg/dL <2.5 mg/dL Acetaminophen level <10 mg/dL <10 mg/dL A CT abdominal and pelvis contrast study showed the liver was normal in size and contour with homogeneous enhancement. There were no masses, but intrahepatic periportal edema was noted. The gallbladder appeared diffusely edematous without any biliary abnormality. It's worth noting that while the CT scan revealed a prominent inferior vena cava (IVC), as in Figure 1, the subsequent echocardiogram (ECHO) did not detect any evidence of right heart failure (RHF) or valvular pathology. Figure 1 Prominent inferior vena cava as shown by a red arrow The patient was admitted for an acute hepatitis workup and management, which included additional tests to evaluate potential causes of hepatitis, such as hepatitis D, autoimmune markers, and viral infections like cytomegalovirus and varicella. All the markers have been tabulated in Table 2. Hepatitis B treatment was started with oral antiviral as per GI recommendation. The patient's history of drug use, including ketamine and cocaine, prompted a urine toxicology screen, which was negative. Cardiac monitoring was ongoing to address the bradycardia observed during the admission. Table 2 Displaying various viral markers Test Patient's result Hepatitis B surface antigen (HBsAg) Positive Hepatitis B surface antibody (HBsAb) Non-reactive Hepatitis B e antigen (HBeAg) Non-reactive Hepatitis B e antibody (HBeAb) Positive Hepatitis B core antibody (HBcAb) Non-reactive Hepatitis C antibody (anti-HCV) Non-reactive Hepatitis C RNA (HCV RNA) Not Detected Hepatitis D antibody (anti-HDV) Non-reactive Hepatitis E IgM antibody (HEV IgM) Non-reactive Herpes simplex 1 IgG antibody Positive Herpes simplex 2 IgG antibody Non-reactive Alpha 1 antitrypsin level Normal Serum ceruloplasmin level Normal Smooth muscle antibody (SMA) Negative Anti-mitochondrial antibody (AMA) Negative Hepatitis A IgM antibody (HAV IgM) Non-reactive During hospitalization the patient improved both clinically and in terms of liver function after inpatient treatment, leading to the decision to defer a liver biopsy. The trend of his liver function test is shown in Figure 2. The patient was discharged and scheduled for a follow-up with the outpatient gastroenterology clinic. The oral antiviral treatment for hepatitis B was continued as per the recommendation of the gastroenterologist. He was also advised to monitor his liver function closely to assess the response to the treatment and ensure the stabilization of his liver enzymes and bilirubin levels. Figure 2 Graph showing the trend of liver function test All values are in U/L. AST: Aspartate Aminotransferase; ALT: Alanine Aminotransferase Discussion The presented case of a 30-year-old male with abdominal pain, jaundice, and a history of acetaminophen use raises several diagnostic challenges. The patient's initial presentation with severe abdominal pain, elevated liver function tests, and jaundice led to the suspicion of drug-induced hepatitis, particularly due to acetaminophen overdose. Acetaminophen toxicity is a well-recognized cause of acute liver injury, marked by specific clinical and laboratory features. These include elevated transaminases and increased bilirubin levels. Additionally, patients may exhibit symptoms such as nausea, vomiting, abdominal pain, and jaundice, while laboratory findings might also reveal prolonged prothrombin time and an elevated international normalized ratio . NAC, an antidote for acetaminophen overdose, was promptly administered to this patient . This decision was made without waiting for the patient's acetaminophen levels due to the worsening condition at presentation. The gastrointestinal team recommended NAC intervention, recognizing the imminent risk of the patient progressing into liver failure. This underscores the critical importance of early intervention in such cases. However, the presence of a positive HBsAg introduced an unexpected twist in the diagnosis. Concurrent hepatitis B infection is an important consideration in patients with acute hepatitis, as it can exacerbate liver injury and complicate the clinical course. While this patient had a positive HBsAg, the hepatitis B e antigen was non-reactive, and the viral load was relatively low (3.32 log IU/mL). These findings raised questions about whether the acute hepatitis was solely due to hepatitis B or if there was a combination of drug-induced and viral hepatitis. The patient was initiated on antiviral treatment for hepatitis B, guided by the hepatologist's recommendations . In the process of differential diagnosis, several other causes of hepatitis were also considered and subsequently ruled out. These included autoimmune hepatitis, assessed with markers such as anti-smooth muscle antibody and anti-mitochondrial antibody. The serological markers for hepatitis A, C, D, and E were all non-reactive, further narrowing down the potential etiologies. In the differential diagnosis, the possibility of cocaine-induced hepatitis was also considered. Chronic cocaine use has been associated with hepatotoxicity, with features such as elevated liver enzymes and histological changes . However, establishing a direct causal link between cocaine and hepatitis can be challenging, as multiple factors, including concomitant substance abuse, can contribute to liver injury . Nevertheless, given the complexity of this case, the exact contribution of cocaine to the hepatic pathology remains unclear and requires further investigation. The discrepancy between the CT scan findings of a prominent IVC and the negative findings on ECHO raised an interesting point . While the prominent IVC could have been associated with right heart congestion, it did not correspond with the absence of findings related to RHF or valvular pathology on ECHO. This highlights the need for comprehensive assessment and consideration of all clinical and radiological findings in complex cases, as they may not always align neatly with the working diagnosis. The patient showed clinical improvement and enhanced liver function following inpatient treatment in this clinical case. Consequently, the decision was made to postpone a liver biopsy due to its invasive nature and the perceived lack of immediate necessity. While this choice of not doing a biopsy had benefits, such as minimizing patient risk and reducing costs, it also had limitations, including the absence of a definitive diagnosis and missed opportunities for detailed information and tailored treatment planning. However, it highlights that refraining from a biopsy can be justified in certain circumstances. The management of this patient involved a multidisciplinary approach, including medical intervention for hepatitis and substance use counseling. The patient's response to treatment and commitment to behavioral change were positive indicators of a favorable outcome. In conclusion, this case emphasizes the complexity and challenges in diagnosing patients with acute hepatitis. It underscores the importance of a thorough evaluation, considering multiple potential etiologies, and highlights the need for ongoing monitoring and follow-up to ensure optimal patient care. Conclusions In conclusion, this case report underscores the complex diagnostic challenges faced by patients with acute hepatitis. Initial suspicions of drug-induced hepatitis, notably due to acetaminophen overdose, can be further complicated by unexpected findings, as demonstrated in this case with the concurrent presence of hepatitis B infection. It is worth noting that this case is likely multifaceted, involving a combination of acetaminophen-induced drug injury, viral hepatitis, and potentially some element of cocaine-induced liver injury. The intricacies of this case emphasize the importance of a comprehensive and nuanced diagnostic approach in managing patients with acute hepatitis. The comprehensive, multidisciplinary approach to this patient's care, which involved both medical interventions for hepatitis and substance use counseling, led to positive clinical outcomes. The case underscores the significance of thorough evaluation, consideration of multiple potential etiologies, and the need for continuous monitoring and follow-up to ensure optimal patient care in cases of acute hepatitis. It also emphasizes the complexity of establishing causality in cases involving multiple contributing factors, such as cocaine use, and the importance of carefully weighing diagnostic invasiveness with patient safety and cost-effectiveness. Author Contributions Human Ethics Concept and design: Nava R. Sharma, Pranay Siriya, Samar Pal Singh Sandhu Acquisition, analysis, or interpretation of data: Nava R. Sharma, Diana Ching, Pranay Siriya, Madalasa Pokhrel Critical review of the manuscript for important intellectual content: Nava R. Sharma, Diana Ching, Madalasa Pokhrel, Samar Pal Singh Sandhu Supervision: Nava R. Sharma, Diana Ching Drafting of the manuscript: Pranay Siriya Consent was obtained or waived by all participants in this study The authors have declared that no competing interests exist. References 1 Acetaminophen (APAP) hepatotoxicity - isn't it time for Apap to go away? J Hepatol Lee WM 1324 1331 67 2017 28734939 2 Estimates of acetaminophen (paracetomal)-associated overdoses in the United States Pharmacoepidemiol Drug Saf Nourjah P Ahmad SR Karwoski C Willy M 398 405 15 2006 16294364 3 Acute liver failure including acetaminophen overdose Med Clin North Am Fontana RJ 761 0 761-94, viii 92 2008 18570942 4 Acetaminophen-induced hepatotoxicity: a comprehensive update J Clin Transl Hepatol Yoon E Babar A Choudhary M Kutner M Pyrsopoulos N 131 142 4 2016 27350943 5 Acetylcysteine for acetaminophen poisoning N Engl J Med Heard KJ 285 292 359 2008 18635433 6 Antiviral therapy in acute viral hepatitis B: why and when Infect Agent Cancer Morelli G Perrella A Sbreglia C Bellopede P Riccio V Perrella O 2 4 2009 19149879 7 A case of cocaine-induced acute liver failure reversed with N-acetylcysteine Cureus Mitchell MC Rogers C 0 15 2023 8 Cocaine and opioid-induced acute liver injury: a rare case report Cureus Dolkar T Hamad AM Han MM Thu MB Gayam VR 0 14 2022 9 Idiopathic dilatation of inferior vena cava: a case report Cureus Malik A Chaudhry M Abdullah M Inam SH Iqbal N 0 12 2020 |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.49147 Anesthesiology Cardiac/Thoracic/Vascular Surgery Radiology Foreign Body Misdiagnosed as Mucus Plugging After Percutaneous Tracheostomy Muacevic Alexander Adler John R Amien Bothayna 1 Harky Amer 1 Hill Amy 2 Mediratta Neeraj 1 1 Cardiothoracic Surgery, Liverpool Heart and Chest Hospital, Liverpool, GBR 2 Anaesthesia and Critical Care, Liverpool Heart and Chest Hospital, Liverpool, GBR Bothayna Amien [email protected] 20 11 2023 11 2023 15 11 e4914720 11 2023 Copyright (c) 2023, Amien et al. 2023 Amien et al. This is an open access article distributed under the terms of the Creative Commons Attribution License CC-BY 4.0., which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from We report a case of a 59-year-old male who presented with a persistent cough for a year after being discharged from critical care following a subarachnoid haemorrhage. As part of his initial critical care management and in order to allow full neurological assessment, the patient required a period of prolonged mechanical ventilation, which necessitated a percutaneous tracheostomy. Following recovery and subsequent discharge, the patient presented on multiple occasions with cough, undergoing serial computed tomography (CT) scans which reported mucus plugging as a possible cause of the cough. As his symptoms continued to worsen, a flexible bronchoscopy was carried out, which identified a foreign body in the trachea. This object was later recognised as a retained part of the guiding catheter, part of the percutaneous tracheostomy tube dilator. After the object was retrieved, the patient reported a complete resolution of symptoms. Percutaneous tracheostomy is a common procedure within critical care units, and early complications such as bleeding or airway obstruction are typically recognised immediately after insertion. This report documents a late complication caused by the retention of a foreign object from insertion, which was misdiagnosed on serial CT scans, leading to persistent cough over a period of months. misdiagnosis persistent cough mucus plug airway foreign body percutaneous tracheostomy pmcIntroduction Percutaneous tracheostomy is a common procedure within critical care units, being performed frequently in patients requiring longer-term mechanical ventilation . Lessening the requirement for any sedative agents that may be needed for endotracheal tube tolerance, it can allow for accurate neurological assessment, easier patient communication, and consistent engagement with physiotherapy, among other reported benefits . Like all invasive procedures, there is the potential for risk, which must be balanced along with the perceived benefits. Reported major early complications include airway obstruction or bleeding at the insertion site present at the time of insertion with defined and acute signs . Other less life-threatening complications such as tracheostomy site infection are easily identifiable but again follow a more defined and easily diagnosed clinical course . Later complications may present with vague symptoms, leading to delays in diagnosis or misdiagnosis, as demonstrated in this case where a foreign body was misdiagnosed as mucus plugging despite serial CT scans and hospital attendances. Case presentation The patient, 59-year-old male, had suffered a subarachnoid haemorrhage (SAH) in July 2020, following which he was managed in a neurological critical care unit for a period of two months. His past medical history consisted of a cerebral vascular accident (CVA) in 2015, gastro-oesophageal reflux, and a high BMI of 44 kg/m2. He had never smoked. During this admission, he required a period of prolonged ventilation, and a subsequent percutaneous tracheostomy in order to allow for sedation-free neurological assessment and weaning from ventilatory support. After successful tracheostomy decannulation and discharge from the speech and language team allowing him to take an oral diet, he was transferred to a neurological rehabilitation unit due to his persistent right-sided weakness and expressive dysphasia. After discharge from the rehabilitation unit, he started to report a persistent cough. In March 2021, he was coincidentally admitted to the hospital with Enterococcus faecalis septicaemia. At this time, his persistent cough was investigated by CT scan, which reported collapse and consolidation in the right lower lobe (unchanged since 2020), and mild mucus secretions in the trachea. The Ear, Nose, and Throat (ENT) team also reviewed him, and the laryngeal assessment showed right vocal cord weakness, attributed to his previous CVA. Upon review by the respiratory team, the symptoms had improved; therefore, further investigation by bronchoscopy wasn't considered necessary at that time. A repeat CT scan in December 2021 showed a stable appearance of the trachea and right middle and lower lobe bronchi. The partial collapse of the right lobe was attributed to mucus plugging, although radiologists were unable to exclude any endobronchial lesion on imaging completely . Figure 1 CT scan showing stable appearance of the trachea and right middle and lower lobe bronchi. The partial collapse of the right lobe was attributed to mucus plugging When the patient's symptoms recurred after this, a bronchoscopy was performed by the respiratory team who found a white tube-like foreign object, which measured 15 cm and reached the right lower lobe bronchus, in the upper trachea seated between the vocal cords and the carina. The patient was referred to our cardiothoracic unit for assessment and removal of the foreign body that was seated between the vocal cords. The cardiothoracic team retrieved the foreign body using a rigid bronchoscopy under general anaesthesia . Figure 2 White fine tube-like structure in the trachea reaching the right lower lobe bronchus Discussion Tracheostomy is more commonly performed in the critical care setting via the percutaneous method, so as to allow mechanical ventilation along with sedation-free neurological assessment . As an invasive procedure, tracheostomies pose potential risks, and complications can be categorised as early or delayed. In-hospital mortality following tracheostomy has been reported as up to 22% in one study . A systematic review by Delaney et al. looking into tracheostomy complications reported an early (within 48 hours) bleeding incidence of 5.7%, commonly attributed to damage to superficial veins . After 48 hours, any bleeding was more likely to be caused by major vessel involvement, e.g. innominate artery. Stomal infections occur in 6.6% of cases . Late complications happen in a further 67% and include delayed closure of the stoma, airway obstruction, tracheal stenosis, tracheomalacia, and tracheoesophageal and tracheoinnominate fistulas . The incidence of tracheostomy obstruction has been reported at 0-3.5% . Common causes include mucus plugging and obstruction resulting from clotted blood in the tube. Although this obstruction typically causes a presentation early after tracheostomy insertion, there have been reports of partial obstruction causing chronic symptoms . Miyata et al. reported a case of an 81-year-old woman with a history of dyspnoea and productive cough, having had a double cannula tracheostomy sited 12 years previously. On this occasion, CT diagnosed a foreign body in the trachea thought to be a granuloma but further investigations revealed this to be a mucus plug . There are very few documented cases in the literature of retention of a foreign body following tracheostomy, either via the surgical or percutaneous method. The first case report identified dates back to 1960 and reports tracheostomy cannula fragments in the right main bronchus, discovered after presenting with respiratory infection with the tracheostomy tube in place This was attributed to season cracking of the cannula, caused by long-continued high internal stress . Mahattanasakul et al. presented a case series of four patients in whom fractured metallic tracheostomy tubes were identified, with the most common presentations being dyspnoea, intolerable cough, and decreased breath sounds on auscultation . The most severe presentation described was that of one patient who suffered a cardiac arrest. The tracheostomy tubes had been in place for an average number of 24 days, and the dislodged tubes were retrieved by either flexible or rigid bronchoscopy . Another case report described a situation where a polyvinyl chloride (PVC) tracheostomy tube fractured and migrated to the right main bronchus and was retrieved using bronchoscopy . In the above cases, all patients presented with respiratory symptoms. In most, the tracheostomy tube was still in place, making the diagnosis easier. In our case, the patient presented with mild respiratory symptoms over a prolonged period after decannulation, making it difficult to correlate with the previous episode of tracheostomy. Moreover, the foreign body was diagnosed as a mucus plug partly as it fits the history of immobility and stroke. This patient eventually underwent bronchoscopy because of persistent symptoms and the retained foreign body tube then became evident and was retrieved under general anesthesia using rigid bronchoscopy. To the authors' knowledge, this is the first case of a part of the insertion kit of the tracheostomy tube to be dislodged into the trachea. Mechanism of retained foreign body In this report, we describe a case of a foreign body inadvertently left within the airways after the insertion of a percutaneous tracheostomy tube. The usual method of insertion is described below, providing an explanation of why the 'guiding catheter' may have been unaccounted for. Via a Seldinger technique, the introducer needle is first passed into the trachea under bronchoscopic guidance, usually between the first and second or the second and third tracheal rings, aiming for as close to the 12-o clock position as possible. A guidewire is then passed through this needle and observed within the airway again using bronchoscopy. A small incision is usually made to make the passage of dilators easier but is not always required using the classical Seldinger technique . Figure 3 The percutaneous tube dilator (1), guiding catheter (2), and guiding wire (3) Image credit: Rashid and Islam, 2017 ; CC BY-NC-ND 4.0 Deed/Attribution-NonCommercial-NoDerivs 4.0 International This specific set requires initial dilation with a 14 French 'introducer dilator', followed by formal dilation using the larger tracheostomy tube dilator. To smooth the passage of the second, larger dilator' and avoid trauma to the airways that could be created from the end of the multi-dilator, a narrow and longer 'guiding catheter' is placed within the larger dilator, through which the guidewire can pass. The two together provide a smooth and gradual increase in size during dilation over the guidewire and are advanced together within the trachea to the necessary marking. The guidewire is then left within the trachea, and the 'guiding catheter' is pulled back in order to allow placement of the definitive tracheostomy over this, again providing a smooth and gradual increase in the size of the kit and avoiding a definitive lip and potential trauma. The tracheostomy, guidewire and 'guiding catheter' are then advanced into the trachea, with the 'guiding catheter' and guidewire being removed. The final position of the tracheostomy is determined again by bronchoscopy . We propose that the 'guiding catheter' was not removed alongside the guidewire after the tracheostomy insertion, most likely due to the need to use this piece of equipment twice, and the requirement to manipulate it to align with both the larger (second) dilator and the actual tracheostomy. In addition to this, components of Seldinger sets are not commonly counted in the same way as surgical swabs and instruments, especially within ward and critical care environments. Conclusions This case report describes persistent and late symptoms years after a percutaneous tracheostomy. The mild symptoms were initially attributed to mucus plugging but the persistence of symptoms led to the late recognition of the retained part of the guiding catheter from the percutaneous tracheostomy insertion kit. Complications of tracheostomy insertion can occur long after the patient has been decannulated and discharged from the hospital. They may present with mild respiratory symptoms rather than acute airway obstruction, and a high index of suspicion is required in patients with a history of previous tracheostomy who present with ongoing respiratory symptoms. We suggest in the event of non-resolving, late symptoms after decannulation, a bronchoscopy should be considered to rule out any retained objects. We also described the mechanism of the retained foreign body; this is to further shed light on a rare incident. This case emphasises the need for careful counting of all parts of Seldinger procedure kits, in order to prevent similar occurrences in the future. Author Contributions Human Ethics Concept and design: Bothayna Amien, Amy Hill, Neeraj Mediratta Acquisition, analysis, or interpretation of data: Bothayna Amien, Amer Harky, Amy Hill, Neeraj Mediratta Drafting of the manuscript: Bothayna Amien, Amy Hill Critical review of the manuscript for important intellectual content: Bothayna Amien, Amer Harky, Amy Hill, Neeraj Mediratta Supervision: Amer Harky, Amy Hill, Neeraj Mediratta Consent was obtained or waived by all participants in this study The authors have declared that no competing interests exist. References 1 Percutaneous dilatational tracheostomy versus surgical tracheostomy in critically ill patients: a systematic review and meta-analysis Crit Care Delaney A Bagshaw SM Nalos M 0 10 2006 2 Tracheotomy outcomes and complications: a national perspective Laryngoscope Shah RK Lander L Berry JG Nussenbaum B Merati A Roberson DW 25 29 122 2012 22183625 3 Retrospective analysis of post-tracheostomy complications Am J Otolaryngol Murray M Shen C Massey B Stadler M Zenga J 103350 43 2022 34974381 4 Tracheostomy tube placement: early and late complications J Bronchology Interv Pulmonol Fernandez-Bussy S Mahajan B Folch E Caviedes I Guerrero J Majid A 357 364 22 2015 26348694 5 Acute airway obstruction by a mucus plug in a patient with a 12-year history of inserting a double cannula tracheostomy tube: a case report SAGE Open Med Case Rep Miyata J Dateoka K Yoshioka T 2050313 10 2022 6 Broken tracheotomy tube as a foreign body Lancet Bassoe HH Johs Boe 1006 1007 1 1960 13797429 7 Fracture outer metallic tracheostomy tube as an airway foreign body Indian J Otolaryngol Head Neck Surg Mahattanasakul P Kaewkongka T Sriprasart T Kerekhanjanarong V 1752 1756 74 2022 36452832 8 Tracheostomy tube as foreign body in right main bronchus: a case report Indian J Otolaryngol Head Neck Surg Waindeskar V Kumar S Agrawal D 4835 4836 74 2022 36742719 9 Percutaneous tracheostomy: a comprehensive review J Thorac Dis Rashid AO Islam S 0 38 9 2017 |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.49142 Obstetrics/Gynecology Oncology Primary Fallopian Tube Carcinoma Presenting as a Broad Ligament Fibroid: A Rare Case Muacevic Alexander Adler John R Joshi Jalormy S 1 Shanoo Amardeep 1 Dave Apoorva 1 Patel Nainita 1 1 Obstetrics and Gynaecology, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND Jalormy S. Joshi [email protected] 20 11 2023 11 2023 15 11 e4914220 10 2023 20 11 2023 Copyright (c) 2023, Joshi et al. 2023 Joshi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License CC-BY 4.0., which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from Primary fallopian tube carcinomas (PFTCs) are quite rare with the incidence ranging from 0.3% to 1.1% amongst all the gynaecological malignancies. Here, we present a rare case of a 44-year-old female (parity-2, live-2 and abortion-2), with one previous classical caesarean section and one vaginal birth after caesarean section (VBAC), bilateral tubal ligation done referred to our gynaecology OPD with complaints of pain in the abdomen since the past six days. The patient also had complaint of spotting per vagina for the past two months. Her ultrasonography and contrast-enhanced CT abdomen and pelvis were suggestive of broad ligament fibroid, which turned out to be a PFTC. Primary fallopian tube malignancies are so rare that this entity may be missed in routine clinical practice and surprisingly noticed during operative procedure or on histopathology reports. Thus, one must be aware of this rare clinical entity and keep it in mind while taking patients on the operating table. pftc primary fallopian tube carcinoma diagnostic dilemma gynecological malignancy broad ligament fibroid pmcIntroduction Primary fallopian tube carcinomas (PFTCs) are the rarest form of all gynaecological malignancies. The PFTC incidence rate ranges from 0.3% to 1.1% . The commonest age of occurrence is 40 to 65 years, with the mean age being 55 years . The term was first defined by Reynaud in 1847 . According to population studies, the mean incidence of PFTCs is 3.6 per million women per year . Metastatic carcinoma of the fallopian tube from the ovaries, gastrointestinal tract (GIT), endometrium and breast is more common as compared to primary cancers . Advanced fallopian tube and adnexal carcinomas are mostly misdiagnosed as ovarian carcinomas, so the true incidence could be higher . As shown by histological, molecular and genetic analyses, most of all high-grade serous carcinomas of the ovary and peritoneum have their origin in the fimbrial end of the fallopian tube . The staging systems and treatment strategies used for epithelial ovarian carcinomas (EOCs), like cytoreductive surgeries and adjuvant chemotherapy, are also applied to PFTCs . This makes the pre-operative diagnosis of PFTCs extremely difficult . PFTCs have a classical triad of symptoms, which include vaginal bleeding, pelvic pain and vaginal discharge . However, the presence of these symptoms is not sufficient to make a pre-operative diagnosis of PFTCs. Here, we present a rare case of primary fallopian tube malignancy that we accidentally encountered while operating on a suspected case of broad ligament fibroid based on ultrasound and contrast-enhanced CT scan findings. Case presentation A 44-year-old female, parity-2, live-2 and abortion-2 (P2L2A2), with a previous classical caesarean section and one VBAC, had bilateral tubal ligation done 15 years ago and had been post-menopausal for the past year. She was referred to gynecology OPD with a chief complaint of pain in the abdomen for the past six days. The pain was dull in nature in the lower abdomen, non-radiating, not associated with food intake, and was relieved by medications. The patient also had complaints of spotting per vagina for the past two months, soaking half a pad per day. The patient also complained of difficulty passing urine and constipation. There was a history of decreased appetite and generalized weakness. There were no other gastrointestinal or menstrual symptoms. The patient had no other medical or surgical illnesses. There was no family history of similar complaints or malignancies. The patient was poorly built, weighing around 42 kg. On examination of the patient, her general condition was moderate; as per the Eastern Cooperative Oncology Group (ECOG) Performance Status, she was grade two; she was afebrile and severely pale, cachexic and malnourished. The patient had tachycardia (pulse rate 122/min) and tachypnea (respiratory rate 22 cycles/min), and her blood pressure was 106/70 mmHg. Her cardiovascular and respiratory examinations were within normal limits. As per abdominal examination, the abdomen was overdistended and tense with no dilated veins. A vertical infra-umbilical classical caesarean section scar was present until pubic symphysis. An irregular mass of 24 to 26 weeks of uterine size was felt arising from the pelvis with globular enlargement. Bulk of the mass felt towards the left side of the abdomen. The margins of the mass were poorly defined with variegated consistency. Mass was non-mobile in nature. Per speculum examination, the vagina was healthy. The cervix was healthy, effaced and pulled up. On per vaginal examination, the uterus was irregularly enlarged with a 22-24-week size and variable consistency. The mobility of the uterus was decreased; uterine movements were transferred to the cervix. Most of the bulk of the mass was felt on the left side of the abdomen. The patient's hemoglobin (Hb) was 6.3 gm% at the time of admission, total leucocyte count (TLC) was 18,600/cumm and platelets were 2.57L/cumm. CA-125 was 46.9 U/mL. The patient's thyroid-stimulating hormone (TSH) was 6.92 mlU/L, and she was started on tab thyroxine 25 mcg before breakfast. Her renal function test (RFT), liver function test (LFT) and coagulation profile were within normal limits. The patient was transfused with a total of four units of packed red cells (PRCs) to reach Hb levels of 9.6 g/mL. A plain radiograph of the chest (CXR P-A view) was within normal limits. An endometrial biopsy of the patient was taken and sent for histopathological examination, which was suggestive of endometrial tissue and glands in the proliferative phase of the cycle. A cervical smear was taken and sent for cytological examination, which was suggestive of an inflammatory smear with absent malignant cells. Ultrasonography was done, which was suggestive of an ill-defined heterogeneously hyperechoic mass of 15.2x13.8x11.4 cm with free hypoechoic areas within it in the right adnexal region extending superiorly up to the umbilicus. The mass was taking minimal vascularity on Doppler. Endometrial thickness was 6 mm. The right ovary was not visualized, and the left ovary was normal. There was the presence of gross ascites with echogenic debris. Contrast-enhanced CT scan of the abdomen and pelvis was done, which was suggestive of a large, well-defined solid-cystic mass showing heterogenous post-contrast enhancement, measuring 16.3x13.4x13.3 cm, noted in the right adnexal region extending superiorly into the abdomen up to the umbilicus and causing displacement of adjacent bowel loops. The right ovary is not visualized separately. The left ovary appears normal. Omental caking with mesenteric fat stranding is noted. Free fluid in the abdomen and pelvis with bilateral pleural effusion is shown in Figures 1-2. Figure 1 Contrast-enhanced CT abdomen and pelvis axial section showing a solid (black arrow)-cystic (white arrow) mass Figure 2 Contrast-enhanced CT abdomen and pelvis sagittal section solid-cystic mass in the right adnexal region (white arrow) An exploratory laparotomy was done for the patient. A midline vertical incision was taken adjacent to the scar of the classical C-section. The abdominal cavity was filled with hemorrhagic ascitic fluid. Around four liters of hemorrhagic ascitic fluid were drained from the cavity and sent for cytological examination. A huge, solid-cystic tumour that was encapsulated with a broken capsule at the inferior surface of the tumour was seen, and necrotic debris from the tumour was seen in the peritoneal cavity. The tumour was occupying the lower abdomen, from the pelvis up to the umbilicus, placed in front of the uterus. The right ovary was incorporated into the tumour and could not be identified separately. The tumour was twisted three times over the right cornual structures. The right fallopian tube was visualized along with para-tubal cysts. The left ovary, left fallopian tube, uterus and cervix were visualized and were normal . Figure 3 An encapsulated mass arising from right fallopian tube that is twisted three times over the right cornual structures (white arrow) Figure 4 A huge, encapsulated solid-cystic tumour (white arrow) with a broken capsule at the inferior surface and necrotic debris (black arrow) The tumour mass was excised, along with total abdominal hysterectomy (TAH) with bilateral salpingo-oophorectomy and partial-omentectomy. Lymph nodal dissection was not done as it was not enlarged when palpated intra-operatively. An intraperitoneal drain was placed in situ for five days. The post-operative period was uneventful. Hemorrhagic ascitic fluid cytology was positive for malignant cells. Histopathological examination revealed adenocarcinoma of the fallopian tube, with the right fallopian tube and omental tissue being positive for infiltration by malignant cells, while the right ovary, left ovary, left fallopian tube, uterus, cervix and retroperitoneal nodes were negative for infiltration by malignant cells . Figure 5 The section shows the lumen filed with fine papillae, tumour cells with a high N:C ratio, loss of polarity and lack of ciliates cells (black arrow) Figure 6 The section shows infiltration of the omental tissue by tumour cells having round to oval nuclei, showing pleomorphism, hyper-chromasia and prominent nucleoli (black arrow) By the International Federation of Gynecology and Obstetrics (FIGO) staging of PFTCs, this cancer is staged as FIGO stage 3A. After debulking surgery, on the basis of the histopathology report, paclitaxel 135 mg/m2 IV infusion over three hours with cisplatin 100 mg/m2 IP on day 1 with paclitaxel 60 mg/m2 IP on day eight, every 21 days for six cycles was given to the patient. The patient tolerated chemotherapy well with minimal gastrointestinal side effects. After that, the patient was lost to follow-up. Discussion Primary malignancies of the fallopian tube are quite rare, and the incidence ranges from 0.3% to 1.1% of all gynaecological cancers. The commonest age of occurrence is 40 to 65 years, with the mean age being 55 years . PFTCs also have associations with tuberculous salpingitis, chronic tubal inflammation, infertility and tubal endometriosis. The high parity of women seems to have a protective effect on PFTCs . The spread is predominantly through the ostia of the tube into the peritoneal cavity. The ovaries and uterus are the most important sites of metastasis. Exfoliation of malignant cells from the primary tumour and their migration towards the fallopian tube to reach the cervix may lead to an early diagnosis of PFTCs by cervical smear examination . Thus, early detection of tumours via cervical cytology may be possible before the disease advances. Initial diagnostic criteria of PFTCs include an essential imaging method in daily practice for the assessment of patients with a potential cancer, such as transvaginal and transabdominal ultrasound . About 90% of fallopian tube carcinomas turn out to be adenocarcinomas by histological examination; among them, half are papillary serous adenocarcinomas . Pelvic and para-aortic lymph node involvement accounts for 34% of all nodal involvements in almost all stages of PFTCs. Although PFTCs and EOCs share many molecular and clinical traits, PFTCs appear to recur more frequently, and metastasis in distant sites and retroperitoneal nodes is more common . Stage, patient age and, among patients with advanced-stage cancer, residual tumour following initial surgery are crucial prognostic factors for survival . In cases of PFTCs, early metastases, direct peritoneal implantation and lymphatic spread are very common. Due to the advanced stage at the time of diagnosis, the prognosis is mostly poor . Patients with PFTCs typically have low overall survival rates, ranging from 22% to 57%, with a five-year survival rate of 47.4% . However, with early clinical presentation and prompt investigations, an early diagnosis can be made, which in turn improves the prognosis. Preoperative diagnosis is rare, so PFTCs are typically verified by a pathologist . All in all, PFTCs are the rarest among gynaecological malignancies; preoperative diagnosis is difficult in these cases . Total abdominal hysterectomy (TAH) with bilateral salpingo-oophorectomy and pelvic and para-aortic lymph node dissection with omentectomy must be done together for surgical staging. Aggressive cytoreductive surgery should be performed in patients with advanced stages of PFTCs . Primary FTC is a rare and difficult-to-treat disease. FTC is treated similarly to epithelial ovarian cancer because of its clinical behavior, which includes surgical debulking and platinum-based chemotherapy. Although there have been significant improvements in the care and treatment of epithelial ovarian cancer over the past few decades, the survival rate has only slowly increased since the development of platinum-based chemotherapy. However, novel treatments for both primary and recurrent disease, such as immunotherapy, poly (ADP-ribose) polymerase (PARP) inhibitors and anti-vascular endothelial growth factor (VEGF) antibodies, are altering the course of the illness and extending patients' lives . Conclusions This case report emphasizes the significance of taking into account unusual and uncommon gynaecological cancers, particularly in patients with alarming clinical characteristics. Early detection and adequate care of primary fallopian tube cancer can dramatically improve patient outcomes. When treating pelvic masses, doctors should always have a high degree of suspicion and be ready to reevaluate their original diagnoses in the event of unexpected findings. Author Contributions Human Ethics Concept and design: Jalormy S. Joshi, Amardeep Shanoo, Apoorva Dave, Nainita Patel Acquisition, analysis, or interpretation of data: Jalormy S. Joshi, Amardeep Shanoo, Apoorva Dave, Nainita Patel Drafting of the manuscript: Jalormy S. Joshi, Amardeep Shanoo, Apoorva Dave, Nainita Patel Critical review of the manuscript for important intellectual content: Jalormy S. Joshi, Amardeep Shanoo, Apoorva Dave Supervision: Amardeep Shanoo, Apoorva Dave Consent was obtained or waived by all participants in this study The authors have declared that no competing interests exist. References 1 Bilateral microscopic adenocarcinoma of the fallopian tubes detected by an endometrial cytologic smear Int J Gynecol Pathol Maeda D Takazawa Y Ota S 273 277 29 2010 20407329 2 Incidence of ovarian cancer of grand multiparous women Gynecol Oncol Marianne H Eero P Pentti K Antti K 207 211 103 2006 16595149 3 Primary fallopian tube carcinoma Eur J Obstet Gynecol Reprod Biol Kalampokas E Kalampokas T Tourountous I 155 161 169 2013 23622731 4 Primary fallopian tube carcinoma diagnosed preoperatively by cervical smear Ann Saudi Med Ural UM Balik G Tekin YB Sehitoglu I Bedir R Sahin FK 444 446 34 2014 25827704 5 Cancer of the ovary, fallopian tube, and peritoneum: 2021 update Int J Gynaecol Obstet Berek JS Renz M Kehoe S Kumar L Friedlander M 61 85 155 2021 34669199 6 The distal fallopian tube: a new model for pelvic serous carcinogenesis Curr Opin Obstet Gynecol Crum CP Drapkin R Miron A Ince TA Muto M Kindelberger DW Lee Y 3 9 19 2007 17218844 7 Fallopian tube carcinoma J Oncol Pract Stasenko M Fillipova O Tew WP 375 382 15 2019 31283415 |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.49185 Internal Medicine Dermatology Drug-Induced Linear IgA Bullous Dermatosis in an Oncologic Patient Muacevic Alexander Adler John R Quispe-Garate Luz A 1 Espinoza-Escudero Renzo B 2 Salas-Rivera Carlos 2 Sanchez-Felix Gadwyn 2 1 Medicine, Universidad Nacional Mayor de San Marcos, Lima, PER 2 Dermatology, Hospital Nacional Edgardo Rebagliati Martins, Lima, PER Luz A. Quispe-Garate [email protected] 21 11 2023 11 2023 15 11 e4918520 11 2023 Copyright (c) 2023, Quispe-Garate et al. 2023 Quispe-Garate et al. This is an open access article distributed under the terms of the Creative Commons Attribution License CC-BY 4.0., which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from Blister formation in the skin can result from various conditions, such as autoimmune disorders, drug reactions, infections, etc. A comprehensive patient assessment may offer clues for diagnosis. Linear IgA bullous dermatosis (LABD) is a rare subepidermal blistering disorder characterized by the deposition of IgA at the basement membrane zone of the skin and mucous membranes. Here, we describe a case of a patient with a new onset of painless blisters located in the skin and oral mucosa after initiating antibiotic treatment. bullous dermatosis clinical dermatology cutaneous adverse drug reaction vancomycin reaction linear iga bullous dermatosis pmcIntroduction Linear IgA bullous dermatosis (LABD) is a rare skin disease due to IgA autoantibodies against the basement membrane zone. It has an incidence rate of 0.2 to 0.4 per million per year, with two peaks in childhood and adulthood, respectively. Diagnosis is made based on clinical, histopathological, and immunological features. It classically presents with clear or hemorrhagic vesicles and blisters with a widespread distribution in the extremities, trunk, buttocks, and face, some with an annular pattern. Mucosal involvement can also occur with blisters, erosions, and ulcerations, mainly in the oral cavity and genital areas . Although LABD is commonly described as an idiopathic disease, some precipitating factors have been identified such as drugs, systemic diseases (such as non-Hodgkin lymphoma, chronic lymphocytic leukemia, ulcerative colitis, and systemic lupus erythematosus), and trauma . Here, we report a case of drug-induced LABD after administering vancomycin therapy. Case presentation A 69-year-old woman presented to the Emergency Department with a six-month history of edema, erythema, and pain in her left arm. Her previous medical history includes cirrhosis, retinal detachment, and a recent diagnosis of hepatic carcinoma with metastatic involvement of the bone and lungs. She was not on chemotherapy at presentation. Tumoral process was identified following a pathologic fracture of the left humerus which was treated with osteosynthesis . She reported being allergic to penicillin and iodine. Figure 1 Radiologic findings (A-C) An 85x65 mm heterogeneous, solid mass with a wedge-shaped morphology located in the hepatic segments VII and VIII. It partially surrounds the right suprahepatic vein near the inferior vena cava, without infiltration of its lumen. Splenomegaly is also appreciated. (D) Left upper arm X-ray showing osteosynthesis of humerus shaft with fracture callus. (E) In the axial plane, there is a neoformative process in the distal-middle third of the left arm that measures 10x10 cm. (A, E: Multislice spiral CT without contrast) (B, C: Contrast-enhanced MRI). Physical examination revealed a temperature of 36 degrees Celsius, blood pressure of 120/60 mmHg, heart rate of 91 beats per minute, respiratory rate of 17 breaths per minute, and oxygen saturation of 98% on room air. Laboratory analysis showed hemoglobin of 11.26 g/dL (reference range: 12-16 mg/dL), white blood cell count of 2.06 x 103/uL (4-10 x 103/uL), neutrophils 1.6 x 103/uL (1.5-7.5 x 103/uL), lymphocytes 0.3 x 103/uL (1-5.2 x 103/uL), platelets 42.4 x 103/uL (150-450 x 103/uL), urea of 17 mg/dL (10-50 mg/dL), creatinine of 0.53 mg/dL (0.5-1.4 mg/dL), C-reactive protein of 1.2 mg/dL (<0.5 mg/dL), and procalcitonin of 0.194 ng/mL (<0.065 ng/mL). She was admitted under the diagnosis of possible cellulitis, and antibiotic coverage with vancomycin was started (1 g IV every 12 hours). She presented a generalized bullous skin eruption on the ninth day of treatment. Physical examination revealed erosions on the oral mucosa and multiple tense vesiculobullous lesions across the neck, chest, abdomen, back, arms, and legs in an arciform or annular configuration with a string-of-pearls appearance . Nikolsky and Asboe-Hansen signs were negative. Antibiotic use was suspended, and lesional and perilesional punch biopsies were taken from a blister on the chest for H&E staining and direct immunofluorescence (DIF) testing. Figure 2 Lesions in oral mucosa (A) Erosions of the vermillion border of both lips; (B) Tense hemorrhagic blister on the tip of the tongue; (C) Erythematous erosions on a white background in the lateral aspect of the tongue. Figure 3 Lesions in skin Multiple tense bullae across the neck (A), arm (B), and back (C), some of them showing a string-of-pearls appearance. Based on the patient's history, vancomycin-induced LABD, paraneoplastic pemphigus, and bullous pemphigoid were considered differential diagnoses. Histopathologic findings revealed a subepidermal blister with a neutrophilic infiltrate in the upper dermis. There was no evidence of apoptotic keratinocytes or interface dermatitis. In DIF, a linear band of IgA at the basement membrane zone was found . A diagnosis of vancomycin-induced LABD was made. Five days after withdrawing the antibiotic, there was no appearance of new lesions. The complete recovery was achieved two weeks later without further treatment . Figure 4 Histopathological and direct immunofluorescence findings (A) Histology specimen showing subepidermal blisters (H&E, x40); (B) There is an inflammatory infiltrate in the upper dermis composed mainly by neutrophils (H&E, x200); (C) Biopsy specimen from perilesional skin revealing linear IgA deposits in the basement membrane zone (arrow) (direct immunofluorescence, x200). Figure 5 (A, B) Improvement of skin lesions one week after the withdrawal of vancomycin Discussion LABD is a skin disorder due to the deposition of IgA autoantibodies in the basement membrane zone. It is commonly described as an idiopathic blistering disorder, but a drug-induced variant has been reported. Pediatric and adult populations are affected, with a mean age of diagnosis of 5.4 and 60.6 years, respectively. It usually manifests with vesiculobullous lesions on an erythematous base involving the limbs, trunk, head, or buttocks. Mucosal involvement has also been described, with oral, genital, and conjunctival lesions in order of frequency . Other common findings include a string-of-pearls pattern, erythematous plaques, erosions, and target-like lesions . Pathogenesis is not clearly understood. IgA autoantibodies bind to different hemidesmosomal antigens. Antibody targets include bullous pemphigoid 180-kDa (BP180), 97-kDa protein (LABD-97), 120-kDa protein (LAD-1) (both extracellular domains of BP180), type VII collagen, laminin 332 and bullous pemphigoid 230 kDa antigen (BP230). These target proteins can be divided into two categories: lamina lucida and sub-lamina densa types. LAD-1 and LABD-97 are the most common targets in the lamina lucida type. In contrast, type VII collagen has been identified as the main target in sub-lamina densa type . Drug-induced LABD was first described in 1981 in a woman under diclofenac therapy . Since then, many other drugs have been linked to this variant. Vancomycin has been identified as the most common triggering factor (46.2%) . However, it can be associated with amoxicillin, amoxicillin-clavulanic acid, imipenem, metronidazole, ketoprofen, enoxaparin, verapamil, atorvastatin, etc. The median time from first drug intake to disease onset is nine days. Compared to idiopathic LABD, erosions and Nikolsky sign are more common in drug-induced LABD, with a higher frequency of lesions mimicking toxic epidermal necrolysis (TEN) when vancomycin is identified as the root cause . Although our patient had a negative Nikolsky sign, the onset and disease localization were consistent with the literature. In H&E staining, there is evidence of subepidermal blisters with neutrophilic infiltration in the papillary dermis. However, this feature is not pathognomonic as it is also visualized in bullous lupus erythematosus, dermatitis herpetiformis, and bullous vasculitis . Additional findings may include eosinophilic infiltration of the upper dermis, neutrophil microabscesses in the dermal papillae, and necrotic keratinocytes. The most important diagnostic feature in DIF is a linear IgA deposition in the basement membrane zone, either alone or accompanied by IgG, IgM, or complement deposits . Management is centered on drug discontinuation. Dapsone is considered the first-line therapy for both adult and pediatric populations. Treatment can be started at low doses (25 mg/day) and titrated up over time based on clinical condition (50-150 mg/day). In children, doses range from 0.5-2 mg/kg/day. Dapsone-induced hemolysis is a serious adverse effect reported in people with glucose-6-phosphate deficiency (G6PD). Therefore, patients must be screened for G6PD before starting drug administration. Sulfonamides (sulfapyridine or sulfamethoxypyridazine) are considered alternative agents that can be used alone or combined with dapsone. Suldapyridine dose ranges from 1000-1500 mg/day, in adults, and 15-60 mg/kg/day, in children . Other therapeutic options include rituximab, IV immunoglobulin, topical and systemic corticosteroids, colchicine, cyclosporine, nicotinamide, and tetracyclin. Depending on the skin and mucosal involvement, these agents can be used alone or in combination, and frequency and dosing vary depending on clinical criteria. In recent years, omalizumab and etanercept have also been used as alternative agents . LABD has a good prognosis. The remission rate ranges from 75-81% in the idiopathic and drug-induced variants . The mean time to complete clinical remission is 13 days (1-21 days) in vancomycin-induced LABD, and 2.7 weeks (1-5 weeks) in drugs other than vancomycin . Finally, vancomycin has been linked to a variety of immune-mediated reactions. Type IV hypersensitivity reactions include, in order of frequency, LABD, drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, Stevens-Johnson syndrome, and TEN . We emphasize the importance of identifying drug-induced cutaneous reactions, especially in patients with multiple comorbidities and a new onset of blistering lesions. Conclusions This case report emphasizes the importance of integrating clinical and pathological features when diagnosing bullous dermatosis. LABD is a rare entity that can be triggered by drug intake that leads to blister formation in skin and oral, genital, and conjunctival mucosa. Lesions usually improve after discontinuing drug treatment, but some agents like vancomycin may increase the risk of developing a life-threatening skin reaction. Therefore, proper monitoring should be provided for early diagnosis and adequate treatment. Author Contributions Human Ethics Concept and design: Luz A. Quispe-Garate, Renzo B. Espinoza-Escudero, Carlos Salas-Rivera, Gadwyn Sanchez-Felix Drafting of the manuscript: Luz A. Quispe-Garate, Renzo B. Espinoza-Escudero, Carlos Salas-Rivera Critical review of the manuscript for important intellectual content: Luz A. Quispe-Garate, Renzo B. Espinoza-Escudero, Gadwyn Sanchez-Felix Supervision: Luz A. Quispe-Garate Consent was obtained or waived by all participants in this study The authors have declared that no competing interests exist. References 1 Linear immunoglobulin A bullous dermatosis Clin Dermatol Fortuna G Marinkovich MP 38 50 30 2012 22137225 2 Linear IgA bullous dermatosis in adults and children: a clinical and immunopathological study of 38 patients Orphanet J Rare Dis Genovese G Venegoni L Fanoni D Muratori S Berti E Marzano AV 115 14 2019 31126328 3 Linear IgA bullous dermatosis: comparison between the drug-induced and spontaneous forms Br J Dermatol Chanal J Ingen-Housz-Oro S Ortonne N 1041 1048 169 2013 23815152 4 Sublamina densa-type linear IgA bullous dermatosis with IgA autoantibodies specific for type VII collagen: a case report and clinicopathological review of 32 cases Dermatol Online J Utsunomiya N Chino T Oyama N 11 23 2017 5 Autoantibody profile of a cohort of 54 Italian patients with linear IgA bullous dermatosis: LAD-1 denoted as a major auto-antigen of the lamina lucida subtype Acta Derm Venereol Cozzani E Di Zenzo G Gasparini G 0 100 2020 6 Drug-induced bullous dermatosis with linear IgA deposits along the basement membrane Acta Derm Venereol Gabrielsen TO Staerfelt F Thune PO 439 441 61 1981 6172936 7 A critical reappraisal of the current data on drug-induced linear immunoglobulin A bullous dermatosis: a real and separate nosological entity? J Am Acad Dermatol Fortuna G Salas-Alanis JC Guidetti E Marinkovich MP 988 994 66 2012 22169257 8 Drug-induced linear immunoglobulin A bullous dermatosis: a French retrospective pharmacovigilance study of 69 cases Br J Clin Pharmacol Garel B Ingen-Housz-Oro S Afriat D 570 579 85 2019 30511379 9 Histologic characterization of cellular infiltration in autoimmune subepidermal bullous diseases in a tertiary hospital in Saudi Arabia Clin Cosmet Investig Dermatol BinJadeed HF Alyousef AM Alsaif FM Alhumidi AA Alotaibi HO 187 194 11 2018 10 A clinical and serological study of linear IgA bullous dermatosis without linear immunoglobulin deposition other than IgA at the basement membrane zone using direct immunofluorescence Br J Dermatol Ohata C Ishii N Koga H Nakama T 152 157 177 2017 27943257 11 Management options for linear immunoglobulin a (IgA) bullous dermatosis: a literature review Cureus Khan M Park L Skopit S 0 15 2023 12 Updates in the diagnosis and management of linear IgA disease: a systematic review Medicina (Kaunas) Shin L Gardner JT 2nd Dao H Jr 818 57 2021 34441024 13 Immune-mediated reactions to vancomycin: a systematic case review and analysis Ann Allergy Asthma Immunol Minhas JS Wickner PG Long AA Banerji A Blumenthal KG 544 553 116 2016 27156746 |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.49130 Preventive Medicine Epidemiology/Public Health Medical Education Trust by Proxy Muacevic Alexander Adler John R Grewal Mehr 1 Chow Eric J 234 1 Post-COVID Recovery and Rehabilitation Research Group, University of Washington, Seattle, USA 2 Department of Public Health, Public Health - Seattle and King County, Seattle, USA 3 Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, USA 4 Department of Epidemiology, University of Washington, Seattle, USA Mehr Grewal [email protected] 20 11 2023 11 2023 15 11 e4913020 11 2023 Copyright (c) 2023, Grewal et al. 2023 Grewal et al. This is an open access article distributed under the terms of the Creative Commons Attribution License CC-BY 4.0., which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from The coronavirus disease 2019 (COVID-19) pandemic revealed the importance of improving the accessibility of quality public health messaging especially among underserved communities. By establishing a robust communication infrastructure, communities may begin to address the disparities exacerbated by misinformation. In this article, we describe the work done by Worth a Shot, a community-led organization that partnered with trusted, informed county residents; the county residents served as "public health ambassadors" who provided accurate, timely information to their communities in a culturally sensitive approach. This youth-led work may serve as a model for other communities that seek to improve outreach to underserved communities. covid-19 community engagement trust in physician misinformation public health messaging pmcEditorial "Look around you. I'm not sick, you're not sick, nobody is sick. I repeat, there is no COVID (coronavirus disease) in these premises," the gentleman emphasized, gesturing to the church and community center where we were gathered. It was March 2020, and I was there with a group of volunteers, distributing hand sanitizers and masks in light of the usual Sunday congregation. While the world was grappling with the declaration of emergency of international concern, my heart sank as I heard his words repeating in my mind. This was my community, one that I cared deeply about. And this gentleman was a trusted community leader whose family I was close with; his grandson was a high school classmate of mine. To hear him amplify misinformation while many around me struggled to decipher the thicket of COVID-19 news left me confused and discouraged. This type of inaccurate information led many in the community to let their guard down, leading to infection, hospitalization, and sometimes death that may otherwise have been preventable. In December 2020, news of highly efficacious COVID 2019 (COVID-19) vaccines was announced , marking a significant turning point in the public health pandemic response. Anticipating initial vaccine hesitancy , I jumped at the opportunity to rally my community. Early on, these efforts included bringing together community physicians, college students, and medical students to develop data-driven education material to inform the community of the benefits of vaccines. Being mindful of the diverse population in our community, informational packets were brought to local community hubs in 26 different languages. We distributed these to more than 200 churches, community centers, and grocery stores across the state, not only in the Seattle area but also in the more rural areas of eastern Washington. Our activities were frequently paired with local public health department outreach to deliver vaccine messaging and vaccines to underserved communities. Our group trained 512 speakers, 449 community advocates, and 256 health leads, and held 23 information sessions. They, in turn, informed their own communities about the importance of vaccine uptake. These combined efforts ultimately coalesced into a nonprofit organization, Worth A Shot , with a mission to amplify public health messaging through community advocacy. During the early days of our organization, activities were centered on bringing public health resources and messaging to communities hit hardest by the pandemic. We set up Seattle Street Sinks at business locations around the greater Seattle area to encourage hand hygiene as the first line of defense against the spread of COVID-19 and other illnesses. We partnered with a community hospital to distribute hand sanitizers, masks, sanitizing wipes, thermometers, and other health essentials to the community during our biannual health fairs. Our most successful activity was our community ambassador program involving more than 300 medical students and healthcare professionals, many of them immigrants and refugees who spoke a variety of languages and served as community ambassadors to raise awareness and answer questions from their communities. Through our program, medical students were able to develop and enhance their professional identity, which helped to reaffirm their commitment to public health. Our activities evolved with the pandemic, initially focusing on preventive measure messaging and then broadening to include COVID-19 vaccination and informing the community. As our organization's members grew, so did our scope of work. We began locally in the Seattle metropolitan area, but gradually expanded to other parts of Washington State, the Pacific Northwest, and then to different regions of the United States (US). As of 2023, we also have international chapters located in Germany, India, Haiti, the United Kingdom (UK), and Nigeria. It was becoming clear to me that it was the young people in the community who were eager to support our work. It was these youth-driven activities that were truly having an impact on community conversations. Through our activities, we would strive towards a mission to educate and empower youth to be health advocates and public health leaders in their own communities. As a direct result, Worth a Shot was loosening the grip of misinformation while also training the next generation of community leaders, scientists, and entrepreneurs. I initially assumed that the body of work we would embark on would require medical degrees and years of training that only individuals established in their careers would offer. But in our youth sessions, we talked about how community youth could make a difference by influencing the conversations and narratives in their communities in a powerful way. By educating and empowering young people, we were also reaching their parents and family members, communicating in a way that their families understood. I sought to extend a youth seminar invitation to my classmate whose grandfather inspired me to take those first steps months ago. He seemed intrigued but also hesitant. "My family keeps saying that all these stories about the virus are made up. I'm not sure whom to believe." I shared that the session would include expert physicians from the community to answer any questions he would have and bring clarity to the topics he had on his mind. Not only was he able to attend our session, but he also asked many questions that reflected general community sentiments and perceptions. The questions were reflective of the distrust and skepticism that had been pervasive in the community. "I heard that the vaccine is an mRNA vaccine," he asked. "Wouldn't it alter my DNA?" The allergy/immunology physician we had on the panel provided reassurance that the mRNA from the vaccine would not enter the nucleus of the cell, where the DNA is stored. Moreover, the mRNA would degrade after the necessary proteins were made. "These vaccines were developed so fast!" he exclaimed. "How could we possibly trust them to be safe?" This time it was the infectious disease physician's turn to answer. She was familiar with the process and had collaborated closely with people involved in the policymaking. "Normally, it takes years to design, test, and authorize a vaccine," she said. "But in light of the current public health emergency, billions of dollars were given worldwide for the vaccine development, which allowed its developers to make rapid progress. Normally, companies may have to wait years to get funding for their work. They underwent rigorous testing, with just as much scrutiny as would normally be given." Behind each of the questions was someone who was sifting through the multiple data sources to get to the truth. I followed up with him after the session and discovered that, in fact, language was a barrier to accessing accurate vaccine information, and frequently educational material was not available to his parents. He overcame this obstacle and shared the information he learned that night. Several weeks later I heard a familiar voice while volunteering at my church's community center. "Hi, everyone," he said a little hesitantly. "I made some comments about COVID-19 when I didn't want to believe what everyone was saying. Recently, someone shared the truth about COVID-19 with me. I realized I had been wrong. COVID-19 is real. The virus is spreading around our community, and we are at risk because many of us aren't wearing masks or taking measures to protect ourselves." He went on to promote mitigation measures including the use of face masks, social distancing, and the uptake of vaccines. The moment led to a palpable wave of emotion that gripped the community center. I stood at the back, beaming because of what I had just witnessed. Listening to those words reaffirmed Worth a Shot's mission to empower the youth of our communities as public health advocates. Whether they realized it or not, these youth leaders were shifting the mindsets of the community in the face of an onslaught of misinformation that is now pervasive in our society. The youth were more knowledgeable and experienced than society gave them credit for. They were able to nimbly navigate the nuances of social media platforms, bridging the information gap in the conversation with their families. These changes could begin with a simple remark at the dinner table. More than ever, children of immigrants or refugees help parents and other family members navigate the informational world around them. By reaching young people today, we were making an impact here and now. While the impact of our programs has been palpable through the >10,000 youth and families we have connected with worldwide, I am most inspired by the experience shared by youth who were able to shape community conversations because of the activities we have sponsored. One such story came from a girl from France whose parents were both immigrants and faced language barriers. Because they had not been able to access public health messaging, they remained unvaccinated. However, after a Worth a Shot seminar, she was able to explain the science behind the vaccine and helped both her parents get vaccinated a month later. These stories are daily reminders that the impact and influence of youth on their communities should not be undervalued . They shape procedures and policies and shift the mindsets of communities, all behind the scenes. Improving our societies doesn't have to involve elaborate community programs. In fact, it can start at home, in our local communities. When you witness these community-level changes started by determined youth, you know the investment was worth a shot. Author Contributions Concept and design: Mehr Grewal, Eric J. Chow Acquisition, analysis, or interpretation of data: Mehr Grewal, Eric J. Chow Drafting of the manuscript: Mehr Grewal, Eric J. Chow Critical review of the manuscript for important intellectual content: Mehr Grewal, Eric J. Chow Supervision: Eric J. Chow The authors have declared that no competing interests exist. References 1 A Timeline of COVID-19 Vaccine Developments in 2021 11 2023 2023 2 COVID-19 vaccine hesitancy in Delaware's underserved communities Dela J Public Health Wang SX Bell-Rogers N Dillard D Harrington MA 168 175 7 2021 34604782 3 Worth A Shot 7 2023 2023 4 Clean Hands Collective 7 2023 2023 5 The role of tailored public health messaging to young adults during COVID-19: "There's a lot of ambiguity around what it means to be safe" PLoS One Cheng T Horbay B Nocos R Lutes L Lear SA 0 16 2021 |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.49071 Dentistry Maxillary Cast Partial Denture and Mandibular Implant-Supported Metal-Ceramic Prosthesis With a Split Framework to Compensate for Mandibular Flexure: A Case Report Muacevic Alexander Adler John R Ananya 1 Rani Priya 1 Sinha Tushar 1 Prakash Jayant 2 1 Prosthodontics, Rajendra Institute of Medical Sciences, Ranchi, IND 2 Dentistry, Sadar Hospital, Muzaffarpur, IND Tushar Sinha [email protected] 19 11 2023 11 2023 15 11 e4907117 11 2023 Copyright (c) 2023, . et al. 2023 . et al. This is an open access article distributed under the terms of the Creative Commons Attribution License CC-BY 4.0., which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from The goal of modern dentistry is to restore optimum oral health, function, and comfort for a patient. For an implant-supported fixed prosthesis, these goals cannot be met if the biomechanical factors governing the success of the prosthesis are overlooked. Mandibular flexure is one such factor that needs to be considered, especially when implants are being placed posterior to the interforaminal region. If not, it can lead to problems like increased stress, bone resorption, poor fit of the prosthesis, screw loosening, and patient discomfort. The use of a split-framework prosthesis is one of the measures that could be taken to decrease the stress, ensure a passive fit of the framework, and long-term maintenance of patient comfort and function. This case report describes the oral rehabilitation of a patient using a maxillary cast partial denture and mandibular split framework fixed prosthesis to compensate for mandibular flexure. implant-supported fixed prosthesis framework splitting mandibular flexure cast partial denture dental implants pmcIntroduction Dental implants have gained popularity over the past few decades for the rehabilitation of edentulous patients and patients with implant-supported prostheses observed marked improvement in oral health, function, and comfort than patients with conventional removable prostheses . However, the recent evolutions in implant dentistry emphasize the use of new geometries and prosthetic designs based on restorative and biomechanical properties and the behavior of implant rehabilitation . One such factor is median mandibular flexure. It is the deformation of the mandible portrayed by the property of the mandible to flex inward with a reduction in the width of the mandibular arch during jaw opening and protrusion . Several authors have demonstrated this sagittal movement of the posterior segment of the mandible due to the contraction of the lateral pterygoid muscle, which causes flexure of the mandible around the mental symphysis [4-8]. The amplitude of the median mandibular flexure increases as the opening or protrusive movement increases and as it approaches the ramus. It also varies with bone volume and density, age of the patient, gonial angle, symphyseal bone height, etc. The amplitude has been measured as 800 mm in the first molar to as much as 1500 mm in the ramus area, while the movement of the natural tooth ranges from 28 to 108 mm . Median mandibular flexure poses testing problems for implant-supported prostheses. It leads to elevated stress in implant prostheses and abutments, ill-fitting prostheses, distortion of impression, implant screw fracture or porcelain crown fracture, pain during function, loosening of cemented prostheses, and resorption of bone around the implant. Hence, for a better outcome and longevity of implant and dental prostheses, it is important to minimize median mandibular flexure [10-14]. Splitting the prosthesis framework between the mental foramen has been suggested as one of the ways to effectively reduce mandibular flexure [9-13]. This article describes full mouth rehabilitation using a maxillary cast partial denture and mandibular implant-supported fixed prosthesis with a split framework to compensate for mandibular flexure. Case presentation Clinical report A 55-year-old female patient reported the chief complaint of missing maxillary teeth and pain and mobility in the remaining mandibular teeth. A detailed case history was recorded, the intraoral examination was done, and a total extraction concerning the mandibular arch was planned owing to generalized periodontitis, followed by mandibular implant-supported metal-ceramic prosthesis and maxillary cast partial denture. After the remaining mandibular teeth were extracted, four implants (Alpha Bio Tec., Petah Tikva, Israel) were placed in the posterior mandible, and two implants (Alpha Bio Tec.) in the interforaminal region. After four months of uneventful healing and radiographic evaluation, second-stage surgery was planned. Punch incisions were made to expose the cover screws followed by their removal and placement of healing abutments. After two weeks, prosthetic rehabilitation was started. Open tray impression copings were placed in implant bodies and an alginate open tray impression was made in alginate after tray customization to allow exposure of impression copings during impression making. Figure 1 Alginate open tray impression The primary cast was poured using type II plaster , which was later used for splinting of impression posts on cast using dental floss and pattern resin (GC Pattern Resin; GC Corp., Tokyo, Japan) , followed by sectioning . Figure 2 Primary cast poured in dental plaster Figure 3 Impression posts splinted using dental floss Figure 4 Pattern resin buildup on floss followed by sectioning The impression posts were placed intraorally and sectioned segments were joined with pattern resin . Figure 5 Joining of sectioned segments intraorally using pattern resin after verification of the position of implants This sectional splinting technique reduced the chairside time and patient discomfort during definitive open tray impression making and decreased polymerization shrinkage. Open tray technique along with sectional splinting increased the accuracy of impression, and hence the precision of passive fit of the implant-supported restorative complex. A panoramic radiograph was taken to ensure complete seating of impression copings into the implant body , followed by an open tray impression using putty and light body elastomeric . Figure 6 Panoramic radiograph to verify complete seating of impression posts Figure 7 Definitive open tray impression using putty and light body elastomer Implant analogs were attached to the impression copings and a cast was poured in type IV plaster. For the maxillary arch, an anteroposterior strap major connector was planned. Rest seats were prepared for direct retainers on 15, 17, 24, and 27 and indirect retainers on 11, 12, 13, 14, 21, and 22, followed by a definitive impression using putty and light body elastomer . Figure 8 Definitive impression of maxillary arch following rest seat preparation The cast was poured with type IV plaster. Denture bases and occlusal rims were fabricated and bite registration was done. A face bow transfer was done and the maxillary and mandibular casts were mounted on a semi-adjustable articulator. A maxillary cast partial denture framework was fabricated and maxillary and mandibular teeth arrangement was completed using PeriCeram two-layer ceramic teeth , followed by a trial procedure . Figure 9 (a) Maxillary cast partial denture framework and teeth arrangement. (b) Mandibular teeth arrangement Figure 10 Trial procedure The maxillary cast partial denture was processed and a screw-retained mandibular framework was fabricated, which was later split into two sections using a carborundum disc . Figure 11 (a) Processed maxillary cast partial denture. (b) Mandibular prosthesis framework A trial of the framework was done and it was evaluated for a passive fit. Ceramic layering was done on the framework and the maxillary and mandibular prostheses were placed , followed by occlusal adjustments. Figure 12 (a) Completed maxillary prosthesis. (b) Splitting of mandibular prosthesis framework and ceramic layering Figure 13 Mounted casts with front, right, and left lateral view of the finished and polished prosthesis in occlusion Figure 14 Placement of maxillary and mandibular prosthesis The separation at the mandibular midline was evaluated using a shim stock to ensure that the sectioned segments of the framework did not come into contact during mandibular opening and protrusive movements. A panoramic radiograph was taken and the patient was educated regarding oral hygiene maintenance and regular recall visits. The patient was evaluated six months, 12 months, and 18 months after loading and presented no complaints, screw loosening, or significant bone loss. Figure 15 Eighteen-month follow-up panoramic radiograph Discussion The mandibular deformation considering movement or shape is an intricate phenomenon involving an interplay of many muscles of the head and neck region and may even occur without jaw movements. Based on the work of Hylander , symphyseal bending, dorsoventral shear, corporal rotation, and anteroposterior shear were postulated as the four patterns of jaw deformation during mandibular flexure. In addition to the lateral pterygoid muscle, the superior constrictor muscles, mylohyoid, and platysma also contribute to the condyle's medial movement. During contraction, the depressor muscles of the mandible also produce some changes in the shape of the mandible. During jaw opening and closure, the muscles of the floor of the mouth along with the medial and lateral pterygoid exert a contracting force upon the mandible. During clenching, occlusion, or biting, forces on the mandible and mandibular flexure have been observed . Apart from muscle-related factors, age, gender, muscle strength, bone density, lower gonial angle, and the symphysis height substantially impact the amount of flexure. Patients with considerable mandibular length, smaller gonial angle, and lesser symphyseal area generally show increased mandibular deformation . The flexure of the mandible certainly affects the definiteness of various stages of implant treatment, like osseointegration of the implant, fabrication of implant prosthesis, mastication-related strain distribution within the framework, and crestal bone surrounding implants. Flexural forces incorporate lateral stresses into the implant body resulting in bone loss around the implants, fracture of material, loss of implant fixation, and mouth opening-related discomfort. Hence, it is imperative to consider maxillo-mandibular fixation while planning any implant-supported prosthesis. Median mandibular flexure leads to microdamage near the bone crest and poor osseointegration owing to micromovements around implants . In 1976, Fischman developed splints for the rehabilitation of full arch and evaluated their effect on maxillo-mandibular flexure. He concluded that the flexure of the mandible would be diminished extensively when rigid splinting was carried out. He also found that a short-span splint without rigid attachments will probably lead to better outcomes . However, later it was found that although rigid splinting reduces mandibular flexure, the teeth are not able to flex in their original manner along with the mandible, leading to stress development around them and further bone loss. Thus, mandibular flexure contributes to the alveolar bone destruction. Apart from crestal bone loss, significant buccolingual forces are also generated when fixed and rigid posterior implants are splinted together in a cross-arch restoration. Thus, significant stress is built around distal implants and the superstructure close to the symphysis due to the flexure of the mandible with the symphysis as a fulcrum . Therefore, sectioning of the superstructure at the symphysis level could substantially restore the natural mandibular flexure in function . However, as per a few studies, the necessity of a segmented framework for implant-supported fixed prostheses is currently debated . A non-segmented prosthesis could be given if the implant-supported fixed restoration is without a cantilever and if it provides an optimal biomechanical environment with good resistance offsetting the effects of mandibular flexure, especially in cases of the posterior single unilateral framework . Conclusions Mandibular flexure is a multifactorial phenomenon occurring contemporaneously with jaw movements. It can substantially affect the treatment outcome and prognosis of an implant-supported ceramometal prosthesis. Therefore, it is of utmost importance to take appropriate measures to negate the flexural movement of the jaw during prosthetic rehabilitation. This would help the clinicians deliver a structurally and functionally acceptable prosthesis with an accurate fit and also maintain the health of the surrounding osseous and periodontal tissues. Present studies focus primarily on the completely edentulous mandible. The effect of flexure of the mandible on implant treatment success is uncertain at this stage; however, many studies do suggest that flexure of the mandible should definitely be considered while designing any such prosthesis. Human Ethics Consent was obtained or waived by all participants in this study. Institutional Ethics Committee, Rajendra Institute of Medical Sciences, Ranchi issued approval R126/21/D The authors have declared that no competing interests exist. References 1 Measuring the effect of intra-oral implant rehabilitation on health-related quality of life in a randomized controlled clinical trial J Dent Res Awad MA Locker D Korner-Bitensky N Feine JS 1659 1663 79 2000 11023260 2 Mandibular flexure and stress build-up in mandibular full-arch fixed prostheses supported by osseointegrated implants Clin Oral Implants Res Zarone F Apicella A Nicolais L Aversa R Sorrentino R 103 114 14 2003 12562372 3 Clinical importance of median mandibular flexure in oral rehabilitation: a review J Oral Rehabil Sivaraman K Chopra A Venkatesh SB 215 225 43 2016 26498998 4 Median mandibular flexure-the unique physiological phenomenon of the mandible and its clinical significance in implant restoration Front Bioeng Biotechnol Gao J Jiang L Zhao B 1238181 11 2023 37744259 5 The rotational aspect of mandibular flexure J Prosthet Dent Fischman B 483 485 64 1990 90049-I 2231461 6 Evaluation of median mandibular flexure values in dentulous and edentulous subjects by using an intraoral digital scanner J Adv Prosthodont Gulsoy M Tuna SH Pekkan G 32 44 14 2022 35284055 7 Biomechanical implications of mandibular flexion on implant-supported full-arch rehabilitations: a systematic literature review J Clin Med Caggiano M D'Ambrosio F Acerra A Giudice D Giordano F 5302 12 2023 37629344 8 Midline mandibular deformation during nonmasticatory functional movements in edentulous subjects with dental implants Int J Oral Maxillofac Implants El-Sheikh AM Abdel-Latif HH Howell PG Hobkirk JA 243 248 22 2007 17465349 9 Dental Implant Prosthetics Louis, Missouri Misch CE 252 254 St. Louis, MO Elsevier Health Sciences 2004 10 The influence of fixed splints on mandibular flexure J Prosthet Dent Fischman BM 643 667 35 1976 90321-8 784954 11 The influence of mandibular deformation, implant numbers, and loading position on detected forces in abutments supporting fixed implant superstructures J Prosthet Dent Hobkirk JA Havthoulas TK 169 174 80 1998 70106-4 9710818 12 Mandibular flexure and its significance on implant fixed prostheses: a review J Prosthodont Law C Bennani V Lyons K Swain M 219 224 21 2012 22044758 13 Split-frame implant prosthesis designed to compensate for mandibular flexure: a clinical report J Prosthet Dent Paez CY Barco T Roushdy S Andres C 341 343 89 2003 12690344 14 Full-mouth rehabilitation of completely edentulous patient using implant-supported fixed prosthesis J Indian Prosthodont Soc Prithviraj DR Gupta A 44 47 8 2008 15 Stress and strain in the mandibular symphysis of primates: a test of competing hypotheses Am J Phys Anthropol Hylander WL 1 46 64 1984 6731608 16 Mandibular flexure associated with muscle force applied in the retruded axis position J Oral Rehabil Omar R Wise MD 209 221 8 1981 6942134 17 Contributing factors of mandibular deformation during mouth opening J Dent Chen DC Lai YL Chi LY Lee SY 583 588 28 2000 00041-5 11082527 18 Experimental and finite element study of a human mandible J Craniomaxillofac Surg Vollmer D Meyer U Joos U Vegh A Piffko J 91 96 28 2000 10958421 19 Mandibular flexure and peri-implant bone stress distribution on an implant-supported fixed full-arch mandibular prosthesis: 3D finite element analysis Biomed Res Int Martin-Fernandez E Gonzalez-Gonzalez I deLlanos-Lanchares H Mauvezin-Quevedo MA Brizuela-Velasco A Alvarez-Arenal A 8241313 2018 2018 29805978 20 The effect of mandibular flexure on the design of implant-supported fixed restorations of different facial types under two loading conditions by three-dimensional finite element analysis Front Bioeng Biotechnol Gao J Li X He J Jiang L Zhao B 928656 10 2022 36105608 |
GENeration DAtaset (AGENDA) dataset 19 34 were found; BART-large pre-trained language model was fine-tuned in the abstract generation problem. 4 A novel methodology for text generation In the framework of the COST's Multi3Generation Action, we organized an intensive training school 20 (class + lab) in which we showed the limitations of the stochastic approaches, and presented an alternative methodology to develop automatic generators, automatic paraphrase generators, and machine translation systems. The basis of this methodology is to formalize every level of the linguistic phenomena involved during the text generation process. For instance, such a system must be able to produce an English sentence that represents the predicate "Joe loves Lea" in the past, aspect +Stop, intensive +High, focus on "Joe", and "Lea" pronominalized, that is " It is Joe who stopped being madly in love with her". Such a system must be able to access linguistic databases that know what aspectual verbs are available in English, how to express intensivity for love, how to pronominalize an object, etc. During the training course, we have described each of the linguistic phenomena that must be considered to construct such a system, including: inflectional morphology ( e.g., to stop - stopped) derivational morphology ( e.g., to love - to be in love with) local syntax ( e.g., Joe loves Lea - it is Joe who loves Lea) coreference ( e.g., Joe loves Lea - Joe loves her) intensifier ( e.g., to be in love - to be madly in love) One characteristic of the novel methodology presented is that all its linguistic formalization is neutral, i.e., it can be used both to parse an existing text and to generate a new text. That makes these linguistic resources suitable not only to develop automatic text generators, but also to parse a text and re-generate it with some different values, such as tense, aspect, modality, or intensifier, i.e., to paraphrase them. Moreover, because there exist linguistic resources in the same format for over 30 languages, it is a matter of parametrizing the application to parse a text in one language and then generate its "paraphrase" in another language, that is, this has allowed us to develop machine translation applications. The workshop was split into two sessions: A theoretical session where the methodology was presented as well as the various types of linguistic resources involved during text generation/paraphrasing/translation. A hands-on session that showed the participants how to build the crucial components and linguistic resources for such a system, using the NooJ linguistic development environment 21 . 5 Tools and resources to paraphrase and translation Generation For NLG, it is crucially important the quality of the data that is used in the generation task, but also the tools that are used, how they were built, their strengths and limitations, the ability for the human to control the process, curate, and improve the quality of a generative system. Most systems are black boxes, built in a way in which humans do not have control over the generative process. Some paraphrases generation or extraction techniques may simply involve semi-automated procedures, while others may consist of supervised alignment trained in manual alignments (used for monolingual or bilingual term extraction). Even when supervised training is used in building a system, at a particular stage, the process may get out of human control. We search for ways of developing glass-box systems having in mind the "human-in-the-loop", that is, the human in control of the system from the very first stage of its development. Some research has been done at INESC-ID Lisboa in the development of tools and resources to generate paraphrases and translation. Within the Multi3Generation COST Action further developments to initial fundamental research has been recently done, namely the creation of novel resources named 'paraphrasaries', which are complex complementary extensions of dictionaries, designed to be used in monolingual or multilingual applications 11, 35 . The concept of "paraphrasary", akin to a dictionary at a multiword level, appeared to fill in a void in the creation of linguistically more sophisticated resources. With regards to MT, it is not possible to achieve quality translation without involving comparable quality paraphrasing knowledge and skills (capabilities), because paraphrases are essential for implanting semantic knowledge edge to ensure high fidelity translation instead of approximate or good enough translation. We trust that it is important to revisit alignment tools and methodologies and to define collaboratively-built guidelines for alignment of paraphrases and translation, defining and measuring different degrees of equivalence, while increasing the volume of paraphrastic units, i.e., pairs of alignments that match semantically identical or similar units of meaning, not only in commonly used corpora, but extend the process to more creative types of text. 6 Impact of Multi3Generation and perspectives for the future of LG - WG5 Several European industries and markets can benefit from the outcomes of this Action, including e-commerce (the ability to translate multi-modal content and, as a result, reach wider audiences), and customer services (through automated assistants). In addition, industries can benefit from Multi3Generation through the development of innovative human-machine Interactions. In this regard, it should be noted that the European modern industry is leaning toward Industry 5.0 which foresees the centrality of the worker in the industrial system 36 . In this new scenario, the interactions between humans and machines (and, in particular, robots) are evolving to bring advantages in terms of efficiency, ergonomics, flexibility, and safety 37 . One of the key features for the evolution of human-machine interactions is communication which can be implemented through the use of NLG. In fact, the latter allows generating written or oral content to give the machine the ability to effectively communicate 38 , thus creating the conditions to realize real applications of human-machine co-working. For instance, it is possible to integrate a human-robot interaction in an assembly process, leveraging NLG and ML to give precise instructions to the operator according to their personal characteristics. This can also be achieved using tailormade chatbots and conversational search Interfaces, which read information about the process and act accordingly. Along with the opportunities, the evolution of the human-machine interaction towards Industry 5.0 22 brings several challenges, both technical and human-related 39 . In particular, NLG-related challenges mainly concern the fluidity and flexibility of the communication and the quality of the generated content 38 . Moreover, among the challenges, it should also be reported the analysis of the ethical repercussions of the adoption of these technologies. In particular, some aspects that should be taken into account are the generation of harmful content or content that can be used to violate the law and the generation and spreading of fake news and misinformation. Regarding challenges and future perspectives for language generation, we should consider, in the first place, the two main existing approaches for NLG systems, as indicated in Section 2: more traditional rule-based approaches, which mostly follow the stages pipeline proposed by 40 and more recent End-To-End (E2E) approaches based on the attention mechanism and the Transformer-based models, e.g. BERT 41 , GPT-2 42 , or GPT-3 43 . Both approaches present high scientific and technological challenges and clear needs to develop computational and linguistic resources for building impactful NLG-based systems and applications. Although E2E approaches have burst recently, rule-based generation is still a valid approach, since it is based in a careful design which, in many cases, is the only option for achieving reliable applications ( e.g., critical applications where reliability is a relevant requirement). The challenge here is that computational resources must be created or improved to automate and facilitate the design process and/or improve the fluidity of the generated texts. In this sense, valuable resources such as the realization libraries SimpleNLG-GL 44 or others should be improved in terms of their efficiency, abstraction, generalization of structures, vocabulary, alternate realizations or paraphrases, among others. On the other hand, E2E models, in general, improve the fluency of the texts when compared to a rule-based model. But, very often, they may suffer from "hallucinations" in which the generated text includes contents which are unrelated to the input data or directly wrong or misleading. The search for an effective method that can foresee, detect, or remedy these situations in NLG E2E models is a major challenge 45 , as it affects the reliability of these systems, especially in critical or sensitive applications, e.g., in which the moral, mental and physical integrity of people are protected. Furthermore, to train the E2E models, it is necessary to have high-quality corpora which, in some areas are hardly available (this is the usual case in data-to-text systems, for instance). Another scientific challenge of extraordinary interest and relevance is the validation and testing of E2E models. There is currently an intense debate in the scientific community about the generalized use of inadequate automatic evaluation metrics in E2E training, and their lack of sensitivity to the problem of hallucination in texts, and their lack of correlation to human (expert) validations. Manual validations by humans may be a solution for small-scale problems, but not for problems where the variety of texts generated is very high, and may also subject to reproducibility issues 46 . In this sense, some of the open challenges in this area are: New automatic metrics that consider the problems currently existing in E2E generation and methodological strategies in validation that ensure the representativeness of the test sets or samples evaluated by human experts. Automated fact-checking mechanisms to prevent or assess the quality and appropriateness of the generated texts against the input data. Another challenge in the field of rule-based NLG is the fluidity of the generated texts. The definition of rigid structures causes the generated texts to be very similar, becoming unnatural when reading several texts in succession. The inclusion of rules, synonyms, and paraphrases is still insufficient, and therefore work remains to be done in this area for improving the fluidity and readability of generated texts. In this sense, since one of the main objectives of the NLG is to produce texts that are as similar as possible to human texts, it is essential to create automated resources that provide the generated texts with naturalness and fluency, while ensuring that they correctly describe the data requested from the model. For this, the Nooj framework has been explored within Multi3Generation 47 . Striking a balance between naturalness, linguistic variety, readability and, at the same time, consistency with respect to the data is a difficult task, but also essential for a complete NLG system. Dealing effectively with the problems of scalability and maintenance of this approach is also a major technological challenge. The hybridization of the two approaches, orienting the E2E systems not to implement the full pipeline, but to the learning of models ( e.g., instances of a grammar), opens a very promising way to improve the quality of texts, the scalability of the approaches and the problem of hallucinations, among others. In Data-To-Text systems, in critical applications, for instance, E2E can be used for simplifying and improving significantly the final linguistic realization stages (merging, for instance, planning and surface realization), whilst content determination is tackled with more reliable classical approaches. Likewise, taking inspiration from the field of machine translation, a major challenge is to consider the "human in the loop" perspective to orientate the creation of texts not towards a fully automated successful final realization, but to the creation of texts with an acceptable level of quality and which facilitate the final post-editing by a human operator who provides the result with the expected quality and precision. In order to investigate the practical exploitation of the main outcomes of Multi3Generation COST Action, also involving industrial stakeholders, it is worth introducing WG5, whose activities are described in the following subsection. Working Group 5 "Industry and End-User Liaison" aims to develop links with industry and end-users. As such, its activities embrace collaboration between academic and industrial partners, both on academic projects and real-world product development, seeking to stimulate ideas for novel cross-modal applications. In addition to having participants from the industry, company stakeholders are welcome to the Industrial Advisory Board, which has the functions of advising and informing the Management Committee's activities, and fostering collaboration between industrial and non-industrial participants, including placements for Early Career Investigators and co-organization of shared tasks including the construction of benchmark datasets. Furthermore, WG5 aims to coordinate user requirement surveys and other methods for obtaining end-user input. In this regard, the potential of the technologies dealing with the action is investigated according to two different activities: 1. Conducting a survey among different industrial and academic stakeholders (involving at the beginning the MC members). The survey will have two different perspectives: (a) Eliciting requirements from end-users; (b) Reporting the available industrial data sources ( e.g. ontologies) which can be used to feed NLG tools; 2. analyzing the state of the art with the aim to identify and classify NLG-based applications already available in the industry ( e.g., such as conversational search interfaces; grounded dialogue models; real-time dialogue models; and conversational robots). The two above activities are currently ongoing. At the end of these activities, the main achieved outcomes will be reported within specific reports. Conclusions There is no doubt that NLG technology has increased in popularity in the last few years. Although its successes, we can also find some limitations and risks associated to the misuse of such potential technologies. Multi3Generation COST Actions brings together researchers whose expertise is related to different angles of NLG. With the joint efforts of the whole Multi3Generation community, relevant progress has been made while the ongoing of the Action, contributing to putting Europe at the forefront of (human-centered) NLG research. In this paper, an overview of Multi3Generation COST Action is provided, discussing also its WGs, activities, and outcomes obtained. Despite the fact that Action will finish in March, 8th 2024, we expect sustained collaborations between Multi3Generation members either in future COST Actions or in other research initiatives. We also plan to continue jointly developed dissemination actions such as training schools. Ethics and consent Ethical approval and consent were not required Notes Data and software availability No data are associated with this article. 10.21956/openreseurope.17604.r36459 Reviewer response for version 1 Polignano Marco 1Referee 1 Department of Computer Science, University of Bari 'Aldo Moro', Bari, Italy 20 12 2023 Copyright: (c) 2023 Polignano M 2023 This is an open access peer review report distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Version 1recommendationapprove The authors present a scientific paper that provides a comprehensive overview of the activities conducted within the framework of COST Action Multi3Generation (CA18231). The contribution is easy to read and understand and well supports the motivation behind the idea of the action. The contributions made throughout the project are both numerous and noteworthy, frequently finding dissemination through prestigious conferences and esteemed scientific journals within the relevant field. To enhance the efficacy of communicating the results obtained from the action, I recommend offering a more detailed exposition of the created artifacts and their corresponding identification procedures within the publicly accessible GitHub repository. This additional information would facilitate a clearer understanding of the artifacts and enable researchers to effectively utilize and build upon the outcomes of the project. Furthermore, it would be advantageous to provide a concise summary of select scientific achievements, supplemented by accompanying experimental results. This would allow readers to grasp the significance of the research conducted and facilitate future exploration and replication of the findings. In conclusion, the contribution presented in this work is meticulously crafted, exhibiting a high level of proficiency in both content and presentation. The thoroughness of the research, the clarity of the writing, and the potential impact of the findings within the scientific community make it a valuable contribution. Where applicable, are recommendations and next steps explained clearly for others to follow? (Please consider whether others in the research community would be able to implement guidelines or recommendations and/or constructively engage in the debate) Yes Does the article adequately reference differing views and opinions? Yes Are all factual statements correct, and are statements and arguments made adequately supported by citations? Yes Is the rationale for the Open Letter provided in sufficient detail? (Please consider whether existing challenges in the field are outlined clearly and whether the purpose of the letter is explained) Yes Is the Open Letter written in accessible language? (Please consider whether all subject-specific terms, concepts and abbreviations are explained) Yes Reviewer Expertise: Natureal Language Processing, Artificial Intelligence, Text Generation, Recommender Systems I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. 10.21956/openreseurope.17604.r35589 Reviewer response for version 1 Martinez-Camara Eugenio 1Referee 1 Computer Science Department, Universidad de Jaen, Jaen, Andalusia, Spain 2 11 2023 Copyright: (c) 2023 Martinez-Camara E 2023 This is an open access peer review report distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Version 1recommendationapprove The paper presents the relevance of natural language generation and the development of its challenges in the COST Action Multi3Generation. From my point of view, the paper presents the progress of the project, and how the consortium is facing the challenges of natural language generation. Likewise, the project also is developing teaching and dissemination activities through the organization of workshops, which is very positive. To sum up, I consider that the paper should be accepted for indexing in its current form. Where applicable, are recommendations and next steps explained clearly for others to follow? (Please consider whether others in the research community would be able to implement guidelines or recommendations and/or constructively engage in the debate) Yes Does the article adequately reference differing views and opinions? Yes Are all factual statements correct, and are statements and arguments made adequately supported by citations? Yes Is the rationale for the Open Letter provided in sufficient detail? (Please consider whether existing challenges in the field are outlined clearly and whether the purpose of the letter is explained) Yes Is the Open Letter written in accessible language? (Please consider whether all subject-specific terms, concepts and abbreviations are explained) Yes Reviewer Expertise: Natural Language Processing I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Lloret Elena Software and Computing Systems, Universidad de Alicante, San Vicente del Raspeig, Alicante, Spain 6 11 2023 Dear Eugenio, thank you very much for reviewing our manuscript and for finding it interesting to the scope of ORE. Natural Language Generation (NLG) has gained popularity in recent years, partly due to the advancements in Generative AI, so from the Multi3generation COST Action, we believe that is important to provide visibility to the activities conducted within the action, as well as to provide insights, prospects and challenges related to NLG. 1 2 3 4 www.unbabel.com/ 5 www.jabberbrain.com 6 7 www.multi3generation.eu/2022/06/24/m3g-cost-action-training-school-on-creative-natural-language-generation/ 8 www.multi3generation.eu/workshop 9 10 11 www.multi3generation.eu/events/participations/ 12 13 14 15 16 A demo version of eSPERTo is available at: 17 Training School 2022 - Representation Mediated Multimodality. 18 19 20 21 22 This terms refers to an approach that provides a vison of industry that aims beyond efficiency and productivity, reinforcing the role and the contribution of industry to society by making European industry more sustainable, human-centric and resilient ( ) Competing interests: No competing interests were disclosed. Competing interests: No competing interests were disclosed. Competing interests: No competing interests were disclosed. |
: "Conversely, fatty acid content was lowest among the species, ranging from 6.73% to 9.48%." should be rephrased to "Fatt acid content was low in all species examined, ranging from 6.73% to 9.48%." " Conclusions: Scale flour from three farmed fish types showed potential for fish fry feed due to its chemical composition and amino acid and mineral contents. To enhance the essential fatty acid content, enriching the flour with oils containing eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and a-linolenic acid (ALA) is essential" I don't agree with this statement. An ideal ingredient for feed formulation need not contain FA (e.g. fishmeal is also low in FA. The conclusion must be that it is a suitable protein source fir fry feed. This should however be validated in a context of AA requirement. Is the AA content comparable to fish meal or another ideal protein source, and would it satisfy the AA requirements of farmed species. Introduction: Do you means seagrass specifically, or seaweeds in general? Methods: Can you be more specific concerning "low mineral content water?" "Mineral content analysis For the analysis of mineral content (Na, Mg, Ca, K, P, Fe, and Zn), the ashed GCTS sample was dissolved in 1 ml of hydrochloric acid (35% v/v Suprapur (r) Merck). Subsequently, the sample was filtered using cellulose filter paper (Watchman No 1, International Ltd; Maidstone, UK) and appropriately diluted for each elemental mineral. Phosphorus (P) levels were analysed using a Perkin-Elmer AA spectrophotometer mod 3110 (Norwalk, CT, USA)." Phosphorous was analysed using the spectrophotometer, is there a reference for the method? How were the other minerals analysed following acid treatment? This information is missing. Proximate composition and mineral content: "The highest protein content was recorded in the fish scale flour of C. carpio, and the content did not differ by more than 23%" - specify whether it is 23% in relative or absolute terms - insert "absolute" before content. Conclusion: As hinted at in the abstract, I would appreciate that as part of the assessment of the value of the protein, that you consider the AA composition relative to other protein sources used for fish feeds (e.g. fish meal, soy) or against the nutritional requirements of selected farmed species (e.g. tilapia, carp) Is the work clearly and accurately presented and does it cite the current literature? Yes If applicable, is the statistical analysis and its interpretation appropriate? Partly Are all the source data underlying the results available to ensure full reproducibility? Yes Is the study design appropriate and is the work technically sound? Yes Are the conclusions drawn adequately supported by the results? Yes Are sufficient details of methods and analysis provided to allow replication by others? Partly Reviewer Expertise: Fish physiology, energetics and nutrition I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Syandri Hafrijal Bung Hatta University, Indonesia 31 10 2023 Abstract: The authors agreed to change the sentence: "Conversely, fatty acid content was lowest among the species, ranging from 6.73% to 9.48%, to Fatty acid content was low in all species examined, ranging from 6.73% to 9.48%. The author will add in the new version that scale flour from three types of cultivated fish has potential as fish seed feed because of its close composition, amino acid, and mineral content. However, this needs to be validated in the context of amino acid requirements. Is it comparable to fishmeal or other ideal protein sources that meet the amino acid requirements for cultured species. Introduction: Do you means seagrass specifically, or seaweeds in general? : The author will change seagrass to seaweed in general in new versions. Methods: Can you be more specific concerning "low mineral content water?". The author will added "low mineral-content water (with a TDS of around 100 mg/L)" in new versions. Phosphorous was analysed using the spectrophotometer, is there a reference for the method?: Phosphorus (P) levels were analysed using a Perkin-Elmer AA spectrophotometer mod 3110 (Norwalk, CT, USA) (Perkin-Elmer (1982) How were the other minerals analysed following acid treatment? This information is missing: The author will add new versions after the sentence dilute appropriately for each mineral element and finally analyze with a Perkin-Elmer AA mod 3110 spectrophotometer (Norwalk, CT, USA). Specify whether it is 23% in relative or absolute terms - insert "absolute" before content: The author state that the highest protein content was relatively recorded in C. carpio fish scale flour, and the content did not differ by more than 23%. Conclusion: In new revisions, in the conclusion part, the author will change the sentence "Consequently, enriching fish scale flour with animal and plant oils rich in omega-3 fatty acids is vital" to "However, this needs to be validated in the context of amino acid requirements with fish meal or other ideal protein sources that meet the requirements for the cultured species." 10.5256/f1000research.154735.r208002 Reviewer response for version 1 Sri Prabakusuma Adhita 1Referee 1 Vocational School of Foodservice Industry, Food Biotechnology Research Group, Universitas Ahmad Dahlan, Yogyakarta, Indonesia 16 10 2023 Copyright: (c) 2023 Sri Prabakusuma A 2023 This is an open access peer review report distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Version 1recommendationapprove-with-reservations The manuscript, entitled "The proximate composition, amino acid profile, fatty acid content, and mineral content of scale flour from three fish species as potential feeds for fish fry," focuses on analyzing the chemical composition, fatty acid profile, and mineral content in fish scale flour of Osphronemus (O) goramy, Cyprinus (C) carpio, and Oreochromis (O) niloticus as potential feed for fish fry, provides insights into chemical properties influencing nutritional aspects in feed formulation for fish fry, and describes the enrichment of the fish scale flour with oils containing essential fatty acids. After careful review of the manuscript, I feel that it is an interesting study supported by a significant amount of data and contains an important topic within the scope of the Agriculture, Food, and Nutrition Gateway of F1000Research. However, there are some critical concerns that require attention to improve the quality of the manuscript before it is accepted for publication. The specific comments are as follows: Please include a statement in the background section of the abstract about the potential of fish scale flour by-products as a potential source of farmed fish feed, not only as a food additive and a functional food ingredient, aligning it with the title and overall context of the paper. Please include the analysis approaches for measuring tested parameters mentioned in the methods section of the abstract, as the authors outlined: proximate was analyzed using standard AOAC methods; amino acid composition was determined using high-performance liquid chromatography (HPLC); and fatty acid composition was examined through gas chromatography-mass spectrometry (GC-MS). Please include the comparative study results of tested parameters (the proximate composition, amino acid profile, fatty acid content, and mineral content) of three fish species in the results section of the abstract. In the introduction section, it is better to elaborate on the recent research on utilizing fish scales both for human consumption and fish feed formulation and to make a gap analysis by evaluating the effectiveness or performance of previous methods or results. In the materials and methods section, put the relevant references to support the procedures for measuring the biometric properties of fish samples and preparing fish scales. Support this statement "This frequent repetition helped ensure that any remaining unnecessary proteins on the fish scales were thoroughly removed," with the relevant references. Why did the authors select a temperature of 121 degC with a pressure of 15 psi to perform the heating process? Why not choose a higher temperature and more pressure for less than or within ten minutes? In the results and discussion section, it is also better to elaborate on the recent research studies and compare those with the findings of this current study. In all sub-sections, mention the function of chemical nutrition, amino acids, and fatty acids to support the growth of farmed fish, their effect on increasing the quality of fish carcasses, and their role in maintaining fish health. Please double-check the use of English grammar in the manuscript. Is the work clearly and accurately presented and does it cite the current literature? Yes If applicable, is the statistical analysis and its interpretation appropriate? Yes Are all the source data underlying the results available to ensure full reproducibility? Yes Is the study design appropriate and is the work technically sound? Yes Are the conclusions drawn adequately supported by the results? Yes Are sufficient details of methods and analysis provided to allow replication by others? Yes Reviewer Expertise: Food safety and quality, food science and technology, food waste management, and agri-food system I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Syandri Hafrijal Bung Hatta University, Indonesia 25 10 2023 Response to comments from Adhita Sri Prabakusuma Abstract: The author could only revise the introduction and method sections in the abstract due to the maximum abstract length of 300 words. We will change in the revised version. Background: Fish scale waste is highly valued as a functional food ingredient and a potential feed source for farmed fish. This study aimed to analyse the chemical composition, amino acids, fatty acids, and mineral content in fish scale flour of Osphronemus (O) goramy, Cyprinus (C) carpio, and Oreochromis (O) niloticus as potential feed for a fish fry. Methods: Fish scales were cleaned with 10% w/v NaCl solution at a ratio of 1:10 (w/w) for 24 hours at 4 degC. Agitation was used every eight hours to remove excess protein. Fish scales were evenly arranged in a cooker and cooked at 121 degC for 10 minutes with 15 psi pressure. After cooking, 100 grams of wet fish scales was dried at 50 degC for four hours. Dried fish scales were transformed into flour for proximate composition analysis via standard AOAC methods, amino acid and fatty acid assessment employing HPLC and GC-MS, while mineral content was determined using AAS. Results: Examined fish scale flour from three species showed significant variations in chemical components, amino acids, and minerals (p<0.01). Crude protein content ranged from 49.52% to 72.94%, while fat content ranged from 0.11% to 0.23%. Magnesium levels varied from 767.82 to 816.50 mg/kg, calcium content from 3.54 to 12.16 mg/kg, iron from 40.46 to 44.10 mg/kg, and zinc from 45.80 to 139.19 mg/kg. Predominantly, glycine was the main free amino acid (FAA), varying from 13.70% to 16.08%, while histidine had the lowest content, 0.39% to 0.71%. Conversely, fatty acid content was lowest among the species, ranging from 6.73% to 9.48%. Conclusion: Scale flour from three farmed fish types exhibits potential as fish fry feed, considering its chemical composition, amino acid, and mineral content. Enriching the flour with EPA, DHA, and ALA-containing oils is crucial to boost essential fatty acids. In the introductory part The author will add to the new revised version a sentence highlighted in yellow in paragraph 3 of the "introduction" section to explain recent research and gaps in evaluating the effectiveness or performance of previous methods or results. Fish scales contain approximately 41-45% organic components, such as collagen, fat, lecithin, sclerotin, and vitamins, and 38-46% inorganic components and mineral elements, including magnesium, iron, zinc, calcium, and vitamins 10. Furthermore, fish scales possess antioxidant and antihypertensive properties 11. Fish scales have been used as a culinary ingredient in baked bread 3, because they are a source of food that is rich in nutrients 5,7.These components are also crucial for the growth and survival of fish fry. In recent years, fish fry feed has primarily been live feed, and expensive artificial feed is a bottleneck in aquaculture 12,13. Therefore, there is a technological gap in exploring alternative ingredients for fish fry feed, such as fish scale flour, which is a rich source of nutrients, has economic value, and provides an element of novelty in this study. Material and Methods Part In the revised version, in the materials and methods section, the author will include relevant references to support procedures for measuring biometry properties of fish samples and preparing fish scales. Upon reaching the laboratory, the fish were individually weighed (TW) using AD-600i scales with a precision of 0.001 grams and measured to their standard length (SL) and maximum height (H), with distance measured from the mouth to the end of the upper lobe of the caudal fin and width measured vertically, excluding the fins (Famoofo and Abdul, 2020). Standard length and width were assessed using a meter ruler with an accuracy of 1 millimeter. The condition factor (CF) was calculated using the formula CF = (TW/SL 3) x 100 (Froese, 2006) This frequent repetition helped ensure that any remaining unnecessary proteins on the fish scales were thoroughly removed (Lou et al., 2020; Boronat et al., 2023). Why did the authors select a temperature of 121 degC with a pressure of 15 psi to perform the heating process? Why not choose a higher temperature and more pressure for less than or within ten minutes? The author ensures that at a temperature of 121degC with a pressure of 15 psi for 10 minutes, it is hoped that no damage will occur to the chemical composition of the fish scale flour to be analyzed. Discussion part In the new revised version, we agreed to add comparisons with current research findings in the discussion section. The author will add to the newly revised version information regarding the function of amino acids, fatty acids, and minerals in the context of increasing fish seed growth. English grammar in the manuscript Please double-check the use of English grammar in the manuscript: The language contained in this manuscript has been checked by the American Journal Experts (AJE) with the English version (United Kingdom English) and is accompanied by a certificate. Competing interests: No competing interests were disclosed. Competing interests: No competing interests were disclosed. Competing interests: No competing interests were disclosed. Competing interests: No competing interests were disclosed. Competing interests: No competing interests were disclosed. Competing interests: No competing interests were disclosed. |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.49154 Pediatrics Pediatric Surgery Otolaryngology Munchausen Syndrome by Proxy Presenting as Pharyngeal Dysphagia and Recurrent Mouth Ulcers: A Case Report Muacevic Alexander Adler John R Alkhattabi Fadiah 1 Alsalameh Sulaiman 2 Alkhani Abdullah 3 Alhuthil Raghad 3 Hatem Ahmad 4 Jebreel Alaeddin 4 1 Department of Pediatrics and Child Health, King Faisal Specialist Hospital and Research Centre, Riyadh, SAU 2 College of Medicine, Alfaisal University, Riyadh, SAU 3 Department of Pediatrics, King Faisal Specialist Hospital and Research Centre, Riyadh, SAU 4 Department of Otolaryngology, King Faisal Specialist Hospital and Research Centre, Riyadh, SAU Fadiah Alkhattabi [email protected] 20 11 2023 11 2023 15 11 e4915415 11 2023 Copyright (c) 2023, Alkhattabi et al. 2023 Alkhattabi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License CC-BY 4.0., which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from We report a Munchausen syndrome by proxy (MSBP) case, which presented as pharyngeal dysphagia and an acquired tracheoesophageal fistula (TEF). A six-month-old Saudi male presented with fever, persistent oral ulcers, intermittent bleeding from the ulcers, failure to thrive (FTT), poor appetite, and possible genetic disease. He had a history of recurring admissions due to infections, including those affecting the chest, ear, and bowel. Additionally, he tested positive for vancomycin-resistant enterococcus. There was no history of surgical procedures or blood transfusions. Due to the patient's nutritional status, a gastrostomy tube was inserted. The patient had recurrent bleeding from the tracheostomy tube during the hospital stay despite normal coagulation and platelet profile. Consequently, after diagnostic laryngoscopy, the otolaryngologist specialist pointed out that such retropharyngeal injuries are seen in patients with inflicted injuries, which is, in this case, caused by the mother, as she was the only one with the child during the recurrent bleeding episodes. Thus, we describe a clinical instance of MSBP, especially imitating pharyngeal dysphagia, leading to a delayed diagnosis. We advise adding MSBP to the possible diagnoses upon encountering pharyngeal dysphagia and oral ulcers. bleeding recurrent mouth ulcers child abuse pharyngeal dysphagia munchausen syndrome by proxy pmcIntroduction Pharyngeal dysphagia, also known as oropharyngeal dysphagia, is a swallowing disorder that affects the coordination and function of the muscles involved in swallowing in the oropharynx . It is characterized by difficulty initiating or completing the swallowing process, which can lead to a range of complications, including malnutrition, aspiration pneumonia, and reduced quality of life . Understanding the underlying causes, clinical manifestations, and diagnostic approaches is essential for effective management and improved patient outcomes . Pharyngeal dysphagia can occur at any age and can be either acute or chronic . The common causes of pharyngeal dysphagia include neurological conditions, such as stroke, Parkinson's disease, and multiple sclerosis, as well as structural abnormalities, such as head and neck cancers, Zenker's diverticulum, or postsurgical complications . It can also be caused by muscular disorders, such as myasthenia gravis or muscular dystrophy; identifying the underlying cause is crucial as it guides appropriate management strategies . Therefore, we report an unusual case that presented as pharyngeal dysphagia and acquired tracheoesophageal fistula (TEF). Case presentation A six-month-old Saudi male presented with a fever for six days (tympanic temperature: 39degC), persistent oral ulcers (more than 10 days), intermittent bleeding from the ulcers, and poor appetite. He was referred for possible immunodeficiency or genetic disease. He is a product of full-term pregnancy and was born via spontaneous vaginal delivery, with no complications during pregnancy; his birth weight was about 3 kg, with no neonatal intensive care unit (NICU) admission. He had delayed umbilical cord separation for 25 days with infection and pus that improved with topical antibiotics, as reported by the mother and clinical notes. He was diagnosed with glucose-6-phosphate dehydrogenase (G6PD) deficiency at two months of age. He had a history of recurrent admission for infections (the chest, ear, and bowel), and he is positive for vancomycin-resistant enterococcus. There was no history of operation or blood transfusion. The patient was doing fine and thriving until four months of age when he started to have severe bloody mucoid diarrhea and poor weight gain. He was treated with a course of antibiotics at a local hospital. He had four other upper respiratory tract and gastrointestinal infections that required two courses of oral and intravenous (IV) antibiotics, respectively. Accordingly, the patient developed reactive airway disease and was treated with low-dose inhaled corticosteroids and as-needed Ventolin. The patient was also advised to stay away from certain foods and medications as he developed jaundice and splenomegaly after certain medications were taken at a local hospital. Regarding the family history, there is no reported consanguinity. However, it is noteworthy to mention that the father has multiple wives and over 20 children. The mother also mentioned that two female siblings, aged four and 3.5 years, passed away due to infections of unclear origin . The mother, who is a 42-year-old housewife with a high school degree, comes from a poor socioeconomic status. She has hypertension and bronchial asthma, and the father has diabetes. The patient is meeting his developmental milestones in all areas. Thus, he was referred to our hospital for further investigations. Figure 1 The family pedigree of the patient. There is a history of two female siblings who died when they were four and 3.5 years old with infections and bleeding (no clear diagnosis as reported by the mother and no autopsy was done from the referring hospital), and the patient has three healthy siblings, one female and two males. There is a history of bronchial asthma in the mother and older brother; there were no other familial diseases. Upon presentation at the emergency department, he was initially admitted with retropharyngeal inflammation and recurrent mouth ulceration . Moreover, according to the growth chart, he had more pronounced poor weight gain, which met the criteria for failure to thrive (FTT) (weight is 5.45 kg below the third percentile) . The initial workup that was done excluded primary immunodeficiency and metabolic diseases. Therefore, the patient was discharged after around nine months of hospital stay (from November to July). However, a few days after discharge, the patient was readmitted for the second time to our emergency department; he was 15 months of age. He was found to be febrile with a temperature of 39degC, with actively bleeding mouth ulcers and a wet cough. Multiple services, including otolaryngology, infectious diseases, immunology, and rheumatology, extensively investigated him. Multiple meetings were held, and the possibility of hereditary hemorrhagic telangiectasia (HHT) and auto-inflammatory diseases was ruled out due to negative results. Figure 2 Right buccal mucosal bleeding with no signs of pus or infectious process. Figure 3 Growth chart showing how initially the patient was below the third percentile for weight-for-age. At 15 months of age, the child starts gaining weight after gastrostomy tube insertion. Later at 21 months of age, it was removed, and the child maintained acceptable weight as the mother was separated. Unluckily, after one month, the mouth ulcers were severely infected, which caused acute retropharyngeal edema requiring broader-spectrum antibiotics and tracheostomy tube insertion due to upper airway obstruction, which required intubation for four days. He stayed in the pediatric intensive care for around 10 days. The patient also had cytomegalovirus (CMV) (quantification: 156 copies/mL) that responded well to the valganciclovir course. The head and neck magnetic resonance imaging (MRI) with contrast revealed diffuse thickening, edema, and prominent enhancement of the retropharyngeal and prevertebral soft tissues, with associated edema; the abnormality is relatively symmetrical without discrete mass lesion . Figure 4 Magnetic resonance imaging (MRI) T1 with contrast coronal view, showing diffuse thickening, edema, and prominent enhancement of the retropharyngeal and prevertebral soft tissues with associated edema. Due to the patient's nutritional status, a gastrostomy tube was inserted. The patient had recurrent bleeding from the tracheostomy tube during the hospital stay despite the normal coagulation and platelet profile (the international normalized ratio {INR} is 1.1, reference range: 0.8-1.1; platelet: 432 x 109/L, reference range for age: 155-435). The following multidisciplinary meeting involving the otolaryngologist specialist after diagnostic laryngoscopy pointed out that such retropharyngeal injuries are seen in patients with non-accidental injuries. This raised the suspicion of child abuse by the mother, as the recurrent bleeding episodes happened when the mother accompanied the child. Adding to that, whenever discharge planning was discussed with the patient's mother, the incidence of hematemesis increased. The mother was confronted, but she did not disclose or admit her actions. Therefore, the pediatrician explained to the patient's father the possibility of Munchausen syndrome by proxy (MSBP), and the father agreed to move forward with the necessary steps. The hospital's social services and the Ministry of Social Affairs were involved in the parent-child separation process. The hospital arranged a babysitter for the patient, and the patient's room was changed daily to prevent the mother from visiting. After three weeks, no more bleeding was noticed from the tracheostomy tube. Four months later, all oral ulcers were resolved; the tracheostomy and gastrostomy tubes were decannulated, and the patient's CMV quantification was no longer detectable. At four years of age, the patient came for follow-up to the child protective clinic accompanied by the father, sister, and aunt. Clinically, the patient was medically free and meeting his developmental milestones and growth parameters (height standard deviation score {SDS} score, 0.02; weight SDS, 0.21), which are both within the normal range (5th-95th percentiles). Socially, the patient was living with his aunt and sister. The mother was evaluated for psychiatric disorders in another hospital (mental institute) and was admitted for one week, as reported by the husband, while maintaining no interaction with her child. However, the mother was not compliant with her psychiatric help. The father and sister were counseled on the importance of maintaining the child's safety, and the patient was discharged as the treatment plan was completed. Discussion MSBP is a term used to describe abuse where the abuser is diagnosed with a factitious disorder imposed on another (FDIA) due to a caregiver-fabricated illness . A systematic review of 796 cases showed that nearly all abusers were female (97.6%), most commonly the victim's mother (95.6%) . Isolating the child from the parent has proven to be an effective diagnostic technique . The key to diagnosis was symptom resolution after a parental absence, which was a recurrent finding, particularly in fabrication cases in the medical literature . Furthermore, according to the American Professional Society Abuse Children (APSAC), the separation of the child from the suspected abuser for a period of time is a diagnostic criterion for MSBP, as it often leads to the resolution of symptoms . The current case is an unusual presentation of MSBP. According to Rees et al.'s systematic review of otolaryngologic manifestations of child abuse, pharyngeal perforations presenting with dysphagia and surgical emphysema were reported in 20 out of 122 cases of maltreated children . The current case bears similarities to a previous case documented in our hospital back in 1993, as reported by Al-Jumaah et al. In this prior case, a 15-month-old Saudi female had been in good health until the age of 13 months when she suddenly developed symptoms such as fever, cough, and the rapid onset of ulcerative lesions primarily affecting her oral cavity and lips . Clinical examination revealed a distressed child who was drooling, with fresh ulcers on the oral mucosa and corners of the mouth, extending into the infra-auricular area. These lesions were indicative of an acute chemical injury and strongly suggested deliberate harm. Upon confrontation, the mother admitted her actions, and she was subsequently referred for psychiatric support . A few other cases regarding MSBP in Saudi Arabia were reported, including a report by Al-Mugeiren and Ganelin about a 17-month-old Saudi male who presented with recurrent episodes of hematemesis, bleeding per rectum, and hematuria . In addition, Alkhattabi et al. reported a case of factitious hypoglycemia . Overall, these case reports collectively underscore the presence of MSBP in Saudi Arabia and provide valuable clinical insights. While each study offers a unique perspective, they all highlight the importance of early recognition, multidisciplinary collaboration, and appropriate legal measures in managing cases of MSBP. To solve instances with unusual combinations of symptoms and a poor response to anti-inflammatory medications, one must have a high suspicion index for MSBP. In our case, the patient had a fever, recurrent mouth ulcers, FTT, and recurrent chest, ear, and bowel infections at admission, and due to his nutritional status, a gastrostomy tube was inserted. Fortunately, the tracheostomy tube did help save his life during the acute bleeding episodes. Moreover, after diagnostic laryngoscopy, the otolaryngologist specialist pointed out that such retropharyngeal injuries are seen in patients with non-accidental injuries. Therefore, it is essential to be aware of presentation patterns and parental behavior to diagnose MSBP early and prevent unnecessary diagnostic and surgical treatments . Pharyngeal or external ear injuries in young children without a detailed history of witnessing harm should elicit a referral to the child protection service for a comprehensive evaluation, and consultation with a child safety specialist is advised because they have the potential to identify these children in their practice, recognizing possible child maltreatment and initiating appropriate safeguarding measures . Conclusions The timely recognition of MSBP is important for early intervention and preventing further complications. The accurate diagnosis of MSBP requires a comprehensive evaluation that may involve multidisciplinary healthcare professionals, including pediatricians, otolaryngologists, radiologists, and social workers. Clinical assessment, taking comprehensive patient history through physical examination, laboratory investigations, and radiology images are particularly important when having an unusual combination of symptoms. These procedures help identify the underlying cause of these symptoms and guide the management plan. Thus, it is essential to include MSBP as a differential diagnosis in children with recurrent unexplained bleeding or infected mouth ulcers. Author Contributions Human Ethics Concept and design: Fadiah Alkhattabi, Abdullah Alkhani, Alaeddin Jebreel Critical review of the manuscript for important intellectual content: Fadiah Alkhattabi, Raghad Alhuthil, Alaeddin Jebreel Acquisition, analysis, or interpretation of data: Sulaiman Alsalameh, Raghad Alhuthil, Ahmad Hatem Drafting of the manuscript: Sulaiman Alsalameh, Abdullah Alkhani, Ahmad Hatem Supervision: Alaeddin Jebreel Consent was obtained or waived by all participants in this study. The institutional review board (IRB) of the King Faisal Specialist Hospital and Research Centre issued approval 2235061. Institutional review board (IRB) approval was taken from the King Faisal Specialist Hospital and Research Centre to publish this case report (reference number: 2235061). In addition, written informed consent was taken from the patient's father to write and publish this case report, including images. The authors have declared that no competing interests exist. References 1 Dysphagia: foundation, theory and practice 1 West Sussex, England John Wiley & Sons, Inc. 11 2006 .+Dysphagia:+Foundation,+theory+and+practice.+John+Wiley+%26+Sons&ots=4pRl4rlo_E&sig=f72WoP9s7DZcfdkoYBNhXmg07zk&redir_esc=y#v=onepage&q&f=false 2 Dysphagia: current reality and scope of the problem Nat Rev Gastroenterol Hepatol Clave P Shaker R 259 270 12 2015 25850008 3 Consequence of dysphagia in the hospitalized patient: impact on prognosis and hospital resources Arch Otolaryngol Head Neck Surg Altman KW Yu GP Schaefer SD 784 789 136 2010 20713754 4 Munchausen syndrome by proxy (MSBP): a review regarding perpetrators of factitious disorder imposed on another (FDIA) CNS Spectr Abdurrachid N Gama Marques J 16 26 27 2022 32772954 5 The perpetrators of medical child abuse (Munchausen syndrome by proxy) - a systematic review of 796 cases Child Abuse Negl Yates G Bass C 45 53 72 2017 28750264 6 Munchausen syndrome by proxy: patterns of presentation to pediatric surgeons J Pediatr Surg Lacey SR Cooper C Runyan DK Azizkhan RG 827 832 28 1993 8331513 7 New practice guidelines available - Munchausen by proxy (MBP): clinical & case management guidance APSAC Task Force 2018 8 Child abuse and fabricated or induced illness in the ENT setting: a systematic review Clin Otolaryngol Rees P Al-Hussaini A Maguire S 783 804 42 2017 27148702 9 Munchausen syndrome by proxy in a Saudi child Ann Saudi Med Al-Jumaah S Al-Dowaish A Tufenkeji H Frayha HH 469 471 13 1993 17590734 10 A suspected case of Munchausen's syndrome by proxy in a Saudi child Ann Saudi Med Al-Mugeiren M Ganelin RS 662 665 10 1990 11 Munchausen syndrome by proxy: a case report J Med Case Rep Alkhattabi F Bamogaddam I Alsagheir A Al-Ashwal A Alhuthil R 148 17 2023 37013583 |
Motivation There now exist thousands of molecular biology databases covering every aspect of biological data. This database infrastructure takes significant effort and funding to develop and maintain. The creators of these databases need to make strong justifications to funders to prove their impact or importance. There are many publication metrics and tools available such as Google Scholar to measure citation impact or AltMetrics covering multiple measures including social media coverage. Results In this article, we describe a series of novel impact metrics that have been applied initially to the UniProt database, and now made available via a Google Colab to enable any molecular biology resource to gain several additional metrics. These metrics, powered by freely available APIs from Europe PubMedCentral and SureCHEMBL cover mentions of the resource in full text articles, including which section of the paper the mention occurs in, grant acknowledgements and mentions in patent applications. This tool, that we call MBDBMetrics, is a useful adjunct to existing tools. Availability and implementation The MBDBMetrics tool is available at the following locations: and National Human Genome Research Institute 10.13039/100000051 National Institutes of Health 10.13039/100000002 pmc1 Introduction Databases of molecular biology data have become central to modern biology and many thousands of resources now exist (Ma et al. 2022). These range from extremely specialized databases that focus on perhaps a single aspect of biology in a single organism, or repositories of data from a single laboratory, up to huge international collections of data on nucleic acids, genetic variation or macromolecular structure. Continued funding or lack of it for these databases has been a constant theme over the last three decades and in more recent years there have been moves to coordinate international funding in this arena, from ELIXIR (Harrow et al. 2021) and the Global Biodata Coalition to NIH Office of Data Science Strategy ). To help justify the funding of these data resources various impact metrics are collected by the resources and sometimes by funders (Imker 2018). Impact metrics can be used to aid assessment of the value of resources and also guide future directions of development of them. Staff at the UniProt database (UniProt Consortium 2023), a large database of protein sequence and annotation, have had many years of experience in calculating metrics, and we have developed a variety of novel metrics which are not widely available. In this work, we have developed a tool to share the methodology to calculate these metrics with other resources. The tool is not aimed to be a comprehensive resource for metrics, but rather provides a suite of information that is not readily available elsewhere. For example, citation information about the papers describing database resources are easily obtained from Google Scholar or a number of other similar resources. Website analytics is also an area that is well provisioned with metric gathering tools. Our tool named MBDBMetrics, for Molecular Biology DataBase Metrics, is a freely available tool that is hosted in Google Colab. This makes it easily accessible and it allows it to be readily modified by others. Alternatively, it can be downloaded as a jupyter notebook from the GitHub code repository, allowing it to be run on a user's computer, independently of the google ecosystem. 2 Tool description MBDBMetrics was implemented as an interactive Jupyter notebook, coded in Python and depending only on the libraries requests (for web data retrieval), plotly (for creating the bar plots), and pandas (for exporting the datasets). The structure of the notebook consists of an initial Code cell (where the procedures are defined), a Parameters cell (where users can select the query strings, the date range, the grant funding agencies and the plots' colour scheme) and a series of Plot cells, each of which is specific to generate a certain type of diagram. In this way, users have the possibility to only retrieve data and generate the plot(s) for the data dimension they are interested in. Once the parameters have been specified, the databases EuropePMC (Ferguson et al. 2021) (for mentions in publications) and SureCHEMBL (Papadatos et al. 2016) (for mentions in patents) are queried via their respective APIs. The retrieved data are then plotted and also made available for download in comma separated tabular format. This allows the possibility of plotting the data using any other external tool. A series of default parameters are accessible via drop down menus, but users can simply type in any value, without being limited to the preset choices. Since each Colab session runs independently and is saved in a user's Google Drive, their own customizations will be preserved across runs. The Colab platform makes it easy for users to experiment with modifying and extending the code, so that it is easy not only to customize the search parameters, but also to add new capabilities and new plots. Similarly, users can clone the GitHub code repository and freely modify the original notebook in their own computer to extend its functionality or customize its output. The current version of MDBDMetrics generates the following plots: Total results (number of papers and number of patents mentioning the specified resource, in the specified time frame and/or acknowledging a certain funding agency). This graph gives an overview of the major metrics calculated by this tool. Publication mentions by year (number of papers mentioning the resource for each year in the specified range, with or without acknowledging a specified funding agency): see example in Fig. 1 below. Publication mentions by grant agency (a total of 28 funding agencies are currently defined but, again, it is easy to modify the code to change or extend this set). This plot enables an understanding of the relative use of a resource by fundees of different agencies. Publication mentions by paper section (18 paper sections are defined). This graph can be useful to highlight for example whether a resource is mostly mentioned in the Methods rather than in the Discussion or in the Abstract of publications. Patent mentions by year (number of patents mentioning the specified resource in the specified time frame). This graph can help to understand how a resource is used in records of new inventions and give a glimpse of industrial use. Figure 1. Example of the plot 'Publication mentions by year' for the date range 2018-23 and the resource UniProt (and its related keywords). Top panel: total number of papers for each year; bottom panel: restricted to those acknowledging 'US funders'. More plot examples are available on the GitHub repository page. There are some important caveats to note when using the tool. Firstly, to find all mentions of the data resource it is important to provide synonyms. Each search term must match exactly, thus 'UniProt' and 'UniProtKB' will match different sets of papers. If the name of the database matches a common English word such as STRING or PRINTS then you will get many false positive matches. A final caveat is that this tool is only searching the full text of the open access portion of EuropePMC, thus the counts of papers will be an underestimate of the total number of mentions in the whole research literature. 3 Comparison with existing tools Currently, the two major metrics for demonstration of a molecular biology database's impact is via citations to an article describing the resource or the number of website visits or users often from Google Analytics. Many database resources are described in the Nucleic Acids Research's Database Issue and the most impactful publications gain thousands of citations making them among the most highly cited papers in all of science (Wren 2016). Citation impact can be easily found for any published paper by inspecting data at sites like Google Scholar, Thompson Reuter's ISI Web of Knowledge or Elsevier's SCOPUS. Although commonly used, the value of citation data has been questioned for many reasons (MacRoberts and MacRoberts 2018). Information about the number of website visits is available to the developers of the resource through tools such as Google Analytics or by analysing web log files directly. There are various challenges to interpreting this kind of data, such as the many papers which may use resources in their work but not cite them. With website analytics the challenges lie in separating out real users from web crawling robots and identifying users uniquely in the data. However, these issues are beyond the scope of this article. We believe that our tool provides a unique and useful combination of metrics to be used alongside existing tools. One of the advantages of our tool is that, rather than relying on citations, we rely on mentions of a resource in the full text of the article. This means that we capture many uses or mentions of a resource that are missed by only counting citations. Having said that, not all articles are available as full text, so these two approaches should be regarded as complementary. In terms of patent searches, one can use the SureChEMBL database directly, but this does not return a result that is grouped by year, so it is not easy to see the growth of patent mentions over time as with our tool. Finally, we are not aware of any other tool that combines grant funding information with database mentions. This enables a better understanding of how much overlap there is for a particular resource with the community of researchers being funded (see case studies in Supplementary Materials). Although the tool was developed in the context of database metrics, the tool can actually be used in a more general way. For example, one could look at the metrics for molecular biology methods such as CRISPR or RNAi, to judge their impact on the research field. 4 Conclusion Molecular biology databases provide a foundation for much of modern biomedical research, saving researchers untold thousands of hours in their research. As collections of data gathered over decades and thousands of unique depositors, databases often do not just save time, they literally enable research that could not be done without a comprehensive database, no matter how many hours available. However, long-term stable funding for these resources is rarely available, meaning that recurrent grant funding applications are the norm (Markosian et al. 2018, Imker 2020). We hope that MBDBMetrics will be a user-friendly online tool for database developers to present the impact of their resources as well as a useful source of information for funders and other interested parties to evaluate database resources. Although we think that MBDBMetrics is immediately useful, there are undoubtedly improvements that can be made over time. Currently the graphs presented in the Colab page are not of publication quality and hence we provide access to the raw data so the researchers can import and generate graphics to fit their own needs. Making higher quality graphs directly available via Google Colab could save researchers time. Currently the grouping of funders is US/UK centric. We are happy to take suggestions of further funder groups to be included within our tool to help justify database resources at the national or international level. Other detailed metrics on the topics of papers mentioning a resource could be included in the future inspired by the detailed analysis carried out by the RCSB PDB database (Markosian et al. 2018), although the subject categories used from the ISI database are not freely available data. We are open to further suggestions for improvements or collaborations on the tool to enhance its utility. We encourage database developers as well as funders to use MBDBMetrics alongside other tools to make the case for future stable funding of resources to ensure the long-term success of biomedical research. Supplementary Material vbad180_Supplementary_Data Click here for additional data file. Acknowledgements The UniProt Consortium: Alex Bateman, Maria-Jesus Martin, Sandra Orchard, Michele Magrane, Shadab Ahmad, Emily H. Bowler-Barnett, Hema Bye-A-Jee, Paul Denny, Tunca Dogan, ThankGod Ebenezer, Jun Fan, Leonardo Jose da Costa Gonzales, Abdulrahman Hussein, Alexandr Ignatchenko, Giuseppe Insana, Rizwan Ishtiaq, Vishal Joshi, Dushyanth Jyothi, Swaathi Kandasaamy, Antonia Lock, Aurelien Luciani, Jie Luo, Yvonne Lussi, Pedro Raposo, Daniel L. Rice, Rabie Saidi, Rafael Santos, Elena Speretta, James Stephenson, Prabhat Totoo, Nidhi Tyagi, Preethi Vasudev, Kate Warner, Rossana Zaru, Supun Wijerathne, Khawaja Talal Ibrahim, Minjoon Kim, and Juan Marin at the EMBL European Bioinformatics Institute; Alan J. Bridge, Lucila Aimo, Ghislaine Argoud-Puy, Andrea H. Auchincloss, Kristian B. Axelsen, Parit Bansal, Delphine Baratin, Teresa M. Batista Neto, Jerven T. Bolleman, Emmanuel Boutet, Lionel Breuza, Blanca Cabrera Gil, Cristina Casals-Casas, Elisabeth Coudert, Beatrice Cuche, Edouard de Castro, Anne Estreicher, Maria L. Famiglietti, Marc Feuermann, Elisabeth Gasteiger, Sebastien Gehant, Arnaud Gos, Nadine Gruaz, Chantal Hulo, Nevila Hyka-Nouspikel, Florence Jungo, Arnaud Kerhornou, Philippe Le Mercier, Damien Lieberherr, Patrick Masson, Anne Morgat, Ivo Pedruzzi, Sandrine Pilbout, Lucille Pourcel, Sylvain Poux, Monica Pozzato, Manuela Pruess, Nicole Redaschi, Catherine Rivoire, Christian J.A. Sigrist, Shyamala Sundaram, and Anastasia Sveshnikova at the SIB Swiss Institute of Bioinformatics.; Cathy H. Wu, Cecilia N. Arighi, Chuming Chen, Yongxing Chen, Hongzhan Huang, Kati Laiho, Minna Lehvaslaiho, Peter McGarvey, Darren A. Natale, Karen Ross, C.R. Vinayaka, Yuqi Wang, and Jian Zhang at the Protein Information Resource. Supplementary data Supplementary data are available at Bioinformatics Advances online. Conflict of interest A.B. is Editor-in-Chief of Bioinformatics Advances but was not involved in the editorial process of this article. Funding This work was supported by the National Human Genome Research Institute (NHGRI), Office of Director (OD/DPCPSI/ODSS), National Institute of Allergy and Infectious Diseases (NIAID), National Institute on Aging (NIA), National Institute of General Medical Sciences (NIGMS), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Eye Institute (NEI), National Cancer Institute (NCI), National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health under Award Number [U24HG007822] (the content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health). |
Lymphangiomas are rare benign tumours of lymphatic vascular origin. They are more common in the paediatric population and manifest mainly in the neck and axillary region. Retroperitoneal lymphangiomas are <1% and pancreatic origin is even rarer. We present a case of a pancreatic cystic lymphangioma in a 60-year-old woman with chronic diffuse symptoms, diagnosed because of newly onset of diabetes mellitus. She was successfully managed with distal pancreatectomy and spleenectomy en-bloc with the cystic mass without any complications. Cystic lymphangioma of the pancreas is a rare entity presenting with a challenging preoperative diagnosis as imaging modalities may provide ambiguous information. The clinician should be aware of its complicated differential diagnosis and its persistent and subtle symptomatology. pancreatic lymphangioma pancreas lymphangioma distal pancreatectomy pmcIntroduction Lymphangiomas are rare benign tumours of lymphatic vascular origin . They occur due to a local obstruction of the lymphatic flow causing lymphangiectasia . They are mostly congenital, in case of lymphatic obstruction during the foetal development, but they may be caused by trauma, fibrosis, inflammation and radiotherapy as well . Lymphangiomas are more typical in the paediatric population and manifest mainly in the neck and axillary region in 75% and 20%, respectively. Retroperitoneal lymphangiomas are <1% and a pancreatic localization is even rarer . Pancreatic lymphangiomas generally are incidentally discovered or present with subtle symptomatology . Considering their rarity and non-specific symptoms or radiologic findings, preoperative diagnosis is a challenge. A biopsy may assist in the differential diagnosis from other cystic tumours of the pancreas, or in case of persistent or deteriorating symptomatology a straightforward surgical excision may take place . We present a case of a pancreatic cystic lymphangioma in a 60-year-old woman diagnosed because of newly onset diabetes mellitus, with emphasis in the occult symptomatology and the therapeutic challenges. This case report was written in accordance with the SCARE criteria . Case presentation A 60-year-old woman presented to the outpatient clinic with newly onset diabetes mellitus complaining of abdominal discomfort and mild epigastric pain for the past year. She had previously visited her endocrinologist who requested an upper abdomen magnetic resonance imaging (MRI). Her past medical history was remarkable for hypertension and tachycardia under medication and her newly acquired diabetes. Her past surgical history included an open appendectomy 52 years ago and a caesarean section 32 years ago. The patient was a moderate smoker and reported no allergies or alcohol intake. Her vital signs were normal while physical examination revealed a palpable upper abdominal mass along with mild epigastric tenderness upon palpation. Blood tests including white blood cells, serum amylase, and lipase as well as carcinoembryonic antigen (CEA) and cancer antigen 19-9 (Ca19-9) were within normal limits. The patient underwent an ultrasound (US) and a MRI before visiting our department and a computed tomography (CT) upon admission. Upper abdominal US revealed cholelithiasis and a large well-defined cystic lesion in close relation with the upper pole of the spleen and the tail of the pancreas measuring 11.6 cm in diameter. Abdominal CT showed a hypodense, cystic lesion with minimal enhancement between the tail of the pancreas and the spleen (Fig. 1). The mass was well-defined, measured 12 cm anterioposterior (AP) x 9.5 cm transverse (TR) x 10 cm cephalocaudal (CC), without any signs of infiltration of adjacent structures. There were no calcifications or soft tissue component. Abdominal MRI confirmed microcholelithiasis without signs of cholecystitis and extrahepatic bile ducts within normal range. It revealed multiple microcystic formations in the body and tail of the pancreas with possible communication with the main pancreatic duct giving the impression of branch-duct intraductal papillary mucinous neoplasm. Furthermore, between the tail of the pancreas and the splenic hilum, expanding to the left hemi diaphragm, a large multilobulated cystic lesion was described. The size of the lesion was 12.8 cm (AP) x 10.2 cm (TR) x 8.65 (CC), originating from the tail of the pancreas and displacing the spleen laterally and caudally and the stomach anteriorly (Fig. 1). The cyst did not present any solid component and no pathological signal intensity. There were no evident pathological lymph nodes or vascular invasion from the mass. MRI findings were suggestive for atypical pseudocyst, mucinous cystic neoplasm, or cystic lymphangioma. Figure 1 CT scan of the abdomen. Transverse scan mass between pancreas and spleen (A), Transverse scan mass expanding below the diaphragm (B), Sagittal scan mass below the diaphragm and over the tail of the pancreas and splenic vessels (C), Coronal scan mass between the diaphragm, upper pole of the spleen and tail of the pancreas (D), MRI scan of the abdomen. Coronal scan mass between the diaphragm, upper pole of the spleen and tail of the pancreas, not enhancing (E), Transverse scan mass between pylorus, pancreas, and spleen (F) ( arrow marking the mass). Due to the increased size and the long-lasting pressure symptoms of the cystic lesion, surgical exploration was decided at the multi-disciplinary team (MDT) meeting with the patient's approval. The patient underwent exploratory laparotomy through a midline incision. The cystic mass was found to originate from the tail of the pancreas, adherent to the upper pole of the spleen. The mass was carefully mobilized from the adjacent structures and the resection was completed by en-bloc distal pancreatectomy with splenectomy and cholecystectomy (Fig. 2). The patient had an uncomplicated postoperative course and was discharged on post-operative day 5. Gross examination revealed a 13 x 11 x 7 cm well-described cystic tumour filled with yellowish fluid. On histopathological evaluation, the lesion consisted of anastomosing lymphatic spaces lined by a single layer of endothelial cells. The endothelial cells were positive for CD34, CD31, and D2-40 and negative for pankeratin (Fig. 3). The diagnosis of lymphangioma was made. There was no evidence of malignancy. Splenic and pancreatic tissues were found to be normal. Gallbladder specimen presented signs of chronic lymphocytic inflammation indicative for chronic calculus cholecystitis. MDT decision was follow-up. The patient is asymptomatic with no evidence of recurrence in 6 months. Figure 2 Surgical specimen of the distal pancreatospleenectomy en-bloc with the lymphangioma. Figure 3 CD34 stain, x100 (A), H-E, x40 (B), and H-E, x100 (C). Discussion Lymphangiomas are rare benign lymphatic tumours caused by congenital malformation of the lymphatic vasculature during the gestational period or by a lymphatic obstruction because of trauma, fibrosis, inflammation, or radiation . They are more common among paediatric patients but due to the lack of symptomatology they are usually diagnosed in adult population. Common presentation sites include the neck and the axillary region in 95% of the cases and only 5% occurs in the mesentery, retroperitoneum, abdominal viscera, lung, or mediastinum . Pancreatic lymphangiomas illustrate < 1% of all abdominal lymphangiomas and solely 0.2% of all pancreatic neoplasms. Initially described by Koch in 1913 , pancreatic lymphangiomas are extremely uncommon with less than 100 cases reported in the literature . A slight female predominance is reported with non-specific age distribution . The size of pancreatic cystic lymphangiomas varies greatly in the literature, from 3 to 20 cm and an average size of 12 cm2. They may develop adjacent to the pancreas, within the pancreatic parenchyma, or connected to the pancreas via a pedicle . A slight predisposition for the tail of the pancreas is also reported . Patients with pancreatic cystic lymphangiomas are mainly asymptomatic. Small lymphangiomas are discovered incidentally. Larger lymphangiomas cause non-specific symptomatology due to their pressure effects which include abdominal pain and palpable mass upon examination. These symptoms were present in our case as well. Pancreatic lymphangiomas, especially large, may also cause acute abdominal symptoms if rupture, haemorrhage, or inflammation takes place which, however, is extremely rare . There are no specific laboratory examinations for pancreatic cystic lymphangiomas and tumour markers are within normal limits in most of the cases . Considering that symptoms, signs and laboratory tests are non-specific, imaging modalities portray an important role in the preoperative diagnosis. On US, cystic lymphangiomas present as multiple hypoechoic or anechoic cysts including multiple septa and rarely contain any echogenic material . In our case, US revealed a single well-defined mass complicating the differential diagnosis. On CT, pancreatic cystic lympangiomas appear as well-defined, homogenous cystic masses with multiple septation which may show enhancement . Microcalcifications because of phleboliths, haemorrhaging content with high attenuation or chyle are uncommon but may be present . MRI imaging generally reveal and strengthen US and CT findings. A cystic mass is observed with multiple septa which are enhanced after gadolinium administration. The cyst is hyperintense in T2 sequence and hypointense in T1 sequence . Haemorrhage, infection or the presence of chyle may alter the cyst appearance on MRI, adding a solid component in its contents . However, imaging studies are still non-specific for pancreatic cystic lympangiomas, as pancreatic mucinous and cystic lesions demonstrate similar features. Therefore, accurate pre-operative diagnosis of a pancreatic cystic lymphangioma remains a challenge and multiple imaging modalities should be combined. Differential diagnosis would mostly include pseudocysts, serous, or mucinous cystadenomas, other congenital cysts and cystic ductal carcinoma . In our case, the patient presented with non-specific symptoms of abdominal pain and a palpable mass. She also presented with new onset of diabetes mellitus which may not be related to pancreatic lymphangioma as it is with pancreatic cancer but eventually led to the diagnosis of the cystic mass of the pancreas. Physical examination and laboratory tests were non-diagnostic and imaging modalities were inconclusive as the cystic characteristics were non-specific and even misguiding. Endoscopic US with fine-needle aspiration (EUS-FNA) was not performed because of the size of the lesion and patient's symptoms as well as the possibility of malignancy or mucinous cystadenoma. Treatment options for pancreatic cystic lymphangiomas, with established diagnosis, depend on their size and symptoms, as it does with other rare tumours of the pancreas like dermoid or epidermoid tumours . If the patient is asymptomatic and the lesion does not cause pressure effects on adjacent organs, imaging surveillance may be embraced. If, as in our case, there is symptomatology due to the size of the cystic lymphangioma or there is a diagnostic dilemma concerning the nature of the lesion, surgical intervention is preferable. Surgical excision includes either simple cystectomy if feasible or more radical resections depending on the size of the lesion, its anatomic location within the pancreas and its relations with the adjacent organs . In our case, the size of the pancreatic lymphangioma its location between the tail of the pancreas and the spleen as well as the diagnostic dilemma, contributed to the decision for distal pancreatectomy with splenectomy. Upon pathology examination pancreatic cystic lymphangiomas are multilobulated and on cut section the smaller cysts interconnect representing multiple dilated lymphatic channels. Histologically, there are three types of lymphangiomas cystic, capillary, and cavernous but only the cystic and cavernous types have been reported in the pancreas. Histologically, dilated lymphatic spaces along with attenuated endothelial cells are observed. Immunohistochemically, lymphangiomas are positive for VIII-R antigen, CD31, and D2-40 and negative for CD34 which however may occasionally be positive as it presented in our case. They are negative for epithelial markers or periodic acid-Schiff stain . In conclusion, cystic lymphangioma of the pancreas is a rare entity with limited data in the current literature. Pre-operative diagnosis is challenging as imaging modalities may provide ambiguous information. The clinician should be aware of the complicated differential diagnosis and the persistent subtle symptomatology, which usually leads to the operative theatre where surgical resection takes place. In the presence of preoperative suspicion and diagnosis along with a small sized and asymptomatic lesion, periodic imaging surveillance may be followed. Conflict of interest statement The authors declare that there is no conflict of interest. Funding This research received no funding. |
Summary Neural morphology, the branching geometry of brain cells, is an essential cellular substrate of nervous system function and pathology. Despite the accelerating production of digital reconstructions of neural morphology, the public accessibility of data remains a core issue in neuroscience. Deficiencies in the availability of existing data create redundancy of research efforts and limit synergy. We carried out a comprehensive bibliometric analysis of neural morphology publications to quantify the impact of data sharing in the neuroscience community. Our findings demonstrate that sharing digital reconstructions of neural morphology via NeuroMorpho.Org leads to a significant increase of citations to the original article, thus directly benefiting authors. The rate of data reusage remains constant for at least 16 years after sharing (the whole period analyzed), altogether nearly doubling the peer-reviewed discoveries in the field. Furthermore, the recent availability of larger and more numerous datasets fostered integrative applications, which accrue on average twice the citations of re-analyses of individual datasets. We also released an open-source citation tracking web-service allowing researchers to monitor reusage of their datasets in independent peer-reviewed reports. These results and tools can facilitate the recognition of shared data reuse for merit evaluations and funding decisions. Availability and implementation The application is available at: The source code at and NIH 10.13039/100000002 R01NS39600 R01NS86082 pmc1 Introduction Omics and structural biology have benefited enormously from the consistent practice of data sharing, with thriving research subfields fueled by seminal discoveries entirely based on publicly available datasets, and vibrant ecosystems of related scientific tools (Field et al. 2009, Chervitz et al. 2011, Wilson et al. 2021). Neuroscience has followed suit only more recently and more gradually, in part due to greater data heterogeneity and the lack of a clear functional code akin to that of genomic sequences (Gardner et al. 2003, Gleeson et al. 2017, Poline et al. 2022). One particular domain of neuroscience, digital reconstructions of neural morphology, is especially amenable to data sharing (Ascoli 2006, 2015, Ascoli et al. 2017). The accelerating development of advanced technologies in microscopic imaging and computational processing has greatly enhanced 3D neural reconstruction methods, enabling the creation of ever larger amounts of digital tracing data (Liu et al. 2022, Manubens-Gil et al. 2023). Capitalizing on this growth requires effective data accessibility to propel scientific discovery in neuroscience. Indeed, this is the goal of NeuroMorpho.Org, an open-access archive of 3D neural reconstructions and associated metadata (Ascoli et al. 2007). Today, this resource comprises hundreds of thousands of downloadable reconstructions, each of them linked to peer-reviewed publications from laboratories worldwide (Akram et al. 2018). Global collaborative efforts and data sharing from multiple sources are extremely valuable to researchers to gain a better understanding of the brain and its cellular constituents given the strong association between neuronal form and function (Parekh and Ascoli 2015). It is essential to determine, however, the effective extent and impact of free data exchange. Previous research quantified the benefits of data sharing to the original authors who shared data, in addition to the data users and the community at large, in specific disciplines such as cancer microarray clinical trials (Piwowar et al. 2007) and noninvasive human brain imaging (Milham et al. 2018). However, it is not yet known whether these findings generalize to other fields, and in particular if neural morphology data sharing provides a positive return on investment for the original data owners and/or significantly impacts scientific throughput. Here, we present a comprehensive bibliometric analysis of published literature pertaining to neural morphology to assess the impact of data sharing on the overall field as well as on individual investigators. We further introduce a dynamic web-based research tool to determine the scientific impact of uniquely identified, shared neural morphology datasets. The application serves as a valuable resource for neuroscientists to demonstrate the direct and indirect benefits of sharing their data. 2 Materials and methods This study relies on datasets retrieved from NeuroMorpho.Org, Semantic Scholar, and Europe PubMed Central (EuropePMC). Semantic Scholar is an Artificial Intelligence-powered engine for research literature including a large neuroscience collection (Jones 2015). EuropePMC is an open-access archive of life science publications (Ferguson et al. 2021). We have selected these databases due to their extensive full-text record coverage and accessibility via Application Program Interface (API). In particular, NeuroMorpho.Org tallies availability and reusage of neural morphology data, while Semantic Scholar and EuropePMC track peer-reviewed citations, broadly considered an expedient proxy for scientific impact. We refer here to publications that generated new digital reconstructions of neural morphology as Describing. NeuroMorpho.Org divides Describing publications into three categories depending on whether the underlying datasets are publicly available (Sharing), unavailable (Unsharing), or determining availability. The database curators determine this information through direct interaction with data owners (Maraver et al. 2019) and update it publicly every month (neuromorpho.org/LS_queryStatus.jsp? status=Available&page=0). NeuroMorpho.Org also tracks the publications that cite the Describing articles and/or utilize the corresponding downloaded digital reconstructions, referred to as Citing and Using, respectively (neuromorpho.org/LS_usage.jsp). We fetch the Describing, Citing and Using metadata via the NeuroMorpho.Org API (neuromorpho.org/apiReference.html#literature) using a Python application, implemented with the Flask framework and released open source ), to populate a MongoDB database. We also retrieve from the NeuroMorpho API (neuromorpho.org/api/neuron) and store in the database the upload date for each dataset. We then fetch citations to and references of Describing and Using/Citing publications programmatically for storage in the MongoDB database. Specifically, the Semantic Scholar API (api.semanticscholar.org/v1/paper/{doi}) returns a JSON formatted response containing both citations and references metadata for a given publication. EuropePMC, in contrast, exposes distinct API endpoints for citations (ebi.ac.uk/europepmc/webservices/rest/MED/{pmid}/citations) and references (ebi.ac.uk/europepmc/webservices/rest/MED/{pmid}/references). We use a union of citations and a union of references from both Semantic Scholar and EuropePMC to provide a more complete record. 3 Results We first investigated whether openly sharing via NeuroMorpho.Org the digital reconstructions of neural morphology described in an article increases the number of citations to that article (Fig. 1). We started by comparing the number of citations to Sharing (N = 1656) and Unsharing (N = 3089) articles. Specifically, we normalized the yearly number of citations for a given Describing article by dividing its accrued citations by the number of years elapsed since publication. The analysis (Fig. 1A) demonstrates a significant difference in yearly citations between groups (Sharing: 8.91 +- 14, Unsharing: 6.19 +- 12; effect size +43.9%, P = 0.006). Figure 1. Publicly sharing digital reconstructions of neural morphology increases the number of citations to the Describing article. (A) Distributions of citations for Sharing and Unsharing articles bin-grouped using logarithmic scale. (B) Relative increase of citations to Sharing articles specifically due to Using/Citing publications. (C) Yearly citations to Sharing article by Using/Citing publications as a function of the time elapsed since the publication of the Sharing article. (D) Cumulative sum of Describing and Using/Citing article counts by year. (E) Citations accrued by Describing and Using/Citing articles by year. (F) Proportion of Using/Citing publications relying on different numbers of Describing articles. Bottom: ratio between the number of Using/Citing publications relying on >=4 Describing articles and those relying on <=3 Describing articles. Right: Mean number of citations accrued by Using/Citing publications as a function of the number of Describing articles cited. The error bars indicate a 95% confidence interval. We then asked whether this increase was specifically due to the citations by the Citing and Using publications. Thus, we calculated the Citation Increase for each Sharing article based on the following formula: CitationIncrease = NMO_Citations/(Citations_since_upload-NMO_Citations), where NMO_Citations represents the citations to the Sharing article by the Using/Citing publications, and Citations_since_upload represents the overall citations to the Sharing article since the upload date of the corresponding dataset. The resultant histogram distribution (Fig. 1B) reveals that the Citation Increase of Sharing articles due to the secondary publications (13.8%) explains less than a third of the difference in citations between Sharing and Unsharing articles. Taken together, these analyses indicate that sharing neural reconstruction data through NeuroMorpho.Org increases the impact of the original publication. Next, we explored if the numbers of citations to Sharing articles due to secondary publications decreases over time after publication. The results suggest a broadly uniform citation likelihood without a tendency to decrease over the whole 16 years of the project activity (Fig. 1C). To help assess the impact of shared data, it is also interesting to compare the number of Describing and Using/Citing publications and their respective citations. Both the cumulative number of Describing articles and of Using/Citing articles increased consistently from the project launch to present (Fig. 1D). Notably, the Using/Citing publications, which rely on shared data, effectively double the Describing data literature. Moreover, comparing the overall citations to Describing and Using/Citing articles (Fig. 1E) again demonstrates that data reusage increases the number of citations in the field by nearly 50%. These results further underscore the added impact of data sharing in neuroscience. Moreover, we found that fewer than a third of Using/Citing studies only refer to a single Describing article, and approximately the same proportion relies on 2-3 data sources (Fig. 1F). In contrast, more than 40% of Using/Citing articles rely on four or more sources, and nearly 10% require ten or more Describing publications. Interestingly, the ratio between the number of Using/Citing publications relying on four or more Describing articles and those relying on three or fewer Describing articles (Fig. 1F, bottom) is substantially greater after 2016 (ratio: 0.82) than before (ratio: 0.54), reflecting the increasing emphasis on big science, data aggregation, and meta-analyses. We then asked whether the Using/Citing articles relying on a greater number of data sources are cited more (Fig. 1F, right). Indeed, while Using/Citing publications relying on 1-3 data sources only accrue on average 60-65 citations, the mean number of accrued citations reaches ~80 for articles using 4-9 sources and exceeds 110 for articles using 10 or more sources. To provide researchers the capability to investigate the impact of Sharing articles on secondary publications, we made the bibliometric functionality utilized in the above analysis available as a public service through a web-based user interface (see Supplementary Materials). 4 Discussion The analysis of neuroscience data sharing among researchers provides insight into current trends and raises awareness to encourage collaborations and open data release (Poldrack and Gorgolewski 2014). It is intuitively obvious that the public availability of data is beneficial to researchers who can reuse it for follow-up analysis and diverse scientific applications (Halavi et al. 2012). However, whether it in fact provides advantages for the data owners to share data has remained a topic for discussion. Our findings demonstrate indeed that sharing digital reconstructions of neural morphology via NeuroMorpho.Org leads to a significant increase of citations to the original article, thus directly benefiting the authors. Moreover, the rate of data reusage remains constant for at least 16 years after sharing (the whole period analyzed), altogether nearly doubling the peer-reviewed discoveries in the field. Furthermore, the recent availability of larger and more numerous datasets fostered integrative applications, which accrue on average twice the citations of re-analyses of individual datasets. These results demonstrate the broader impact of open sharing of neural reconstructions on scientific discovery. We also designed and deployed an open-source bibliometric tracking web-service that allows researchers to monitor reusage of their datasets in independent peer-reviewed reports. This tool can facilitate the recognition of shared data reuse for promotion and tenure considerations, merit evaluations, and funding decisions. Supplementary Material btad746_Supplementary_Data Click here for additional data file. Acknowledgements The authors thank Dr Patricia Maraver for helping with the NeuroMorpho.Org literature management system. Supplementary data Supplementary data are available at Bioinformatics online. Conflict of interest None declared. Funding This work was supported by NIH [R01NS39600 and R01NS86082]. |
Summary The profusion of sequenced genomes across the bacterial and archeal domains offers unprecedented possibilities for phylogenetic and comparative genomic analyses. In general, phylogenetic reconstruction is improved by the use of more data. However, including all available data is (i) not computationally tractable, and (ii) prone to biases, as the abundance of genomes is very unequally distributed over the biological diversity. Thus, in most cases, subsampling taxa to build a phylogeny is necessary. Currently, though, there is no available software to perform that handily. Here we present TADA, a taxonomic-aware dataset selection workflow that allows sampling across user-defined portions of the prokaryotic diversity with variable granularity, while setting constraints on genome quality and balance between branches. Availability and implementation TADA is implemented as a snakemake workflow and is freely available at Swedish Research Council 10.13039/501100004359 2018-4135 pmc1 Introduction Taxon sampling is the selection of a representative set of taxa to be used in evolutionary analysis to understand the evolution of the entire clade from which the taxa have been sampled. In general, more data is beneficial to phylogenomic and comparative genomic analysis, as including a greater fraction of the diversity increases the resolution of the analyses. However, affordable genome sequencing caused an overrepresentation of clinically and agriculturally relevant taxa (Wu et al. 2009). Similarly, metagenomics databases are skewed toward abundant taxa, and have systematic biases (McLaren et al. 2019). The number of possible tree topologies increases with the number of taxa in a super-exponential way (Felsenstein 1978), making it key to limit the size of the dataset to save computation time when inferring phylogenies. It thus is important to reduce redundancy in a dataset but ensure that diversity is well covered. Also, due to compositional biases and differences in the evolutionary rates among taxa, the way taxa are sampled for a dataset might affect the resulting phylogeny. An automated process to generate datasets for this type of analysis can help test the robustness of evolutionary hypotheses using datasets with different taxa compositions. Several tools and workflows, such as GToTree (Lee 2019), anvi'o (Eren et al. 2021), and GEN-ERA toolbox (Cornet et al. 2022) have been designed to automate the process of generating phylogenomic trees from provided datasets. Sub-sampling large datasets may be performed by clustering genomes with e.g. FastANI (Jain et al. 2018), which uses average nucleotide identity (ANI) to compare genomes. However, the process of selecting one representative per cluster, and processing the data downstream, must be done manually. The Perl-based phyloSkeleton (Guy 2017) is, to the best of our knowledge, the only tool that can build these datasets, and provides the user with a concatenated alignment of marker proteins for the included taxa. However, phyloSkeleton is slow, cannot sample arbitrary numbers of genomes per clade, and does not offer the ability to parse data from GTDB (Parks et al. 2022). PATS (Powell and Battistuzzi 2022) can be used to test the effect of taxon sampling by iteratively removing taxa or groups of taxa and calculating new phylogenies but also requires an initial provided dataset. Here, we present a snakemake workflow (Molder et al. 2021), to assemble bacterial and archaeal genome datasets for comparative genomics and phylogenetic analysis purposes, based on phylogenomic-aware sampling. Based on user-defined configuration and sampling schemes, the workflow constructs and downloads datasets ready for downstream analysis. 2 Approach and features TADA generates datasets for evolutionary and comparative genomic studies of bacterial and archaeal genomes. Given a few user-defined options and rules, it downloads taxonomic and phylogenomic information from publicly available sources and then performs a sampling procedure. After sampling, TADA can also download genomic data and construct BLAST databases for the sampled genomes. The sampling step can either be based on taxonomic information or phylogenomic information (Fig. 1A). Figure 1. (A) Overview of the TADA workflow. (B) An example of a sampling scheme used for taxonomic sampling with a denser sampling of Planctomycetota compared to the rest of the PVC-superphylum. (C) Number of sampled genomes per class from the Planctomycetota phylum in datasets created by random sampling (blue), TADA taxonomic sampling (orange), and TADA phylogenomic sampling (green). A more even distribution across classes is likely to better cover the diversity in the sampled taxon. (D) Distribution of the distances between internal nodes (bifurcations) and the root for maximum-likelihood phylogenies of the Planctomycetota phylum based on random sampling (blue), TADA taxonomic sampling (orange), and TADA phylogenomic sampling (green). Tip-to-root distances (not shown) were very similar for all three distributions. Shorter and more evenly distributed distances from internal nodes to the root reduce the risk for artifacts, among others long-branch attraction, when inferring phylogenies. Taxonomic sampling can be configured to use the taxonomy provided by GTDB or by NCBI Taxonomy. In this approach, TADA relies on a user-created file containing a sampling scheme with one or several sampling criteria, each defined by the name of the taxon to sample from (e.g. "Enterobacterales"), the taxonomic level to sample at (e.g. "genus"), and the number of genomes to sample from each clade at the given taxonomic level. A sampling scheme can contain several sampling criteria to sample different numbers of genomes for different parts of the taxonomy. In those cases, TADA will perform a hierarchical sampling by first sampling taxa from the lowest taxonomic rank and continuing to higher ranks, excluding clades it already has sampled from (Fig. 1B). In the cases where there are intermediate taxonomic levels between the taxon to sample from (e.g. the class Enterobacterales) and the taxonomic level to sample at (e.g. sample from each genus), sampling probabilities are adjusted so that each intermediate taxon (e.g. the families Enterobacteraceae, Yersiniaceae) has an equal probability of being sampled. Furthermore, the user can also provide a file containing assembly accessions for required genomes which should be included in the dataset. Phylogenomic sampling aims at even better retaining taxon diversity in the sample by pruning GTDB's bacterial and archaeal phylogenies down to a user-set number of genomes. Optionally, the user can specify that only a part of the tree should be sampled. The pruning is done iteratively by finding the leaf pair with the shortest evolutionary distance and removing one of the taxa from this pair. The default setting is to keep the taxon with the shortest branch to remove fast-evolving organisms, as these are often more prone to introduce artifacts in phylogenies. The workflow can also be configured to randomly select a taxon from the leaf pair or keep the taxon with the longest branch. When GTDB is used as the source, for taxonomic or phylogenomic sampling, additional criteria such as completeness and contamination estimates can be used to exclude low-quality assemblies. When NCBI taxonomy is used, the user can select either GenBank or RefSeq as the source database. After sampling, irrespective of the method used, TADA can also download genomes, genes, and proteomes for the sampled taxa, using NCBI Datasets. The workflow will run Prokka (Seemann 2014) to annotate genes and proteins whenever an annotation is unavailable through NCBI. Finally, the user can also select to create local alignment databases, for use with NCBI BLAST (Altschul et al. 1990) or Diamond (Buchfink et al. 2014). The downloaded genomes and proteomes can be then used to generate orthologous gene clusters, e.g. with OrthoFinder (Emms and Kelly 2019). The clusters may then in turn be used for phylogenomic reconstructions. Further examples of user cases can be found in TADA's documentation, available at the GitHub repository page. 3 Implementation TADA is implemented as a snakemake workflow with additional scripts written in Python. The workflow is accompanied by an environmental file to create a Conda environment for the execution of the workflow and additional software used by the workflow is also handled by Conda. The pruning in the phylogenomic sampling step is performed with the ETE3-package (Huerta-Cepas et al. 2016). Other software like Treemmer (Menardo et al. 2018) can be used to prune phylogenies. However, Treemmer is too computationally intensive to handle the very large phylogenies provided by GTDB. This is due to Treemmer identifying leaf pairs and calculating the distance between them after each pruning step. TADA reduces this runtime by only updating the distance for the newly created leaf-pair after each pruning step. TADA was up to 10-fold faster than Treemmer to prune GTDB's archaeal tree (Supplementary Fig. S1). 4 Usage Below, we highlight the usage of the two different sampling approaches in TADA to create datasets for a phylum with a skewed abundance of species. 4.1 Taxonomic and phylogenomic sampling of the Planctomycetota phylum In GTDB r214, the Planctomycetota phylum includes 2450 taxa divided into 28 classes. Most of them (78%) are located in the two classes of Planctomycetia and Phycisphaera. Thus, a phylogeny of the Planctomycetota using all species or a random subsampling will be highly unbalanced. Using TADA we constructed three datasets of high-quality genomes and metagenome-assembled genomes of the Planctomycetota phylum, one using taxonomic sampling, a second using phylogenomic sampling, and a third dataset using random sampling. A rough phylogeny based on a concatenated alignment of the same 120 marker genes used by GTDB was constructed for each dataset. See Supplementary Information for detailed methods. The dataset constructed by random sampling only contains nine of the classes from the phylum and has a large overrepresentation of species from Planctomycetia and Phycisphaera class (Fig. 1C), leading to fewer and longer branches in the deep part of the phylogeny (Supplementary Fig. S2). Instead, the datasets constructed by TADA cover a larger diversity of the Planctomycetota phylum, where both datasets include 23 of the classes (Fig. 1C). The phylogenies constructed from the taxonomic sampling (Supplementary Fig. S3) and phylogenomic sampling (Supplementary Fig. S4) have more and shorter branches close to the root compared with the phylogeny based on the random sampled dataset (Fig. 1D). In the TADA sampling, the only classes missing were those where no high-quality genome was available. Whereas the phylogenies constructed from the TADA-sampled datasets share the same overall topology, the topology of the phylogeny from the randomly sampled dataset differs. The most notable difference is the class UBA8742 which forms a clade with other classes in this phylogeny compared to phylogenies from the TADA-constructed datasets. Furthermore, the Colless indexes (Ci) (Colless and Wiley 1982) for the three phylogenies show that taxonomic sampling generates the most balanced phylogeny (Ci = 272), followed by phylogenomic sampling (Ci = 314), and random sampling (Ci = 338). 5 Conclusion TADA can be used as a first step in evolutionary and comparative genomic studies to easily assemble robust and balanced genome datasets. Compared to phyloSkeleton, designed for a similar purpose, TADA is significantly easier to install, provides a more user-friendly interface, a higher granularity in how taxa should be sampled, and the possibility to work directly with GTDB's phylogenies. It also conveniently prepares the following steps by preparing BLAST databases. Implementation in snakemake ensures reproducibility and the possibility to extend the workflow with additional downstream steps. Supplementary Material btad742_Supplementary_Data Click here for additional data file. Acknowledgements We would like to thank Karl Dyrhage for testing TADA. Supplementary data Supplementary data are available at Bioinformatics online. Conflict of interest None declared. Funding This work was supported by the Swedish Research Council [2018-4135 to S.G.E.A.]. Data availability Phylogenies and alignments underlying Fig. 1D are available from |
Clin Case Rep Clin Case Rep 10.1002/(ISSN)2050-0904 CCR3 Clinical Case Reports 2050-0904 John Wiley and Sons Inc. Hoboken 10.1002/ccr3.8321 CCR38321 CCR3-2023-09-2089.R1 Cardiovascular Disorders Case Report Case Report Infective endocarditis associated with atopic dermatitis Tamura and Abe Tamura Yamato 1 [email protected] Abe Takehisa 1 1 Department of Cardiovascular Surgery Nara Prefectural Seiwa Medical Center Nara Japan * Correspondence Yamato Tamura, Department of Cardiovascular Surgery, Nara Prefectural Seiwa Medical Center, 1-14-16 Mimuro, Sango-cho, Ikoma-gun, Nara 636-0802, Japan. Email: [email protected] 21 12 2023 12 2023 11 12 10.1002/ccr3.v11.12 e832115 11 2023 26 9 2023 26 11 2023 (c) 2023 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd. This is an open access article under the terms of the License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. Key Clinical Message Infective endocarditis caused by atopic dermatitis is common in young patients and has a high potential for causing embolism. Because of the high risk of mediastinitis postoperatively, minimally invasive cardiac surgery could be effective. Transthoracic echocardiogram: The verruca was approximately 10 mm in diameter, attached near the posterior mitral valve leaflet and mobile. LA, left atrium, LV, left ventricular. atopic dermatitis infective endocarditis methicillin-sensitive Staphylococcus aureus minimally invasive cardiac surgery source-schema-version-number2.0 cover-dateDecember 2023 details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.3.6 mode:remove_FC converted:21.12.2023 Tamura Y , Abe T . Infective endocarditis associated with atopic dermatitis. Clin Case Rep. 2023;11 :e8321. doi:10.1002/ccr3.8321 pmc1 INTRODUCTION Without prompt diagnosis and appropriate treatment, infective endocarditis can lead to numerous complications and even death. Causes of bacteremia include infections from intravascular catheters, hemodialysis, and dental procedures; furthermore, recently there have been reports of its connection with atopic dermatitis. Atopic dermatitis is associated with a decreased production of antimicrobial peptides, 1 , 2 which are involved in skin defense against infection, rendering the skin susceptible to infection with Staphylococcus aureus, a common microbial resident of the skin. Additionally, bacteria can easily invade because of itchiness and scratching. The incidence of atopic dermatitis among patients with infective endocarditis reportedly ranges from 1% to 7%. 3 , 4 It is more common in younger patients, with a mean age of 28.4 years in 8 reported patients; therefore, failure to recognize this association may delay diagnosis. 4 Among patients with infective endocarditis and atopic dermatitis, the rate of embolism is high, requiring close management and appropriate timing of surgery. There is a high possibility of postoperative mediastinitis after median sternotomy; hence, minimally invasive cardiac surgery (MICS) can be considered. Herein, we report a patient with infective endocarditis associated with atopic dermatitis who underwent successful MICS with no postoperative wound infection or pyothorax. 2 CASE REPORT An 18-year-old man presented to his local doctor with a 5-day fever and transient loss of consciousness. The loss of consciousness was not preceded by any signs, and no seizure activity was observed before or after the event. Thoracoabdominal computed tomography (CT) and head CT did not indicate any source of fever or cause of loss of consciousness; however, echocardiography showed a suspected verruca at the posterior mitral valve leaflet, prompting referral to our hospital with a diagnosis of infective endocarditis. The patient had no history of cardiac disease, areas in the oral cavity requiring treatment, or history of drug use that may have contributed to the development of infective endocarditis. However, he had atopic dermatitis since childhood and had an exacerbation of facial erythema 4 months earlier, which subsequently improved 1 month prior. Upon arrival at our hospital, he was alert but had a temperature of 38.7degC. No paralysis or other neurological abnormalities were noted. His skin condition was not poor, and his abrasions were mild. Osler's nodes were observed in both hands, and the right shoulder was tender, prompting suspicion of a septic shoulder. The blood tests showed a white-blood cell count (WBC) of 14,700 IU/dL, with neutrophilia but no leftward shift; C-reactive protein (CRP) level of 14.20 mg/dL; and procalcitonin level of 1.00 ng/mL. There was no anemia, and the liver and renal functions were normal. Blood culture showed methicillin-sensitive S. aureus (MSSA). No other bacteria were detected. Echocardiography showed a verruca on the posterior mitral valve leaflet, which was mobile and about 10 mm in size ; mitral regurgitation was mild. Head magnetic resonance imaging (MRI) showed multiple acute cerebral infarctions in the left frontal deep white matter, bilateral occipital lobes, and corpus callosum ampulla . Enhanced CT showed renal infarction and splenomegaly . Spinal MRI showed no evidence of pyogenic spondylitis. FIGURE 1 Transthoracic echocardiogram: The verruca was approximately 10 mm in diameter, attached near the posterior mitral valve leaflet and mobile. LA, left atrium, LV, left ventricular. FIGURE 2 (A) Head magnetic resonance imaging showing multiple cerebral infarcts (arrows). (B) Enhanced computed tomography of the abdomen showing multiple renal infarcts in the bilateral kidneys (arrows). Antibiotic therapy was started, and the patient was referred to our cardiovascular surgery department. Since systemic embolism was observed, we considered further embolism as highly likely and decided on urgent surgery. MICS was performed through a small right thoracotomy. A verruca was found on the left atrial wall near the posterior mitral valve annulus. A small verruca was also seen on the anterior mitral valve leaflet . Since there was no destruction of the mitral annulus and leaflet, verrucous excision was performed. Culture of the excised verruca also showed MSSA. FIGURE 3 Intraoperative findings: Verrucous lesions on the left atrial wall of the posterior mitral valve annulus (black arrow). There was no destruction of the mitral valve leaflet and annulus. A small verruca was also attached to the anterior mitral valve leaflet (white arrow). Postoperatively, vancomycin and ceftriaxone were continued for 2 weeks and 6 weeks, respectively. There were no neurological complications, and his general condition improved. His right shoulder pain was relieved, allowing him to elevate his right shoulder. Postoperative head MRI showed no new cerebral infarcts, and the abnormal signals disappeared. Further, there was no evidence of abscess formation or hemorrhage. Enhanced CT of the abdomen showed no significant evidence of renal infarction and no exacerbation. There was no renal dysfunction. Echocardiography also showed no recurrence of verrucae. The patient was discharged from the hospital after his fever abated. Blood tests showed a WBC count of 7800 IU/dL and a CRP level of 0.05 mg/dL. One year postoperatively, the patient had no recurrence of infection and no complications. 3 DISCUSSION Infective endocarditis is not a disease of high incidence, but when it occurs, it can lead to several complications and even death, requiring prompt diagnosis and appropriate treatment. In recent years, infective endocarditis associated with atopic dermatitis has been reported. Nakatani et al. 3 reported that of 513 cases of infective endocarditis, 322 had some background factors, including atopic dermatitis in 5 cases. Fukunaga et al. 4 reported 120 cases of infective endocarditis, of which 8 were associated with atopic dermatitis (6.7%). In atopic dermatitis, the production of IL-4, IL-10, IL-13, etc. is high, suppressing the production of antibacterial peptides such as b-defensin and cathelicidin, which are related to skin defense. 1 Given the synergistic antibacterial activity of b-defensin and cathelicidin against S. aureus, decreased production of these peptides can gradually weaken defense against and enhance susceptibility to S. aureus colonization, 5 rendering the skin susceptible to infection. Consequently, S. aureus is detected in more than 90% of patients with atopic dermatitis. 2 Skin breakage due to scratching may allow bacterial invasion, resulting in bacteremia and infective endocarditis. In particular, patients with atopic dermatitis experience intense itching, which can lead to bacteremia and infective endocarditis caused by S. aureus invading through skin abrasions. Infective endocarditis with a background of atopic dermatitis is common in young patients, and the most common causative organism is MSSA. It is also characterized by a high rate of embolism. 6 These findings were observed in the present case. While there have been cases of infective endocarditis related to atopic dermatitis that were successfully managed with antibiotics 7 and a report of a patient who used dupilumab to improve atopic dermatitis before undergoing standby surgery, 8 it is crucial to recognize the potential fatality of cerebral infarction resulting from infective endocarditis. Early surgical intervention is necessary when there is a high likelihood of recurrent embolization due to verrucous disease. Some reports suggest that early surgery for infective endocarditis is associated with early death, recurrent infective endocarditis, and valve dysfunction 9 ; contrarily, other reports suggest that early surgery is useful for large verrucae. 10 Infective endocarditis, especially when associated with atopic dermatitis, has been reported to have a high rate of embolism, and early surgery should always be kept in mind. Even right-sided infective endocarditis, which is considered sensitive to antibiotic therapy, may cause embolization or exacerbation of sepsis during treatment if atopic dermatitis is present in the background. 11 , 12 In the present case, the patient had a mobile 10-mm verruca with a high likelihood of repeated embolization, prompting the policy of urgent surgery. Additionally, the most common approach for surgical treatment of infective endocarditis is median sternotomy; however, there is a high possibility of postoperative mediastinitis with a median sternotomy, and some reports recommend a right thoracotomy. 13 Although reliable verrucous resection and treatment of valvular disease are the highest priorities, a right small thoracotomy should be considered. In our case, we performed MICS and were able to avoid mediastinitis; the patient improved without wound infection. Vancomycin and ceftriaxone were used for postoperative antibiotic therapy. The antibacterial activity of vancomycin and ceftriaxone against S. aureus has been reported to be inferior to that of cefazolin 14 ; however, given the multiple cerebral emboli, we chose ceftriaxone due to its good cerebrospinal fluid transfer. 15 Close observation and skin treatment should be continued; moreover, the patient should be treated for atopic dermatitis in collaboration with a dermatologist. 4 CONCLUSION We encountered a case of a young patient with infective endocarditis in a background of atopic dermatitis. Due to the high risk of embolism, it is necessary to keep in mind that atopic dermatitis can cause infective endocarditis and to make an early diagnosis. It is also important to ensure that appropriate antibiotic therapy and surgery are timed correctly. To prevent recurrence, skin treatment is necessary after surgery, as well as collaboration with a dermatologist. AUTHOR CONTRIBUTIONS Yamato Tamura: Conceptualization; data curation; formal analysis; investigation; methodology; project administration; resources; software; supervision; validation; visualization; writing - original draft. Takehisa Abe: Supervision; validation; writing - review and editing. FUNDING INFORMATION None. CONFLICT OF INTEREST STATEMENT Yamato Tamura and Takehisa Abe have no conflicts of interest. ETHICS STATEMENT Ethics approval and consent to participate are not applicable for this type of study. CONSENT Written informed consent was obtained from the patient to publish this report in accordance with the journal's patient consent policy. ACKNOWLEDGMENTS None. DATA AVAILABILITY STATEMENT The data that support the findings of this study are available from the corresponding author upon reasonable request. REFERENCES 1 Bieber T . Atopic dermatitis. Ann Dermatol. 2010;22 (2 ):125-137. doi:10.5021/ad.2010.22.2.125 20548901 2 Bieber T . Atopic dermatitis. N Engl J Med. 2008;358 (14 ):1483-1494. doi:10.1056/NEJMra074081 18385500 3 Nakatani S , Ohara T , Ashihara K , et al. JCS 2017 guideline on prevention and treatment of infective endocarditis. Circ J. 2019;83 (8 ):1767-1809. doi:10.1253/circj.CJ-19-0549 31281136 4 Fukunaga N , Okada Y , Konishi Y , Murashita T , Koyama T . Pay attention to valvular disease in the presence of atopic dermatitis. Circ J. 2013;77 (7 ):1862-1866. doi:10.1253/circj.cj-12-1371 23535217 5 Ong PY , Ohtake T , Brandt C , et al. Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N Engl J Med. 2002;347 (15 ):1151-1160. doi:10.1056/NEJMra021481 12374875 6 Aoyagi S , Oda T , Wada K , Nakamura E , Kosuga T , Yasunaga H . Infective endocarditis associated with atopic dermatitis. Int Heart J. 2018;59 (2 ):420-423. doi:10.1536/ihj.17-078 29563378 7 Park BW , Shin YS , Cho EB , Park EJ , Kim KH , Kim KJ . Two cases of endocarditis in patients with atopic dermatitis. Ann Dermatol. 2019;31 (1 ):70-74. doi:10.5021/ad.2019.31.1.70 33911542 8 Nakanishi M , Oota E , Tomita Y , Kato T , Imanishi T . A case of infective endocarditis associated with atopic dermatitis perioperatively treated with dupilumab. J Dermatolog Treat. 2019;30 (7 ):674-676. doi:10.1080/09546634.2019.1568379 30628496 9 Bannay A , Hoen B , Duval X , et al. The impact of valve surgery on mortality in left-sided infective endocarditis: do differences in methodological approaches explain previous conflicting results? Eur Heart J. 2011;32 (16 ):2003-2015. doi:10.1093/eurheartj/ehp008 19208650 10 Thuny F , Beurtheret S , Mancini J , et al. The timing of surgery influences mortality and morbidity in adults with severe complicated infective endocarditis: a propensity analysis. Eur Heart J. 2011;32 (16 ):2027-2033. doi:10.1093/eurheartj/ehp089 19329497 11 Shioya N , Inoue N , Miyano E , et al. Isolated tricuspid valve infective endocarditis with multiple septic pulmonary emboli in a patient with atopic dermatitis. Clin Case Rep. 2021;9 (2 ):1043-1044. doi:10.1002/ccr3.3706 33598299 12 Woodun H , Bouayyad S , Sahib S , Elamin N , Hunter S , Al-Mohammad A . Tricuspid valve infective endocarditis in a non-IVDU patient with atopic dermatitis. Oxf Med Case Reports. 2020;2020 (7 ):omaa045. doi:10.1093/omcr/omaa045 32728448 13 Fukunaga N , Yuzaki M , Shomura Y , Fujiwara H , Nasu M , Okada Y . Clinical outcomes of open heart surgery in patients with atopic dermatitis. Asian Cardiovasc Thorac Ann. 2012;20 (2 ):137-140. doi:10.1177/0218492311433311 22499959 14 Carr DR , Stiefel U , Bonomo RA , Burant CJ , Sims SV . A comparison of cefazolin versus ceftriaxone for the treatment of methicillin-susceptible S. aureus bacteremia in a tertiary care VA medical center. Open forum. Infect Dis. 2018;5 :ofy089. doi:10.1093/ofid/ofy089 15 Cleeland R , Squires E . Antimicrobial activity of ceftriaxone: a review. Am J Med. 1984;77 (4C ):3-11. |
A 53-year-old female was referred for visual electrophysiology following a routine optometric eye examination in which yellow flecks were noted in both fundi and the patient had reported a recent near accident whilst driving at night. There was no reported family history of eye disease. Retinal examination identified bilateral yellow punctate and irregularly shaped lesions throughout the posterior poles sparing the macula region. Fundus autofluorescence showed coinciding hyperfluorescence with the lesions and bilateral hypofluorescent crescents superior to the macular with corresponding retinal thinning. Visual fields and color vision were normal. ISCEV standard 20 min and extended 60-min dark adapted electroretinograms were recorded. Recovery to normal b-wave amplitudes was noted in the DA0.01 flash but reduced a-wave amplitudes were noted in the DA3 and DA10 flash following both dark adapted periods. Cone function was reduced but within normal limits. Genetic screening revealed a previously unreported variant of unknown significance in the gene PLA2G5:c.40 + 5del (rs1364254561) which is a member of the phospholipase A2 family and is associated with familial benign flecked retina. Fundus images illustrating discrete yellow flecks in the retina with corresponding hyperfluorescence of the retinal pigment epithelium. genetics and genomics ophthalmology physiology source-schema-version-number2.0 cover-dateDecember 2023 details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.3.6 mode:remove_FC converted:21.12.2023 Constable PA , Loh L , Grigg JR . Suspected case of benign familial fleck retina with functional loss. Clin Case Rep. 2023;11 :e8362. doi:10.1002/ccr3.8362 pmc1 INTRODUCTION Familial Benign Fleck Retina (FBFR) (OMIM #228980) is an autosomal recessive condition caused by biallelic mutations in the gene PLA2G5 that encodes a family V phospholipase A2 which has multiple roles including signal transduction, phospholipid metabolism, and regulating phagocytosis. 1 , 2 , 3 , 4 , 5 , 6 This rare condition has been observed predominantly in children and young adults that present with yellow to white symmetrical flecks bilaterally with otherwise normal acuity, visual fields, and retinal function. 7 , 8 Isaacs et al. 8 reported a case in a young female of an Australian aboriginal and Caucasian decent whose fundi had multiple yellow-white flecks sparing the macula with only a slight delay in the left eye of the 30 Hz flicker with normal light-adapted flash electroretinograms (ERGs). Audo et al. 9 reported a case of an Indian boy aged 6 with bilateral flecks in the retina and normal electrophysiology whose parents were third cousins. Bin et al. 10 found an association with mutation in exon 3 of PLA2G5 (p.Gly45Cys) resulting in discrete bilateral yellow flecks in one affected triplet. Garcia et al. 11 described a case of FBFR in a female 27-year-old with normal dark and light adapted ERGs and electrooculogram, although the authors noted a "selective reduced amplitude of the oscillatory potentials" but did not quantify these observations. Reduced mfERGs amplitudes and reduced sensitivity using microperimetry have been observed in FBFR but typically full-field ERGs and electrooculograms are normal. 12 Neriyanuri et al. 13 reported four cases aged from 19 to 35 years with flecked retina and normal ERGs except one case who had a reduced light-adapted ERG with two cases reporting parental consanguinity. Electrooculograms were normal but color discrimination was reduced in two cases, and all had normal visual acuity. Most recently, a presentation of FBRF was reported incidentally in a 44-year-old female who presented with a unilateral posterior scleritis. 14 We report a suspected case of FBFR in a 53-year-old female who presented with early stages of nyctalopia, flecked retina, a family history of consanguinity in her great-grandparents. In contrast to previous cases of FBRF, this subject had and reduced dark-adapted a-wave amplitudes with a variant of unknown significance in PLA2G5. 2 CASE HISTORY/CLINICAL EXAMINATION A 53-year-old female of Italian ethnicity from the villages of Santa Croce del Sannio and Morcone in the Campania region. She was referred for visual electrophysiology following a routine optometric eye examination in which yellow fleck like lesions were noted in both fundi. Ophthalmic review was prompted following a near collision at night with a cyclist that "she did not see" to her right. A previous ophthalmic examination had identified retinal flecks 5 years previously. Fluorescein angiography was normal at that presentation. This presentation, in March 2022, found her refraction to be: RE +0.50/-0.25 x 177 and LE +0.75/-0.50 x 87 Add +2.25, visual acuities 6/6 OU and Goldman applanation IOPs of 13 mmHg OU. Visual fields HFA-II 24-2 were normal with mean deviation RE -0.03 dB and LE -0.90 dB. Color vision (binocular) with the D-15 was normal. The patient reported a marriage between cousins in her grandparent's lineage, but no family members had reported any ocular disorders, and her two children had no significant ophthalmic history. Fundus photos and red free revealed multiple yellow flecks in the peripheral retina with more punctate type lesions within the arcades. Fundus autofluorescence showed marked hyperfluorescence associated with the lesions as well as bilateral superior arcuate areas of hypofluorescence associated with retinal thinning. OCT revealed lesions at the level of the RPE-Bruch's membrane and disruption to the ellipsoid zone in the presence of the retinal lesions. See Figures 1 and 2 for retinal imaging. The sister of the case had a normal fundus appearance with images in the Data S1. FIGURE 1 Upper rows (A, B) shows fundus photos with multiple yellow flecks and punctate lesions scattered throughout the retina but sparing the fovea. Middle panel (C, D) red free images revealing similar underlying flecked retina. Lower panels (E, F) fundus autofluorescence showing marked hyper fluorescence associated with the yellow flecks scattered throughout the retina. Foveal region is spared but an arcuate region of hypofluorescence is visible superior to the foveae representing loss of the retinal pigment epithelium. FIGURE 2 Upper images (A) shows OCT scan through the regions of retinal pigment epithelial atrophy with lesions present at the level of the RPE with overlying disruption to the ellipsoid zone in the right and left eye. Lower images (B) show thinning of the superior macula in the superior region with left eye greater than right and preservation of the foveae. 2.1 Investigations Full field dilated standard ISCEV ERGs were recorded using the RETeval (LKC Technologies, Gaithersburg, MD) with skin electrodes following either 20 min or 60 min dark adaptation (DA). 15 All values are reported as the response value with the centile in brackets based on normative data from LKC Technologies. Following 20 min DA the DA0.01 b-wave amplitudes were RE 26.6 mV (95th) and LE 24.3 mV (97th) with normal timings. Following 60 min DA the b-wave amplitudes returned to within normal limits with RE 37.4 mV (21st) and LE 39.2 mV (26th). The DA3 a-wave amplitude was outside normal limits for the RE -21.0 mV (98th) and LE -14.4 mv (100th) with within normal limits a-wave timing and b-wave amplitude and timing. The a-wave amplitude did not recover following 60 min of dark adaptation with RE -23.4 mV (100th) and LE -24.7 mV (100th). Similar findings were observed with the DA10 with a reduced a-wave amplitudes RE (-23.4 mV) and delayed time to trough 14.6 ms (100th) and LE a reduced a-wave amplitude only -24.7 mV (100th). Following 60 min of dark adaptation the DA10 a-wave amplitude recovered mildly but was still outside normal limits with RE -33.1 mV (97th) and LE -31.5 mV (98th) with normal a-wave time to troughs OU and b-wave amplitudes and time to peak. Light adapted (LA) responses were overall within normal limits with values following 20 min dark adaption for the LA3 in the RE a-wave amplitude -3.4 mV (11th) and -6.4 mV (46th) with normal time to trough and b-wave amplitudes and time to peak. Following 60 min dark adaption the LA3 responses were similar with the a-wave amplitude RE being -5.1 mV (30th) and LE -6.1 mV (43rd) with other parameters within normal limits. The 30 Hz flicker was performed after the 60-min dark adaption period and the RE showed a significantly reduced amplitude 12.9 mV (98th) and normal LE amplitude 19.6 mV (19th) suggestive of some loss of function in the cones in the RE more than LE at this stage. See Figure 3 and Data S1 for full ERG reported waveforms. FIGURE 3 Electroretinograms after 20 min (blue) and 60 min (red) dark adaptation compared to a representative control (black). The DA0.01 b-wave amplitude returned to normal levels after 60 min of dark adaptation. The a-wave amplitude of the DA3.0 and DA10.0 failed was below normal limits after 60-min dark adaptation. The LA3.0 responses were within normal limits although the right eye amplitude for the 30 Hz flicker was lower than normal. Right eye waveforms on the right-hand side. For full reports see Data S1. DA, dark adaption. 2.2 Genetic screening Next generation sequencing was performed on whole blood using whole exome capture (IDTxGen Exome v2) sequenced on the Illumina NextSEq sequencing system. Genes analyzed using the PanelApp Australia Retinal Disorders Superpanel v6.44 (Green and Amber). One homozygous variant of unknown significance was identified in PLA2G5 c.40 + 5del containing a single nucleotide substation in intron 2 of 4 at +5 nucleotides from the last nucleotide of exon 2. This variant (rs1364254561) has not been previously described and is absent from the population database (PM2). Computational analysis supports a damaging effect, predicting the loss of the normal wildtype splice donor site (Alamut Visual Plus 1.6.1, SpliceAI) (PP3). 3 DISCUSSION This case highlights an atypical presentation of FBFR with a novel variant in PLA2G5 resulting in a loss of retinal function. FBFR is part of a group of retinal conditions that present with yellow to white flecks in the retina that spare the macula. 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 Given the partial recovery of rod function with extended dark adaption in this case and adult presentation of symptoms our initial suspicions were directed to fundus albipunctatus and an RDH5 mutation. 17 When compared to previous cases of FBFR, this case has common features such as normal color vision, visual acuity, and a familial history of consanguinity; however, the abnormal ERG findings are not typically part of the clinical picture with usually normal retinal function. Given the normal ocular findings in her family there is evidence supporting an autosomal recessive pattern of inheritance consistent with FBFR. In the most detailed description of the genetic variants associated with FBFR Sergouniotis et al. 6 describe pathologic changes in one family consisting of a homozygous missense change c.133G > T (p.Gly45Cys) in exon 3 of PLA2G5 and homozygous nonsense mutation c.185G > A (p.Trp62X), altering the last base of exon 3 in a separate individual. Two heterozygous changes c.133G > T (p.Gly45Cys) and c.383delA (p.Gln128ArgfsX88) were also identified in an unrelated individual, with no pathological mutation found in one further unrelated individual. The authors confirmed localization of phospholipase A2 with immunohistochemistry to be predominantly expressed in the inner and outer plexiform layers in an elderly human donor retina, in contrast to the main deposition of lipofuscin at the level of the retinal pigment epithelium. The authors speculate that this may be due to the role of phospholipase A2 reducing phagosome maturation, 3 thereby reducing the ability of the retinal pigment epithelium to phagocytose outer segments. Genetic screening identified a homozygous variant in intron 2 of PLA2G5 c.40 + 5del may produce a splice variant of phospholipase 2 and result in the characteristic flecked retina with lipofuscin deposits sparing the macula. The current American College of Medical Genetics (ACMG) classification classes this as a variant of uncertain significance. Phenotypically, the electrophysiological findings are more akin to fundus albipunctatus with a delayed recovery of the dark-adapted ERGs that characterize a loss of function in an enzyme such as 11-cis-retinol dehydrogenase encode by RDH5 as a likely candidate. 16 , 17 , 18 Thus, this case is the first to report a novel mutation in an intronic region of PLA2G5 with clinical features of both fundus albipunctatus and FBFR. Other potential differential diagnoses may be tamoxifen retinopathy that may present with small and discrete white yellowish refractile elements in the retina. 19 The reduced a-wave amplitudes under DA conditions suggest a loss of rod function and the reduced 30 Hz flicker amplitude in the right eye suggest early cone involvement in this case. Further genetic analysis on siblings and parents were not possible, but there is no reported family history of eye disease or difficulties with night vision. Further studies may help identify if the mutation identified has a direct pathological role in the clinical findings and the progression of the disease. Currently the case is managing with her daily routines and is aware of her reduced time to adapt to dark conditions. Clinicians should be alert to late onset retinal dystrophies and the need for clinical electrophysiology and genetic screening to identify possible pathogenic variants. Whilst the ISCEV standard series of ERGs may suffice in most cases it is important to consider extended protocols such as prolonged DA, extended flash to dissect the 20 or the x-wave that is a DA cone response 21 to aid diagnosis of retinal disorders. Inherited retinal dystrophies typically affect vision in early childhood, however, this case highlights a late onset retinal dystrophy presenting in midlife. Such dystrophies that affect the macular may be misinterpreted as aging changes and patients presenting in adulthood with signs or symptoms of a retinal dystrophy should be investigated using visual electrophysiology. 15 AUTHOR CONTRIBUTIONS Paul A. Constable: Investigation; project administration; writing - original draft. Lynne Loh: Investigation; writing - review and editing. John R. Grigg: Conceptualization; methodology; writing - review and editing. FUNDING INFORMATION This work was unfunded. CONFLICT OF INTEREST STATEMENT The authors declare that they have no conflicts of interest. ETHICS STATEMENT All procedures performed in this case report involving a human participant were in accordance with the ethical standards of Flinders University and with the Declaration of Helsinki and its later amendments. This report does not contain any studies with animals performed by any of the authors. CONSENT Written informed consent was obtained from the patient to publish this report in accordance with the journal's patient consent policy. Supporting information Data S1: Click here for additional data file. ACKNOWLEDGMENTS The authors thank the case for her consent to report her case. We thank My-Linh Huynh or assistance in image collection. Open access publishing facilitated by Flinders University, as part of the Wiley - Flinders University agreement via the Council of Australian University Librarians. DATA AVAILABILITY STATEMENT Raw electroretinogram data available on request to Paul A. Constable. |
This case report highlights the diagnostic challenges encountered in a 30-year-old female presenting with fever followed by Wernicke's aphasia without right-sided weakness, ultimately diagnosed as tumefactive demyelination (TD). TD is a rare neurological condition often misidentified as brain tumors or inflammatory disorders. The case emphasizes the importance of precise differentiation through advanced magnetic resonance imaging, showing restricted diffusion at lesion edges and the absence of gadolinium enhancement. Accurate diagnosis is crucial for tailored treatment and prognostic assessment. This case contributes to our understanding of TD and underscores the need for continued research and collaboration in the field of rare neurological disorders. cerebral spinal fluid (CSF) magnetic resonance imaging (MRI) magnetic resonance spectroscopy (MRS) multiple sclerosis tumefactive demyelination (TD) Wernicke's aphasia source-schema-version-number2.0 cover-dateDecember 2023 details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.3.6 mode:remove_FC converted:21.12.2023 Inban P , Akuma O , Elavia Z , et al. A rare case of tumefactive demyelination of brain: A case report and literature review. Clin Case Rep. 2023;11 :e8369. doi:10.1002/ccr3.8369 pmc1 INTRODUCTION Multiple sclerosis is an infrequent inflammatory disease of the central nervous system (CNS) that is distinguished by its assorted clinical and radiological presentations. 1 , 2 Tumefactive demyelination (TD), or tumefactive multiple sclerosis, stands apart as a distinctive entity within this spectrum. Demyelinating lesions in the CNS are a sign of these diseases. These lesions can be big, measuring 2 cm or more in diameter, or small, measuring between 0.5 cm and 2 cm, but they have the potential to cause mass effects. This unique feature may result in these lesions being initially misidentified as tumor-like space-occupying lesions; however, they typically exhibit a characteristic appearance on radiographic imaging and are clinically benign. 3 , 4 , 5 Tumefactive demyelination, which is distinct from multiple sclerosis, occurs at an estimated rate of about 1-2 per 1000 cases of MS, although some studies propose a higher incidence ranging from 1.4% to 8%. 6 , 7 However, tumefactive demyelinating lesions can occur concurrently with autoimmune diseases (e.g., Sjogren disease, lupus erythematosus, neuromyelitis optica), infectious diseases (e.g., Human Immunodeficiency Virus), malignancy (e.g., renal cell carcinoma), drug-related conditions (e.g., tacrolimus, fingolimod), and postinfectious conditions (e.g., acute disseminated encephalomyelitis, acute hemorrhage leukoencephalitis). TD can show up on its own at the start of a disease or as other diseases progress, but the pathophysiology of how it happens is not well understood. On magnetic resonance imaging (MRI) scans, these lesions can appear either as a single large lesion or several lesions exhibiting varying degrees of contrast enhancement. We present here a case study involving a thirty-year-old female who presented with a fever lasting 3 days followed by Wernicke's aphasia without right-sided weakness and whose MRI findings were consistent with tumefactive brain demyelination. 2 CASE PRESENTATION We present a case of a 30-year-old female with a recent history of fever lasting for 3 days. She developed Wernicke's aphasia, which is characterized by difficulty understanding and producing spoken language without any associated weakness, 6 days after the fever started. The patient remained conscious throughout the course of her illness. No significant past medical history is noted. Upon admission, a comprehensive physical examination was conducted. Vital signs, including blood pressure (120/80 mm Hg), heart rate (78 beats per minute), respiratory rate (16 breaths per minute), and oxygen saturation (98% on room air), fell within normal ranges, except for an elevated temperature of 38.5degC (101.3 F), likely due to a recent three-day fever. The patient's general appearance was consistent with her stated age, and she exhibited no signs of acute distress. Notably, she remained alert and oriented throughout the examination, indicating her continued consciousness. The neurological examination showed intact cranial nerve functions, normal muscle strength, and sensory function in all extremities, with no signs of ataxia or abnormal reflexes. However, the notable finding was the presence of Wernicke's aphasia, characterized by fluent but non-meaningful speech, word-finding difficulties, comprehension deficits, and impaired repetition. The rest of the neurological examination was normal. Examination of other systems revealed no significant abnormalities. The presence of Wernicke's aphasia suggested a potential neurological origin, warranting further diagnostic evaluation. Routine blood tests were normal. Inflammatory markers (erythrocyte sedimentation rate/C reactive protein (ESR/CRP)) and an autoimmune screen including autoantibodies, extractable nuclear antigen, double-stranded DNA, anti-neutrophil cytoplasmic antibody, as well as serum angiotensin-converting enzyme (ACE), were also normal. Based on clinical exam findings and laboratory results that were within normal limits, there was low suspicion for various infectious and inflammatory differentials such as tuberculosis, sarcoidosis, vasculitis, and malignancies. A magnetic resonance (MR) brain scan was performed to investigate the neurological symptoms. The MR scan revealed mild diffusion restriction at the edges of certain brain regions, suggesting an alteration in water movement within the affected areas. Additionally, gadolinium contrast administration showed no enhancement, indicating the absence of active inflammation or vascular changes in the brain. Gradient echo (GRE) and susceptibility-weighted imaging (SWI) were not included in the imaging assessment, as shown in Figure 1. FIGURE 1 Multi-contrast Magnetic Resonance Imaging (MRI) Showing Mild Diffusion Restriction at the Edges of Brain Lesions Across Fluid Attenuated Inversion Recovery (FLAIR) and T2-weighted (blue arrows). The T2-weighted MRI exhibited mild diffusion restriction at the periphery of brain lesions, suggesting limited water molecule movement and potential pathology, possibly indicative of demyelinating disorders or altered tissue integrity. Despite concerns raised about neurological conditions, the absence of gadolinium enhancement in imaging results diminished the likelihood of active inflammation or vascular changes, lessening the possibility of an acute neurological condition. Elevated protein and low glucose levels in the cerebral spinal fluid (CSF) analysis, as shown in Table 1, imply potential neurological issues, necessitating additional clinical assessment and testing to establish a precise diagnosis and treatment plan. TABLE 1 Cerebral spinal fluid (CSF) lab values. Parameter Patient value Normal range CSF Protein 54 mg/dL 15-45 mg/dL CSF Glucose 50 mg/dL 60-100 mg/dL CSF Cells 60 mm3 N/A (No Range) Differential Count P60% L40% N/A (No Range) In the cerebrospinal fluid (CSF), six oligoclonal bands (OCBs) were observed, but there were no OCBs detected in the serum. Additionally, there were no indications of neuroinfection present in the CSF. Magnetic resonance spectroscopy (MRS) revealed normal levels of metabolites in the affected brain regions. Specifically, there would be no significant abnormalities in the concentrations of metabolites such as N-acetyl aspartate (NAA), creatine, choline, and lactate, as shown in Figure 2. FIGURE 2 MRS reveals normal metabolite levels in affected brain regions, providing clarity on NAA, creatine, choline, and lactate concentrations. Based on the clinical presentation and diagnostic findings, this case appears to be consistent with tumefactive demyelination; the absence of gadolinium enhancement indicates that there is no active inflammation or vascular changes. This normal MRS profile would further support the diagnosis of tumefactive demyelination, as it would not show the characteristic changes seen in other conditions like tumors or acute inflammation, aligning with the absence of gadolinium enhancement in the MRI findings. The patient underwent a five-day course of intravenous methylprednisolone at a daily dose of one gram and was subsequently switched to a tapering regimen of prednisone. Following this treatment, she was discharged in a stable neurological condition and admitted to inpatient rehabilitation, where the plan was to initiate immunomodulatory therapy on an outpatient basis. A review of the patient's medical records 4 months later indicated that she has been progressing favorably. At present, she is actively participating in speech therapy sessions aimed at enhancing her mild language-related challenges, which include improvements in auditory comprehension, verbal expression, and thought organization. We recommended that the patient be closely monitored and additional neurological assessments that may be necessary to determine the extent and progression of the demyelinating lesions be carried out. Additionally, ongoing support for the patient's language difficulties, such as speech therapy, may be beneficial in managing Wernicke's aphasia. 3 DISCUSSION The presented case of a 30-year-old female with an initial presentation of fever for 3 days followed by the development of Wernicke's aphasia 6 days later, along with no right-sided weakness, raises important diagnostic considerations. The patient is diagnosed with tumefactive demyelination (TD), and the aim of this case report is to shed light on the complex diagnostic challenges often encountered in the evaluation of this rare neurological condition. It emphasizes the crucial importance of precise differentiation in directing treatment approaches and, ultimately, enhancing patient outcomes. Our patient's case underscores the complexity involved in diagnosing TD. Tumefactive demyelination typically presents with a wide range of acute neurological symptoms that may include focal deficits such as weakness, sensory disturbances, visual disturbances, and speech difficulties. Patients with TD may experience severe headaches, which can be mistaken for migraines or tension headaches. TD can lead to cognitive and behavioral changes, including confusion, memory problems, and personality changes. 8 Clearly, our patient initially presented with a fever and developed Wernicke's aphasia 6 days later. These non-specific symptoms added complexity to the diagnostic procedure. Common differential diagnoses typically include brain tumors (such as multifocal glioma, metastatic lesions, and CNS lymphoma), brain abscess, tuberculoma, and various inflammatory conditions like sarcoidosis and Sjogren's syndrome. 9 , 10 In contrast to acute disseminated encephalomyelitis (ADEM), tumefactive demyelinating lesions typically do not have a post-infective origin. Also, people with multiple sclerosis (MS) can sometimes get large tumefactive demyelinating plaques that look like these lesions. This is called tumefactive multiple sclerosis. However, people who first show up with a single tumefactive demyelinating lesion rarely go on to get MS. 5 , 9 The diagnostic challenge in our case was to distinguish TD from brain tumors, abscesses, and other inflammatory conditions. Tumefactive Multiple Sclerosis (TMS) with a large tumefactive demyelinating lesion on imaging is a rare occurrence. Traditional MRI may not be very effective in distinguishing TDL from primary brain neoplasms or abscesses. 9 Magnetic resonance (MR) may reveal specific characteristics that aid in the diagnostic process. Advanced magnetic resonance (MR) imaging of tumefactive demyelinating lesions reveals specific characteristics, including a high apparent diffusion coefficient, restricted diffusion at the periphery of the lesions, and low cerebral blood volume. 11 Peripheral restriction is more common in inflammation and demyelinating disorders than in abscesses or tumors, whereas central restriction is specific to abscesses. 10 Our patient had mild diffusion at the edges or periphery. This helped us to exclude tumors and abscesses. Nevertheless, despite these findings, diagnosis can be challenging, especially when a patient presents with a first neurological event and a solitary lesion on routine imaging. 9 Notably, in suspected TMS cases, additional tests like CSF analysis for oligoclonal bands may not contribute significantly, as they are positive in only around 30% of TMS patients. 10 The next diagnostic test that was done was gadolinium contrast. On imaging, TD shows absent or mild enhancement, indicating preserved blood-brain barriers. The absence of gadolinium enhancement also suggests that there is no active inflammation or vascular changes. 10 , 12 Our patient's diagnostics were negative for gadolinium contrast, ruling out any active inflammation. In recent times, proton MR spectroscopy, employing cerebral biochemical substrate quantification, has emerged as a valuable non-invasive diagnostic tool for delineating tumefactive brain lesions. 9 MR spectroscopy has the capability to differentiate the presence and relative amounts of various chemical metabolites in the brain, making it a useful technique for further assessment of various intracranial diseases. It is particularly beneficial in determining the major category of disease manifested by the observed lesion, such as neoplastic, inflammatory, or ischemic. A neoplastic profile typically includes an attenuated NAA peak, indicative of neuronal loss; an elevated Cho resonance, suggesting increased turnover of cell membrane and myelin components; a reduced Cr peak, reflecting depressed cellular energetics and/or cell death from lesional necrosis; and, in some cases, detectable Lip and Lac peaks, signifying areas of cellular necrosis with the release of free lipids and anaerobic metabolism resulting in lactate production. 13 , 14 Elevation of lactate and choline peaks together, possibly explained by reactive astrogliosis, demyelination, and inflammation, leading to cell membrane breakdown, and reduction of NAA peak due to neuronal destruction, axonal damage, and neuronal mitochondrial dysfunction, are suggestive of demyelination. 14 However, lactic peak is not specific to TMS. 14 Despite the potential of MR spectroscopy, the existing literature, marked by study design heterogeneity, variable imaging timing, and a lack of histopathological data, remains insufficient to provide a definitive guideline for the use of MRS in clinical practice as a diagnostic tool. 9 Further studies involving larger patient groups and standardized protocols are advisable before the full clinical utility of the technique can be determined. In summary, this case underscores the complexity of diagnosing rare neurological conditions like TD. On MRI scans, the unique pattern of restricted diffusion at the edges makes TD different from brain tumors and abscesses. Negative gadolinium contrast makes TD different from any active inflammatory disorders, which shows how important it is to make a clear distinction. An accurate diagnosis is essential for customizing suitable treatment approaches, addressing patient expectations, and assessing the prognosis effectively. In an era of advancing medical knowledge, dedication to research and clear communication among healthcare professionals continue to be crucial in enhancing outcomes for patients dealing with such conditions. This case adds to the expanding pool of information related to TD, underscoring the ongoing requirement for exploration and cooperation in the realm of rare neurological disorders. 4 CONCLUSION Tumefactive demyelination, a rare neurological condition, often mimics brain tumors or inflammatory disorders, making accurate differentiation crucial for tailored treatment and improved outcomes. By presenting this case report, we aim to raise awareness about rare neurological manifestations, such as TD and we primarily focused on how we can rule out any other conditions such as brain tumors, abscesses, and active inflammatory conditions. It underscores the significance of including these rare and atypical presentations in the list of potential diagnoses. Moreover, we anticipate that our case report will address the paucity of literature regarding this demyelinating disorder, potentially catalyzing further research efforts to develop a more comprehensive diagnostic method and simplifying the differential diagnosis pathway. AUTHOR CONTRIBUTIONS Pugazhendi Inban: Writing - original draft. Ogbonnaya Akuma: Writing - original draft. Zenia Elavia: Investigation. Chinaza Mercy Akuma: Resources. Mansi Singh: Writing - review and editing. Meet Popatbhai Kachhadia: Data curation. Agaba Barnett James Musiime: Methodology. FUNDING INFORMATION None. CONSENT Written informed consent was obtained from the patient to publish this report in accordance with the journal's patient consent policy. DATA AVAILABILITY STATEMENT The datasets analyzed during the current study are available from the corresponding author upon reasonable request. Additionally, comprehensive literature sources used for the literature review are cited appropriately within the manuscript. |
Osseous choristoma is an unusual growth of ectopic bone in the soft tissue. This lesion is extremely rare, with a few cases reported in the literature, and they typically appear in the head and neck region, particularly the posterior tongue. The current report presents a case of osseous choristoma in the palate of a 51-year-old female. The patient had slight discomfort, which was resolved after surgical excision of the lesion, and no recurrence was observed. This research presents an instance of osseous choristoma in a less common location and concurrently acts as a review of this rare condition. Microscopic sections of the lesion revealed hard tissue composed of osseous tissue surrounded by cartilage, which was covered with parakeratnized squamous epithelium. choristoma oral mucosa osseous palate source-schema-version-number2.0 cover-dateDecember 2023 details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.3.6 mode:remove_FC converted:21.12.2023 Shamloo N , Modanloo K , Khaleghi A . Osseous choristoma: Report of a case on the palate and a literature review. Clin Case Rep. 2023;11 :e8355. doi:10.1002/ccr3.8355 pmc1 INTRODUCTION Choristoma is considered an abnormal but non-neoplastic growth of histologically normal tissue in an ectopic body location. 1 , 2 Choristoma can originate from many different tissues, including bone, cartilage, salivary glands, or muscle, and they are named after the tissue of origin. 3 , 4 , 5 , 6 , 7 , 8 Osseous choristomas are typically composed of thin bones with harvester-like structures. 2 The cause of their formation is believed to be either a developmental deformity or a reactive mechanism. 9 These lesions tend to manifest more frequently in the head and neck region, particularly at the posterior of the tongue. Moreover, they are found mostly in the third and fourth decades of life and are more common in females. 2 , 9 Nevertheless, oral choristomas, specifically the osseous variant, are extremely rare findings, with very few documented cases in the existing literature. It is, therefore, of paramount importance to conduct a study on this topic. In addition to providing a literature review on features of this lesion reported in the literature, this case report aims to present a unique case in a less frequently observed location. This endeavor seeks to expand the knowledge on this condition. 2 CASE REPORT A 51-year-old healthy female was referred to the Oral and Maxillofacial Surgery Department. The patient presented with mild oral discomfort but reported no pain. On clinical examination, a 10-mm pink swelling was observed in the posterior midline of the hard palate. The swelling had a smooth surface and firm consistency, appeared pedunculated, and was covered with normal mucosa. The patient had no history of infection or trauma. Reactive, salivary gland, and mesenchymal lesions are possibilities for an exophytic lesion in the oral cavity. Among these, reactive lesions are more prevalent. Irritation fibroma was considered as the first diagnosis due to its similar appearance, and also, the common occurrence in the oral cavity and palatal area. Peripheral ossifying fibroma was ruled out based on location. Additionally, palatal torus and other bony lesions were ruled out due to the firm consistency of the reported lesion. A radiographic image was not essential at the time due to this diagnosis. Under local anesthesia, the lesion was excised completely. Grossly, the lesion was measured 7 x 3 x 2 mm. The histopathologic sections revealed hard tissue composed of osseous tissue surrounded by cartilage . The lesion was covered by parakeratinized squamous epithelium. Therefore, based on the microscopic features, the diagnosis of osseous choristoma was made. FIGURE 1 Microscopic views of osseous choristoma, (A) 4x magnification, (B) 10x magnification. The patient's discomfort significantly improved post-surgery; a three-month follow-up showed no signs of recurrence. 3 DISCUSSION The term "choristoma" was initially introduced in 1913 in a report by Monserrat. 10 Subsequently, numerous investigations have been conducted on lesions exhibiting comparable features. The majority of these studies have focused on the tongue. However, less frequent locations within the head and neck region have also been documented, as similar to the case with our research. Consequently, we have undertaken a search on this subject matter. Previous literature was evaluated using "Osseous OR Bony" AND "Choristoma" queries in PubMed and Google Scholar search engines. A total of 139 cases of osseous choristoma were found. Among these reported cases, 107 (77%) were found in the tongue, which makes it the most common site for osseous choristoma of the head and neck. Following the tongue, 13 cases (9.4%) were reported in the buccal mucosa. Osseous choristoma of the palate was mentioned previously in three separate reports, which makes our report the fourth one in the list. Other studies reported this lesion in less common sites, including gingiva, 11 , 12 , 13 , 14 , 15 alveolar mucosa, 16 submental region, 17 , 18 submandibular region, 19 masseter, 20 medial aspect of the lateral pterygoid, 21 lips, 22 , 23 and tonsils. 24 The mean age for the reported cases were 31.97 +- 18.04, ranging between 1 month to 89 years old. The youngest patient ever diagnosed with osseous choristoma was a 1-month-old infant girl. In this case, the lesion was accompanied by Tessier no.7 or transverse facial cleft. 25 Moreover, osseous choristoma tends to appear more in females and the mean age of the female patients was relatively lower than males. Regarding clinical features, 58 cases (41.7%) were pedunculated, 17 cases (12.2%) were sessile, and 30 cases (21.6%) were described as nodular masses. The consistency of the lesions was stated as firm in 23 cases, hard in 18 cases, and bony hard in 14 cases. These specific features were not consistently documented in previous studies. In terms of lesion size, the largest osseous choristoma ever reported was 10 cm, located on the tongue. 26 However, most of them were between 0.5 to 2 cm. Osseous choristomas on the lips and the palate had an average size of less than 1 cm, which is relatively smaller than lesions in other sites. The size discrepancy may be attributed to the limited number of reported cases in these locations or to the fact that lesions on the lips and palate are more visually conspicuous, leading to earlier diagnoses. Table 1 compares osseous choristomas location-wise. TABLE 1 Locations of osseous choristoma. Location Frequency N (%) Gender (N) Recurrent cases (N) Male Female Unknown Tongue 107 28 73 6 - Buccal mucosa 13 4 8 1 2 Gingiva 5 2 3 - - Palate 3 2 1 - - Lips 2 1 1 0 - Submental 2 0 2 0 - Tonsil 2 1 1 - 1 Alveolar mucosa 1 1 0 - - Lateral pterygoid 1 0 1 - - Masseter 1 1 0 - - Retromolar pad 1 1 0 - - Submandibular 1 1 0 - - Total 139 42 90 7 3 Abbreviations: N, number; SD, standard deviation. Most patients affected by osseous choristoma were asymptomatic or no symptoms were reported (51.7%). However, among symptomatic patients, various manifestations were observed. The most common symptom was the feeling of a lump or a swelling (23.7%), followed by dysphagia (8.6%), pain (5.7%), gag feeling (5%), globus pharyngeus (3.6%), hoarseness (2.9%), and odynophagia (1.4%). Also, airway distress, snoring, bleeding, infection, and ulceration were reported in one case each. In most of the reports, the duration of the lesion's existence was asked from the patient. In 34 cases (24.5%), the lesions were found upon oral examination and patients were not aware of the lesion. However, 16 patients (11.5%) were aware of the lesion for less than 1 year, 33 (23.7%) between 1 to 10 years, and 5 (3.6%) for more than 10 years. Four patients (2.9%) were alert of the lesion since birth or precisely since they had remembered. Some of the studies reported a history of the patients, whether medical, habitual, or any trauma that could have contributed to lesion formation. No pattern was observed in the history of patients. Three patients mentioned smoking, all of whom had tongue lesions. Only one of the patients with a lesion on the upper lip, reported trauma to the site before the lesion formation. 23 Also, gastroesophageal reflux disease (GERD) was mentioned in three cases which could have contributed as a traumatic factor in the lesion growth. Treatment of osseous choristoma is surgical removal. Out of the 139 reported cases in the literature, only three of them were recurrent. Two of them were on the buccal mucosa and one was on the masseter muscle. Recurrency could be explained if we suppose that these lesions are of traumatic origin and the recurrent lesion was the result of surgical trauma. 27 In addition, it could have been a similar lesion that was found later due to a slower increase in size or delayed ossification. Further reports are needed for an explanation of recurrence. Numerous osseous lesions can manifest on the palate, and a broad spectrum of differential diagnoses should be considered. These may include palatal torus, ossifying myositis, ossifying fasciitis, peripheral ossifying fibroma, progressive ossifying fibrodysplasia, intraosseous osteosarcoma, osteolipoma, phlebolith, and sialolith. 27 Comparison between palatal osseous choristomas is illustrated in Table 2. Our study serves as the fourth report of osseous choristoma on the palate. TABLE 2 Palatal osseous choristoma. Study Year Gender Age Size (cm) Clinical presentation Symptoms Feenstra et al. 28 1977 Male 14 NR NR NR Wada et al. 27 2010 Female 16 0.9 Nodular/hard None Sasaki et al. 29 2016 Male 37 0.7 Pedunculated/hard None Present case 2023 Female 51 1.0 Pedunculated/firm Discomfort Abbreviation: NR, not reported. Several studies have been conducted to unravel the etiology of osseous choristomas. Previous research suggested a congenital basis for these lesions. 25 , 30 The tongue is formed by the fusion of two parts: the anterior two-thirds of the tongue is derived from the first branchial arch, while the posterior third is from the third branchial arch. These branchial arches also give rise to normal osseous structures such as the hyoid bone, malleus, incus, and styloid process, through a process called endochondral ossification. 31 The developmental theory posits that oral choristoma arises from the entrapment of branchial arches I, II, and III derivatives in the facial region. As most lesions are located at the midline, this explanation appears plausible. 30 However, this theory falls short of providing a complete understanding of the full range of lingual or other intraoral osseous choristomas and the higher incidence of such lesions in females. 23 , 32 Environmental factors have also been proposed to contribute to intraoral osseous choristoma development, challenging the congenital viewpoint. 33 , 34 , 35 Nonetheless, the presence of well-developed lamellar bone is not consistent with chronic irritation. 29 Conducting more research in this field could yield valuable insights and aid in establishing a correlation between environmental factors and the formation of intraoral osseous choristomas. While the role of environmental factors in the development of intraoral osseous choristomas should not be disregarded, a multifactorial etiology is probably involved. Further research is necessary to establish the precise causality of these lesions. AUTHOR CONTRIBUTIONS Nafise Shamloo: Investigation; methodology; supervision; writing - review and editing. Kiarash Modanloo: Data curation; investigation; resources; validation; writing - original draft. Armin Khaleghi: Conceptualization; formal analysis; investigation; project administration; writing - original draft. FUNDING INFORMATION None. CONFLICT OF INTEREST STATEMENT The authors have no conflicts of interest to declare. CONSENT Written informed consent was obtained from the patient to publish this report in accordance with journal's patient consent policy. DATA AVAILABILITY STATEMENT The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. |
and flow chart, which include patients who contributed to outcomes but were censored by the end of the grace period. b Opioid exposure is defined as the presence of at least one prescription opioid fill during the last 30 days of the baseline period. c The Elixhauser score is modified to exclude depression, substance abuse, alcohol abuse, and psychosis as these are included as separate covariates. Among those without opioid exposure, the adjusted cumulative incidence of death 1 year after the start of follow-up was 5.5% (95% CI, 5.4%-5.8%) for discontinuers and 3.5% (95% CI, 3.4%-3.6%) for nondiscontinuers , corresponding to an absolute risk difference estimate of 2.1 percentage points (95% CI, 1.9-2.3 percentage points) higher among discontinuers. The mortality risk at 12 months for discontinuers without baseline opioid use was 1.6 (95% CI, 1.6-1.7) times that of nondiscontinuers. Figure 2. Standardized Cumulative Incidence Curves Examining the Association Between Benzodiazepine Discontinuation and Mortality, Stratified by Opioid Exposure Shaded areas indicate 95% CIs. The grace period is the 6-month period during which a given patient is assigned to a treatment group. Total numbers at risk were 213 011 patients for the analyses of the without opioid exposure group (panels A and C) and 140 565 patients in the opioid exposure group (panels B and D). Table 3. Mortality and Secondary Outcomes by Treatment Strategy Among Patients Prescribed Stable Long-Term Benzodiazepine Therapy, Stratified by Opioid Exposure in the Intention-to-Treat Approach Outcome Adjusted cumulative incidence, % (95% CI)a Discontinued (vs not discontinued) Discontinuedb Not discontinued Absolute risk difference, percentage points (95% CI) Risk ratio (95% CI) All-cause mortality Without opioid exposurec 5.5 (5.4-5.8) 3.5 (3.4-3.6) 2.1 (1.9-2.3) 1.6 (1.6-1.7) With opioid exposure 6.3 (6.0-6.6) 3.9 (3.8-4.1) 2.4 (2.2-2.7) 1.6 (1.5-1.7) Secondary outcomes Nonfatal overdose Without opioid exposure 1.1 (1.0-1.1) 0.9 (0.9-1.0) 0.1 (0.1-0.2) 1.2 (1.1-1.3) With opioid exposure 2.2 (2.0-2.3) 1.8 (1.7-1.9) 0.4 (0.2-0.5) 1.2 (1.1-1.3) Suicide attempt or self-inflicted injury Without opioid exposure 0.5 (0.5-0.6) 0.5 (0.4-0.5) 0.1 (0.0-0.1) 1.1 (1.0-1.1) With opioid exposure 0.8 (0.7-0.9) 0.7 (0.6-0.7) 0.1 (0.0-0.2) 1.2 (1.1-1.4) Suicidal ideation Without opioid exposure 1.0 (0.9-1.1) 0.8 (0.7-0.8) 0.3 (0.2-0.3) 1.4 (1.2-1.5) With opioid exposure 1.3 (1.1-1.4) 0.9 (0.9-1.0) 0.4 (0.2-0.5) 1.4 (1.2-1.5) Emergency department use Without opioid exposure 42.7 (42.4-43.1) 36.6 (36.4-36.9) 6.1 (5.7-6.5) 1.2 (1.2-1.2) With opioid exposure 54.3 (53.8-54.8) 45.2 (44.9-45.5) 9.1 (8.5-9.5) 1.2 (1.2-1.2) a Outcome measure (eg, mortality) computed at the end of follow-up (ie, 360 days). b Discontinuation is defined as 31 consecutive days without prescription benzodiazepine coverage. c Opioid exposure is defined as the presence of at least 1 prescription opioid fill during the last 30 days of the baseline period. Among those with opioid exposure, the adjusted cumulative incidence of death 1 year after start of follow-up was higher, at 6.3% (95% CI, 6.0%-6.6%) for discontinuers and 3.9% (95% CI, 3.8%-4.1%) for nondiscontinuers. The absolute risk difference estimate was 2.4 percentage points (95% CI, 2.2-2.7 percentage points) higher among those who discontinued benzodiazepine vs not, yielding a mortality risk at 12 months for discontinuers 1.6 (95% CI, 1.5-1.7) times that of nondiscontinuers. The relative risk of mortality was similar in analyses with subgroups for both age and opioid use (eTable 7 in Supplement 1). Per-Protocol Results Characteristics of stable long-term benzodiazepine users at the end of the grace period for the per-protocol analysis are presented in eTable 8 in Supplement 1. Among those without recent opioid exposure, balance across treatment groups was similar except discontinuers were older (age 65 years and older: 10 033 of 18 924 [53.0%] vs 70 990 of 140 924 [50.4%]), varied by geography (eg, West: 4603 of 18 924 [24.3%] vs 24 939 of 140 924 [17.7%]), and had more pain (13 952 of 18 924 [73.7%] vs 100 577 of 140 924 [71.4%]) and insomnia (3645 of 18 924 [19.3%] vs 22 856 of 140 924 [16.2%]). Nondiscontinuers filled a slightly higher volume of prescription medications (eg, mean [SD] 30-day supplies of antidepressants among patients without opioid exposure: 8.09 [8.87] vs 7.51 [8.43]). Balance across treatment groups was similar for those with opioid exposure. After applying the clone-censor-weight approach, these small imbalances were mitigated (eTables 9 and 10 in Supplement 1). Per-protocol results are presented in eTable 11 in Supplement 1. For all outcomes, discontinuers were at higher risk than nondiscontinuers, and the risks were higher than in the intention-to-treat approach. Correspondingly, risk ratios were higher among discontinuers overall, and slightly higher than found in the intention-to-treat approach. Secondary Outcomes There were small increases in the absolute risk differences for nonfatal overdose and suicidal ideation for discontinuers in both those without and with recent opioid exposure (Table 3). For example, the absolute risk difference for those without opioid exposure was 0.1% (95% CI, 0.1%-0.2%) for nonfatal overdose and 0.3% (95% CI, 0.2%-0.3%) for suicidal ideation. There were larger absolute risk differences in emergency department use between groups (eg, without opioid exposure: 6.1%; 95% CI, 5.7%-6.5%). Suicide attempt or self-inflicted injury was not significantly different between groups (eg, without opioid exposure: 0.1%; 95% CI, 0.0%-0.1%). Among discontinuers without opioid exposure, the relative risks for nonfatal overdose, suicidal ideation, and emergency department use increased 1.2 (95% CI, 1.1-1.3), 1.4 (95% CI, 1.2-1.5), and 1.2 (95% CI, 1.2-1.2) times, respectively. For all outcomes, the absolute risk differences for those with opioid exposure (vs without) were slightly higher; risk ratios were similar. Sensitivity Analysis Results Results where we defined discontinuation as 61 consecutive days of no benzodiazepine coverage were consistent with the primary analysis. A cumulative incidence of mortality after 1 year was higher among discontinuers than nondiscontinuers in both the intention-to-treat and per-protocol analyses, and higher among those with recent opioid exposure than those without (eTable 12 in Supplement 1). Discussion In this quality improvement study using target trial emulation of over 350 000 adults prescribed stable long-term benzodiazepine, there was a small absolute increase in mortality among those with their prescription benzodiazepine discontinued over 1 year of follow-up: 2.1 and 2.4 percentage points higher for those without and with recent opioid exposure, respectively. Discontinuation was also associated with absolute increases in nonfatal overdose, suicidal ideation, and emergency department use. While the absolute magnitude of the increased risk for these outcomes was relatively small, the direction of the effect size was not as hypothesized. Given the increased OD risk and mortality associated with benzodiazepine prescribing,3 particularly when coprescribed with opioids,14,33 we anticipated that discontinuing benzodiazepine prescriptions would be associated with a lower mortality risk. Indeed, the FDA call to develop benzodiazepine tapering guidelines, part of the US Department of Health and Human Services Overdose Prevention Strategy, is explicitly framed as an effort to minimize risks associated with long-term benzodiazepine use.7 However, for every outcome examined in this analysis, discontinuation was associated with some degree of increased risk at odds with the assumption underlying ongoing policy efforts that reducing benzodiazepine prescribing to long-term users will decrease harms. Future work is needed to examine mechanisms. It is possible that, having become physiologically dependent on benzodiazepine, patients experience adverse outcomes from withdrawal.23 Alternatively, patients may experience adverse consequences if they seek alternative sedating substances (eg, cannabis or alcohol) following benzodiazepine discontinuation. These results were unexpected given findings from randomized clinical trials and reviews of benzodiazepine discontinuation. The EMPOWER (Eliminating Medications Through Patient Ownership of End Results) trial of patient education conducted 6-month follow-up interviews with participants, none of whom reported adverse events requiring hospitalization although interviews could only be conducted with participants who completed the trial.27 In a 12-month primary care-based study, just 2 adverse events were reported among 542 participants.28 A meta-analysis of studies examining benzodiazepine discontinuation strategies captured whether included studies addressed adverse effects, but these were not actually reported in the meta-analysis.34 In a scoping review of deprescribing benzodiazepine, the only mention of potential adverse events was where they were related to other medications prescribed during the discontinuation process.35 There may be several reasons for the disagreement between our findings and prior studies. While emulated trials may address immortal time and survival biases, confounding may remain, whereby clinicians discontinue benzodiazepine treatment in patients otherwise at increased risk of death. However, there are other possible explanations. Our emulated trial followed patients for up to 1 year after discontinuation, which is longer than most randomized trials. Our inclusion criteria were more strict (ie, baseline year with 90% or more days covered; no coverage gaps longer than 30 consecutive days; monthly average daily dose within 30% of baseline grand mean) than those for randomized trials of benzodiazepine discontinuation, identifying a population potentially more likely to experience discontinuation-related distress and adverse effects. Patients willing to participate in a benzodiazepine discontinuation trial likely do not generalize to the broader population of those with stable long-term benzodiazepine use. Limitations Our study has several limitations. Claims data cannot precisely determine when a patient stopped consuming their prescription benzodiazepine and patients may continue to receive medication from another source. Because benzodiazepine prescribing may predate plan enrollment, we cannot account for the full duration of patient benzodiazepine treatment, which may moderate the relationship between discontinuation and outcomes. While we employed multiple strategies to address bias in this trial emulation, unobserved confounding likely remains. Our analysis cannot account for prescribing indication or nature of the discontinuation process (eg, rate, adjunctive pharmacotherapy). Information was not available to identify which specific causes of death are elevated (eg, if discontinuers shifted to alternative substances with associated risks such as alcohol), which may have elucidated mechanisms. Finally, while this analysis includes a diverse population from across the US, it reflects those with commercial insurance or Medicare Advantage and thus may not generalize to other populations. Conclusions In this emulated trial of benzodiazepine discontinuation among adults prescribed a stable long-term benzodiazepine regimen, there were small absolute increases in mortality and additional harms. Given the interest in reducing long-term prescribing, it will be important to conduct prospective studies or use observational approaches to replicate these findings and examine characteristics of patients and the discontinuation process that either attenuate or exacerbate this association. In addition, given questions raised about the safety of discontinuing benzodiazepine prescriptions among stable long-term users, clinicians should be judicious in initiating new prescriptions and carefully limit conversion to long-term use. Supplement 1. eFigure. Flowchart Presenting Cohort Identification eTable 1. Identification of Exclusion Criteria eTable 2. Diagnosis Codes Used to Identify Comorbidities eTable 3. American Hospital Formulary Service Codes for Medication Classes eTable 4. Outcome Definitions eMethods. eTable 5. Characteristics of Patients Prescribed Stable Long-term Benzodiazepine Therapy without Baseline Opioid Use at the End of the Grace Period, Overall and by Discontinuation Status: Before and After Weighting in the Intention-to-Treat Analysis eTable 6. Characteristics of Patients Prescribed Stable Long-term Benzodiazepine Therapy with Baseline Opioid Use at the End of the Grace Period, Overall and by Discontinuation Status: Before and After Weighting in the Intention-to-Treat Analysis eTable 7. Results of a Secondary Analysis Examining Benzodiazepine Discontinuation and Mortality Risk Among Patients Prescribed Stable Long-term Benzodiazepine Therapy, Stratified by Age, Intention-to-Treat Analysis eTable 8. Characteristics of Patients Prescribed Stable Long-term Benzodiazepine Therapy Stratified by Opioid Exposure at the End of the Grace Period for the Per-Protocol Analysis, Overall and by Benzodiazepine Discontinuation Status eTable 9. Characteristics of Patients Prescribed Stable Long-term Benzodiazepine Therapy without Opioid Exposure at the End of the Grace Period, Overall and by Discontinuation Status: Before and After Weighting in the Per-Protocol Analysis eTable 10. Characteristics of Patients Prescribed Stable Long-term Benzodiazepine Therapy with Opioid Exposure at the End of the Grace Period, Overall and by Discontinuation Status: Before and After Weighting in the Per-Protocol Analysis eTable 11. Adjusted Incidence, Risk Difference, and Risk Ratio of Mortality and Secondary Outcomes Among Patients Prescribed Stable Long-term Benzodiazepine Therapy, Stratified by Opioid Exposure, by Treatment Strategy eTable 12. Results of Sensitivity Analysis Examining Benzodiazepine Discontinuation and Mortality Risk Among Patients Prescribed Stable Long-term Benzodiazepine Therapy, Stratified by Opioid Use Click here for additional data file. Supplement 2. Data Sharing Statement Click here for additional data file. |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.49167 Ophthalmology Mixed Clinical Pictures of Endogenous Endophthalmitis in a Relapse Leukemic Patient Muacevic Alexander Adler John R Azmi Annuar Z 1 Patrick Sylves 2 Isa Mohamad Israk B 1 Ab. Ghani Shuaibah 3 1 Department of Pediatric Ophthalmology, Sabah Women and Children Hospital, Kota Kinabalu, MYS 2 Department of Ophthalmology, University Malaysia Sabah, Kota Kinabalu, MYS 3 Department of Ophthalmology, Universiti Malaysia Sabah, Kota Kinabalu, MYS Annuar Z. Azmi [email protected] 21 11 2023 11 2023 15 11 e4916720 11 2023 Copyright (c) 2023, Azmi et al. 2023 Azmi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License CC-BY 4.0., which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from Endogenous endophthalmitis is rare but sight-threatening in leukemic patients, which can have devastating sequelae. We report a case of a 15-year-old teenager with acute myeloid leukemia on relapse, presented with a mixed picture of endogenous endophthalmitis. The diagnosis dilemma in this patient proved difficult as Investigations and management can be challenging as young teenagers are usually less cooperative than adults. Endogenous endophthalmitis is not uncommon in this group of patients; however, mixed clinical pictures are almost unheard of, and the final diagnosis can be misleading if not treated accordingly. Viral infections such as cytomegalovirus (CMV), bacterial, and fungal are all considered potential opportunistic infections. Diagnosis of endogenous endophthalmitis is complex and relies heavily on the clinical characteristics of each organism supported by intravitreal tapping and culture samples. However, data from endogenous endophthalmitis in leukemic patients is scarce nowadays across the board. In this case report, we highlight the challenges of managing endogenous endophthalmitis in a young leukemic patient due for bone marrow transplantation. Future studies are needed to investigate the current microorganism trends and treatments available. An algorithm for managing endophthalmitis in immunosuppressed patients should be done to provide a better approach from the get-go. endophthalmitis acute myeloid leukaemia relapse leukaemia endogenous endophthalmitis pmcIntroduction Patients with immunosuppressive conditions such as leukemia are prone to a get secondary infection . Those receiving chemotherapy had a higher risk of infection due to reduced cell-mediated immunity . Endogenous endophthalmitis is a possible infection that may cause debilitating outcomes in this group of patients . In younger children and teenagers, getting a diagnosis seems treacherous as the patient may be uncooperative, and a thorough examination has to be done under general anesthesia. Viral, bacterial, and fungal causes are known culprits for opportunistic infection in those with weakened immune systems . Subsequent treatment may be challenging as patients may require multiple intravitreal medications depending on the isolated organisms. Case presentation A 15-year-old girl with underlying relapsed acute myeloid leukemia (AML) presented with left eye blurring of vision associated with eye pain for four days before being referred for ocular screening. She was diagnosed with AML in November 2020. The patient needed urgent treatment and clearance from the ophthalmology team as she was due for a bone marrow transplant in June 2021. However, in June 2021, she had a relapsed AML, and another cycle of chemotherapy was planned for her. On day nine of her second cycle of chemotherapy, she developed neutropenic fever and was covered with intravenous IV meropenem (40 mg/kg/day). During this time, she developed generalized body rashes, and IV amphotericin (1 mg/kg/day) was commenced to cover for fungal skin candidiasis. Septic workup from blood and urine was unremarkable for bacterial and fungal growth. Shortly after, she developed the aforementioned eye symptoms in early July 2021. The blurring of vision was gradual in onset and not associated with scotoma. No floaters or photophobia were noted. The eye pain was mild and generalized, with no precipitating factors that aggravated the pain. Upon examination, the best corrected visual acuity (BCVA) was 6/9 in the right eye (RE) and 6/60 in the left eye (LE). No relative afferent pupillary defect (RAPD) was noted. LE anterior segment examination revealed anterior uveitis with 2+ cells in the anterior segment (AC)-otherwise, neither keratoprecipitates (KP), iris nodule, nor hypopyon noted in the anterior chamber. Intraocular pressure was normal for both eyes. Dilated fundus examination of the LE revealed extensive pre-retinal and intra-retinal hemorrhages , extending one disc diameter (DD) from the fovea to the far temporal. The view was hazy due to cells in the anterior chamber. Perivascular sheating can be seen over the temporal aspect of the bleeding. Retinitis can be seen at the superotemporal arcade and nasally next to the optic disc. The optic disc was hyperemic and had no vitritis during the initial assessment. Examination of the RE anterior and posterior segment was otherwise unremarkable. Figure 1 Dilated fundus examination of the LE revealed extensive pre-retinal and intra-retinal hemorrhages (green arrow) LE - left eye Figure 2 Retinitis (white arrow) at the superotemporal arcade next to the optic disc Figure 3 Retinitis can be seen nasal to the optic disc (white arrow) The initial impression was LE CMV retinitis, and the patient was treated with IV ganciclovir (10 mg/kg/day) for two weeks. Examination under anesthesia (EUA) was subsequently planned with an intravitreal (IVT) tap and IVT ganciclovir (2mg in 0.05ml) injection. IVT tap result revealed coagulase-negative staphylococci (CONS), which is sensitive to Vancomycin. Otherwise, the vitreous sample for fungal, viral studies, and cytology was negative. The case was further discussed with a medical retina specialist, and the patient was commenced with IVT vancomycin (2mg in 0.1ml) every 72 hours until marked clinical improvement. Initially, the patient showed a response to treatment by the evidence of contracting hemorrhages and retinitis area . Localized vitritis surrounding the nasal retinitis was noted, with a suspicious string of pearls forming anterior to the macula region during the eighth EUA. Therefore, IVT amphotericin B (5mcg in 0.1ml) was given in addition to IVT vancomycin. Subsequent EUA shows the retinitis became more well-defined and flatter; however, the pearl of strings remained. IVT voriconazole (2.5mcg in 0.1ml) was added and given during the subsequent EUA, and vitreoretinal (VR) opinion was sought. After discussion with the VR team, trans-pars planar vitrectomy (TPPV) was planned for this patient with IV Voriconazole(8mg/kg/day) for two weeks. All this while the areas of hemorrhage maintained 1 DD away from the fovea, and her vision never dropped below 6/60. Following the TPPV, the areas of hemorrhages and Vitritis resolved, and the retinitis area became flatter , replaced with what remained of scars. BCVA improved to 6/12 for the LE. Following endophthalmitis's resolution, the patient underwent a bone marrow transplant in February 2023. Figure 4 Contracting hemorrhages (green arrow) and retinitis (white arrow) Figure 5 Localized vitritis surrounding the nasal retinitis (blue arrow), with a suspicious string of pearls forming anterior to the macula region (white arrow) Figure 6 Following the TPPV, the areas of hemorrhages and vitritis resolved, and the retinitis area (white arrow) became flatter TPPV - trans-pars planar vitrectomy Discussion Endophthalmitis is a sight-threatening condition and needs urgent treatment. Since leukemic patients are immunocompromised, patients with underlying Leukaemia possess higher risks of developing endophthalmitis. Frequent chemotherapy will lead to bone marrow suppression and increase exposure to opportunistic infections . One retrospective study of 271 patients for endogenous endophthalmitis found one patient with a background of immunocompromised secondary to Leukaemia . Patients with Leukaemia are prone to opportunistic infection because of the nature of the disease coupled with chemotherapy . A variety of infections in the form of viral, bacterial, and fungal can attack the immunocompromised patient . For this patient, the initial presentation mimicked a CMV retinitis infection with the pattern of hemorrhagic retinitis. The diagnosis was initially made by clinical judgment as the pattern matches CMV presentation. CMV is one of the most common viral that can infect immunocompromised patients . The initial management was to commence treatment with intravitreal ganciclovir and IV Ganciclovir for two weeks. IVT tapping for this patient revealed coagulase-negative staphylococcus (CoNS), which shows sensitivity to vancomycin, and therefore, the diagnosis and management were changed to endogenous bacterial endophthalmitis. Zhang et al., in their series of endophthalmitis cases, highlight that the coagulase-negative staphylococcus group is one of the top two common isolates alongside the Streptococcus group . CoNS are part of the average human skin commensal and have low virulence, but they can cause severe infections, especially in immunocompromised patients . After initiation of intravitreal vancomycin, the patient was showing improvement in the area of retinitis contracting; however, during the eighth EUA, we noted the appearance of strings of pearl that raised the question of whether this patient had a co-infection with fungal endophthalmitis considering that patient was treated for fungal skin rashes during her neutropenic fever episode. Due to the clinical pictures resembling fungi at the later stage of the disease, we give the benefit of no doubt and commence treatment with IVT voriconazole and systemic anti-fungal despite no fungal growth isolated from the IVT tapping. The prevalence of fungal endophthalmitis is lower than bacterial endophthalmitis and is a clinical diagnosis that may be supported by vitreous culture . It is also possible for the patient to have more than one infection as she is immunosuppressed, as evidenced by early bacterial culture isolated from the initial IVT tap and fungal pictures in the later stage of the disease. This case is the first presentation of endophthalmitis in leukemic patients reported in a literature review with mixed clinical pictures. In our case, the decision not to do PPV earlier is because the area of involvement never involved the central fovea, and the patient's LE vision never dropped beyond 6/60; therefore, we committed to the IVT vancomycin injection as it was initially improved until the appearance of the string of pearls that may be signifying overlapping fungal infection in the later stage of the disease. Thus, we refer to a vitreoretinal (VR) surgeon for intervention, as fungal endophthalmitis is more virulent and associated with poorer outcomes . Conclusions Patients with endogenous endophthalmitis who are immunosuppressed can be challenging to treat, especially with mixed clinical pictures. Co-infection with multiple organisms is a possibility due to the weakened immune system. It is time to develop guidelines for endogenous endophthalmitis, especially in leukemic patients. When in doubt, pars plana vitrectomy can be a savior. We would like to thank the director-general of Health Malaysia for his permission to publish this case report. Author Contributions Human Ethics Concept and design: Sylves Patrick, Mohamad Israk B. Isa Drafting of the manuscript: Sylves Patrick, Annuar Z. Azmi, Mohamad Israk B. Isa Acquisition, analysis, or interpretation of data: Annuar Z. Azmi, Shuaibah Ab. Ghani Critical review of the manuscript for important intellectual content: Shuaibah Ab. Ghani Consent was obtained or waived by all participants in this study The authors have declared that no competing interests exist. References 1 Infections in patients with acute leukemia Infections in Hematology Rolston KV 3 23 2014 2 Updates in infection risk and management in acute leukemia Hematology Am Soc Hematol Educ Program Logan C Koura D Taplitz R 135 139 2020 2020 33275701 3 Endogenous endophthalmitis: yield of the diagnostic evaluation BMC Ophthalmol Regan KA Radhakrishnan NS Hammer JD Wilson BD Gadkowski LB Iyer SS 138 20 2020 32264861 4 Disseminated fusariosis and endogenous fungal endophthalmitis in acute lymphoblastic leukemia following platelet transfusion possibly due to transfusion-related immunomodulation BMC Ophthalmol Kah TA Yong KC Rahman RA 30 11 2011 22044440 5 Pediatric infectious endophthalmitis: A 271-case retrospective study at a single center in China Chin Med J (Engl) Zhang M Xu GZ Jiang R Ni YQ Wang KY Gu RP Ding XY 2936 2943 129 2016 27958225 6 Ophthalmic manifestations of acute leukaemias: the ophthalmologist's role Eye (Lond) Sharma T Grewal J Gupta S Murray PI 663 672 18 2004 15002029 7 Opportunistic infections of the eye in immunocompromised patients Ophthalmologica Guembel HO Ohrloff C 53 61 211 1997 8 Ocular manifestations in adult T-cell leukemia/lymphoma Ann Hematol Shibata K Shimamoto Y Nishimura T Okinami S Yamada H Miyahara M 163 168 74 1997 9174543 9 Coagulase-negative staphylococci Clin Microbiol Rev Becker K Heilmann C Peters G 870 926 27 2014 25278577 10 Fungal endophthalmitis: a comprehensive review J Fungi (Basel) Haseeb AA Elhusseiny AM Siddiqui MZ Ahmad KT Sallam AB 996 7 2021 34829283 11 Exogenous endophthalmitis in pediatric age group Ocul Immunol Inflamm Al-Rashaed SA Abu El-Asrar AM 285 292 14 2006 17056462 |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.49163 Internal Medicine Cardiology Ventricular Tachycardia as a Presentation of Isolated Cardiac Sarcoidosis: How to Manage It When We Do Not See Granulomas Muacevic Alexander Adler John R Puglla Sanchez Luis Rene 1 De Escalante Yanguela Begona 2 Escota-Villanueva Javier 1 Vallejo Grijalba Juan 3 Samaniego Pesantez Dario J 4 1 Cardiology, Hospital Clinico Universitario Lozano Blesa, Zaragoza, ESP 2 Autoimmune Diseases Unit, Hospital Clinico Universitario Lozano Blesa, Zaragoza, ESP 3 Internal Medicine, Hospital Clinico Universitario Lozano Blesa, Zaragoza, ESP 4 Cardiology, Hospital Universitario Miguel Servet, Zaragoza, ESP Luis Rene Puglla Sanchez [email protected] 21 11 2023 11 2023 15 11 e4916320 11 2023 Copyright (c) 2023, Puglla Sanchez et al. 2023 Puglla Sanchez et al. This is an open access article distributed under the terms of the Creative Commons Attribution License CC-BY 4.0., which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from A 47-year-old male was referred for rapid palpitations and an electrocardiogram compatible with sustained monomorphic ventricular tachycardia (VT) that required synchronized electrical cardioversion due to hemodynamic instability. After the initial clinical certainty, an etiological search is carried out. The transthoracic echocardiogram (TTE) revealed moderate dilatation and left ventricular systolic dysfunction due to global hypokinesia. Coronary angiography did not show significant coronary stenosis. Cardiac magnetic resonance (CMR) guarantees a nonischemic dilated cardiomyopathy with moderate systolic dysfunction and a pattern of subepicardial and intramyocardial late gadolinium enhancement (LGE) in medial-lateral and median inferolateral segments. Lastly, a positron emission tomography-computed tomography (PET-CT) scan showed diffuse fixation of the radiotracer in the left ventricular (LV) walls, with greater uptake on the lateral and inferolateral surfaces of inflammatory origin. After ruling out other alternative pathologies and according to current diagnostic criteria, the clinical judgment of probable isolated cardiac sarcoidosis (ICS) is established. An implantable cardioverter-defibrillator was implanted as secondary prevention of the acute arrhythmic event. Specific treatment for systolic dysfunction was prescribed, as well as immunosuppressive therapy with corticosteroids and methotrexate, after which the patient remained in clinical remission, with disappearance of active inflammation on cardiac imaging tests and progressive ventricular systolic function. The initial diagnosis of isolated cardiac sarcoidosis can be complex and challenging, especially in those patients in whom the diagnosis of extracardiac sarcoidosis has not been previously established. The limitations of endomyocardial biopsy in this entity make it necessary to have a high index of clinical suspicion with the early use of new cardiac imaging techniques and to include this picture in the differential diagnosis of patients with sustained ventricular arrhythmias or left ventricular systolic dysfunction of nonspecific etiology clarified. Early initiation of aggressive immunosuppressive therapy has been shown to prevent disease progression and limit its potential cardiac complications. positron emission tomography-computed tomography cardiac sarcoidosis ventricular tachycardia magnetic resonance imaging heart failure with reduced ejection fraction pmcIntroduction Sarcoidosis is an autoimmune disease of unknown etiology with systemic involvement that is associated with the development of noncaseating granulomas. It can affect any organ, and cardiac involvement is estimated at 5%, although in autopsy series, it is confirmed in up to 25% of patients with systemic disease. Cardiac sarcoidosis (CS) can represent 13%-25% of the causes of death from this disease . Isolated cardiac sarcoidosis (ICS) is a term coined for exclusive cardiac involvement, with high mortality if it is not suspected or diagnosed on time, and it is a frequent cause of sudden cardiac death in autopsy studies. Myocardial inflammation, granuloma formation, and scarring changes can cause conduction disturbances, especially auricular-ventricular atrioventricular blocks, sustained ventricular arrhythmias, ventricular systolic dysfunction, and heart failure in these patients . The current gold standard to confirm cardiac involvement by sarcoidosis is based on the histopathological finding of confirmed noncaseating granulomas in an endomyocardial biopsy or to recognize cardiac symptoms or signs in patients with sarcoidosis histologically confirmed in other organs . Establishing the diagnosis of ICS without histopathological confirmation, based on the combination of clinical data, cardiac imaging techniques, and favorable response to its specific treatment, represents a paradigm shift in the current management of this entity and a reasonable alternative in specific cases. Case presentation A 47-year-old male, with no toxic habits and no relevant medical or family history, was referred to the emergency department due to palpitations and thoracic discomfort while working in the office. An electrocardiogram was performed, documenting sustained monomorphic ventricular tachycardia (VT) with right bundle branch block and inferior axis morphology. Due to hemodynamic instability, we proceeded to perform synchronized electrical cardioversion at 200 J biphasic, passing to sinus rhythm with repolarization abnormalities, presenting T wave inversion in inferior and high lateral leads. Figure 1 A: SMVT with right bundle branch block morphology in a patient with ICS. B: CMR with subepicardial LGE in the midposterior segment (white arrow). SMVT: sustained monomorphic ventricular tachycardia, ICS: isolated cardiac sarcoidosis, CMR: cardiac magnetic resonance, LGE: late gadolinium enhancement After initial clinical stabilization, different cardiology tests were performed to find arrhythmic substrates. Both physical examination and blood tests did not show relevant findings (including the determination of angiotensin-converting enzyme). A transthoracic echocardiogram (TTE) showed moderate dilatation and left ventricular systolic dysfunction (left ventricular ejection fraction (LVEF): 37%) due to global hypokinesia, without myocardial scarring. Coronary angiography revealed the absence of significant coronary lesions, which ruled out a coronary ischemic cause. Subsequently, a cardiac magnetic resonance (CMR) was performed, which confirmed moderate systolic dysfunction (LVEF: 40%) with a pattern of late gadolinium enhancement (LGE) predominantly subepicardial and intramyocardial in the anterolateral and inferolateral medial segments of LV , suggestive of focal fibrosis in these locations. An ischemic etiology was definitively excluded, and we ruled out other diseases such as hemochromatosis, Fabry disease, autoimmune diseases with negative autoantibodies, infectious diseases with negative serologies, and Chagas disease. There was no recent history of infections. Because of the clinical presentation (sustained ventricular arrhythmia) and exclusion of other diseases such as infectious myocarditis, we consider that cardiac sarcoidosis was the most plausible diagnosis. For this reason, a fluor-18 positron emission tomography-computed tomography (18F-PET-CT) was performed to establish the presence of an active myocardial inflammatory phase and try to show evidence of extracardiac involvement (potentially for biopsy). PET showed diffuse fixation of the radiotracer in the walls of the left ventricle, with greater uptake on the lateral and inferolateral sides in relation to inflammatory activity in this area . Likewise, the presence of extracardiac hypermetabolism was ruled out. Figure 2 A: 18F-PET-CT with radiotracer uptake in LV walls in the lateral and posterior region. B: Control 18F-PET-CT with no uptake of the radiotracer after two years of starting treatment. 18F-PET-CT: fluor-18 positron emission tomography-computed tomography, LV: left ventricle In a patient with nonischemic dilated cardiomyopathy with moderate systolic dysfunction that debuted as sustained monomorphic VT, with a predominantly anterolateral and inferolateral subepicardial LGE pattern on CMR and intense myocardial uptake on 18F-PET-CT in those segments without extracardiac involvement, the diagnosis of a probable ICS in the phase of active inflammation was considered. For definitive confirmation, an endomyocardial biopsy was ordered, but the patient refused to proceed, with no alternative biopsy in another organ in view of the PET-CT result. The placement of an implantable cardioverter defibrillator (ICD) was discussed. Finally, it was decided to implant ICD as secondary prevention related to sustained VT with hemodynamic instability and the existence of intense myocardial fibrosis in the ventricular wall. Regarding pharmacological treatment, in agreement with the Autoimmune Diseases Unit, we started immunosuppressive therapy with prednisone 30 mg daily and methotrexate 15 mg weekly. In addition, the patient received neurohormonal treatment for left ventricular systolic dysfunction (sacubitril/valsartan, eplerenone, bisoprolol, and empagliflozin) titrated to their effective doses. In the clinical follow-up at two years, the patient has remained asymptomatic with no cardiovascular events, without ICD therapies needed, and with progressive improvement in systolic function, reaching an LVEF of 55% in the last transthoracic echocardiography control. Likewise, in the repeated PET-CT controls, a progressive decrease in myocardial uptake was observed until its complete remission after two years of treatment , allowing de-escalation of the corticoids and withdrawal of methotrexate after five years of treatment. Discussion Isolated cardiac sarcoidosis (ICS) is defined by histological changes due to noncaseating granulomas with exclusive involvement of the heart, in the absence of extracardiac sarcoid disease . Its diagnosis is complex, since the endomyocardial biopsy, although highly specific, is only positive in 25% of cases due to nonhomogeneous involvement, but patchy in most cases . In ICS, the presence of ventricular arrhythmias seems to be due to scarring from the inflammatory damage of sarcoid granulomas and is associated with high morbidity and mortality. For this reason, it is important to include ICS in the differential diagnosis of patients with "de novo" monomorphic VT in whom coronary ischemic etiology has been ruled out, even without a known history of sarcoidosis, like our case . Although endomyocardial biopsy is the gold standard for the diagnosis of this entity, its performance has several risks, and its utility is limited by its low sensitivity. In this context, the appearance of advanced cardiac imaging tests such as PET-CT and CMR represents an indisputable advance in the noninvasive diagnosis of this disease to confirm the diagnosis of CS. The Japanese Society of Cardiology already includes, among its major diagnostic criteria for CS, the typical uptake pattern of this entity in the most advanced cardiac imaging tests such as 18F-PET-CT or CMR. Other major diagnostic criteria of this society that are also present in our case were as follows: the presence of sustained ventricular arrhythmias with no other alternative cause and left ventricular systolic dysfunction of unknown etiology . The Heart Rhythm Society has added a favorable response to steroid therapy as an additional diagnostic criterion, which should also be considered in suspected CS in the absence of a confirmatory biopsy . However, it is evident that both scientific societies still consider biopsy as an element essential in the definitive diagnosis of CS. As we have already mentioned, it is important to carry out an exhaustive differential diagnosis with other diseases that present with ventricular arrhythmias and abnormal uptake in imaging tests. Pathologies such as infectious myocarditis, arrhythmogenic right ventricular cardiomyopathy, and other infiltrative pathologies such as Fabry disease, hemochromatosis, or infections such as Chagas disease, HIV, and other autoimmune diseases must be ruled out, as was done in our case . In the management of this condition, the treatment of active myocardial inflammation is essential, for which there are studies that support the initiation of early corticosteroid therapy and immunosuppressive therapy with methotrexate, thereby reducing the inflammatory response, stopping the appearance of myocardial fibrosis, and stopping the progression of the disease. Subsequent monitoring of response to treatment should include cardiac imaging tests such as 18F-PET-CT, which is especially sensitive for establishing the degree of myocardial inflammation and the presence of sarcoidosis in the active phase . On the other hand, the management of the evolutionary complications of the disease, such as left ventricular systolic dysfunction and sustained ventricular arrhythmias, must not be forgotten. In our case, neurohormonal treatment has been maintained with the four current pharmacological pillars that include the use of sacubitril/valsartan, beta-blocker, sodium-glucose cotransporter 2 (SGLT2) inhibitors, and mineralocorticoid receptor antagonist. Although treatment for ICS has not been evaluated in randomized studies, it is assumed that early immunosuppressive treatment and treatment of derived cardiac complications (left ventricular systolic dysfunction and ventricular arrhythmias) could clearly reduce symptoms and improve long-term prognosis . Conclusions The initial clinical presentation of a patient with ICS can be challenging, especially if there is no known prior diagnosis of extracardiac sarcoidosis. It is important to take this pathology into account in our clinical practice in order to be able to apply, through multidisciplinary collaboration, correct guidelines for action that do not delay diagnosis or treatment in these patients and thus be able to improve their quality of life and life expectancy. Author Contributions Human Ethics Concept and design: Luis Rene Puglla Sanchez, Begona De Escalante Yanguela, Juan Vallejo Grijalba, Dario J. Samaniego Pesantez Acquisition, analysis, or interpretation of data: Luis Rene Puglla Sanchez, Javier Escota-Villanueva, Juan Vallejo Grijalba, Dario J. Samaniego Pesantez Drafting of the manuscript: Luis Rene Puglla Sanchez, Javier Escota-Villanueva, Juan Vallejo Grijalba, Dario J. Samaniego Pesantez Critical review of the manuscript for important intellectual content: Luis Rene Puglla Sanchez, Begona De Escalante Yanguela, Javier Escota-Villanueva Supervision: Luis Rene Puglla Sanchez, Begona De Escalante Yanguela Consent was obtained or waived by all participants in this study The authors have declared that no competing interests exist. References 1 Sarcoidosis Med Clin (Barc) Brito-Zeron P Perez-Alvarez R Ramos-Casals M 195 204 159 2022 35680449 2 Comparison of necropsy findings in patients with sarcoidosis dying suddenly from cardiac sarcoidosis versus dying suddenly from other causes Am J Cardiol Tavora F Cresswell N Li L Ripple M Solomon C Burke A 571 577 104 2009 19660614 3 Challenges in cardiac and pulmonary sarcoidosis: JACC state-of-the-art review J Am Coll Cardiol Trivieri MG Spagnolo P Birnie D 1878 1901 76 2020 33059834 4 Performance of diagnostic criteria in patients clinically judged to have cardiac sarcoidosis: is it time to regroup? Am Heart J Ribeiro Neto ML Jellis C Hachamovitch R 106 109 223 2020 32240829 5 Ventricular arrhythmias in cardiac sarcoidosis Circulation Okada DR Smith J Derakhshan A 1253 1264 138 2018 30354431 6 [Sarcoidosis] Ugeskr Laeger Moller J Hellmund V Hilberg O Lokke A 180 2018 7 Cardiac sarcoidosis: diagnosis and management Rev Cardiovasc Med Markatis E Afthinos A Antonakis E Papanikolaou IC 321 338 21 2020 33070538 8 A positive endomyocardial biopsy result for sarcoid is associated with poor prognosis in patients with initially unexplained cardiomyopathy Am Heart J Ardehali H Howard DL Hariri A Qasim A Hare JM Baughman KL Kasper EK 459 463 150 2005 16169324 9 Diagnosing isolated cardiac sarcoidosis J Intern Med Kandolin R Lehtonen J Graner M Schildt J Salmenkivi K Kivisto SM Kupari M 461 468 270 2011 21535250 10 How common is isolated cardiac sarcoidosis? Extra-cardiac and cardiac findings on clinical examination and whole-body (18)F-fluorodeoxyglucose positron emission tomography Int J Cardiol Juneau D Nery P Russo J de Kemp RA Leung E Beanlands RS Birnie DH 189 193 253 2018 29306462 11 Sarcoidosis: causes, diagnosis, clinical features, and treatments J Clin Med Jain R Yadav D Puranik N Guleria R Jin JO 9 2020 12 HRS expert consensus statement on the diagnosis and management of arrhythmias associated with cardiac sarcoidosis Heart Rhythm Birnie DH Sauer WH Bogun F 1305 1323 11 2014 24819193 13 Cardiac sarcoidosis: a clinical overview Curr Probl Cardiol Alba AC Gupta S Kugathasan L 100936 46 2021 34400001 |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.49168 Pediatrics Rheumatology Allergy/Immunology Siblings With Thrombocytopenia Found To Have a Pathogenic Variant in the NFkB1 Gene Muacevic Alexander Adler John R Bakheet Kholoud 12 Habiballah Saddiq 134 Basahl Emtenan 1 Algiraigri Ali 567 Alsaidalani Ashwag 1 Nashawi Mohammed 124 1 Pediatrics, King Abdulaziz University Faculty of Medicine, Jeddah, SAU 2 Pediatric Rheumatology, King Abdulaziz University Hospital, Jeddah, SAU 3 Pediatric Allergy/Immunology, King Abdulaziz University Hospital, Jeddah, SAU 4 Immunology Unit, King Fahd Medical Research Center, Jeddah, SAU 5 Hematology, King Abdulaziz University Faculty of Medicine, Jeddah, SAU 6 Hematology, King Abdulaziz University Hospital, Jeddah, SAU 7 Hematology Research Unit, King Fahad Medical Research Center, Jeddah, SAU Mohammed Nashawi [email protected] 21 11 2023 11 2023 15 11 e4916821 11 2023 Copyright (c) 2023, Bakheet et al. 2023 Bakheet et al. This is an open access article distributed under the terms of the Creative Commons Attribution License CC-BY 4.0., which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from Immune thrombocytopenic purpura is one of the most common causes of low platelet count in the pediatric population. Secondary thrombocytopenia has a wide differential diagnosis in children, including rheumatological, hematological, and immunological etiologies. Underlying etiologies must be excluded if suspected before labeling the patient as primary thrombocytopenia. Here, we report two siblings with persistent and profound thrombocytopenia. A 10-year-old girl presented with profound and treatment-refractory thrombocytopenia. Given the patient's family history of thrombocytopenia of unknown pathology in her older brother, immune dysregulation-related thrombocytopenia was suspected. Whole exome sequencing confirmed a previously reported pathogenic variant in the NFKB1 gene linked to common variable immunodeficiency 12 (CVID-12) diagnosis for both patients. nfkb1 cytopenia cvid itp thrombocytopenia pmcIntroduction Immune thrombocytopenic purpura (ITP) is the most common form of primary thrombocytopenia . It is a platelet-destructive disorder. Platelet count is usually below 150,000/ul at the time of diagnosis, with no other systemic involvements. Patients aged two to six years are the most affected. The disease incidence is one in 10,000 children with nearly equal gender distribution . A family history of thrombocytopenia raises suspicion toward an inherited cause of thrombocytopenia, as ITP cases are usually sporadic. The formation of autoantibodies against platelet antigens within the reticuloendothelial system leads to the destruction and premature clearance of those platelets. While this explanation is widely acceptable, the exact underlying pathophysiology is still not fully understood and seems to be multifactorial . Depending on the degree of platelet depletion and other risk factors such as trauma, ITP might present with signs of external "mucocutaneous", or internal "gastrointestinal, urinary, or intracranial" bleeding . Despite low platelets, the complete blood count of those patients typically shows normal values of other parameters, including hemoglobin and white blood cells . The presence of another cell line abnormality should provoke questioning toward ITP diagnosis . Multiple systems could be involved in the pathophysiology of secondary thrombocytopenia in pediatrics. Hemato-oncological, and immune-mediated conditions in addition to infections can lead to thrombocytopenia in this vulnerable population . In addition to ITP, systemic lupus erythematosus (SLE) is an important cause of secondary thrombocytopenia in childhood [6-9]. Another important hidden disease entity to consider in cases of refractory or recurrent ITP is common variable immune deficiency (CVID) disorders . Many CVID patients have an overlap in the clinical phenotypes with other autoimmune diseases as autoimmune disorders were reported in nearly two-thirds of CVID patients regardless of the genetic variants involved . Autoimmune hemolytic anemia (AIHA) and ITP were the most common conditions that have led to the diagnosis of CVID in about half of these cases in a retrospective chart review of over 300 cases . Genetic variants in nuclear factor Kappa-B1 (NFKB1) have been linked to common variable immune deficiencies. Recent reports have shown patients with variants of this gene presenting with autoimmunity and lymphoproliferation in high frequency . In this article, we present two siblings with an NFKB1 variant. First, an adolescent girl with chronic thrombocytopenia was initially diagnosed with ITP but further workup was performed as she lacked response to the conventional management of ITP. Her older brother presented with a similar phenotype, in addition to evidence of lymphoproliferation. Both siblings' whole exome sequence confirmed the presence of the NFKB1 variant and were diagnosed with an immune dysregulation disorder. Case presentation Case 1 The first patient (P1) is an 11-year-old girl without a significant past medical history who presented at nine years of age with an abrupt onset of purpura and ecchymosis for two weeks. She had a similar presentation a year earlier, with spontaneous resolution of symptoms. No other symptoms were reported at both times. Her ecchymosis and purpuric lesions were mainly in her arms, legs, and upper back. She was admitted as a suspected case of immune-mediated thrombocytopenic purpura. She initially had no evidence of lymphoproliferation, but she developed mild hepatomegaly and lymphadenopathy later in her disease course. Initial labs at our hospital showed mild leukopenia, neutropenia, and thrombocytopenia of 2.4 k/ul (normal range 4.5-13.5), 0.2 k/ul (normal range 2-7), and 1 k/ul (normal range 150-450)), respectively (Table 1). Hemoglobin level was normal at 13.4 g/dl (normal range 12.0-15.0). An infectious workup was done to exclude nonimmunological causes of her bi-cytopenia and was completely negative, including tuberculosis, Epstein-Barr virus (EBV), and parvovirus. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing was also negative. Table 1 Changes in the lymphocytes and neutrophils of P1 during follow-up Day 0 Day 30 Day 60 Day 120 Day 180 Day 270 Automated lymphocytes (normal range 1.5 - 7 K/uL) 1.33 1.56 1.36 1.7 1.92 1.48 Automated Neutrophils Count (normal range 1 - 8 K/uL) 0.39 0.39 0.25 0.59 0.31 0.74 As a case of suspected ITP, she received Rh immunoglobulins of 75 mcg/kg as intravenous immunoglobulin (IVIg) was unavailable at that time. Her platelet counts responded well to that treatment, and she was discharged after 96 hours with a platelet count of 186 k/ul. In less than a month, her platelet count dropped again to 3 k/ul, so she received a second dose of anti-D antibodies, followed by multiple courses of 2 mg/kg/day of oral prednisone . As her platelet counts continued to drop after reducing steroids, she was referred to pediatric rheumatology. Figure 1 Changes in the platelet count after ITP management for P1 ITP: immune thrombocytopenic purpura Upon further evaluation, her past medical history was not significant for frequent infections, respiratory symptoms, or complaints, nor did she have skin, mucosal, or joint issues. Her complement levels were normal, the SLE autoantibodies panel was negative, and bone marrow aspiration showed mild hypocellularity with increased megakaryocytes as expected. Expecting immune dysregulation underlying etiology, immune phenotyping was done and showed low IgM 0.33 g/L (normal range 0.5-1.80), CD3 756 mL (normal range 1200-2600), CD4 407 mL (normal range 650-1500), and absence of protective antibodies against tetanus despite her being fully vaccinated for that. Unfortunately, she had received multiple courses of IVIgs at this point, so assessing IgG level was non-informative . Figure 2 Immunoglobulin levels of first patient during follow-up period of four months Her family history was interesting in terms of a family member with thrombocytopenia (her brother, referred to as "P2" from now on in this report), in addition to lymphoproliferation . Figure 3 Family pedigree showing carrier and affected individuals As the concern for underlying immune dysregulation was highly suspicious, a whole exome sequencing was sent for her, being the kindred here. Her next-generation sequencing revealed a previously reported, disease-causing heterozygous variant in the NFKB1 gene (c.607C>T, P. Gln203*). Case 2 The second patient (P2) is a 21-year-old male, who is a brother of P1 . He was 18 years old when he was found to have thrombocytopenia and hepatosplenomegaly incidentally as he was completely asymptomatic. As tuberculosis is endemic in the area, and in the absence of any evidence of another underlying etiology, he was started on an anti-tuberculosis regimen. While on that regimen, he developed mild and transient transaminitis that resolved with no sequala but persisted to be thrombocytopenic, lymphopenic, and neutropenic, in addition to his generalized lymphadenopathy and hepatosplenomegaly. Despite those findings, he continues to be asymptomatic and free of infections, so no specific treatment was started. Limited immune phenotyping was done and revealed an IgG level of 495 mg/dl (540-1822), with protective antibodies against mumps, rubella, and hepatitis B. After the presence of the NFKB1 gene variant was confirmed in his sister, the family segregation study uncovered the same variant for him, a heterozygous variant of the NFKB1 gene (c.607C>T, P.Gln203*). The father's testing was also positive for the same variant, but he was completely asymptomatic, and his complete blood count result was normal. As the genetic variant was confirmed for P2, and as he continued to show evidence of autoimmunity and lymphoproliferation, further laboratory and radiological evaluations were carried out. Immune phenotyping showed an IgG level of 486 mg/dl (normal range, 540-1822 mg/dl), normal IgM and IgA levels, and protective titers against measles, mumps, and tetanus vaccines. His lymphocyte subset showed severe CD4+ T-cells lymphopenia at 277 cells/uL (normal range, 430-1800 cells/uL), and low CD16+ NK-cells at 21 cells/uL (normal range, 78-470 cells/uL). CD8+ T-cells and CD19+ B-cells were normal in the setting of an absolute lymphocyte count of 900 cells/uL (normal range, 900-3100 cells/uL), but unfortunately B cell memory panel was not available. His absolute neutrophil count was low at 0.59 X 109/L (normal range, 1.7-7.0), and his platelet count was 41 K/UL (normal range, 150-450 K/UL). A high-resolution chest computed tomography scan for both siblings showed normal results. Both patients started on Ig replacement therapy in addition to azathioprine and are under active treatment and follow-up currently. P1 did not show optimal response to azathioprine, so she was switched to rituximab, while P2 continued on azathioprine pending further follow-up. Discussion CVID disorders are a group of diseases with primary B cell defects, and multisystem involvement . The usual age of presentation for CVID is around adolescence and early adulthood years. Males and females are equally affected. It is sporadic in most cases. A wide range of clinical manifestations have been identified including recurrent infections involving the sinopulmonary or gastrointestinal system. Deep-seated infections, allergic diseases, improper response to antibiotics or vaccines, and autoimmune diseases were also reported . As immune dys-regulatory disorders, patients with those diseases can present with granulomatous inflammation of the lung, lymph nodes, and solid tumors such as lymphomas due to their lack of host immunity . Genetic testing should be highly considered in patients presenting with immune deficiency/dys-regulatory concerns. To diagnose a patient with CVID, the European Society for Immunodeficiencies (ESID) proposed diagnostic criteria that required a low IgG level, either low IgA or IgM, in addition to evidence of specific antibody deficiency . Over the past few years, more monogenetic causes of CVID have been described, but the majority of cases still with no identifiable genetic defect. NFKB1 is one of the identified genes harboring disease-causing variants. This disease is classified as a CVID-12 phenotype. In a recent cohort, 105 heterozygous variants were identified causing variable clinical presentations. The presentation ranged from infectious susceptibility, autoimmunity, and immune dysregulation . As P1 already received multiple courses of IVIg and anti-CD20 treatment, in addition to no pre-treatment immunophenotyping, we could not assess for the ESID proposed diagnostic criteria for CVID. Instead, she was diagnosed with CVID-12 based on her clinical presentation with autoimmunity and lymphoproliferation evidence, in addition to her identified genetic variant. Her brother was also labeled as a CVID-12 patient given his clinical presentation, and the genetic variants he harbors, but his Igs were low prior to treatment. The identified variant in our patients (NFKB1, P.Gln 203*) has been reported as pathogenic in one female patient who presented with CVID/autoimmune lymphoproliferative syndrome (ALPS) phenotype . Autoimmunity is reported in nearly two-thirds of CVID patients, with almost half of them presenting with autoimmune cytopenia . Other common immune-mediated diseases associated with CVID are rheumatoid arthritis, psoriasis, celiac and thyroiditis . Joint manifestations resembling rheumatoid arthritis or juvenile idiopathic arthritis occur in 1-10 % of patients with CVID . SLE with CVID is uncommon, but patients may develop SLE features as a complication of immune dysregulation of CVID . Hypogammaglobulinemia may delay the diagnosis of autoimmunity in CVID patients as auto-antibodies (including antinuclear antibody (ANA) and rheumatoid factors) may be impeded . The mainstay of CVID-12 (NFKB1 deficiency) treatment is Ig replacement and immune suppressive therapy as needed per individual patients . Hematopoietic stem cell transplantation is an option that still does not have enough data in patients with CVID-12 . It is also important to closely follow patients with evidence of immune dysregulation as they are at higher risk of developing malignancies such as lymphomas. Conclusions By presenting these two cases, we are reinforcing the importance of re-questioning the diagnosis of chronic and replacing thrombocytopenia in the presence of other evidence such as lymphoproliferation and family history in our scenario. Moving to genetic testing is strongly recommended in such cases to unveil the underlying pathology. We would like to thank both patients and their family. Author Contributions Human Ethics Concept and design: Mohammed Nashawi, Kholoud Bakheet, Saddiq Habiballah Acquisition, analysis, or interpretation of data: Mohammed Nashawi, Emtenan Basahl, Saddiq Habiballah, Ashwag Alsaidalani, Ali Algiraigri Drafting of the manuscript: Mohammed Nashawi, Emtenan Basahl, Kholoud Bakheet Supervision: Mohammed Nashawi Critical review of the manuscript for important intellectual content: Saddiq Habiballah, Ashwag Alsaidalani, Ali Algiraigri Consent was obtained or waived by all participants in this study The authors have declared that no competing interests exist. References 1 The incidence of immune thrombocytopenic purpura in children and adults: a critical review of published reports Am J Hematol Terrell DR Beebe LA Vesely SK Neas BR Segal JB George JN 174 180 85 2010 20131303 2 ITP in children: pathophysiology and current treatment approaches J Pediatr Hematol Oncol D'Orazio JA Neely J Farhoudi N 1 13 35 2013 23073045 3 Bleeding complications in immune thrombocytopenia Hematology Am Soc Hematol Educ Program Arnold DM 237 242 2015 2015 26637728 4 Management of immune thrombocytopenia: 2022 update of Korean experts recommendations Blood Res Park YH Kim DY Kim S 20 28 57 2022 5 Immune thrombocytopenic purpura N Engl J Med Cines DB Blanchette VS 995 1008 346 2002 11919310 6 Thrombocytopenia and thromboembolism in pediatric systemic lupus erythematosus J Pediatr Schmugge MR Hiraki L Rand ML Blanchette VS Silverman ED 666 669 143 2003 14615743 7 Platelet autoantibodies and lupus-associated thrombocytopenia Br J Haematol Michel M Lee K Piette JC Fromont P Schaeffer A Bierling P Godeau B 354 358 119 2002 12406068 8 Prevalence and burden of pediatric-onset systemic lupus erythematosus Nat Rev Rheumatol Kamphuis S Silverman ED 538 546 6 2010 20683438 9 The management of peripheral blood cytopenias in systemic lupus erythematosus Rheumatology (Oxford) Hepburn AL Narat S Mason JC 2243 2254 49 2010 20823093 10 Common variable immunodeficiency: a new look at an old disease Lancet Park MA Hagan JB Maddox DE Abraham RS 489 502 372 2008 18692715 11 Treatment and outcome of autoimmune hematologic disease in common variable immunodeficiency (CVID) J Autoimmun Wang J Cunningham-Rundles C 57 62 25 2005 15994061 12 Common variable immunodeficiency and autoimmune diseases: a retrospective study of 95 adult patients in a single tertiary care center Front Immunol Mormile I Punziano A Riolo CA 652487 12 13 Characterization of the clinical and immunologic phenotype and management of 157 individuals with 56 distinct heterozygous NFKB1 mutations J Allergy Clin Immunol Lorenzini T Fliegauf M Klammer N 901 911 146 2020 32278790 14 Morbidity and mortality in common variable immune deficiency over 4 decades Blood Resnick ES Moshier EL Godbold JH Cunningham-Rundles C 1650 1657 119 2012 22180439 15 Common variable immunodeficiency disorders: division into distinct clinical phenotypes Blood Chapel H Lucas M Lee M 277 286 112 2008 18319398 16 Osteoarticular infectious complications in patients with primary immunodeficiencies Curr Opin Rheumatol Bloom KA Chung D Cunningham-Rundles C 480 485 20 2008 18525364 17 Common variable immunodeficiency in systemic lupus erythematosus Semin Arthritis Rheum Fernandez-Castro M Mellor-Pita S Citores MJ 238 245 36 2007 17276173 18 Multicenter experience in hematopoietic stem cell transplantation for serious complications of common variable immunodeficiency J Allergy Clin Immunol Wehr C Gennery AR Lindemans C 988 997 135 2015 25595268 |
Inj Epidemiol Inj Epidemiol Injury Epidemiology 2197-1714 BioMed Central London 481 10.1186/s40621-023-00481-2 Commentary Reducing fall injuries with better data Hemenway David [email protected] 1 Peterson Elizabeth W. 2 Howland Jonathan 3 1 grid.38142.3c 000000041936754X Department of Health Policy and Management, Harvard T.H. Chan School of Public Health, 677 Huntington Avenue, Boston, MA 02115 USA 2 grid.185648.6 0000 0001 2175 0319 Department of Occupational Therapy, University of Illinois at Chicago, Chicago, IL USA 3 grid.189504.1 0000 0004 1936 7558 Department of Emergency Medicine, Boston University Chobanian and Avedisian School of Medicine, Boston, MA USA 21 12 2023 21 12 2023 2023 10 6929 9 2023 13 12 2023 (c) The Author(s) 2023 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit The Creative Commons Public Domain Dedication waiver ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Background Fall deaths in the USA almost tripled in the twenty-first century. While various interventions have been effective in reducing fall deaths, they have failed to make a substantial impact at a population level. Main body An overarching factor that has been relatively neglected in fall injury prevention is the need for more and better data. We need better data on the causes and circumstances of older adult fall deaths. While there are excellent national surveillance systems on the circumstances of other injury deaths (e.g., motor vehicle crashes, suicides, and homicides), such a system is lacking for fall deaths. These other data systems have been instrumental in indicating and evaluating policies that will reduce injury. It is also important to provide consumers with better information concerning the many products that affect the likelihood of fall injury (e.g., flooring, hip protectors, footwear). Automotive buyers are provided with relevant up-to-date make-model safety information from crash tests and real-world performance. Such information not only helps protect buyers from purchasing dangerous products, but it provides producers with the incentive to make ever safer products over time. Conclusion We believe that creation of a national surveillance system on the circumstances of fall deaths, and increased testing/certifying of fall-related products, are two steps that would help create the conditions for continuous reductions in fall fatalities. Fall prevention should apply some of the same basic strategies that have proved effective in addressing other injuries. Keywords Falls Fall deaths Fall injuries Surveillance systems Data systems Standards Certification issue-copyright-statement(c) Columbia University Center for Injury Epidemiology and Prevention 2023 pmcBackground In the past two decades (2001-2021), the number of Americans dying from unintentional falls increased from 15 thousand to over 44 thousand as the crude death rate rose from 5.3 (per 100,000 population) to 13.5 (Centers for Disease Control and Prevention 2023). Deaths from falls are expected to continue to rise as the baby boom generation moves through retirement age and experiences the frailty, chronic conditions, and medications that are associated with increased fall risk. While various interventions have been effective in reducing fall deaths (Montero-Odasso et al. 2022) by reducing intrinsic risk factors (e.g., improving strength, vision, balance) and/or extrinsic risk factors (e.g., shaping the built environment so falls are less likely and less serious) they have failed to make a substantial impact at a population level. In this essay, we focus on an overarching factor we believe has been relatively neglected but is crucial for reducing fall fatalities: data. We need better data both on (a) the causes and circumstances of fall deaths and on (b) the types of products that can reduce fall injuries. Main text National fall fatality surveillance system The first step in the public health approach to fall injury prevention is to create a national surveillance system to provide information on the circumstances of fall fatalities. The existing WISQARSTM injury surveillance system provides demographic information (e.g., age, sex, region) on fatal fall victims but does not yield the circumstantial data needed to inform high-impact interventions. By contrast, motor vehicle fatalities have such a data system (the national Fatality Analysis Reporting System or FARS) as do suicides and homicides (the National Violent Death Reporting System, or NVDRS). Federal data systems on the circumstances of fatalities have been instrumental in indicating and evaluating policies intended to reduce injuries. For example, data from FARS showed that 16-year-old drivers were at high risk of death and were at the highest risk in two situations when they were driving at night and when only other teenagers were in the vehicle. With that information, Michigan initiated a graduated driver licensing program in which 16-year-olds are allowed to drive, but not in those two situations. Analyses using FARS data found that the program reduced fatalities among these drivers by 30%. Other states quickly adopted similar measures, with similar success, and soon all 50 states had graduated driver licensing programs, saving many lives (Hemenway 2009). We need a similar national data system for fall deaths that will provide consistent and comparable circumstantial information across states and over time. The method by which the NVDRS was created might provide a template for creating such a system. Calls for a firearm data system (Teret et al. 1992) led a consortium of foundations to provide funding for three inter-related private activities: creating a pilot for the program across a variety of states, creating descriptive materials (e.g., pamphlets, quizzes) to demonstrate the social benefits of the system, and organizing lobbying support from scores of key private associations (e.g., American Medical Association, American Bar Association). With funding, an important early step was a national conference that brought together experts in injury surveillance, research, and policy from government, academia, and other non-profits. At this conference, issues were resolved, barriers overcome, and key strategic decisions agreed upon such as to focus on fatalities only, to include non-firearm violent deaths in the system, and that the Centers for Disease Control and Prevention (CDC) was the appropriate federal agency for the system. Within 3 years, the nascent NVDRS was housed at the CDC and was beginning to collect state-level data (Hemenway et al. 2009). The new fatality system for fall deaths, like NVDRS, could be housed at the CDC, or in an independent agency (as FARS is). The cost would be but a rounding error in the federal budget; the FY 2023 budget for NVDRS was $24.5 million. A national data system on the circumstances of fall deaths can increase the consistency of coroner/medical examiner reports (Walsh et al. 2007) and improve on the accuracy of Vital Statistics. NVDRS helped demonstrate that death certificate data alone (WISQARS) resulted in a large undercounting of both unintentional firearm fatalities to children and victims killed by law enforcement officers. NVDRS is now the accurate federal source for such data. Similarly, a falls fatality data system may improve the accuracy of vital statistics data-including the data reported in the first sentence of this Commentary. Consumer information For markets to work well, consumers need good information. Good product quality information can protect buyers from unsafe products and provide suppliers with incentives to make ever safer products over time. Accurate information on fall causation could stimulate the development of new products to prevent or mitigate falls and accelerate the deployment of existing fall prevention/mitigation products. The twenty-first-century reduction in motor vehicle deaths shows that it is possible to create an environment that creates incentives for continuous reductions in injury deaths (Hemenway and Lee 2022). The key to providing the right incentives appears to have been the combination of an excellent national data system (FARS) along with data on product safety that is continually provided to buyers. The National Highway Traffic Safety Administration (NHTSA) (that has a mission to prevent traffic injuries) along with the Insurance Institute for Highway Safety (IIHS) (that crash-tests cars and rates vehicles), provide car buyers with relevant up-to-date make-model safety information from crash tests and real-world performance. Car manufacturers, that historically resisted competing on safety, now actively promote new safety features. Cars today are much safer than they were in 2000. For example, automatic emergency braking, blind spot detection, side airbags, and rear-facing cameras are now commonly available. Many products potentially affect the likelihood of experiencing fall-related injuries including flooring, hip protectors, and footwear. It would be useful for older Americans to know what shoes are the most slip resistance and for suppliers and general contractors to have better information and stronger incentives to provide effective impact absorbing surfaces in high-risk spaces. It would be ideal to have a NHTSA-type federal agency whose mission is to reduce fall injuries, along with an insurance-sponsored non-profit institute that evaluates the effectiveness of fall prevention initiatives and promotes policies that reduce the likelihood and severity of serious falls. Standards and certification help ensure that safety products are effective. Many public and private organizations provide standards for industries, based on testing and other research. UL standards for electrical equipment are one example. The US federal government helped create voluntary quality standards for fire safe cigarettes. These standards were then mandated throughout the USA, reducing the likelihood of cigarette-caused fire deaths. Conclusion The importance of systematically collected data on the circumstances of injury is well known. In its 1985 seminal report Injury in America, the National Research Council and the Institute of Medicine concluded that the "development of effective intervention strategies requires an adequate national surveillance system for monitoring injuries..." (Committee on Trauma Research, Commission on Life Sciences 1985) and the "lack of brand or even generic information on products associated with injuries is clearly a major barrier to the prevention of injuries" (Committee on Trauma Research, Commission on Life Sciences 1985). The fall prevention field has fallen behind in its ability to provide researchers and the marketplace with the types of information needed to counter current global trends in fall-related death. We should apply to falls the same strategies that have been effective in addressing other injuries. Abbreviations CDC Centers for Disease Control and Prevention FARS Fatality Analysis Reporting System IIHS Insurance Institute for Highway Safety NHTSA National Highway Traffic Safety Administration NVDRS National Violent Death Reporting System WISQARSTM Web-based Injury Statistics Query and Reporting System Acknowledgements Not applicable. Author contributions DH conceived of the article and wrote the initial draft. EWP and JH edited and supplemented the draft. All authors read and approved the final submission. Funding No funding. Availability of data and materials Not applicable. Declarations Ethics approval and consent to participate Not Applicable. The paper does not considered "research involving human subjects." It does not examine identifiable individual data, documents, records, or specimens. Consent for publication Not applicable. Competing interests The authors declare they have no competing interests. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. References Centers for Disease Control and Prevention. WISQARS Accessed June 2023. Committee on Trauma Research, Commission on Life Sciences National Research Council, & Institute of Medicine. Injury in America 1985 Washington DC National Academy Press 2933 Hemenway D While we were sleeping: success stories in injury and Violence prevention 2009 Berkeley University of California Press Hemenway D Barber CW Gallagher SS Azrael DR Creating a national violent death reporting system: a successful beginning Am J Prev Med 2009 37 68 71 10.1016/j.amepre.2009.03.005 19524145 Hemenway D Lee LK Lesson from the continuing motor vehicle success Inj Prev 2022 28 480 2 10.1136/ip-2022-044635 35790347 Montero-Odasso M, van der Velde N, Martin FC, et al. Task force on global guidelines for falls in older adults. World guidelines for falls prevention and management for older adults: a global initiative. Age Aging 2022. Teret SP Wintemute GJ Beilenson PL The firarm fatality reporting system: a proposal JAMA 1992 267 3073 4 10.1001/jama.1992.03480220091035 1588724 Walsh S Dignan M Caldwell G The PAPM, diffusion theory, and violent death surveillance Am J Health Behav 2007 31 451 61 10.5993/AJHB.31.5.1 17555376 |
J Med Case Rep J Med Case Rep Journal of Medical Case Reports 1752-1947 BioMed Central London 38124073 4268 10.1186/s13256-023-04268-3 Case Report Acute cardiac tamponade during atrial flutter ablation: improved hemodynamics after positive pressure ventilation: a case report Royster Roger L. [email protected] 1 Coleman Scott R. 1 Goenaga-Diaz Eduardo J. 13 Richardson Karl M. 2 Whalen S. Patrick 2 1 grid.241167.7 0000 0001 2185 3318 Department of Anesthesiology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1009 USA 2 grid.241167.7 0000 0001 2185 3318 Department of Cardiology, Wake Forest University School of Medicine, Winston-Salem, NC USA 3 grid.239552.a 0000 0001 0680 8770 Department of Anesthesiology and Critical Care Medicine, Children's Hospital of Philadelphia, Philadelphia, PA USA 21 12 2023 21 12 2023 2023 17 52316 10 2023 16 11 2023 (c) The Author(s) 2023 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit The Creative Commons Public Domain Dedication waiver ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Introduction Acute cardiac tamponade is a rare event during any type of interventional or surgical procedure. It can occur during electrophysiology procedures due to radiofrequency ablation, lead or catheter manipulation, transseptal puncture, laser lead extractions, or left atrial appendage occlusion device positioning. Cardiac tamponade is difficult to study in a prospective manner, and case reports and case series are important contributions to understanding the best options for patient care. Case summary An 87-year-old Caucasian male patient breathing spontaneously developed acute tamponade during an atrial flutter ablation. Pericardial drain insertion was difficult, and hypotension failed to respond to epinephrine boluses. The patient became hypoxemic and hypercarbic, requiring intubation. Unexpectedly, the blood pressure markedly increased postintubation and remained in a normal range until the pericardium was drained. Conclusion Spontaneous ventilation is considered important to maintain venous return to the right heart during cardiac tamponade. However, spontaneous ventilation reduces venous return to the left heart and worsens the paradoxical pulse in tamponade. Intravenous vasopressors are thought to be ineffective during cardiac tamponade. Our patient maintained pulmonary blood flow as indicated by end-tidal carbon dioxide measurements but had no measurable systemic blood pressure during spontaneous ventilation. Our case demonstrates that tracheal intubation and positive pressure ventilation can transiently improve left heart venous return, systemic perfusion, and drug delivery to the systemic circulation. Keywords Atrial flutter ablation Cardiac resuscitation Cardiac tamponade Catecholamines Mode of ventilation Departments of Anesthesiology and Cardiology, Wake Forest University School of Medicineissue-copyright-statement(c) BioMed Central Ltd., part of Springer Nature 2023 pmcBackground Cardiac tamponade is a rare complication during electrophysiology procedures, occurring in less than 1% of patients. Tamponade occurs in lead or catheter manipulation, in procedures requiring transseptal puncture, in laser lead extractions, and in left atrial appendage occlusion device positioning. A steam pop is an audible sound that occurs during radiofrequency ablation resulting from interstitial fluid heating to as high as 100 degC and forming a gas that causes an intramyocardial explosion, which can perforate the heart. There are few patient studies of cardiac tamponade with most clinical information resulting from case reports or case series . Research on tamponade performed in animals requiring instrumentation of various cardiothoracic structures may or may not mimic the physiology of tamponade in humans . Cardiopulmonary interactions in tamponade are related to the impact of spontaneous ventilation (SV) and positive pressure ventilation (PPV) . We report an unusual case of steam pop-induced cardiac tamponade that hemodynamically improved after intubation and PPV prior to the drainage of pericardial blood. Case presentation An 87-year-old Caucasian male patient with history of typical atrial flutter was scheduled for a right heart atrial flutter ablation. Preoperative electrocardiogram showed typical atrial flutter with negative flutter waves in leads 2, 3, and aVF, positive flutter waves in V1, and a ventricular rate of 144 beats per minute (bpm). Preoperative transesophageal echocardiogram (TEE) revealed no clot in the left atrial appendage, mildly reduced left ventricular function, and no pericardial effusion. The patient received intravenous propofol titrated to 65 mg/kg/minute, breathing spontaneously with mask delivery of 60% oxygen. End-tidal carbon dioxide (EtCO2) was measured continuously. The blood pressure (BP) via cuff was 116/66 mmHg. Radiofrequency ablation was performed using an open irrigation, contact force-monitoring catheter delivering 30-35 watts of power. During a 7-second ablation at 35 watts, the attending cardiologist felt a sudden resistance in his ablation catheter and a steam pop was noted. Over the next few minutes, the BP became unmeasurable, and 100 mg of intravenous (IV) epinephrine was administered twice over several minutes (Fig. 1). Propofol was discontinued. The cardiologist performed a transthoracic echocardiogram (TTE) that showed a large pericardial effusion and began preparation for a pericardial drain. Blood pressure was measured as 44/29 mmHg, and an additional 100 mg of epinephrine was administered (Table 1). The pericardium was punctured, and a guidewire and catheter were inserted; however, positioning the catheter to drain the pericardium was difficult. The patient had continuous measurements of EtCO2 but without a BP measurement. The cardiologist reported a weak femoral pulse. Another 200 mg of epinephrine was administered and, several minutes later, 300 mg of epinephrine. At this time, the patient was receiving 100% oxygen, but the pulse oximetry saturation had decreased to 70% with an EtCO2 of 59 mmHg. The patient was administered 100 mg of rocuronium and intubated. The BP postintubation was measured at 74/42 mmHg and, surprisingly, slowly increased to 190/105 mmHg and remained in a normal range until 600 ml of blood was drained from the pericardium; the BP stabilized at 100/70 mmHg.Fig. 1 Electronic anesthesia record of hemodynamic events during pericardial tamponade secondary to ablation of atrial flutter demonstrating the marked increase in blood pressure minutes after intubation and positive pressure ventilation Table 1 Timeline of events* Time (hours) Event 1245 Steam pop 1249 BP 139/83 mmHg 1253 100 mg epinephrine 1255 BP 44/29 mmHg 1256 Pericardial effusion seen on TTE 1257 100 mg epinephrine 1302 Pericardium puncture 1304 Pericardial catheter inserted, 200 mg epinephrine 1306 Unable to drain blood, 300 mg epinephrine, Sat% 71, EtCO2 59 1307 Intubation 1308 BP 74/42 mmHg, Sat% 100, EtCO2 38 1309 BP 150/98 mmHg 1312 BP 190/105 mmHg 1319 BP 85/48 mmHg 1320 600 ml blood drained from pericardium, BP 100/70 mmHg 1330 Femoral arterial line inserted, TEE probe inserted 1338 BP 95/45 mmHg, 400 ml plasmalyte 1350 BP 128/74 mmHg *Times taken from electronic medical record and records of electrophysiology lab BP blood pressure, TTE transthoracic echocardiograph, EtCO2 end-tidal carbon dioxide, Sat% saturation percentage, TEE transesophageal echocardiography After pericardial drainage, an arterial catheter was placed in the femoral artery and a TEE probe was inserted, which revealed reduced heart volumes and a small amount of blood in the pericardium with right ventricular diastolic collapse. Low pressure tamponade was diagnosed and crystalloid (500 ml) was administered; the BP increased to 125/70 mmHg. The patient required one further pericardial drainage because of recurrent tamponade diagnosed by transthoracic echocardiogram (TTE) in the intensive care unit and was discharged from the hospital in several days after repeat TTEs showed no pericardial effusion. Discussion and conclusion Kussmaul described the arterial pulse "going away" during inspiration and coined the term "paradoxical pulse" . This was the first description in which SV inhibited left ventricular stroke volume by reducing left ventricular venous return. Multiple studies since have demonstrated that inspiration reduces left ventricular stroke volume under normal physiologic conditions with a reduction of systolic BP of less than 6 mmHg . Spontaneous ventilation normally augments right heart venous return by creating negative intrathoracic pressure. During tamponade, because of increased ventricular interdependence caused by pericardial constraint, a "downhill" pressure gradient develops between the high pressure extracardiac venous system and the low pressure pulmonary circulation. Echocardiograms show that inspiration causes a significantly greater increase in venous return during tamponade, demonstrated by increased tricuspid valve in-flow velocities and a greater reduction in left heart venous return seen by reduced mitral valve in-flow velocities (Table 2) . The venous return to the left heart is inhibited because of the "uphill" pressure gradient moving blood from the low-pressure pulmonary circulation into the tamponaded left heart (Fig. 2A). This results in an interventricular septal shift to the left and an increased paradoxical pulse with a reduction in systolic BP during inspiration of greater than 10 mmHg.Table 2 Impact of spontaneous and positive pressure ventilation on mitral and tricuspid valve peak flow velocities and paradoxical pulse with and without cardiac tamponade MV TV PP Spontaneous ventilation without tamponade Inspiration | < 10% | < 6 mmHg Expiration | | < 25% Spontaneous ventilation with tamponade Inspiration || 25-65% || 58-85% > 10 mmHg Expiration || 22% || Positive pressure ventilation without tamponade Inspiration | | Reverse paradox Expiration | | Positive pressure ventilation with tamponade Inspiration | | Absent Expiration | | MV mitral valve, TV tricuspid valve, PP paradoxical pulse Fig. 2 Diagram illustrating cardiac systolic and diastolic pressures and pericardial pressure during global tamponade, relative changes in pulmonary arterial and pulmonary venous blood flow, and pulmonary pooling of blood in A during spontaneous ventilation and in B during positive pressure ventilation. PP pericardial pressure, CVP central venous pressure, RV right ventricle, LA left atrium, LV left ventricle, PA pulmonary artery, PV pulmonary vein, ITP intrathoracic pressure. All pressures in mmHg In our case, despite maintaining good pulmonary blood flow indicated by good EtCO2 measurements with SV, systemic hypotension developed. Blood tends to pool in the lungs with a resultant increase in extravascular lung water because of the reduced left heart venous return . However, with cardiac compressive syndromes such as tamponade even with intracardiac pressures equal to pressures in congestive heart failure alveolar edema often does not develop . Some hypothesize that natriuretic peptide secretion is not increased in compressive syndromes as compared with disease states that stretch the heart, and this has an impact on capillary permeability . The pulmonary pooling of blood and negative impact on left heart diastolic filling may explain why intravenous vasopressors are often ineffective during tamponade . Additionally, chest compressions were not performed in our case and may not be effective in tamponade . In animal studies of cardiac tamponade, PPV reduces venous return to the right ventricle but improves left heart filling and systemic pressures . The paradoxical pulse in tamponade has been described in case reports in humans to be reduced, to disappear, or to be reversed with PPV . This reduction of ventricular interdependence and the resultant loss of the paradoxical pulse suggests improved venous return from the lungs to the left ventricle that increases systemic blood flow, pressures (Fig. 2B), and catecholamine delivery. There are case reports of patients with tamponade who need intubation for respiratory support, pericardiocentesis, or pericardial windows and do well hemodynamically. Data from 105 patients undergoing pericardial window for tamponade indicate that the outcome is no different between patients managed with local anesthesia and sedation and patients receiving general anesthesia and intubation, although more vasopressor administration was required during general anesthesia . However, prolonged PPV without pericardial drainage may eventually have a detrimental effect on right heart venous return and hemodynamics. Elimination of positive end expiratory pressure and reduction in tidal volumes with increased respiratory rates during mechanical ventilation may help reduce the negative impact of PPV . After pericardial drainage, the BP remained marginal and a TEE demonstrated a small amount of pericardial blood causing right ventricular diastolic collapse indicating low-pressure tamponade. This results when pericardial pressure becomes greater than right atrial or right ventricular end diastolic pressure in patients who are hypovolemic. Tamponade can occur in patients and animals at pericardial pressures less than 5 mmHg . The maintenance of SV is more important in patients with low-pressure tamponade to maintain right ventricular volumes and pressures. Administration of fluid can increase right heart pressures above pericardial pressure and markedly improve systemic pressures in low-pressure tamponade with systolic BP less than 100 mmHg being the best predictive factor . This case demonstrates a patient in cardiac tamponade whose systemic perfusion improved with intubation and PPV prior to pericardial drainage. This suggested improved left ventricular filling and increased perfusion and drug delivery to the systemic circulation. PPV in patients with worsening respiratory distress should not be avoided, especially when pericardial drainage is eminent. These are important physiologic points for physicians to consider when trying to make the right decision about how to manage these acutely ill, often unstable, patients. Abbreviations BP Blood pressure EtCO2 End-tidal carbon dioxide PPV Positive pressure ventilation SV Spontaneous ventilation TEE Transesophageal echocardiography TTE Transthoracic echocardiography Acknowledgements The authors thank Addie Larimore for her consistent and timely help in preparing and editing this manuscript for publication. The Wake Forest University Health Sciences Review Board does not require review of case reports. Author contributions RLR was responsible for writing and figures and correspondence. SRC was responsible for writing and figures. EJG was responsible for writing and figures. KMR was responsible for writing and echocardiographic information. SPW was responsible for writing and ablation data. All authors approved the final manuscript. Funding Funded by the Departments of Anesthesiology and Cardiology, Wake Forest University School of Medicine, Winston-Salem, NC, USA. No external funding. Availability of data and materials Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study. Declarations Ethics approval and consent to participate Not applicable. Consent for publication Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal Competing interests All the authors declare they have no competing interests in regards to this manuscript. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. References 1. White JB Macklin S Studley JG Marshall RD Cardiac tamponade: a review of diagnosis and anaesthetic and surgical management illustrated by three case reports Ann R Coll Surg Engl 1988 70 386 391 3061355 2. Faehnrich JA Noone RB Jr White WD Leone BJ Hilton AK Sreeram GM Effects of positive-pressure ventilation, pericardial effusion, and cardiac tamponade on respiratory variation in transmitral flow velocities J Cardiothorac Vasc Anesth 2003 17 45 50 10.1053/jcan.2003.9 12635060 3. Moller CT Schoonbee CG Rosendorff C Haemodynamics of cardiac tamponade during various modes of ventilation Br J Anaesth 1979 51 409 415 10.1093/bja/51.5.409 109108 4. Bilchick KC Wise RA Paradoxical physical findings described by Kussmaul: pulsus paradoxus and Kussmaul's sign Lancet 2002 359 1940 1942 10.1016/S0140-6736(02)08763-9 12057571 5. Claessen G Claus P Delcroix M Bogaert J La Gerche A Heidbuchel H Interaction between respiration and right versus left ventricular volumes at rest and during exercise: a real-time cardiac magnetic resonance study Am J Physiol Heart Circ Physiol 2014 306 H816 H824 10.1152/ajpheart.00752.2013 24464754 6. Appleton CP Hatle LK Popp RL Cardiac tamponade and pericardial effusion: respiratory variation in transvalvular flow velocities studied by Doppler echocardiography J Am Coll Cardiol 1988 11 1020 1030 10.1016/S0735-1097(98)90060-2 3281990 7. Sznajder JI Evander E Pollak ER Becker C Little AG Pericardial effusion causes interstitial pulmonary edema in dogs Circulation 1987 76 843 849 10.1161/01.CIR.76.4.843 3652423 8. Kitashiro S Sugiura T Tamura T Izuoka T Miyoshi H Saito D Factors associated with increased extravascular lung water in cardiac tamponade and myocardial ischemia Crit Care Med 1999 27 2229 2233 10.1097/00003246-199910000-00027 10548212 9. Spodick DH Cardiogenic pulmonary edema and its absence in cardiac tamponade and constriction. A role for atrial natriuretic factor? Chest 1992 101 258 260 10.1378/chest.101.1.258 1530837 10. Kearns MJ Walley KR Tamponade: hemodynamic and echocardiographic diagnosis Chest 2018 153 1266 1275 10.1016/j.chest.2017.11.003 29137910 11. Luna GK Pavlin EG Kirkman T Copass MK Rice CL Hemodynamic effects of external cardiac massage in trauma shock J Trauma 1989 29 1430 1433 10.1097/00005373-198910000-00022 2810421 12. Michard F Changes in arterial pressure during mechanical ventilation Anesthesiology 2005 103 419 428 10.1097/00000542-200508000-00026 16052125 13. O'Connor CJ Tuman KJ The intraoperative management of patients with pericardial tamponade Anesthesiol Clin 2010 28 87 96 10.1016/j.anclin.2010.01.011 20400042 14. Mattila I Takkunen O Mattila P Harjula A Mattila S Merikallio E Cardiac tamponade and different modes of artificial ventilation Acta Anaesthesiol Scand 1984 28 236 240 10.1111/j.1399-6576.1984.tb02050.x 6730888 15. Sagrista-Sauleda J Angel J Sambola A Permanyer-Miralda G Hemodynamic effects of volume expansion in patients with cardiac tamponade Circulation 2008 117 1545 1549 10.1161/CIRCULATIONAHA.107.737841 18332261 |
Reprod Health Reprod Health Reproductive Health 1742-4755 BioMed Central London 38124182 1725 10.1186/s12978-023-01725-6 Comment How can civil society organizations contribute to the scale-up of comprehensive sexuality education? Presentation of a scaling framework illustrated with examples from Indonesia Kockelkoren Ardan [email protected] 1 Rahmah Amala 2 Pangestu Muhammad Rey Dwi 2 Sawitri Ely 2 Widyastuti Elisabet Setya Asih 3 Astiti Ni Luh Eka Purni 4 Michielsen Kristien 5 Van Reeuwijk Miranda 1 1 grid.475749.c Rutgers, the Netherlands Centre on Sexuality, Arthur van Schendelstraat 696, 3511 MJ Utrecht, The Netherlands 2 Rutgers Indonesia, Graha Inti Fauzi, 9th Floor, Pasar Minggu, Greater Jakarta, Indonesia 3 PKBI Jawa Tengah, Jl. Jembawan Raya No. 8-12, Semarang, Jawa Tengah Indonesia 4 PKBI Bali, Jl. Gatot Subroto IV No.6, Dangin Puri Kaja, Kec. Denpasar Utara, Kota Denpasar, Bali 80233 Indonesia 5 grid.5596.f 0000 0001 0668 7884 Department of Neurosciences, Faculty of Medicine, Institute for Family and Sexuality Studies, KU Leuven, Herestraat 49, 3000 Louvain, Belgium 20 12 2023 20 12 2023 2023 20 1869 10 2023 12 12 2023 (c) The Author(s) 2023 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit The Creative Commons Public Domain Dedication waiver ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Comprehensive sexuality education (CSE) can substantially contribute to the health and well-being of young people. Yet, most CSE interventions remain limited to the small piloting or research phase and scale-up is often an afterthought at the end of a project. Because of the specificities of CSE, including it being a controversial topic in many contexts and a topic on the fringe between health, education and youth, a specific scaling approach to CSE is needed. The commentary presents a practical framework to support civil society organisations (CSOs), to address barriers to scaling up CSE in their contexts. The utilization and relevance of the framework is demonstrated in this article, by featuring examples from the scale up process of CSE in Indonesia. The framework identifies key principles for scaling up, including: taking a scaling mindset from the start, government ownership and political commitment for scale-up, and identifying the added value of CSOs. The framework starts with a self-assessment by the CSO and then follows four phases: making the case, engaging in dialogue, establishing building blocks and implementation and scale-up. Each of these phases are illustrated with examples from Indonesia. This framework is a call to action with practical guidelines to support CSOs to take on this role, because with the right scaling strategies, the largest generation of young people ever alive can become healthy, empowered and productive adults. Keywords Comprehensive sexuality education Scaling-up Civil Society Organizations Development of the framework was made possible through financial support from Global Affairs Canada via IPPF's Centers of Excellence programmeissue-copyright-statement(c) BioMed Central Ltd., part of Springer Nature 2023 pmcIntroduction Comprehensive sexuality education (CSE) can substantially contribute to the health and well-being of young people ; evaluations of CSE programs indicated clear positive effects on several aspects, including on health outcomes, equitable relationships, partner violence and safe sexual behaviors [2-4]. Furthermore, multiple studies focused on how to implement CSE effectively . Yet, most CSE interventions remain limited to the small piloting or research phase and fade out after the project funding ends. The sustainability and scale-up of CSE programs are often perceived as an afterthought at the end of a project and are not commonly scheduled for from the initiation phase . This has implications for young people globally, and many are left behind because of the inability to provide universal CSE coverage. Many CSE programs are implemented by civil society organizations (CSOs). If the CSO industry wants to become better at leaving no one behind and addressing the underlying structural barriers to access to CSE, this has implications for the role of CSOs and the way CSE is designed and implemented, because sustainability and scaling require different skills, approaches, and ways of collaborating than those required for successful implementation of shorter, smaller-scale community projects. Knowledge gap There are several frameworks for scaling up education and health interventions, such as from Management Systems International , ExpandNet , or the Implementing Best Practices Consortium . These frameworks are interesting and inspirational. However, they do not address the specific role and contribution of CSOs or the specificities of CSE, which is a controversial and contested health intervention in many countries. CSE often raises controversy, as adolescent sexuality is a taboo topic in most countries around the world . Furthermore, it is on the fringe of health, education, and youth, therefore oftentimes the responsibility for CSE is pushed around. CSE needs a specific scaling approach that considers these sensitivities and specificities. In 2018, the United Nations Educational, Scientific and Cultural Organization (UNESCO) formulated ten principles that underpin successful scale-up of sexuality education, including principles as i) choose an intervention/approach that can be scaled up within existing systems, ii) clarify the aims of scaling up and the roles of different players, and ensure local/national ownership/lead role or iii) understand perceived need and fit within existing governmental systems and policies . While important, these principles are often not operationalized in real-life settings . Therefore, there is a need for a practical framework to support CSOs to address the barriers to scaling up CSE in their contexts by assessing the scalability of their CSE projects, designing for scale from the onset, and systematically thinking through the key elements, ingredients, and factors for success. Objectives and approach Around the world, there are several examples of CSE programs that have been successfully scaled up. Based on these experiences, Rutgers, the Netherlands Centre on Sexuality, which works in 27 countries around the world, has developed a framework to support CSOs to scale their CSE programs . The framework provides an overview of key steps in scale-up and issues for CSOs to consider in deciding if and how they can provide support for scale-up. The framework is based on implementation research, program evaluations, and through firsthand experiences of direct engagement in scaling processes from a variety of countries: Benin, India, Indonesia and Zambia. For the purpose of this Commentary article, the framework will be illustrated with on the ground experiences from Indonesia. Key principles A few key principles can be identified for the role CSOs can take in scaling up CSE. Firstly, taking a scaling approach from the start. Most CSO-developed CSE programmes are boutique interventions that are not scalable because they are too costly per beneficiary. Using a scaling lens from the start means collecting data/learning/adapting to develop lean programs that can reach all youth. Second, government ownership and political commitment for scale-up of CSE are critically essential. Therefore, buy-in is necessary from the policymakers, administrations, and other relevant stakeholders. CSOs often perceive the government as a black box they need to advocate against rather than build trusted relationships with. Learning how to engage, motivate, capacitate, and support civil servants is what will make the difference. Finally, CSOs should think about the added value they bring to the table in terms of technical support for scale-up. Key areas to consider are strengthening teacher training institutes and the capacities of the monitoring and examination department. The framework The practical framework is built around a CSE scale-up trajectory and follows four key areas where CSOs can make a valuable contribution to scaling up CSE. Here, we provide a summary of the key steps. The framework itself provides more details and practical suggestions on what CSOs can do to support CSE scale-up. A summary of the framework is provided in Fig. 1.Fig. 1 CSE scale-up framework for civil society organisations (taken from ) The framework starts with conducting a self-assessment. This self-assessment will allow a CSO to identify how it can best support CSE scale-up, as this depends on a range of factors, including the country context, the CSO's relationship with government, its skills, expertise and capacity, its comparative advantage vis-a-vis other stakeholders, and its relationship with different stakeholders. CSOs need to consider these and other questions when deciding if they should support CSE scale-up and how they can best do this, as well as to identify whether they require additional skills and capacity. In the next paragraphs, we will highlight key elements of the framework and present how CSOs can contribute to scaling up CSE supported by examples from Indonesia. Stage 1: Make the Case. This stage is about understanding the context and building the case for CSE through a thorough situation analysis. This analysis can be done by a CSO and can serve as the basis for engaging in dialogue (stage 2) and developing a scale-up plan (stage 3). The situation analysis includes identifying the need for CSE, key partners, champions, and opposition, assessing the policy, legal and socio-cultural context, understanding the status of CSE and assessing the educational system and its capacity. Frequently, CSOs have a longer history of working in a particular community or geography, have an established basis of trust there, and existing relationships with the local leadership. This can be a good base to work out a cost-effective and contextually supportable local implementation model for CSE that details how the CSE intervention is embedded in policies and how it can be implemented effectively (sometimes referred to as 'pilot model').In Denpasar (Bali) and Semarang (Central Java) in Indonesia, the Setara programme is implemented by local branches of Perkumpulan Keluarga Berencana Indonesia (PKBI, the Indonesian Family Planning Association), in close collaboration with Rutgers Indonesia and the city governments. The program was introduced as a way to help implement city government priorities and policies such as the 'child-friendly schools' policy, and 'prevention of child sexual abuse' . Setara was positioned as a solution to address the problems that these policies want to address. Through their longstanding work in the communities in these cities and the existing relationships with their city's leadership, PKBI managed to engage in meaningful discussions about the goals, content and evidence of effectiveness with the relevant government offices in their city, resulting in a memorandum of understanding for joint coordination and implementation. Denpasar and Semarang then continued to serve as an example ('pilot model') for other cities and for the national government and Ministry of Education on how policies could be operationalized through decentralized systems. Stage 2: Engaging in dialogue. This step focuses on building support for CSE. For the scale up of CSE, leadership, ownership and capacity of government decision-makers and civil servants is critical. CSOs can contribute by identifying and engaging with allies and champions from both the legislative and administrative branches of the curriculum development, teacher training and education standards units within the Ministry of Education as well as those who directly influence them. Key success factors include the perceived credibility and trustworthiness of the organizations and individuals advocating for CSE and their personal networks and connections across these cadres. The way in which CSE is framed also has a significant influence on its acceptability and the success of ensuring political ownership. Finding an entry point for CSE involves presenting CSE as a solution to contextual issues of concern and linking it to the existing priorities and KPIs of relevant institutional stakeholders. These frames are to be further supported by evidence. Evidence demonstrating the contextual need, effectiveness, financial resources, capacity and institutional changes required for CSE scale-up. Collaborations with universities and research institutions can often provide such evidence to support the rationale and provide legitimacy to the messages.In the Setara program, Rutgers Indonesia and PKBI collaborated with the University of Gadjah Mada, center of reproductive health (UGM-CRH) to evaluate the program in Semarang and Denpasar, using the Global Early Adolescent Study (GEAS) Survey. The evaluation was technically supported by John Hopkins University, Karolinska Institutet and Rutgers . Having these research partners studying the intervention helped to create legitimacy to the intervention, enhanced transparency and provided entry points to engage in dialogue about the intervention through sharing of research results with multiple stakeholders, including schools and representatives from relevant government offices (organized in 'Local Advisory Committees'). This also brought the opportunity to bring in youth voices into the dialogue. Having UGM-CRH present about Setara's effectiveness helped to create space for a more neutral, 'scientific' dialogue about CSE instead of the otherwise often moral values-loaded discourse. UGM-CRH leadership was also frequently consulted by the national government as expert on Reproductive Health issues, providing an entry point to bring in CSE as a strategy to address several reproductive health priorities. Finally, Rutgers Indonesia and PKBI facilitated exchange visits to promote the Semarang and Denpasar models. They engaged media, teachers and faith leaders into these visits and built out a pool of champions for CSE. First on the city level, and later also on the national level. Stage 3: Establish building blocks. Once political support for CSE has been established, the more practical building blocks for scaling up CSE need to be put in place. These include, amongst others, identifying all implementation partners and their roles and responsibilities (making sure CSE has an 'institutional home' within the education ministry), setting up coordination mechanisms, estimating the costs (what does the program cost per person, what funding is currently available and its source, as well as the funding gap and possible resource mobilization strategies), agreeing on the curriculum, delivery model (including the linkages with services and community support mechanisms) and the to be used materials, the phased roll-out plan, and clear targets. Often a Memorandum of Understanding between the CSOs, government and other collaborating institutions and organizations is a good basis for developing such a costed workplan.In Indonesia, Setara also included a costing evaluation for its implementation in Denpasar and Semarang. The results of this evaluation were used by the implementation partners to reflect on their cost-efficiency and how they could reduce costs, and to make insightful the cost-categories. Political support for Setara had grown through the process and the city governments were now committing to further rolling out Setara to other schools in their city. Data from the costing study helped to guide division of tasks between PKBI and government departments, including who would finance what, and for lobbying budgets at the cities government level. Stage 4: Implementation and scale-up. In this stage, the scaling plan is put into action, and CSE is integrated into existing educational systems. Teachers delivering CSE in the classroom will require training, as well as school principals, district and provincial education cadres and syllabi and examination developers. Lecturers at teacher training institutes will require training to enable a roll-out of in-service and pre-service training, and gatekeepers such as parents will need sensitization. Tools such as the annual school census, teacher lesson and school inspection forms and the Education Management Information System often need to be adapted to include CSE components and indicators . Scale-up takes time and needs to be phased. Advocacy and alignment between CSOs and the government are critical to maintaining CSE in the face of opposition.On the national level, Rutgers Indonesia, in collaboration with UNFPA, positioned itself as a technical partner to the government in achieving their key performance indicators. Political commitment was established to roll out the government-owned Reproductive Health Education curriculum, or the Setara curriculum, as a formally approved alternative, to 250 cities by 2025. A Memorandum of Understanding was established between the ministries of Health and Education, UNFPA and Rutgers Indonesia, including co-financing and division of tasks, with Rutgers Indonesia responsible for the training of teachers. Rutgers Indonesia signed memoranda of understanding with 6 district governments to jointly implement Setara with these districts' education offices, incorporating the CSE program as a vital component of the government's policies and strategies to reduce the prevalence of child marriage, teenage pregnancy and sexual and gender-based violence. Phase 1 (making the case and identifying partners and policies) was repeated with these districts through engaging various stakeholders and jointly thoroughly analyzing the need for CSE and developing implementation plans. Youth engagement played an important part in this process, where students provided real-life experiences of SGBV in their schools. On the national level, Rutgers Indonesia and UGM are currently facilitating workshops with government and CSE stakeholders to look at possibilities of integrating indicators for quality of implementation into the national education and management system. During COVID-19 school closures, Rutgers Indonesia developed digital solutions to continue to provide CSE to students and supporting teachers to address (digital) implementation challenges. Through the collaboration with the Ministry of Education, Rutgers Indonesia can bring in these innovations and lessons to further improve implementation at scale. Conclusion Engaging in the scale-up of sexuality education requires a shift in mindset about what we perceive as our role and responsibilities as the CSO sector. A transformation is required from CSO-led CSE delivery with government support to government-led CSE delivery with CSO support. This requires acquiring different skills and applying different approaches than we are used to when successfully implementing community projects or engaging in SRHR policy advocacy. We call upon CSOs to take on a long-term scaling lens, and to invest in the development of lean and cost-effective CSE programs and in motivating, capacitating and supporting champion civil servants. This framework is a call to action with practical guidelines to support CSOs to take on this role, because with the right scaling strategies, the largest generation of young people ever alive can become healthy, empowered and productive adults. Abbreviations CSE Comprehensive sexuality education CSO Civil Society Organization PKBI Perkumpulan Keluarga Berencana Indonesia SRH Sexual and Reproductive Health SRHR Sexual and Reproductive Health and Rights UGM-CRH University of Gadjah Mada, Center of Reproductive Health UNESCO United Nations Educational, Scientific and Cultural Organization Acknowledgements The authors would like to acknowledge Audrey Kettaneh and Kathy Attawell who contributed to the development of the framework. Author contributions KM wrote the first draft of the commentary, based on documents and texts previously developed by AK and MVR. AR, MRDP and ES provided the practical examples from Indonesia to illustrate application of the framework. AK, AR, MRDP, ES, ESAW, NLEPA, KM and MVR reviewed and revised the manuscript. AK, AR, MRDP, ES, ESAW, NLEPA, KM and MVR read and approved the final manuscript. Funding Development of the framework was made possible through financial support from Global Affairs Canada via IPPF's Centers of Excellence programme. Availability of data and materials Not applicable. Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Competing interests All authors declare that they have no financial or non-financial competing interests. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. References 1. UNESCO, UNAIDS, UNFPA, UNICEF, UN Women, WHO. The International Technical Guidance on Sexuality Education. 2018. 10.54675/NFEK1277. 2. Michielsen K, Ivanova O. Comprehensive sexuality education: why is it important? Brussels: Policy Department for Citizens' Rights and Constitutional Affairs Directorate-General for Internal Policies. 2022. Available at: 719998_EN.pdf. Accessed 15 Dec 2023. 3. Montogemry P, Knerr W. Review of the evidence on sexuality education: report to inform the update of the UNESCO International technical guidance on sexuality education. 2018. Available at: Accessed 15 Dec 2023. 4. Goldfarb E Lieberman L Three decades of research: the case for comprehensive sexuality education J Adolesc Health 2021 68 1 13 27 10.1016/j.jadohealth.2020.07.036 33059958 5. Ivanova O Rai M Michielsen K Dias S How sexuality education programs have been evaluated in middle income countries? A systematic Review Int J Environ Res Public Health 2020 17 21 E8183 10.3390/ijerph17218183 6. Woltering L Fehlenberg K Gerard B Ubels J Cooley L Scaling from "reaching many" to sustainable systems change at scale: a critical shift in mindset Agric Syst 2019 176 102652 10.1016/j.agsy.2019.102652 7. Management Systems International. Scaling Up. From Vision to Large-Scale Change. A Management Framework for Practitioners. Available at: Accessed 15 Dec 2023. 8. ExpandNet. Scaling-up framework. Available at: Accessed 15 Dec 2023. 9. Implementing Best Practices Consortium. A Guide for fostering change to scale up effective health services. 2007. Available at: Accessed 15 Dec 2023. 10. Ipas. False Pretenses: The Anti-Comprehensive Sexuality Education Agenda Weaponizing Human Rights. 2023. Available at: Accessed 15 Dec 2023. 11. Neil Datta. Tip of the Iceberg: Religious Extremist Funders against Human Rights for Sexuality and Reproductive Health in Europe 2009-2018. 2021. Available at: Accessed 15 Dec 2023. 12. UNESCO. CSE: The challenges and opportunities of scaling up. 2014. Paris: UNESCO. Available at: Accessed 15 Dec 2023. 13. Rutgers. Scaling up sexuality education: Lessons learned and considerations for civil society organisations. 2021. Utrecht: Rutgers. Available at: Accessed 15 Dec 2023. 14. Van Reeuwijk M Rahmah A Mmari K Creating an enabling environment for a comprehensive sexuality education intervention in indonesia: findings from an implementation research study J Adolesc Health 2023 73 1 S15 S20 10.1016/j.jadohealth.2022.07.016 37330817 15. Rutgers. Explore4Action. S.d. Available at: Accessed 15 Dec 2023. 16. UNESCO. CSE scale-up in practice. Case studies from eastern and southern Africa. 2017. Available at: Accessed 15 Dec 2023. |
s and reorganizes elicited clinical findings in memory, using semantic qualifiers (such as paired opposites that are used to describe clinical information [e.g., acute and chronic]) to compare and contrast the diagnoses being considered when presenting or discussing a case; shows the emergence of pattern recognition in diagnostic and therapeutic reasoning that often results in a well-synthesized and organized assessment of the focused differential diagnosis and management plan Reorganizes and stores clinical information (illness and instance scripts) that lead to early directed diagnostic hypothesis testing with subsequent history, physical examination, and tests used to confirm this initial schema; demonstrates well-established pattern recognition that leads to the ability to identify discriminating features between similar patients and to avoid premature closure; Selects therapies that are focused and based on a unifying diagnosis, resulting in an effective and efficient diagnostic work-up and management plan tailored to address the individual patient Current literature does not distinguish between behaviors of proficient and expert practitioners. Expertise is not an expectation of GME training, as it requires deliberate practice over time b. PC3: Develop and carry out management plans Develops and carries out management plans based on directives from others, either from the health care organization or the supervising physician; is unable to adjust plans based on individual patient differences or preferences; communication about the plan is unidirectional from the practitioner to the patient and family Develops and carries out management plans based on one's theoretical knowledge and/or directives from others; can adapt plans to the individual patient, but only within the framework of one's own theoretical knowledge; is unable to focus on key information, so conclusions are often from arbitrary, poorly prioritized, and time-limited information gathering; develops management plans based on the framework of one's own assumptions and values Develops and carries out management plans based on both theoretical knowledge and some experience, especially in managing common problems; follows health care institution directives as a matter of habit and good practice rather than as an externally imposed sanction; is able to more effectively and efficiently focus on key information, but still may be limited by time and convenience; begins to incorporate patients' assumptions and values into plans through more bidirectional communication Develops and carries out management plans based most often on experience; effectively and efficiently focuses on key information to arrive at a plan; incorporates patients' assumptions and values through bidirectional communication with little interference from personal biases Develops and carries out management plans, even for complicated or rare situations, based primarily on experience that puts theoretical knowledge into context; rapidly focuses on key information to arrive at the plan and augments that with available information or seeks new information as needed; has insight into one's own assumptions and values that allow one to filter them out and focus on the patient/family values in a bidirectional conversation about the management plan Table 2 a, b, and c The new Patient Care 1, 2, and 3 (PC1. PC2, and PC3) of Milestones 2.0 Level 1 Level 2 Level 3 Level 4 Level 5 a. PC1: History Acquires a comprehensive and developmentally appropriate pediatric medical history Reviews available medical records Acquires an endocrine history and a comprehensive pediatric medical history, including pubertal development and other pertinent positives and negatives Identifies relevant findings in the medical record Acquires a tailored endocrine history, including growth, historical subtleties, and psychosocial aspects Independently requests additional information to supplement available medical records Efficiently integrates the patient history with the complete medical record, supplemental information, and tailored assessment of potential endocrine disorders Is identified as a peer resource in interpreting subtleties and recognizing ambiguities in the patient history b. PC2: Physical Exam Performs a developmentally appropriate complete physical examination, with awareness of patient comfort Performs a developmentally appropriate complete physical examination using strategies to optimize patient comfort and identifies abnormal endocrine findings Performs a tailored physical examination using strategies to optimize patient comfort and identifies subtle abnormal endocrine findings Detects, pursues, and integrates key physical examination findings to distinguish nuances among competing, often similar diagnoses Is identified as a peer resource for performing tailored physical exams, maximizing patient comfort c. PC3: Patient Management Reports and implements management plans developed by others for routine endocrine presentations Develops and implements management plans that require modification for routine endocrine presentations Develops and implements management plans for routine endocrine presentations Develops and implements management plans for complex endocrine presentations, and modifies plans as necessary Is identified as a peer resource for development of management plans for complex endocrine presentations, and modifies plans as necessary While the total number of sub-competencies for pediatric endocrinology has increased from 21 to 24, we expect that milestone assignments should be more straightforward and therefore ideally faster to complete. Changes to phrasing and interpretation of milestone levels Among the most important changes in Milestones 2.0 is how the milestone levels are phrased and applied to fellows. Milestones 1.0 created five levels based on the Dreyfus model of adult skill acquisition . These levels were meant to follow trainees from novice (level 1) to expert (level 5). Because level 5 represented individuals who were experts in pediatric endocrinology, it represented an "aspirational" target that would rarely, if ever, be achieved by fellows. It was also unclear if fellows should "reset" to level 1 after achieving 3 s and 4 s in a particular milestone at the time of residency graduation. Milestone 2.0 intends to document developmental progression during fellowship, rather than the entire training or career trajectory. Thus, it is expected that many fellows will enter fellowship at a level 1 (novice fellow) and subsequently progress at varying rates to level 2 (advanced beginner), level 3 (competent) and level 4 (proficient). This is especially true for the patient care (PC) and medical knowledge (MK) competencies, which are now specific to pediatric endocrinology. While not a graduation requirement, it is expected that most fellows will achieve a level 4 in most milestones prior to graduation. Level 5 now represents an expert fellow, corresponding to a fellow performing exceptionally in a given sub-competency. For a given sub-competency, ACGME provides guidance that appropriately 8-10% of fellows should achieve a level 5 prior to graduation. The phrasing of Milestones 2.0 has also been changed to promote a growth mindset. Milestones 1.0 frequently used negative language that emphasized skills that a fellow was not doing or was doing incorrectly. Milestones 2.0 focuses on what the fellow is correctly doing at each developmental stage. For example, Milestones 1.0, sub-competency PM, Level 2 includes the description "is unable to focus on key information so conclusions are often from arbitrary, poorly prioritized, and time-limited information gathering." In Milestones 2.0, Level 2 of the same sub-competency reads "Develops and implements management plans that require modification for routine endocrine presentations." It is recognized that some fellows may not yet have achieved level 1 when they enter fellowship. Therefore, Milestones 2.0 retains the option of selecting "not yet completed level 1" for assessments. Creation of harmonized milestones A major change for Milestones 2.0 is the creation of "harmonized" milestones in four competencies: Professionalism (PROF), Practice-based learning and improvement (PBLI), Interpersonal and communication skills (ICS), and Systems-based practice (SBP). In Milestones 1.0, specialties created their own content for each competency, leading to highly variable themes and descriptions . These inconsistencies created challenges in comparing milestone progression among specialties and in sharing learning tools and resources. Having recognized that PROF, PBLI, ICS, and SBP have common, overlapping themes for most specialties, the ACGME assembled four diverse groups to develop cross-specialty "harmonized" milestones for Milestones 2.0 . Pediatric Endocrinology Milestones 2.0 adopts harmonized milestones in each of these four competencies. Creation of milestones specific to pediatric endocrinology Pediatric Endocrinology Milestones 2.0 modifies the sub-competencies and milestones for Patient Care (PC) and Medical Knowledge (MK) to be more tailored to pediatric endocrinology. The changes to the PC sub-competency milestones are outlined in Table 3 below. Table 3 Comparison of the PC sub-competencies between Milestones 1.0 and 2.0 Patient Care (PC) Changes Milestones 1.0 Milestones 2.0 PC1: Provide transfer of care that ensures seamless transitions PC1: History PC2: Make informed diagnostic and therapeutic decisions that result in optimal clinical judgement PC 2: Physical Exam PC3: Develop and carry out management plan PC3: Patient Management PC4: Provide appropriate role modeling PC4: Diagnostic testing (including labs, imaging, and functional testing) PC5: Clinical Consultation Milestones 1.0 included PC1: Provide transfer of care that ensures seamless transitions; PC2: Make informed diagnostic and therapeutic decisions that result in optimal clinical judgment; PC3: Develop and carry out management plan and PC4. Provide appropriate role modeling. In Milestones 2.0 this was changed to PC1: History; PC2: Physical Exam; PC3: Patient Management; PC4: Diagnostic Testing (including Labs, imaging, and functional testing) and PC5: Clinical Consultation. Each of these sub-competencies then had milestone language specific to pediatric endocrine fellowship training with the supplementary guide illustrating examples in a particular scenario. A fifth PC sub-competency of consultation was added as it was felt to be a core skill acquired during fellowship training. Many other subspecialty Milestones 2.0 incorporate the consultation sub-competency, including the adult endocrinology Milestones. Table 4 (below) outlines the changes to the MK sub-competencies. Milestones 1.0 was limited to MK1: locate, appraise, and assimilate evidence from scientific studies related to their patients' health problems. The milestone language under this sub-competency was long and multipronged, making assessments challenging. In Milestones 2.0 MK is separated into three sub-competencies: MK1: Physiology and Pathophysiology, MK2: Clinical Reasoning; MK3: Therapeutics (Behavioral, Medications, Technology, Radiopharmaceuticals). This change intuitively makes more sense and will allow fellows and faculty to identify specific areas of strength and need for improvement. Table 4 Comparison of the MK sub-competencies between Milestones 1.0 and 2.0 Medical Knowledge (MK) Changes Milestones 1.0 Milestones 2.0 MK1: locate, appraise, and assimilate evidence from scientific studies related to patients' health conditions MK1: Physiology and Pathophysiology MK2: Clinical Reasoning MK3: Therapeutics (behavioral, medications, technology, radiopharmaceuticals) New sub-competency concepts Milestones 2.0 addresses several topics that were not emphasized in Milestones 1.0. SBP now includes a specific sub-competency on population and community health that incorporates the concept of health disparities. A separate SBP sub-competency focuses on patient safety, which was previously combined with medical errors and inter-professional teamwork in Milestones 1.0. Additionally, a new PROF sub-competency centers on the concept of well-being. This sub-competency does not evaluate a fellow's personal well-being but instead recognizes and emphasizes the importance of understanding factors that affect fellow and physician well-being . Creation of the supplemental guide Finally, an important addition to Milestones 2.0 is the creation of a Supplemental Guide that clarifies the intentions of the working group for each milestone. The guide will be available for program directors, clinical competency committees (CCCs), and fellows to promote a shared mental model, which is one of the primary goals of Milestones 2.0. The Supplemental Guide is available as a word document as well as PDF so that individual programs can edit the guide to make it more meaningful to their program. The Supplemental Guide includes five sections for each sub-competency: 1) the overall intent for the sub-competency, 2) a general example for each level, 3) suggested assessment tools to be used by programs in determining level, 4) curriculum mapping (left blank as it is to be completed by the individual program), and 5) notes or resources. The examples included for each level are not comprehensive nor are they indicative of a specific requirement. Instead, the examples are a conversation starting point in creating the shared mental model. What is the same Despite many changes with Milestones 2.0, some key concepts remain the same. Fellows should be assigned a milestone level that fits their current performance, regardless of their year in fellowship. A fellow should have met the criteria of their assigned level and those of the preceding level(s). The ACGME has no level requirement that a fellow must achieve to graduate. Instead, graduation readiness is determined by the fellow's program director, scholarly oversight committee, and CCC . Similarly, Milestones 2.0 is not part of the endocrinology certification eligibility requirements established by the American Board of Pediatrics (ABP) and milestone levels are not reported to the ABP. Finally, the milestone set is intended to monitor fellow progression over extended periods of time. Therefore, it has limited utility in short rotations of 2-8 weeks . Discussion Ways to implement milestones into practice The new ACGME common program requirements state that milestones are to be incorporated into the semiannual evaluation process. Following determination by the CCC, fellows should receive feedback on milestone levels as these may be useful to identify areas of strength and weakness and to establish learning plans. Milestones can also be utilized for fellow self-assessment or to monitor the areas for improvement in a program. Programs may choose to have fellows complete a self-assessment of milestone levels each time the CCC is going to meet. The program director and fellow can then compare both sets of assessment which may be helpful for both the program and the resident. The program will have insight into the fellow's understanding of their knowledge skills and attitudes and the fellow will be able to calibrate their own awareness. Similarly, CCCs can review the milestones of all of their fellows to determine if there are common areas in which their trainees are not progressing as expected, which could represent areas in which their fellowship should focus on improving education. Conclusion The Milestones were developed to be an important tool in career progression of trainees, but implementation has been hindered by being overly complex and burdensome. The new pediatric endocrine Milestones 2.0 and the supplemental guide are intended to make the milestones more applicable to our field, easier to utilize, focused on individual growth, and more attentive to important issues of health equity and population health. Further research and feedback on the Milestones 2.0 after implementation will determine whether these goals were met. While the Milestones are required only in fellowships accredited by the ACGME, their general principles are applicable to trainees worldwide and can be another tool in the evaluation of a fellow's progress through their career. Supplementary Information Additional file 1. Additional file 2. Acknowledgements The authors wish to acknowledge and thank the other members of the Pediatric Endocrine Milestones 2.0 working group (listed below) for sharing their expertise, time, and effort to develop these new milestones. The authors also wish to thank Laura Edgar, Sydney McLean, and Ida Haynes, and all the staff at the ACGME for their guidance and support throughout the process. The Pediatric Endocrine Milestones 2.0 working group includes all authors of this paper plus Dr. Robert Hoffman, Dr. Michele Hutchison, and Dr. Juan Lado. Authors' contributions Cara Tillotson: contributed to three sections (abstract, background, conclusion) and served as primary editor of manuscript. Imen Becet: contributed to the background section. Laura Page: contributed to the discussion section (Major Changes, Changes to milestone complexity and wording, creation of harmonized milestones, new sub-competency concepts, Creation of the Supplemental Guide). Katherine Hwu: contributed to the discussion section (Major Changes, Changes to milestone complexity and wording, creation of harmonized milestones, new sub-competency concepts, Creation of the Supplemental Guide). Sowmya Krishnan: contributed to the discussion section (Major Changes, Changes to milestone complexity and wording, creation of harmonized milestones, new sub-competency concepts, Creation of the Supplemental Guide). Diane Stafford: contributed to the discussion section (Major Changes, Changes to milestone complexity and wording, creation of harmonized milestones, new sub-competency concepts, Creation of the Supplemental Guide). Patricia Vuguin: additional editing of overall manuscript and preparation/formatting for submission. Takara Stanley: additional editing of overall manuscript and preparation/formatting for submission. Jennifer Barker: wrote methods section (Identification of the Working Group, Governing Principles, Milestone Development, Supplemental Guide Development, and Community Feedback) and acted as senior advisor in manuscript preparation, preparation/formatting, and delegation of sections. Funding The ACGME provided funding for travel expenses (airfare, lodging, and meals) to the members of the Milestones 2.0 workgroup for their attendance at the in-person meeting. Availability of data and materials Not applicable. Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Competing interests The authors declare no competing interests. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
Int J Emerg Med Int J Emerg Med International Journal of Emergency Medicine 1865-1372 1865-1380 Springer Berlin Heidelberg Berlin/Heidelberg 575 10.1186/s12245-023-00575-0 Case Report Bilateral adrenal infarction and insufficiency associated with antiphospholipid syndrome and surgery: a case report Iijima Yoshihito [email protected] Ishikawa Masahito Motono Nozomu Uramoto Hidetaka grid.411998.c 0000 0001 0265 5359 Department of Thoracic Surgery, Kanazawa Medical University, 1-1 Daigaku, Uchinada-Machi, Kahoku-Gun, Ishikawa, 920-0293 Japan 21 12 2023 21 12 2023 2023 16 933 7 2023 14 12 2023 (c) The Author(s) 2023 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit The Creative Commons Public Domain Dedication waiver ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Background Antiphospholipid syndrome causes systemic arterial and venous thromboses due to the presence of antiphospholipid antibodies. Adrenal insufficiency is a rare complication of antiphospholipid syndrome that may result in fatal outcomes if left untreated. Therefore, we report adrenal insufficiency as a rare complication of bilateral adrenal infarction associated with antiphospholipid syndrome and trauma surgery. Case presentation A 64-year-old male patient underwent surgery for a left traumatic hemothorax. He concurrently had antiphospholipid syndrome and was receiving warfarin. Postoperatively, the patient complained of severe lumbar back pain despite resuming anticoagulation therapy, and he experienced paralytic ileus and shock. Abdominal contrast-enhanced computed tomography revealed adrenal swelling and increased surrounding retroperitoneal adipose tissue density. Diffusion-weighted abdominal magnetic resonance imaging showed high-intensity areas in the bilateral adrenal glands. Cortisol and adrenocorticotropic hormone levels were 3.30 mg/dL and 185.1 pg/dL, respectively. Subsequently, the patient was diagnosed with bilateral adrenal infarction and acute adrenal insufficiency, and hydrocortisone was immediately administered. Adrenal insufficiency improved gradually, and the patient was discharged after initiating steroid replacement therapy. Conclusions The timing of postoperative anticoagulant therapy initiation remains controversial. Therefore, adrenal insufficiency due to adrenal infarction should be monitored while anticoagulant therapy is discontinued in patients with antiphospholipid syndrome. Keywords Traumatic hemothorax Antiphospholipid syndrome Adrenal insufficiency Adrenal infarction Magnetic resonance imaging issue-copyright-statement(c) Springer-Verlag GmbH Germany, part of Springer Nature 2023 pmcBackground Antiphospholipid syndrome (APS) is an autoimmune disease that causes systemic arterial and venous thromboses due to antiphospholipid antibodies (aPL). Adrenal insufficiency (AI) is a rare complication of APS that occurs in only 0.4% of patients and can lead to fatal outcomes if left untreated. The mortality rate of APS complicated with AI is 3.81% . Here, we report AI as a rare complication of bilateral adrenal infarction associated with APS and trauma surgery. Case presentation Ethics approval was not needed for this case report. Written informed consent was obtained from the patient for the publication of this report and its accompanying images. A 64-year-old male patient underwent surgery for a left traumatic hemothorax (Fig. 1A). He concurrently had atrial fibrillation and APS with an inferior vena cava filter placement and was receiving warfarin. The preoperative prothrombin international normalized ratio and hemoglobin level were 3.18 and 5.9 g/dL, respectively, and the blood volume in the thoracic cavity at thoracotomy was 1800 g. Bleeding from a right internal thoracic vein branch was suspected, although the bleeding point was unclear (Fig. 1B). Bleeding could not be controlled with cauterization but was managed using multiple hemostatic agents. The intraoperative blood loss was 200 g; hence, 560 and 480 mL of red blood cells and fresh frozen plasma, respectively, were transfused. Autologous blood (1021 mL) was transfused intraoperatively using a cell saver system. A hematoma extending from the right inguinal to the femoral lesions was observed, and it expanded postoperatively; therefore, the initiation of oral warfarin at 1 mg as an anticoagulation therapy was delayed and resumed on postoperative day (POD) 4. Additional continuous intravenous heparin was administered at 100 IU/kg, and oral warfarin was increased to 2 mg on POD 5. However, the patient complained of severe lumbar back pain on POD 6. Abdominal contrast-enhanced computed tomography (CECT) showed no aortic dissection, intra-abdominal hemorrhage, organ infarction, or adrenal swelling. On POD 8, the patient developed paralytic ileus (Fig. 2A) and shock, and his blood pressure decreased to 70/40 mmHg. Septic shock was ruled out based on blood and urine cultures, and disseminated intravascular coagulation was excluded based on the results of the coagulation fibrinolysis tests. Repeated abdominal CECT revealed adrenal swelling and increased surrounding retroperitoneal adipose tissue density (Fig. 2B). The white blood cell count, C-reactive protein level, sodium level, potassium level, serum creatinine level, glucose level, cortisol level, and adrenocorticotropic hormone level were 8340/mm3, 27.54 mg/dL, 130 mmol/L, 4.4 mmol/L, 1.08 mg/dL, 69 mg/dL, 3.30 mg/dL, and 185.1 pg/dL, respectively. Acute AI was suspected, and hydrocortisone (HC) was intravenously administered immediately. Abdominal magnetic resonance imaging revealed high-intensity areas in both adrenal glands on diffusion-weighted images (Fig. 2C), and a diagnosis of AI caused by bilateral adrenal infarctions was made. HC was intravenously administered for 5 days, followed by oral administration at a dosage of 50 mg/day, and AI improved gradually. The patient was discharged on POD 20 after steroid replacement therapy was initiated. HC was tapered and switched to prednisolone (PSL; 5 mg/day) on POD 111. One year has passed since the surgery, and the patient continues to receive PSL (5 mg/day) as an outpatient.Fig. 1 Preoperative and intraoperative findings. A Preoperative computed tomography shows a hematoma in the anterior mediastinum and fluid accumulation in the left thoracic cavity. B Bleeding from a right internal thoracic vein branch was suspected; however, the bleeding point was unclear Fig. 2 Postoperative findings. A Abdominal radiography shows intestinal gas. B Contrast-enhanced computed tomography reveals adrenal swelling and increased surrounding retroperitoneal adipose tissue density. C Abdominal magnetic resonance imaging reveals high-intensity areas in both adrenal glands on diffusion-weighted images Discussion and conclusions APS can cause hemorrhagic adrenal gland infarction and is typically associated with stress factors, including surgery . Bleeding is the leading cause of AI in APS, followed by infarction . Adrenal involvement is usually bilateral , and the vascular system of the adrenal gland is unique and complex . Capillary branches from three main arteries form a vascular plexus around the zona reticularis. Furthermore, the transition from the artery to the capillary plexus is known as the "vascular dam," which is drained by the medullary sinusoids and eventually forms a single central adrenal vein. Venous stasis and hypercoagulability in this region can promote thrombosis, infarction, and subsequent bleeding . Berneis et al. reported a novel mechanism involving the zona fasciculata's cellular characteristics . In this zone, cells have a high density of late endosomes, which are organelles involved in cholesterol exchange and protein sorting. The membranes of these organelles contain lysobisphosphatidic acid, which is the target of aPLs. These aPLs react locally and promote cholesterol accumulation in cells, leading to cell death and release of lysosomal proteinases, consequently activating endothelial cells, which favors coagulation and causes micro-thromboses . The timing of postoperative anticoagulant therapy initiation is controversial. APS increases the risk of developing venous thromboembolism according to the American College of Chest Physicians guidelines for the perioperative management of antithrombotic therapy . Therefore, heparin bridging is recommended when warfarin is discontinued. However, caution is required when using high-intensity therapeutic dose heparin bridging postoperatively, paticularly in patients undergoing high bleeding-risk surgeries and procedures. If therapeutic dose bridging is used in patients at a high risk of postoperative bleeding, its initiation should be delayed for 48-72 h postoperatively when adequate surgical hemostasis is achieved . However, the intraoperative bleeding point was unclear in our case, and various hematomas were observed from the right inguinal to the femoral lesions. Therefore, heparin and warfarin were resumed 72 h postoperatively. AI caused by adrenal infarction should be monitored while anticoagulant therapy is discontinued in patients with APS. Abbreviations AI Adrenal insufficiency aPL Antiphospholipid antibodies APS Antiphospholipid syndrome CECT Contrast-enhanced computed tomography POD Postoperative day Acknowledgements We would like to thank Editage (www.editage.jp) for the English language editing. Authors' contributions YI participated in the surgery, conceived and conducted the study, and performed a literature search. YI, MI, and HU participated in the surgery. NM and HU supervised the manuscript preparation and critically revised the manuscript. All authors have read and approved the final manuscript. Funding Not applicable. Availability of data and materials All data generated or analyzed during this study are included in this published article. Declarations Ethics approval and consent to participate Not applicable. Consent for publication Written informed consent was obtained from the patient for the publication of this report and its accompanying images. Competing interests The authors declare that they have no competing interests. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. References 1. Lee KH Lee H Lee CH Kim JY Kim JM Kim SS Adrenal insufficiency in systematic lupus erythematosus (SLE) and antiphospholipid syndrome (APS): a systematic review Autoimmun Rev 2019 18 1 8 10.1016/j.autrev.2018.06.014 30408580 2. Caron P Chabannier MH Cambus JP Fortenfant F Otal P Suc JM Definitive adrenal insufficiency due to bilateral adrenal hemorrhage and primary antiphospholipid syndrome J Clin Endocrinol Metab 1998 83 1437 1439 10.1210/jcem.83.5.4833 9589635 3. Tan JW Shukla A Hu JR Majumdar SK Spontaneous adrenal hemorrhage with mild hypoadrenalism in a patient anticoagulated with apixaban for antiphospholipid syndrome: a case report and literature review Case Rep Endocrinol 2022 2022 6538800 36504598 4. Berneis K Buitrago-Tellez C Muller B Keller U Tsakiris DA Antiphospholipid syndrome and endocrine damage: why bilateral adrenal thrombosis? Eur J Haematol 2003 71 299 302 10.1034/j.1600-0609.2003.00145.x 12950241 5. Douketis JD Spyropoulos AC Spencer FA Mayr M Jaffer AK Eckman MH Perioperative management of antithrombotic therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines Chest 2012 141 e326S e350 10.1378/chest.11-2298 22315266 |
Front Cardiovasc Med Front Cardiovasc Med Front. Cardiovasc. Med. Frontiers in Cardiovascular Medicine 2297-055X Frontiers Media S.A. 10.3389/fcvm.2023.1325442 Cardiovascular Medicine Case Report Case Report: Fluoroless implantation of left branch bundle pacing in a pregnant patient Li Jun 1 + Li Xiaofang 2 + Zhang Anxin 1 Li Fanqi 3 Wang Haixiong 1 * 1 Department of Cardiology, Shanxi Cardiovascular Hospital, Taiyuan, China 2 Department of Digestive Oncology, Shanxi Bethune Hospital, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Shanxi Academy of Medical Sciences, Taiyuan, China 3 Department of Cardiology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China Edited by: Vincenzo Santinelli, IRCCS San Donato Polyclinic, Italy Reviewed by: Manuel Conti, IRCCS San Donato Polyclinic, Italy Luigi Cocchiara, Federico II University Hospital, Italy * Correspondence: Haixiong Wang [email protected] + These authors share first authorship 07 12 2023 2023 10 132544221 10 2023 23 11 2023 (c) 2023 Li, Li, Zhang, Li and Wang. 2023 Li, Li, Zhang, Li and Wang This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. A pregnant patient had symptomatic atrial standstill and indications for pacing therapy with an expected high ventricular pacing ratio. With the consideration of potential pacing-induced cardiomyopathy in the future we conducted zero-fluoro left bundle branch pacing (zLBBP) implantation for heart failure prevention. An ex vivo 3D cardiac model (Medtronic, USA) was used preoperatively to simulate the zLBBP implantation to improve procedure safety and efficiency. Intraoperatively, the simulation steps were followed, and a combination of electroanatomic navigation systems (EANS) and intracardiac echocariography (ICE) were used to ensure that the procedure was performed efficiently and safely. left branch bundle pacing fluoroless implantation 3D cardiac model pregnant patient pacemaker Natural Science Foundation of Shanxi Province20210302123346 Shanxi Provincial Health Commission "Four batch" Science and Technology Innovation Project of Medical Development2021XM45 The author(s) declare financial support was received for the research, authorship, and/or publication of this article.The research was supported by Natural Science Foundation of Shanxi Province (No. 20210302123346 to Dr Wang), and the Shanxi Provincial Health Commission "Four batch" Science and Technology Innovation Project of Medical Development (No. 2021XM45 to Dr Wang). section-at-acceptanceCardiac Rhythmology pmcBrief summary A pregnant patient showed indications for pacing therapy, with an expected high ventricular pacing ratio. Considering potential pacing-induced cardiomyopathy in the future, we conducted zero-fluoro left bundle branch pacing (zLBBP) implantation for heart failure prevention. An ex vivo 3D cardiac model (Medtronic, USA) was used preoperatively to simulate the zLBBP implantation in order to improve the safety and efficiency of the procedure. Intraoperatively, the simulation steps were followed. A pregnant patient had symptomatic atrial standstill and indications for pacing therapy, with an expected high ventricular pacing ratio. Considering the potential for pacing-induced cardiomyopathy in the future, we conducted zero-fluoro left bundle branch pacing (zLBBP) implantation for heart failure prevention. An ex vivo 3D cardiac model (Medtronic, USA) was used preoperatively to simulate the zLBBP implantation in order to improve the safety and efficiency of the procedure. Intraoperatively, the simulation steps were followed, and a combination of electroanatomic navigation systems (EANS) and intracardiac echocariography (ICE) were used to ensure that the procedure was performed efficiently and safely. Case description A 28-year-old female patient experienced intermittent dizziness at 18 weeks of gestation, and an electrocardiogram revealed atrial standstill and junctional escape rhythm . Cardiac magnetic resonance imaging (CMRI) could not be performed owing to the patient's claustrophobia. The patient showed an indication for pacemaker implantation, with an expected high ventricular pacing ratio. Figure 1 (A) Twelve-lead ECG. (B) RA and RV models and labeled His potential. (C) Models of RA and RV in RAO and LAO positions, the position of the lead tip in relation to the labeled HIS, and the recorded left bundle branch potential. (D) The tip of the C315HIS sheath was perpendicular to the septum under ICE. (E) Preoperative ECG with a QRS duration of 120 ms. (F) RV septal pacing ECG with a QRS duration of 145 ms. (G) LBBP ECG with a QRS duration of 110 ms. (H) Lead inserted into the septum at a depth of 9 mm under the ICE. ECG, electrocardiogram; RA, right atrium; RV, right ventricle; LBBP, left bundle branch pacing; SVC, superior vena cava; IVC, inferior vena cava; RAO, right anterior oblique; LAO, left anterior oblique; LV, left ventricle, ICE, intracardiac echocardiography. The final decision was to perform zLBBP. An ex vivo 3D cardiac model was used preoperatively to simulate the procedure. First, we introduced a navigation catheter (Biosense-Webster) in the model to create a 3D electroanatomical map of the superior vena cava (SVC), right atrium (RA), and right ventricle (RV). Then, we simulated the process of zLBBP implantation and sheath removal in the model. The intraoperative procedure, combined with the simulation, is described in the following. The SVC, RA, and RV maps were created in the CARTO3 system using a PentaRay catheter (Biosense-Webster, USA), and His potential was labeled . Voltage mapping revealed the RA and coronary sinus orifice to be low-voltage zones; furthermore, all RA regions could not be recaptured at 5.0 V/0.5 ms output, which confirmed atrial standstill. We punctured the subclavian vein and inserted a guidewire into the vein, then connected alligator clips to the CARTO3 system to verify that the guidewire was inserted into the vein. Then, a C315HIS sheath (Medtronic, USA), the most commonly used sheath for left bundle branch pacing (LBBP) implantation, was chosen as the supporting sheath, as the three-dimensional configuration of its tip was very favorable for vertical affixation to the ventricular septum, thus facilitating the screwing of the leads into the myocardium. With the support of the sheath, a 3,830 lead (Medtronic, USA) was delivered into the RV and the lead trajectory was continuously tracked in the CARTO3 system. The lead helix was advanced just outside the sheath and highlighted by connecting alligator clips for visualization in the system by configuring a biopolar catheter in the "catheter setup" menu and placing the pinned ends of two alligator-clip cables connected to the lead in the corresponding pin box locations. Then, the lead tip was positioned 1.5 cm anterior to the labeled His at the line between the HIS and the RV apex in the system . On ICE visualization, the C315HIS sheath was oriented so that its tip was perpendicular to the septum , and the lead tip was gradually screwed into the septum. During gradual screwing, the QRS waveform of the lead tip pacing changed gradually from a "W-shape" to an "M-shape" in V1 leads, and the QRS duration changed from 145 ms in RV septal pacing to 110 ms in LBBP . The left bundle branch (LBB) potential was also recorded , and the pacing stimulus to LV activation time was 75 ms . The depth of insertion of the lead tip in the septum was 9 mm, as measured by ICE . The lead pacing thresholds, sensing, and impedance were all normal. The length from the puncture point to the beginning of the 3,830 lead connector was assessed and marked . Then, the C315 sheath was removed and the length from the puncture point to the lead marked point was measured again; it remained unchanged at 30 cm , ensuring no withdrawal of the deployed lead tip at the LBB. The 3,830 lead was advanced an additional 2.5 cm (27.5 cm from the puncture point to the marked point), with the lead slacked to prevent dislocation . On ICE visualization, it was further confirmed that the lead position was acceptable, with an appropriate length in the RA without falling into the inferior vena cava. The lead was connected to the IS-1 port of a generator (X3SR01; Medtronic, USA). The procedure took 1 h and 50 min. Figure 2 (A) The length from the puncture point to the beginning of the thickened 3,830 lead connector was gauged and marked. (B) After removing the C315HIS sheath, the length from the puncture point to the lead marked point was measured again, and remained at 30 cm. (C) The 3,830 lead was advanced by an additional 2.5 cm (27.5 cm from the puncture point to the marked point), keeping the lead slacked to prevent dislocation. Discussion LBBP has been shown to be an effective and safe physiological pacing method (1). Usually, pacing leads are implanted using x-ray guidance; however, x-ray exposure may increase the risk of cancer or genetic mutations in exposed individuals. Our pregnant patient had atrial standstill, with an expected high ventricular pacing ratio, which could lead to heart failure. Thus, LBBP was considered be an optimal option for heart failure prevention in this patient. Zero-fluoro procedures should be preferred for special patients such as pregnant women (2). A study of fluoroscopy-free LBBP showed that all device parameters remained stable during follow-up; however, lead slack was suboptimal (too tight or too loose) in some cases (3). This could increase the risk of long-term complications such as lead dislodgement, septum perforation, or an increased capture threshold. In this article, a novel approach to ensure optimal lead slack during the zLBBP implantation procedure is presented and validated by in vitro model demonstration and intraoperative ICE monitoring. To the best of our knowledge, reports on procedures using the zLBBP implantation approach in pregnant women are rare. The following key points should be emphasized during the procedure: (1) preoperative simulation of the zLBBP implantation procedure using an ex vivo 3D cardiac model is important in order to shorten the procedure time and to increase the safety of the procedure; (2) it is important to map the His region using the navigation catheter in order to localize the LBB region; (3) on ICE visualization, the C315HIS sheath should be oriented so that its tip is perpendicular to the septum; (4) in zLBBP, it is important to retain the appropriate lead length in the RA to avoid lead dislocation. In this article, a novel approach is presented , which was validated by in vitro model demonstration and further confirmed intraoperatively with ICE; and (5) ICE application provides timely monitoring of the depth of lead screwing in order to avoid complications such as perforation. The patient had no complications such as lead dislodgement, septum perforation, or heart failure during implantation or for 6 months thereafter, and all device parameters remained stable during follow-up. This case demonstrates that it is safe and feasible to perform zLBBP implantation using EANS for the treatment of special patients such as pregnant women. However, the main limitation of our study is the unavailability of more cases. We look forward to more clinical investigations to further evaluate the effectiveness and long-term effects of this new technology in more patients. Data availability statement The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. Ethics statement The studies involving humans were approved by Ethics Committee of Shanxi Cardiovascular Hospital. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article. Author contributions JL: Investigation, Writing - original draft, Visualization, Conceptualization, Data curation, Resources. XL: Investigation, Writing - original draft, Data curation, Methodology, Software, Visualization. AZ: Investigation, Visualization, Writing - original draft. FL: Investigation, Writing - original draft. HW: Funding acquisition, Investigation, Project administration, Writing - review & editing. Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Publisher's note All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. References 1. Sharma PS Vijayaraman P . Conduction system pacing for cardiac resynchronisation. Arrhythm Electrophysiol Rev. (2021) 10 (1 ):51-8. 10.15420/aer.2020.45 33936744 2. Qiu J Wang Y Chen G Zhao C Wang DW . Progress in zero-fluoroscopy implantation of cardiac electronic device. Pacing Clin Electrophysiol. (2020) 43 (6 ):609-17. 10.1111/pace.13930 32348595 3. Ramos-Maqueda J Melero-Polo J Montilla-Padilla I Ruiz-Arroyo JR Cabrera-Ramos M . Feasibility and safety of zero-fluoroscopy left bundle branch pacing: an initial experience. J Cardiovasc Electrophysiol. (2023) 34 (2 ):429-36. 10.1111/jce.15765 36448425 |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.49173 Pain Management Orthopedics Trauma Discovering the Forgotten Trauma Behind Chronic Shoulder Pain: The Critical Role of a Thorough Medical Interview Muacevic Alexander Adler John R Watanabe Akihisa 1 Machida Takahiro 2 Takashima Katsura 1 Hirooka Takahiko 3 1 Rehabilitation, Machida Orthopaedics, Kochi, JPN 2 Orthopaedics, Machida Orthopaedics, Kochi, JPN 3 Orthopaedic Surgery, Onomichi Municipal Hospital, Onomichi, JPN Akihisa Watanabe [email protected] 21 11 2023 11 2023 15 11 e4917320 11 2023 Copyright (c) 2023, Watanabe et al. 2023 Watanabe et al. This is an open access article distributed under the terms of the Creative Commons Attribution License CC-BY 4.0., which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from We report a rare case of a patient experiencing pain and dysfunction attributable to bone fragments from a trauma sustained over two decades prior. A 43-year-old Japanese woman presented with persistent left shoulder pain. Initial radiographs revealed glenohumeral joint osteoarthritis, an unusual finding for her age. Her medical history included a previously overlooked traumatic dislocation of the left acromioclavicular joint over 20 years ago. Computed tomography scans later uncovered bone fragments below the coracoid process without signs of scapular or tuberosity fractures. The fragments were arthroscopically removed, resulting in significant pain relief. The patient's Shoulder Pain and Disability Index score improved from 60 to 9 at the six-month postoperative follow-up. This case underscores the importance of considering historical trauma in patients presenting with atypical shoulder pain and highlights the potential diagnostic value of revisiting a patient's medical history when unusual lesions are discovered. acromioclavicular joint/injuries upper extremity trauma arthroscopy chronic pain management glenohumeral osteoarthritis shoulder joint pain pmcIntroduction While numerous studies have explored various shoulder disorders, such as osteoarthritis (OA), rotator cuff tears, and other pathologies , reports linking shoulder pain to bone fragments from past trauma are sparse, with the literature mainly focusing on scapular and lesser tuberosity fractures . In this case, we illustrate how discovering atypical lesions prompted a review of the patient's medical history, revealing a long-forgotten injury as the source of her current pain and dysfunction. Case presentation A 43-year-old Japanese woman (height 1.58 m, weight 60.0 kg, body mass index 24.0 kg/m2) consulted us for left shoulder pain that had worsened progressively over the preceding two months, affecting her profession as a cook. She reported no recent trauma or other precipitating incidents. Radiographic examination showed glenohumeral OA, which was peculiar given her young age and a critical shoulder angle of 32 degrees . Magnetic resonance imaging showed no rotator cuff pathology. The unexpected presence of OA prompted a thorough review of her medical history, revealing an almost forgotten traumatic dislocation of her left acromioclavicular joint from over 20 years ago. Computed tomography scans later identified bone fragments under the coracoid process with no associated scapular or tuberosity fractures. Figure 1 Initial radiograph and computed tomography scans of the patient's left shoulder (A) Radiograph shows the glenohumeral joint osteoarthritis and a critical shoulder angle of 32 degrees; (B) Computed tomography scans show bone fragments (arrow); (C) Three-dimensional computed tomography scans show bone fragments (arrow). During arthroscopic surgery, a large bone fragment under the coracoid process was discovered and excised . Site redness was noted post excision, which appeared to be the pain source . Additional smaller fragments were also removed . Pathologic examination confirmed the fragments as osteophytes due to OA, with no malignant transformation detected. Arthroscopy confirmed that the rotator cuff was intact. Figure 2 Arthroscopic view and resected bone fragments (A, B) Arthroscopy revealing a large bone fragment embedded inferiorly in the coracoid process (arrowhead); (C) Arthroscopy showing redness around the bone fragment; (D) Resected bone fragments. The patient underwent standard postoperative rehabilitation, including range-of-motion and strengthening exercises, supported by celecoxib (100 mg as needed) for pain management. The patient's Shoulder Pain and Disability Index score improved dramatically from 60 preoperatively to nine at the six-month follow-up. She resumed her cooking career three months post-surgery and was able to work with a maximum pain level below three on the 11-point Numerical Rating Scale (Table 1). Table 1 Course of the patient's function and pain NRS, 11-pont numerical rating scale; SPADI, Shoulder Pain and Disability Index. a Pain intensity in daily activity at its worst point; b Average pain intensity in daily activity. Function/Pain Assessments Preoperative Months Postoperative 1 2 3 6 Anterior elevation 100 120 155 160 160 Lateral elevation 90 120 145 145 145 Pain at worst (NRS)a 6 3 4 3 3 Pain at average (NRS)b 6 3 3 1 1 SPADI Score 60 19 22 16 9 Discussion The critical observation from this case is the role of bone fragments, likely originating from past trauma, in causing pain and dysfunction. This underscores the importance of a comprehensive review of a patient's historical injuries when faced with unusual shoulder presentations. In our practice, glenohumeral joint OA is infrequent in the Japanese population [4-6]. This rarity may be partially explained by the fact that individuals from East Asian populations, such as Japan, typically have larger critical shoulder angles than Western populations . A larger critical shoulder angle has been associated with decreased mechanical stress on the glenohumeral joint . In the present case, the patient's critical shoulder angle was 32 degrees, positioning her at a lower risk for developing glenohumeral joint OA, as angles below 30 degrees are considered high risk . Additionally, risk factors for glenohumeral joint OA commonly include aging, Caucasian ethnicity, obesity, and previous trauma . Although rotator cuff arthropathy might have been suspected in the presence of a rotator cuff lesion, no rotator cuff lesion was found in this patient. The discovery of glenohumeral joint OA in this Japanese patient led us to a meticulous reassessment of her medical history, which revealed a significant but nearly forgotten traumatic event. The significance of investigating prior trauma lies in its potential for causing lasting complications. Although literature regarding post-dislocation bone fragments in the acromioclavicular joint is sparse , studies on other joints, such as the ankle, have shown that trauma can result in long-term biomechanical and anatomical alterations . We hypothesized that the biomechanical alterations from the patient's previous acromioclavicular joint dislocation might have contributed to the development of her glenohumeral joint OA and subsequent osteophyte formation, culminating in her current symptoms. While the connection between past trauma and current symptoms remains a hypothesis in this case, the patient's improvement following the removal of bone fragments suggests that the impact of the glenohumeral joint OA was minimal. Since redness observed on arthroscopy is often associated with pain symptoms, we hypothesized that this was the cause of the patient's pain. This finding has been confirmed by previous studies and our own experience . Conclusions We presented a case demonstrating a potential link between a traumatic injury occurring more than two decades prior and present-day symptoms. This case reinforces the importance of considering historical trauma in patients with atypical shoulder conditions. It serves as a reminder that shoulder disorders can present in unexpected ways, necessitating thorough clinical evaluation. Author Contributions Human Ethics Concept and design: Akihisa Watanabe, Takahiko Hirooka, Katsura Takashima, Takahiro Machida Acquisition, analysis, or interpretation of data: Akihisa Watanabe, Takahiko Hirooka, Katsura Takashima, Takahiro Machida Drafting of the manuscript: Akihisa Watanabe Critical review of the manuscript for important intellectual content: Takahiko Hirooka, Katsura Takashima, Takahiro Machida Supervision: Takahiko Hirooka Consent was obtained or waived by all participants in this study The authors have declared that no competing interests exist. References 1 Anatomic shoulder parameters and their relationship to the presence of degenerative rotator cuff tears and glenohumeral osteoarthritis: a systematic review and meta-analysis J Shoulder Elbow Surg Zaid MB Young NM Pedoia V Feeley BT Ma CB Lansdown DA 2457 2466 28 2019 31353303 2 Current challenges and controversies in the management of scapular fractures: a review Patient Saf Surg Pires RE Giordano V de Souza FS Labronici PJ 6 15 2021 33407725 3 Isolated avulsion fracture of the lesser tuberosity of the humerus in an adolescent amateur boxer JSES Int Park SG Shim BJ Seok HG 759 764 4 2020 33345212 4 Association between the critical shoulder angle and rotator cuff tears in Japan Acta Med Okayama Watanabe A Ono Q Nishigami T Hirooka T Machida H 547 551 72 2018 30573908 5 Differences in risk factors for rotator cuff tears between elderly patients and young patients Acta Med Okayama Watanabe A Ono Q Nishigami T Hirooka T Machida H 67 72 72 2018 29463941 6 Critical shoulder angle in an East Asian population: correlation to the incidence of rotator cuff tear and glenohumeral osteoarthritis J Shoulder Elbow Surg Shinagawa K Hatta T Yamamoto N Kawakami J Shiota Y Mineta M Itoi E 1602 1606 27 2018 29731396 7 Morphologic variability of the shoulder between the populations of North American and East Asian [sic] Clin Orthop Surg Cabezas AF Krebes K Hussey MM Santoni BG Kim HS Frankle MA Oh JH 280 287 8 2016 27583111 8 A biomechanical confirmation of the relationship between critical shoulder angle (CSA) and articular joint loading J Shoulder Elbow Surg Villatte G van der Kruk E Bhuta AI 1967 1973 29 2020 32499200 9 Is there an association between the individual anatomy of the scapula and the development of rotator cuff tears or osteoarthritis of the glenohumeral joint?: a radiological study of the critical shoulder angle Bone Joint J Moor BK Bouaicha S Rothenfluh DA Sukthankar A Gerber C 935 941 95-B 2013 23814246 10 Optimal management of glenohumeral osteoarthritis Orthop Res Rev Ansok CB Muh SJ 9 18 10 2018 30774456 11 Complications of treatment of acromioclavicular and sternoclavicular joint injuries Clin Sports Med Rudzki JR Matava MJ Paletta GA Jr 387 405 22 2003 12825538 12 Acromioclavicular joint injuries and reconstructions: a review of expected imaging findings and potential complications Emerg Radiol Kim AC Matcuk G Patel D Itamura J Forrester D White E Gottsegen CJ 399 413 19 2012 22639336 13 Epidemiology of posttraumatic osteoarthritis J Athl Train Thomas AC Hubbard-Turner T Wikstrom EA Palmieri-Smith RM 491 496 52 2017 27145096 14 Epidemiology of ankle arthritis: report of a consecutive series of 639 patients from a tertiary orthopaedic center Iowa Orthop J Saltzman CL Salamon ML Blanchard GM Huff T Hayes A Buckwalter JA Amendola A 44 46 25 2005 16089071 15 Synchronization of blood flow velocity in the anterior humeral circumflex artery and reduction in night pain after arthroscopic rotator cuff repair: a case report Cureus Watanabe A Katayama H Machida T Hirooka T 0 14 2022 |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.49165 Cardiac/Thoracic/Vascular Surgery Cardiology Transplantation Successful Heart Transplantation With Myocardial Bridging: A Case Report on Unroofing Technique Muacevic Alexander Adler John R Tsukioka Yusuke 1 Jeevanandam Valluvan 2 1 Cardiothoracic Surgery, University of Chicago Medicine, Chicago, USA 2 Cardiac Surgery, University of Chicago Medicine, Chicago, USA Yusuke Tsukioka [email protected] 21 11 2023 11 2023 15 11 e4916520 11 2023 Copyright (c) 2023, Tsukioka et al. 2023 Tsukioka et al. This is an open access article distributed under the terms of the Creative Commons Attribution License CC-BY 4.0., which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from Myocardial bridging (MB), a common anatomical variation where a segment of a coronary artery is covered by myocardium, poses a relative contraindication in heart transplantation due to the risk of post-transplant ischemia. This report presents a case of successful transplantation of a donor heart with MB, where unroofing (removal) of the myocardial bridge was performed. The donor was a 42-year-old male with mild nonobstructive coronary artery stenosis and MB. The recipient, a 55-year-old male, suffered from ischemic cardiomyopathy and severe heart failure. During transplantation, unroofing of the donor heart's MB was executed to mitigate the risk of myocardial ischemia. The transplantation was successful with preserved postoperative cardiac function. The unroofing procedure did not significantly extend ischemic or operative time. Postoperative electrocardiogram (ECG) and echocardiography showed no signs of myocardial ischemia. Donor hearts with MB can be utilized for transplantation with appropriate surgical intervention. This case demonstrates the potential of unroofing procedures in expanding the suitability of donor hearts for transplantation, without increasing the risk of postoperative complications or mortality. postoperative cardiac function coronary artery stenosis unroofing procedure heart transplantation myocardial bridging pmcIntroduction Myocardial bridging (MB) is a normal anatomical variation, defined as a segment of a coronary artery being covered by the myocardium. It is associated with a range of clinical scenarios, from being completely asymptomatic to causing acute pump failure [1-4]. In patients with MB, tachycardia is known to increase the risk of myocardial ischemia. Post-transplant denervated hearts, which tend to develop sinus tachycardia, make the transplantation of donor hearts with MB relatively contraindicated . In this case report, we present a case where unroofing of MB was successfully performed on a donor's heart during transplantation, yielding favorable outcomes, which are illustrated with videos and photographs. Case presentation Donor information The donor was a 42-year-old male, 178 cm in height and 68 kg in weight (body mass index: 21.5 kg/m2), with no significant medical history. He was admitted to the donor hospital, which was near the transplant center, following asphyxiation and was declared brain dead after 14 days. Echocardiography showed good left ventricular function with an ejection fraction (EF) of 60%. Coronary angiography revealed a mild nonobstructive coronary artery stenosis approximately 3 cm in length with MB in the mid-left anterior descending artery (LAD) but was otherwise normal . The donor's electrocardiogram (ECG) was within normal limits, with no signs of myocardial ischemia. Figure 1 Mildly stenosed LAD due to myocardial bridging Coronary angiography revealed a mild nonobstructive coronary artery stenosis approximately 3 cm in length with myocardial bridging in the mid-LAD. LAD: Left anterior descending artery. Recipient information The recipient was a 55-year-old male, 190 cm in height and 101 kg in weight (body mass index: 28.0 kg/m2), with a history of coronary artery disease, including myocardial infarction in the LAD territory treated with percutaneous coronary intervention (PCI). His cardiac function was reduced, with an EF of 15%. He was diagnosed with ischemic cardiomyopathy and had undergone cardiac resynchronization therapy with a defibrillator (CRT-D) implantation. Despite aggressive medical therapy, he experienced New York Heart Association (NYHA) class III heart failure symptoms six months before transplantation and was on milrinone infusion under intra-aortic balloon pump (IABP) support preoperatively. Implantation procedure During procurement, the donor heart was vented in both the right and left atrium before antegrade perfusion with a University of Wisconsin (UW) cardioplegic solution. The heart was preserved in UW solution at 4degC and transported to our facility. Under general endotracheal anesthesia and in the supine position, the patient was prepped and draped in a standard aseptic manner. A right femoral arterial catheter was placed for monitoring. A median sternotomy was performed. Preparation for cardiopulmonary bypass (CPB) included ACT-guided heparinization, cannulation of the transverse arch under the innominate vein with a 22 French (Fr) cannula (3-0 Surgipro sutures; Covidien, Mansfield, MA), and bicaval cannulation (superior vena cava [SVC], 3-0 Surgipro, 24 Fr DLP; inferior vena cava [IVC], 3-0 Surgipro, 31 Fr DLP). A transverse incision was made in the aorta, and the heart was explanted by transecting the pulmonary artery (PA) and the aorta. The right atrium was removed, and the posterior portion of the left atrium, IVC, and SVC were left for anastomosis. The ascending aorta was resected to the undersurface of the arch. The donor's heart was prepared for transplantation by separating the PA, aorta, SVC, and pulmonary veins. The MB location was identified based on the coronary angiography images. By palpating the coronary artery, the lesion of the myocardial bridge could be estimated. The adipose tissue was incised with a 10-watt electrocautery (coagulation mode) to expose the muscle. A right-angle clamp was slid between the exposed muscle and the coronary artery, and the muscle was incised with the electrocautery. Care was taken to lift the right-angle clamp sufficiently to avoid damaging the coronary artery during the incision. The cut ends of the myocardium were meticulously cauterized to prevent postoperative bleeding. The unroofing procedure was completed in a duration of merely 4 minutes and 25 seconds (Video 1). Video 1 Unroofing technique for myocardial bridging A DeVega tricuspid annuloplasty was performed with pledgeted 2-0 Surgipro sutures. The left atrial anastomosis was completed with 3-0 Surgipro sutures. The IVC and SVC (4-0 Surgipro sutures), PA, and aortic (4-0 Surgipro) anastomoses followed. Antegrade cardioplegia was administered into the aortic root after each anastomosis. Warm blood was given antegrade for deairing the coronary arteries. The patient was rewarmed, the pressure was decreased to 50 mmHg, the aortic root suction was applied, and the cross-clamp was released. After deairing the heart, the right atrial incision was closed, and the ascending aorta vent was removed. The rhythm reverted to normal sinus rhythm immediately after the aortic clamp was removed. Cardiac function was excellent. The patient was weaned from CPB with low-dose dopamine and dobutamine. After decannulation and protamine administration, hemostasis was adequate, and 32 Fr chest tubes (posterior/anterior mediastinal, right pleural) were placed. The sternum was closed with wires and plates due to poor sternal condition, immunosuppression, and transverse sternal fractures. A dressing was applied, and the patient was transferred to the intensive care unit in stable condition with normal sinus rhythm. Details of the cardiopulmonary bypass, including duration and flow rates, are comprehensively presented in Table 1. Table 1 Cardiopulmonary bypass data CPB: Cardiopulmonary bypass. CPB data Bypass time 133 minutes Cross-clamp time 115 minutes Core temperature 34degC Flow 5.8 L/min Implant time 73 minutes Donor heart ischemic time 134 minutes Postoperative examination The ECG showed normal sinus rhythm with no ST elevation. A transesophageal echocardiogram revealed normal left ventricular performance with a left ventricular EF of 60%. No left ventricular regional wall motion abnormalities were noted after the injection of echocardiographic contrast. No valvular abnormalities were identified. The postoperative course was uneventful, with stable hemodynamics, and the patient was discharged home two weeks postoperatively. Discussion Congestive heart failure remains one of the leading causes of death in the United States, and the need for heart transplantation remains high, despite a shortage of donor hearts. Many transplant centers are expanding their selection criteria to provide heart transplants to more recipients. While donor hearts with MB are considered a relative contraindication for transplantation, reports by Singhal et al. have shown that safe heart transplantation can be performed by releasing the myocardial bridge . Our report is the only case report demonstrating the unroofing technique with video. The unroofing procedure by Singhal et al. and our team is supported by case reports on MB by Pittaluga et al. . Their report highlighted a case where a donor heart with an asymptomatic myocardial bridge, which did not undergo surgical intervention such as unroofing before transplantation, resulted in infarction at the LAD myocardial bridge site in the recipient, leading to heart failure and death. In our case, unroofing did not significantly prolong ischemic or operative time. Postoperative cardiac function was preserved, and no ischemic changes were observed on the ECG. Our report demonstrates that donor hearts with MB, which do not compromise cardiac function, can be easily modified and used for transplantation without increasing the risk of postoperative complications or mortality. The incidence of MB varies depending on the diagnostic method used, generally reported to be less than 5%. However, autopsy studies report incidences ranging from 40% to 50% to as high as 85% [1-4]. These intramuscular arterial segments generally do not exhibit atheromatous arteriosclerosis , and atherosclerotic lesions are more commonly found proximal to the myocardial bridge segment . Previous reports have indicated post-transplant myocardial infarction due to occlusion at the site of MB , with an incidence rate of approximately 30% in heart transplant recipients . In cases involving young donors, coronary catheterization is not routinely performed. Nevertheless, it is advisable to employ catheterization for the detection of MB. Conclusions We employed a donor heart exhibiting a myocardial bridge in the LAD. MB can cause underperfusion and hemodynamic disturbances in the heart, so unroofing was performed before transplantation. The surgery was completed without significantly extending the operative time, and the recipient showed no postoperative complications. Thus, donor hearts with MB can be surgically modified and used for transplantation without increasing the risk of mortality or complications. Author Contributions Human Ethics Concept and design: Yusuke Tsukioka, Valluvan Jeevanandam Acquisition, analysis, or interpretation of data: Yusuke Tsukioka, Valluvan Jeevanandam Drafting of the manuscript: Yusuke Tsukioka, Valluvan Jeevanandam Critical review of the manuscript for important intellectual content: Yusuke Tsukioka, Valluvan Jeevanandam Supervision: Valluvan Jeevanandam Consent was obtained or waived by all participants in this study The authors have declared that no competing interests exist. References 1 Symptomatic myocardial bridges: overview of ischemic mechanisms and current diagnostic and treatment strategies J Am Coll Cardiol Bourassa MG Butnaru A Lesperance J Tardif J-C 351 359 41 2003 12575960 2 The incidence and significance of myocardial bridge in a prospectively defined population of patients undergoing coronary angiography for chest pain Tokai J Exp Clin Med Soran O Pamir G Erol C Kocakavak C Sabah I 57 60 25 2000 11127508 3 Coronary atherosclerosis within a myocardial bridge, not a benign condition Heart de Winter RJ Kok WE Piek JJ 91 93 80 1998 9764069 4 Left anterior descending coronary artery bridge. A cause of early death after cardiac transplantation Chest Pittaluga J de Marchena E Posada JD Romanelli R Morales A 511 513 111 1997 9042008 5 Successful transplantation of an older donor heart with documented myocardial bridging: a case report J Heart Lung Transplant Singhal AK McClurken JB Fisher CA Macha M Mohara J Furukawa S 340 342 24 2005 15737763 6 Myocardial bridging: an up-to-date review J Invasive Cardiol Lee MS Chen CH 521 528 27 2015 25999138 7 The incidence of myocardial bridges in heart transplants Cardiovasc Intervent Radiol Wymore P Yedlicka JW Garcia-Medina V Olivari MT Hunter DW Castaneda-Zuniga WR Amplatz K 202 206 12 1989 2513117 |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.49172 Ophthalmology A Multifaceted Presentation of Xerophthalmia in Autistic Patients Muacevic Alexander Adler John R Azmi Annuar Zaki 1 Patrick Sylves 2 Isa Mohamad Israk B 1 Ab. Ghani Shuaibah 2 1 Department of Paediatric Ophthalmology, Sabah Women and Children Hospital, Kota Kinabalu, MYS 2 Department of Ophthalmology, Faculty of Medicine and Health Sciences, University Malaysia Sabah, Kota Kinabalu, MYS Annuar Zaki Azmi [email protected] 21 11 2023 11 2023 15 11 e4917221 11 2023 Copyright (c) 2023, Azmi et al. 2023 Azmi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License CC-BY 4.0., which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from We report the manifestations of vitamin A deficiency (VAD) in three children with underlying autism of different stages. These children were under developmental paediatrician follow-up for autism, and the VAD was not detected until these children presented to Ophthalmology screening for varying stages of signs and symptoms. On further assessment, all of our patients have VAD secondary to poor dietary intake, as autistic patients are associated with having selective eating habits. In our case series, we discuss the spectrum of xerophthalmia presentations, which can be mild and can manifest as punctate epithelial erosions to the more blinding complications at the advanced stage of the disease, mainly irreversible optic neuropathy. The primary management is to address the dietary routine coupled with systemic administration of vitamin A. xerosis keratomalacia autism xerophthalmia vitamin a deficiency pmcIntroduction Vitamin A is an essential fat-soluble protein that plays multiple roles in our body. Vitamin A regulates the differentiation and proliferation of most cells in the human body . In the eye, it maintains the integrity of mucosal cells. Children with underlying autism are prone to develop vitamin A deficiency (VAD) due to their selective eating . Xerophthalmia is the spectrum of eye diseases caused by severe depletion of Vitamin A. One of the blinding complications of VAD is severe keratomalacia with potential corneal perforation . Another blinding sequelae is optic neuropathy which is thought to be irreversible and signifying the end stage of the disease . Case presentation Case 1 A seven-year-old boy with underlying mild autism complained to his parents that the child kept looking down with droopy eyelids for the past two weeks before the presentation. The father claimed that the child became more clumsy and watched television nearer than previously. Magnetic resonance imaging (MRI) was done, and no intracranial pathology was detected. Visual acuity (VA) upon presentation was perception to light for both eyes (BE). Examination under anaesthesia revealed bilateral conjunctival xerosis and generalized punctate epithelial erosions (PEE) all over the cornea bilaterally but worst over the right eye (RE) . No Bitot's spot was seen. Fundus examination showed pale optic discs bilaterally. Investigation of serum vitamin A revealed a low vitamin A status of 0.12 umol/l (0.9-3.0 umo/l). Figure 1 RE conjunctival xerosis RE: right eye The child's diet consisted of french fries thrice daily and junk food such as nuggets and chocolate. He also consumed plain porridge sometimes but refused meat and vegetables. He drinks formula milk twice a day. The patient was referred to a dietician, given systemic vitamin A therapy by the paediatrician and treated with frequent artificial tears. The child is keeping well with the resolvent of the corneal PEE and conjunctival xerosis. However, vision is poor with hand motion (HM) over the RE and 1/60 over the left eye (LE). Case 2 A seven-year-old boy with autism presented with what was thought of as an LE perforated corneal ulcer upon presentation. The mother complained of LE redness intermittently for the past one month. There was no previous history of trauma. The best corrected visual acuity (BCVA) of RE was 6/12, and there was no light perception (NPL) for the LE. Upon examination, LE was shown to have severe leukomalacia with perforated cornea . RE shows severe keratosis with generalized PEE . Posterior segment examination of the RE shows a swollen optic disc; otherwise, the retina is flat. No view of the posterior segment of the LE. Serum vitamin A was taken and revealed a low vitamin A status of <0.10 umol/l (0.9-3.0 umo/l). Figure 2 LE severe keratomalacia with perforated cornea LE: left eye Figure 3 RE shows severe keratosis with generalized PEE. RE: right eye, PEE: punctate epithelial erosions The child's diet consisted of plain porridge for lunch and dinner and chocolate bars for breakfast (Kit Kat). He refused milk and only drank plain water and milo. The LE was unsalvageable and eventually had to be eviscerated. The patient was referred to a dietitian, and the paediatrician started systemic treatment of vitamin A. He was also given intensive topical artificial tears for RE. As of today, the RE cornea has only minimal PEE, but the conjunctival xerosis resolved. LE healed well following the evisceration. Case 3 A nine-year-old boy with underlying autism presented with bilateral eye redness on and off for the past two months prior to presentation. Upon examination, VA was 6/180 by using Lea Grating (uncooperative patient), and bilateral eye shows PEE and conjunctival xerosis but no Bitot's spot was noticed . The posterior segment was otherwise unremarkable. Serum vitamin A revealed a low vitamin A status of <0.10 umol/l (0.9-3.0 umo/l). The patient was referred to a dietician and started systemic vitamin A therapy by the paediatrician. Intensive lubricants were also started. Figure 4 RE shows severe keratosis with generalized PEE. RE: right eye, PEE: punctate epithelial erosions Figure 5 LE PEE and conjunctival xerosis LE: left eye, PEE: punctate epithelial erosions Currently, the bilateral cornea is clear, with no conjunctival xerosis seen. Discussion Vitamin A plays crucial roles in the eyes, specifically the conjunctiva, cornea and retina. 11-cis-retinal is the active form of vitamin A and is essential for the visual pathway. It allows electrochemical signalling to be generated from the light that falls onto the retina . Vitamin A aids in the maintenance of the ocular surface and mucosal tissue integrity. Its presence is vital in tissue differentiation, particularly stratified squamous epithelium on the conjunctival surface . Nutritionally, vitamin A can be obtained from dietary intake. Animal sources of vitamin A-rich food include dairy products, eggs, fish, and cod liver oil. They can also be found in vegetable produce such as spinach, lettuce, carrot and sweet potato . Malaysia is currently at the level of mild subclinical VAD status. This study is based on a survey done by the Ministry of Health and UNICEF of more than 400 children under five years old and younger. Based on this survey alone, 4.5% of girls and 2.5% of boys had serum retinol levels <= 0.7 mmol/L . Another local study was done using a semi-quantitative food frequency questionnaire (FFQ) to assess dietary intake, and the resulting nutrient intakes were then compared to Recommended Nutrient Intakes (RNI) by the Ministry of Health. The result shows that only 4.4% of Malaysian children between 6 months and 12 years old have low levels of vitamin A . The presentation of vitamin A may be challenging to detect initially, especially in children with autistic disorders because the early manifestations usually start from the retina. It begins with photoreceptor dysfunction that manifests as night blindness or nyctalopia. As the vitamin A level gets low, the disease will start to affect the activity of the normal mucosal surface leading to their atrophy. This disease will present as Bitot's spot appearing as a glistening surface caused by desquamated epithelium. As the disease progresses, the conjunctiva's wrinkling, or conjunctival xerosis, will ensue, followed by loss of goblet cells . All of our patients show the presence of conjunctival xerosis, which indicates that the disease has been there for some time - the second patient presented with severe leukomalacia leading to corneal perforation. To our knowledge, there is only one perforation case in VAD with autism secondary to severe corneal ulcer . The second patient shows optic nerve swelling for the third case, indicating that optic nerve involvement is possible, albeit rare. Optic atrophy is another optic nerve involvement indicating end-stage disease with poor visual prognosis . Autistic children are associated with selective diets with decreased protein, vegetables, fruits and even dairy intakes . Some studies also show that they have preferentiality towards a starch diet . Nutritional progress should be monitored in autistic patients, especially those with selective intakes. It is known that VAD is becoming scarcely rare in the developed world, but caution should be looked upon for autistic children with picky eating. On top of the developmental assessment, they should be considered for vitamin A serum level testing and prompt ophthalmology screening from the onset of diagnosis . The principal treatment for VAD is to correct the deficiency and manage the eye manifestations . For children with a developmental disorder such as autism, a holistic approach is needed to address its developmental aspect and any nutritional deficiencies to prevent sinister sequelae that may be initially undetected. In the presence of behavioural and visual changes, one should consider serum testing of vitamin levels. The input of a dietician is valuable to help autistic children cope with their changing dietary needs once the child passes the acute stages of disease manifestations . Conclusions Children with autism have a high index of suspicions towards VAD and other nutrients due to their tendency for selective eating. A routine examination should be co-managed with a developmental paediatrician and dietician. Nutritional aspects for autistic patients should be explored from the get-go to prevent sinister complications, as mentioned. A baseline of vitamin A should be taken with periodic testing of vitamin A in a patient with dietary issues until the child establishes an acceptable dietary routine. We would like to thank the Director-General of Health Malaysia for his permission to publish this case report. Author Contributions Human Ethics Acquisition, analysis, or interpretation of data: Sylves Patrick, Shuaibah Ab. Ghani Critical review of the manuscript for important intellectual content: Sylves Patrick, Shuaibah Ab. Ghani Concept and design: Annuar Zaki Azmi, Mohamad Israk B. Isa Drafting of the manuscript: Annuar Zaki Azmi, Mohamad Israk B. Isa Consent was obtained or waived by all participants in this study The authors have declared that no competing interests exist. References 1 Role of vitamin A in the immune system J Clin Med Huang Z Liu Y Qi G Brand D Zheng SG 258 7 2018 30200565 2 Research progress in vitamin A and autism spectrum disorder Behav Neurol Liu Z Wang J Xu Q Hong Q Zhu J Chi X 5417497 2021 2021 34917197 3 Vitamin A deficiency-associated corneal perforation in a boy with autism spectrum disorder: a case report and literature review Nutrition Adachi S Torio M Okuzono S 111275 90 2021 34004415 4 Optic neuropathy in an autistic child with vitamin A deficiency: a case report and literature review Cureus Cheah JA Muhammed J Tharmathurai S Hamzah N Rahmat J 0 14 2022 5 The role of vitamin A in retinal diseases Int J Mol Sci Sajovic J Meglic A Glavac D Markelj S Hawlina M Fakin A 1014 23 2022 35162940 6 Xerophthalmia and vitamin A deficiency in an autistic child with a restricted diet BMJ Case Rep Chiu M Watson S 0 2015 2015 7 Effects of short-term oral vitamin A supplementation on the ocular tear film in patients with dry eye Clin Ophthalmol Alanazi SA El-Hiti GA Al-Baloud AA 599 604 13 2019 31040640 8 Micronutrient status and intervention programs in Malaysia Food Nutr Bull Khor GL 0 5 26 2005 9 Nutritional status and dietary intakes of children aged 6 months to 12 years: findings of the Nutrition Survey of Malaysian Children (SEANUTS Malaysia) Br J Nutr Poh BK Ng BK Siti Haslinda MD 0 35 110 Suppl 3 2013 10 Xerophthalmia and vitamin A status Prog Retin Eye Res Sommer A 9 31 17 1998 9537797 11 Permanent visual loss due to dietary vitamin A deficiency in an autistic adolescent J Child Neurol McAbee GN Prieto DM Kirby J Santilli AM Setty R 1288 1289 24 2009 19638639 12 How to manage children with the eye signs of vitamin A deficiency Community Eye Health Gilbert C 68 26 2013 24782582 |
SAGE Open Med Case Rep SAGE Open Med Case Rep SCO spsco SAGE Open Medical Case Reports 2050-313X SAGE Publications Sage UK: London, England 10.1177/2050313X231213927 10.1177_2050313X231213927 JCMS Case Report Lichenoid drug reaction after ipilimumab/nivolumab combination therapy: A case report Moore Zonia Robenne 12 Zajdman-Faitelson Dalit 2 Campillo Arely Tamariz 2 Brito Bustillos Diana Karen 3 Toussaint-Caire Sonia 3 Berumen-Glinz Cristina 2 1 University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA 2 Dermatology Department, Manuel Gea Gonzalez General Hospital, Tlalpan, CDMX, Mexico 3 Dermatopathology Department, Manuel Gea Gonzalez General Hospital, Tlalpan, CDMX, Mexico Zonia Robenne Moore, University of Pennsylvania Perelman School of Medicine, 3400 Civic Center Boulevard, Philadelphia, PA 19104, USA. Email: [email protected] 20 12 2023 2023 11 2050313X2312139274 7 2023 17 10 2023 (c) The Author(s) 2023 2023 SAGE Publications This article is distributed under the terms of the Creative Commons Attribution 4.0 License ) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ). Nivolumab (PD-1 inhibitor) and ipilumumab (CTLA-4 inhibitor) are recently approved checkpoint inhibitors for treatment of non-small cell lung cancer. Immune-related adverse events related to the usage of checkpoint inhibitors are growing with their popularity. We present the case of a patient in combination treatment of nivolumab and ipilimumab who developed a lichenoid drug reaction, notable because it worsened to a bullous lichenoid drug reaction. Treatment with prednisone and withdrawal of checkpoint inhibitors aided in clinical resolution. Initial presentation of a lichenoid reaction that progressed to a bullous, desquamated presentation indicates the possibility of the prodromal rash progressing to a Stevens-Johnson Syndrome-like dermatosis. When dermatologists are consulted for rashes developed during checkpoint-inhibitor therapy, they should be aware that early treatment may prevent progression to bullae formation and desquamation and develop their treatment plans with this in mind. Bullous lichenoid drug reaction ipilimumab nivolumab combination therapy mesothelioma cover-dateJanuary-December 2023 typesetterts1 pmcBackground Checkpoint inhibitors are gaining popularity in the treatment of skin and lung cancers. Nivolumab is a PD-1 inhibitor that was first approved to treat metastatic melanoma in 2014 by the Food and Drug Administration. Ipilimumab is a CTLA-4 inhibitor approved in March 2011 to treat late-stage unresectable melanoma. Both drugs have since been approved for treatment of non-small cell lung cancer (NSCLC).1,2 Mesothelioma is a lung cancer most frequently caused by asbestos exposure; usage of checkpoint inhibitors as treatment is being established.1,2 Immune-related adverse events (ir-AE) are more frequent as checkpoint inhibitor popularity grows. Most ir-AEs are low grade: a review, including 5,744 NSCLC patients from 23 studies treated with anti-PD-1, found an incidence of ir-AEs of 64% with anti-PD-1 agents (14% grade 3).1,2 These grade 3 reactions exist on a spectrum from lichenoid drug reaction to Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN). Here we present a case of a lichenoid dermatitis from ipilimumab/nivolumab combination therapy prevented from evolving into an SJS-like dermatosis through early management. Case presentation We present the case of a 68-year-old man diagnosed with unresectable biphasic mesothelioma in February 2022, and underwent four cycles of chemotherapy with gemcitabine (410 mg) and cisplatin (57 mg). Due to disease progression, treatment changed to an immune checkpoint inhibitor. In August 2022, he received two cycles of combination ipilimumab (63 mg)/nivolumab (180 mg) treatment. Two weeks after his last nivolumab/ipilimumab dose, he developed a generalized scaly erythematous eruption with thick scale and associated burning sensation, pruritus, chills, and fatigue. Due to erythroderma and acute skin failure, treatment was started with prednisone 60 mg daily (1 mg/kg) and a punch biopsy was performed. One week later, the patient had worsened. He experienced generalized 8/10 pain, chills, fatigue, and pain with eating. Cutaneous examination revealed additional poorly delimited erosions on his back, abdomen, penis, scrotum, and inguinal and intergluteal folds that affected affecting approximately 20% of body surface area . He also presented scaly erythematous plaques and fissures on his hands and elbows with poorly defined ulcerations on his vermilion lip, buccal, and palatine mucosa. The patient was admitted to Instituto Nacional de Cancerologia, for treatment with IV methylprednisolone 70 mg/day, Kaomycin mouth washes every 8 h, and vaseline-bandage changes on denuded skin every 48 h. Figure 1. Initial presentation of the patient's dermatosis on day 1 of hospital admission. Flaccid bullae had burst, leaving exulcerations on the patient's skin. Two days later, the erosions on his back and his intraoral ulcers were partially re-epithelialized, and associated symptoms had improved. He was able to stand and eat, and much of the thick scale had fallen off. Four days later, the patient continued with improvements on his extremities and thorax, with approximately 80% re-epithelization. He was discharged with continued prednisone. On his first follow-up visit he presented complete re-epithelialization and total symptomatic improvement. Histopathological results were obtained by then, showing an orthokeratotic stratum corneum with focal parakeratosis, hypergranulosis, necrotic suprabasal keratinocytes, and vacuolar damage to the dermal-epidermal interface. A band of lymphocyte and histiocyte infiltration with erythrocyte extravasation was observed beneath a subepidermal separation. An immunostain for collagen IV confirmed the presence of that collagen at the bottom of the separation. These findings are presented in Figure 2. Immune checkpoint-inhibitor therapy was discontinued. He received third and fourth line of therapy with pemetrexed and vinorelbine, respectively, with disease progression. His skin re-epithelialization can be seen in Figure 3. Figure 2. Histopathology results. A, 20x, Hypergranulosis and the beginning of the subepidermal cleft with pigment deposition, a chronic inflammatory infiltrate of histiocytes and lymphocytes along with extravasation of erythrocytes. B, 40x, Immunohistochemical stain for type IV collagen showing the basement membrane at the bottom of the cleft. Figure 3. Patient recovery at the end of therapy. Photos taken 6 months after hospital discharge. Discussion This case presentation is unusual due to the bullous presentation of checkpoint-inhibitor-induced lichenoid reaction. The physiology behind this presentation is unknown, but our histopathological and clinical results support a hypothesis of a lichenoid drug reaction with extensive epidermal detachment producing a bullous lichenoid reaction or Stevens-Johnson Syndrome-like (SJS-like) reaction. In Figure 2, we see epidermal detachment and a subepidermal cleft, which supports the above theory. Collagen IV is found beneath the epidermis in bullous lichen planus and in pemphigoid reactions, which does not distinguish the disorders. 3 Attempts were made to obtain autoantibody titers; however, (Dsg) 1, anti-DSG3, and anti-BP-180 autoantibody titers are unavailable at the time of writing in our zone. 3 In this case, early intervention with prednisone 1 mg/kg and checkpoint withdrawal prevented full SJS-like development. The rapid response to therapy makes a diagnosis of a bullous lichenoid drug reaction more likely than a pemphigoid reaction. The initial liquenoid-like reaction worsened to flaccid bullae development before resolving. In their systematic review of 29 cases of anti-PD1 therapy-associated bullous disorders, Zhao et al. found six cases of SJS/TEN/Erythema Multiforme (EM) reactions with an atypical prodrome and an interface dermatitis shown on biopsy prior to development of SJS/TEN/EM. 4 Potts et al. report a case of a drug-induced lichen planus evolving into SJS in 2022. Their patient had "pruritic erythematous coalescing patches and plaques most severe on the forearms and lower legs. After a third dose of nivolumab, the rash worsened. Biopsy showed a non-specific lichenoid dermatosis. Nine months after starting nivolumab and six months after her last dose, the patient's rash worsened over a number of weeks, with intense pruritus and hemorrhagic skin sloughing." 1 The clinical course in this case is quite similar to ours. We intervened earlier with a similar dosage of prednisone and stopped administration of nivolumab, preventing progression to SJS-like symptoms. Enomoto et al. reported on a man in his 50s with advanced lung adenocarcinoma, treated with nivolumab every 2 weeks. Three days after his 10th dose, the patient developed severe pain in his oral cavity. The patient did not respond to topical corticosteroid, and nivolumab was discontinued. One month later, the patient complained of dysphagia and severe sore throat, and was diagnosed with severe pharyngolaryngitis. Oral prednisone (1 mg/kg) was administered with resolution 3 weeks later. Histological analysis of biopsies taken after administration of topical corticosteroid showed a band-like infiltration of lymphocytes in the subepithelium with separation of the basal layer. 5 This clinical course similarly supports our hypothesis, with the histological findings in Figure 2 showing our separation of the basement layer. Conclusion Dermatologists should consider regularly following patients on checkpoint-inhibitor therapy as a part of preventative care. SJS-like reactions may progress from a lichenoid drug eruption through a mechanism of basement membrane exposition, placing bullous lichenoid eruptions on the same spectrum with SJS-like reactions of cutaneous cytotoxicity. Early intervention with 1 mg/kg prednisone and cessation of the checkpoint-inhibitor prevent the development of life-threatening grade 4 cutaneous adverse reactions. Careful clinical judgment and coordination with the treating oncologist needs to be used on whether to continue or withdraw the checkpoint inhibitor. The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article. ORCID iD: Zonia Robenne Moore References 1. Potts J Lee RR Hilliard CA . Lichenoid dermatitis preceding Stevens-Johnson syndrome in a patient treated with nivolumab. BMJ Case Rep 2022; 15 : e251233. 2. Remon J Mezquita L Corral J , et al . Immune-related adverse events with immune checkpoint inhibitors in thoracic malignancies: focusing on non-small cell lung cancer patients. J Thorac Dis 2018; 10 : S1516-S1533. 3. Campos-Dominguez M Silvente C De La Cueva P , et al . Liquen plano penfigoide eritrodermico. Actas Dermo-Sifiliograficas 2006; 97 : 583-586.17173763 4. Zhao CY Hwang SJE Consuegra G , et al . Anti-programmed cell death-1 therapy-associated bullous disorders: a systematic review of the literature. Melanoma Res 2018; 28 : 491-501.30169429 5. Enomoto Y Nakatani H Kondo S , et al . Drug-induced oral lichenoid reaction during nivolumab therapy. Int J Oral Maxillofac Surg 2019; 48 : 488-491.30170775 |
mSystems mSystems msystems mSystems 2379-5077 American Society for Microbiology 1752 N St., N.W., Washington, DC 37874165 00927-23 10.1128/msystems.00927-23 msystems.00927-23 Observation pathogenesis-and-host-responsePathogenesis and Host ResponseCharacterization of spatial lipidomic signatures in tick-bitten guinea pig skin as a model for host-vector-pathogen interaction profiling Scott Alison J. 1 2 Conceptualization Formal analysis Investigation Methodology Visualization Writing - original draft Writing - review and editing [email protected] Smith Alexis A. 3 Conceptualization Investigation Methodology Heeren Ron M. A. 2 Funding acquisition Resources Software Pal Utpal 3 Conceptualization Funding acquisition Investigation Resources Supervision Ernst Robert K. 1 Conceptualization Funding acquisition Investigation Supervision 1 Department of Microbial Pathogenesis, University of Maryland , Baltimore, Maryland, USA 2 Maastricht MultiModal Molecular Imaging (M4i) Institute, Maastricht University , Maastricht, Limburg, the Netherlands 3 Department of Veterinary Medicine, University of Maryland , College Park, Maryland, USA Editor Anderton Christopher R. Pacific Northwest National Laboratory , Richland, Washington, USA Address correspondence to Alison J. Scott, [email protected] The authors declare no conflict of interest. Nov-Dec 2023 24 10 2023 24 10 2023 8 6 e00927-2331 8 2023 09 9 2023 Copyright (c) 2023 Scott et al. 2023 Scott et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license. ABSTRACT Spatially aware de novo discovery methods are essential tools for therapeutic target identification in complex interphylum interactions such as arthropods and mammals. Notably, the methods should ideally be species agnostic, showing unique features of all interacting species. We evaluated the possibilities for matrix-assisted desorption/ionization mass spectrometry imaging (MALDI-MSI, referred to here as MSI) as a spatial "omics" method to simultaneously profile both an arthropod vector (Ixodes tick) and a mammalian skin (guinea pig) in a bite model. We demonstrated the feasibility of MSI using gelatin-stabilized sample mounting that allowed for serial sectioning and mapping lipids in control and bitten skin, including the tick body and embedded mouthparts. We identified unique lipid ion patterns and observed lipid reorganization beneath the bite site consistent with histological changes. Furthermore, several ions were observed in the tick body with lower intensity in the dermis and control skin, suggesting the transmission of lipids from the tick to mammalian skin. These results establish a multi-system approach for discovering cross-species molecular interactions that can be further developed as targets to disrupt the vector-host interface. IMPORTANCE Here, we demonstrate the adaptability of spatial "omics" methods to identify interphylum processes regulated at the vector-host interface of ticks during a mammalian blood meal. This approach enables a better understanding of complex bipartite or tripartite molecular interactions between hosts, arthropod vectors and transmitted pathogens, and contributes toward the development of spatially aware therapeutic target discovery and description. KEYWORDS vector-borne diseases Ixodes guinea pig spatial lipidomics lipids host-vector interaction University of Maryland School of Dentistry Startup Funds Scott Alison J. HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID) R01AI080615 Pal Utpal HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID) P01AI138949 Pal Utpal Provincie Limburg (Limburg) LINK program Heeren Ron M. A. cover-dateNovember/December 2023 pmcOBSERVATION Mass spectrometry imaging (MSI) presents new opportunities for mechanistic discovery in host-pathogen and vector-host interactions (1-4). Notable examples include arthropod vectors biting host skin (mosquitos, ticks, and fleas), a common mode of intradermal disease transmission (5). Despite extensive research, the complex interface formed by a tick biting mammalian skin remains poorly understood (6). The initial phase of the tick bite consists of mouth parts penetrating the epithelium, followed by remodeling of the underlying skin (7). In the later bite phase, the skin is conditioned for bacterial transmission, resulting in microbial transmission (8). The vector-pathogen interaction influences infection transmission efficiency and is an intriguing target for anti-infective strategy development (9). Preparing samples from the interphylum interaction interface can present technical challenges. Under optimal sampling, the tick body, mouth parts, and host skin layers would all be present in a thin section for the analysis by MSI. Complete embedding of a tick-bitten skin biopsy makes it challenging to target the section plane meeting those criteria. This study aimed to evaluate the potential use of pathogen-vector-host interactions for multi-system interaction imaging in a model for vector-borne disease transmission. Guinea pig bite model Adult female Hartley guinea pigs were housed with food and water available ad libitum. Uninfected nymphal Ixodes scapularis were placed on guinea pigs and biopsied with the bite area before the blood meal (48 hours). Skin biopsies were collected post-mortem from both dorsal bitten skin (embedded tick) and ventral control skin (unbitten) (10). Sample preparation Samples were frozen on a liquid nitrogen float and mounted (unembedded) with 4% porcine gelatin media to create a support. Cryosections were cut (12 mm) on a Leica CM 1950, thaw-mounted on indium tin-oxide slides, sealed, and stored at -80degC. Slides were thawed in a vacuum desiccator for 5 min. Norharmane (NRM) matrix was prepared in 2:1 (vol:vol) chloroform:methanol at 10 mg/mL and sonicated for 1 min in a water bath sonicator. Slides were coated with NRM matrix (both positive and negative modes) using an HTX TM sprayer with the following settings: 14 passes at 0.1 mL/min, then 2 passes at 0.04 mL/min, 1,200 mm/min, 2.5 mm track, CC pattern, 10 psi, 2 L/min, 30degC nozzle, with 2 s dry time at 40 mm height (11), and vacuum desiccated for 5 min. Matrix was removed with 70% ethanol (two dips at 30 s), stained with hematoxylin and eosin (H&E) (11), and brightfield images collected on a Zeiss AxioImager M2. Data capture and analysis Data were collected on a 9.4T MALDI-FT-ICR-MS solariX instrument (Bruker Daltonics; Cryogenics) calibrated to red phosphorus using a quadratic function for positive and negative modes. Images were collected at 100 mm step size over a mass range of m/z 345-1,700 (neg.) and 300-2,000 (pos.) with 0.5 s transients (both modes, resolution at m/z 400:121,000). Full-spectrum raw data were imported into SCiLS Lab (v11.00.14179) using axes limited to m/z 345-1,700 neg. and 600-900 pos. using default binning with a weak (200) top hat baseline removal function and normalized (root mean squared). Feature lists of 208 negative and 413 positive peaks were generated, and images were segmented using a bisecting k-means clustering with weak denoising considering individual spectra. Segments were assigned manually using histology based on the H&E image. Raw data are available on Zenodo (12). Embedded tick induces epidermal and dermal changes in lipid organization Negative (Fig. 1a through e) and positive (Fig. 1f through j) ion mode data sets were segmented, identifying off-tissue and on-tissue segments (Fig. 1b, c, g and h, respectively). A segment representing the tick body in the bite site skin samples was isolated from the surrounding bitten skin. In both modes, the epithelium of the control skin formed a narrow continuous line of pixels (blue, Fig. 1b through h). In contrast, the epithelium in the bite site was thickened and disrupted in negative ion mode but remained intact in the positive ion segment (Fig. 1b and c asterisk, 1h). In negative ion mode, a segment was isolated in the papillary dermis of the control with an additional element colocalizing with the hair and secretory features in the reticular dermis (Fig. 1c). The average spectra from the control versus bitten skin segment showed changes across the phospholipid mass range in negative and positive ion modes (Fig. 1d and i). In contrast, the tick body showed distinctive ion signatures compared to the surrounding skin in both ion modes (Fig. 1e and h). Fig 1 Unique lipid ion patterns mapped in tick-bitten skin distinct from control. Post-MSI histology reference (H&E) for control and bitten skin samples (a, f; 12 mm sections) oriented with epidermis facing left. Labels: I, off-tissue; II, epidermis; III, dermis and hypodermis; IV, tick; V, papillary dermis; VI, reticular dermis with hair follicles and glands. (b) Negative ion mode segments. (c) Segmentation of III colocalized to the papillary dermis and hair/secretory features of the reticular dermis. (d and e) Average negative spectra from control (purple), bite site skin (green), and tick body (black) segments with tissue outline shown. (g) Positive ion mode segments. (h) Segmentation of III as in panel c. (i and j) Average positive spectra as in panels d and e. MALDI-MSI, normalized (root mean squared[RMS]), 100 mm spatial resolution. Tick-associated features are unique from guinea pig Tick-bitten samples showed abundant changes in spatial organization and intensity of various lipids, and the tick body resulted in a unique signature. Two examples of lipid changes were demonstrated by the negative ions m/z 786.526 and 714.506 ([PS 36:2-H+]- and [PE 34:2-H+]- all identities putative, <5 ppm) (Fig. 2a and b). The ion m/z 786.526 showed increased intensity in tick-bitten skin in the hypodermis, and the ion m/z 714.506 increased specifically in the epidermis. Interestingly, these ions were increased in tick-bitten skin but did not appear within the tick body. At the epidermal border with the tick bite, there was decreased abundance of m/z 714.506, suggesting interference resulting from the bite. In contrast, several ions were found in the tick body and increased in the underlying tick-bitten skin. The ion m/z 752.557 ([PE-O 38:4-H+]-) was found with high intensity in the tick body and within the dermal skin layer underneath the bite site (Fig. 2c). While it is not possible to determine the species origin in this experiment, we speculate that this ion is associated with the tick, possibly explaining the dermal distribution. Alternatively, the ion could be coincidentally associated with the host response. The ions m/z 859.531 ([PI 36:3-H+]-) and m/z 770.603 ([PC-O 34:0+Na+]+) showed strong intensity in the tick body with minor intensity in the bitten skin (Fig. 2d and e). Finally, a group represented by the positive ion m/z 774.512 ([MGDG 35:8+NH4+]+) showed higher intensity in the unbitten skin compared to either the tick body or the underlying bitten skin (Fig. 2f). The ion m/z 752.557 yielded a unique pattern in the dermis. We isolated regions control (unbitten) skin, embedded skin, tick body, and the dermal region of interest (Fig. 2g) and observed a trend between the intensity within the tick body and the dermis. Fig 2 Discriminatory ion patterns from lipid images of tick-bitten skin versus control. White outline: embedded tick. (a-d) Negative ions, as given, and H&E (e, duplicated from Fig. 1a). (f-g) Positive ions, as given, and H&E (h, duplicated from Fig. 1f). (a-d, f, and g) Normalized (RMS) with hotspot removal and weak denoising. (i) Inset showing ion map from panel c with outlined regions for pixel intensity distributions on control skin, bite site skin segment, sub-bite dermis segment (cyan outline on inset), and tick body. (a-d, f, and g) Receiver-operator characteristic area under the curve x <0.2 or (1x) <0.2. Tick bodies were stabilized and successfully sectioned with attached mammalian skin using fresh frozen samples. We collected serial sections (approximately four to five total) containing the tick and the embedded skin area. We observed structural rearrangements in the dermis; lipid signatures were associated with those histological changes. Furthermore, we identified several ion patterns enriched in the tick body compared to control or bitten skin. The most striking patterns were those ions that showed strong intensity in the tick body and appeared underneath the bite site (but were very low or absent from control skin). This is a singlet observation, and while ion identities can be approximated from accurate mass, no orthogonal methods were used, and the identities are putative. Regarding the sample preparation, most of the tissue section remained attached, but half of the exoskeleton did not remain attached to the slide this is a sample challenge that must be addressed for future studies. Ongoing work at the host-vector interface includes finding novel mechanisms to render the bite victim less appealing for arthropod vectors, thereby preventing pathogen transmission due to the lack of a mature bite site (7). Future work will expand this method to include infected ticks to model Borrelia burgdorferi transmission at the bite site to understand lipids and other small molecules in vector transmission. We present a feasible starting place for future studies involving uninfected and infected ticks to simultaneously model pathogen transmission and host response. ACKNOWLEDGMENTS The authors acknowledge Tialfi Bergamin de Castro for critical review of this manuscript. U.P. acknowledges support from National Institute of Allergy and Infectious Diseases (R01AI080615 and P01AI138949 to U.P.), R.M.A.H. acknowledges financial support from the LINK program of the Dutch province of Limburg, and A.J.S. acknowledges startup funds from the University of Maryland School of Dentistry. DATA AVAILABILITY The data from this study (MSI and brightfield images) are available on Zenodo using the digital object identifiers 10.5281/zenodo.7909128 and 10.5281/zenodo.7884760, respectively. REFERENCES 1 Scott AJ, Flinders B, Cappell J, Liang T, Pelc RS, Tran B, Kilgour DPA, Heeren RMA, Goodlett DR, Ernst RK. 2016. Norharmane matrix enhances detection of endotoxin by MALDI-MS for simultaneous profiling of pathogen, host and vector system. Pathog Dis 74 :ftw097. doi:10.1093/femspd/ftw097 27650574 2 Scott AJ, Post JM, Lerner R, Ellis SR, Lieberman J, Shirey KA, Heeren RMA, Bindila L, Ernst RK. 2017. Host-based lipid inflammation drives pathogenesis in Francisella infection. Proc Natl Acad Sci U S A 114 :12596-12601. doi:10.1073/pnas.1712887114 29109289 3 Cassat JE, Moore JL, Wilson KJ, Stark Z, Prentice BM, Van de Plas R, Perry WJ, Zhang Y, Virostko J, Colvin DC, Rose KL, Judd AM, Reyzer ML, Spraggins JM, Grunenwald CM, Gore JC, Caprioli RM, Skaar EP. 2018. Integrated molecular imaging reveals tissue heterogeneity driving host-pathogen interactions. Sci Transl Med 10 :eaan6361. doi:10.1126/scitranslmed.aan6361 29540616 4 Moore JL, Becker KW, Nicklay JJ, Boyd KL, Skaar EP, Caprioli RM. 2014. Imaging mass spectrometry for assessing temporal proteomics: analysis of calprotectin in Acinetobacter baumannii pulmonary infection. Proteomics 14 :820-828. doi:10.1002/pmic.201300046 23754577 5 Laroche M, Raoult D, Parola P. 2018. Insects and the transmission of bacterial agents. Microbiol Spectr 6 . doi:10.1128/microbiolspec.MTBP-0017-2016 6 Wikel S. 2013. Ticks and tick-borne pathogens at the cutaneous interface: host defenses, tick countermeasures, and a suitable environment for pathogen establishment. Front Microbiol 4 :337. doi:10.3389/fmicb.2013.00337 24312085 7 Kitsou C, Fikrig E, Pal U. 2021. Tick host immunity: vector immunomodulation and acquired tick resistance. Trends Immunol 42 :554-574. doi:10.1016/j.it.2021.05.005 34074602 8 Strobl J, Mundler V, Muller S, Gindl A, Berent S, Schotta A-M, Kleissl L, Staud C, Redl A, Unterluggauer L, Aguilar Gonzalez AE, Weninger ST, Atzmuller D, Klasinc R, Stanek G, Markowicz M, Stockinger H, Stary G. 2022. Tick feeding modulates the human skin immune landscape to facilitate tick-borne pathogen transmission. J Clin Invest 132 :e161188. doi:10.1172/JCI161188 36166299 9 Kitsou C, Pal U. 2021. Vaccine design, methods and protocols, volume 2. Vaccines for 213 veterinary diseases. Methods Mol biology 2411 :269-286. 10 Kurokawa C, Narasimhan S, Vidyarthi A, Booth CJ, Mehta S, Meister L, Diktas H, Strank N, Lynn GE, DePonte K, Craft J, Fikrig E. 2020. Repeat tick exposure elicits distinct immune responses in Guinea pigs and mice. Ticks Tick Borne Dis 11 :101529. doi:10.1016/j.ttbdis.2020.101529 32993942 11 Scott AJ, Chandler CE, Ellis SR, Heeren RMA, Ernst RK. 2019. Maintenance of deep lung architecture and automated airway segmentation for 3D mass spectrometry imaging. Sci Rep 9 :20160. doi:10.1038/s41598-019-56364-4 31882724 12 Scott AJ. 2023. Zenodo. Guinea Pig Skin & Tick Bite Site - MSI Raw Data Files. Available from: 10.5281/zenodo.7909128. |
mSystems mSystems msystems mSystems 2379-5077 American Society for Microbiology 1752 N St., N.W., Washington, DC 38126780 01189-23 10.1128/msystems.01189-23 msystems.01189-23 Editorial 2023 Acknowledgment of mSystems Ad Hoc Reviewers Gilbert Jack A. Editor in Chief, mSystems 1 [email protected] 1 University of California San Diego School of Medicine , La Jolla, California, USA Address correspondence to Jack A. Gilbert, [email protected] Nov-Dec 2023 21 12 2023 21 12 2023 8 6 e01189-23Copyright (c) 2023 Gilbert. 2023 Gilbert. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license. cover-dateNovember/December 2023 pmcEDITORIAL As we take a moment to reflect on the trajectory of scientific publishing, it is clear that the core of its evolution and integrity lies in peer review. This cornerstone of science not only ensures rigorous scrutiny but also represents a tradition of mentorship, collaboration, and shared responsibility. Peer review, in its true essence, bridges the past with the future and embodies the continuum of scientific discovery. Today, we find ourselves in a world of ever-accelerating technological advancements and boundless research arenas, and yet the backbone of scientific authenticity remains deeply rooted in the dedicated work of peer reviewers. Every manuscript reviewed, every piece of constructive feedback given, and every suggested edit signifies the silent dedication of a global community that places the sanctity of scientific rigor above all else. It's not just about upholding standards, but about mentoring the next generation, refining theories, and facilitating a culture of collective growth. Each review is a conversation, a critical examination, and, most importantly, an act of trust in the broader scientific ecosystem. Yet, challenges persist. As we stand on the cusp of new frontiers in microbiology, the demand for reviewers and the challenges they face have never been more pressing. In this fast-paced digital age, where information dissemination is instantaneous, the need for meticulous, unbiased, and rigorous peer review cannot be understated. Misinformation, if left unchecked, can spread rapidly, eroding public trust and potentially leading to costly missteps. We, at mSystems, deeply value the multifaceted roles that each scientist assumes: as researchers, as authors, and, most crucially, as peer reviewers. It's this trifecta that creates a balanced perspective, ensuring that every piece of research we publish stands up to the highest standards of scrutiny. To each and every reviewer who has dedicated time and expertise to mSystems, we extend our profound gratitude. Your commitment not only serves the present but secures the legacy of scientific excellence for future generations. You are the unsung heroes, that we now identify, that ensure that the beacon of scientific integrity continues to shine brightly. In championing the cause of the American Society for Microbiology and the broader community, you are paving the path for a future where science is not just pursued, but celebrated, trusted, and integrated into the very fabric of society. Thank you for upholding the legacy and propelling us into a future built on truth and shared discovery. Bruno Lopes Abbadi Sophie Saphia Abby Karim Abdelkader Michael C. Abt Silvia G. Acinas Amanda N. D. Adams Adeyinka Joseph Adebo Benjamin Austin Adler Nisheeth Agarwal Narij Agarwala Surya D. Aggarwal Niyaz Ahmed Tae-Hyuk Ahn Muhammad Taj Akbar Yukihiro Akeda Armin Alaedini Davide Albanese Rodolpho Mattos Albano Daniele Alberoni Anna Alemany Alison Felipe Alencar Chaves Gajender Aleti Leena Al-Hassan Celeste Allaband Alexander B. Alleman Charlotte J. Alster Hassan M. Al-Tameemi Mustafa Altindis Artur Alves Fairoz Ali Al-Wrafy Nana Ama Amissah Xinli An Karthik Anantharaman Cheryl P. Andam Daniel S. Andersen Alexander C. Anderson Lindsey N. Anderson Rika Anderson Nana Y. D. Ankrah Hector Arguello Hector Arguello Rodriguez Stephane Aris-Brosou Alix Augusto Armero Villanueva Allegra Aron Janelle C. Arthur Aleksandr A. Arzamasov Phil Ashton Sandrine Auger Caroline Autenrieth Charlotte Avanzi Ranen Aviner Joseph Atia Ayariga Frank O. Aylward Ali Azghani Elizabeth Bach Herwig Bachmann Haoxiang Bai Jinna Bai Marc Alex Bailie Jasmohan Bajaj Djordje Bajic Jonathon L. Baker Ramya Balasubramanian Nitin S. Baliga Emily P. Balskus Sreejata Bandopadhyay Yuanyuan Bao Roman Alfredo Barco Sonia L. Bardy Didier Barradas-Bautista Wiley Barton Arianna Basile Franco Basile Tiffany Batarseh Buzz Baum Megan G. Behringer Aeriel D. Belk Rebecca L. Bell Daniel Bellieny-Rabelo Alfonso Benitez-Paez Stephane Louis Benoit Tom Berben Christian Berens Hanna Leah Berman Anthony Bertagnolli Maria T. Bertoli Aaron A. Best Omolola Comfort Betiku James E. Bina Jordan E. Bisanz Pradeep Bist Aitor Blanco-Miguez Lars M. Blank Jon S. Blevins Rahul Bodkhe Jian Sheng Boey Nick Bohmann Tobias Bollenbach Alte Bones Cyril Bontemps Emmanuelle S. Botte David G. Bourne Ben Bourrie Jason Brenchley Arianna Brevi Colin J. Brislawn Jose A. Brito Chequita Brooks Bryan Paul Brown Shawn P. Brown Mark P. Brynildsen Bryan D. Bryson Andrew A. Buckley Daniel H. Buckley Shelly Buffington James Bull Ashley N. Bulseco Zachary M. Burcham Liana T. Burghardt Susheel Bhanu Busi Mariaelena Caboni Elisabetta Cacace Lindsay K. Caesar Jingyi Cai Benjamin Calfee Douglas Campbell Fabricio Souza Campos Thaisa M. Cantu-Jungles Andres Mauricio Caraballo Rodriguez Miguel Carda-Dieguez Michael Carlson Carolina Carpenter William Franklin Carson Monica Cartelle Gestal Kayla A. Carter John R. Casey Santiago Castillo-Ramirez Sergio Castro-Gonzalez Jonatas da Silva Catarino Florian Centler Jorge Cervantes Miguel Angel Cevallos Yunrong Chai Rishi Chanderraj Yanjie Chao Trevor C. Charles Bala Chaudhary Biao Chen Chen Chen Congying Chen Guo Fu Chen Hongbin Chen Jie Chen Liang-Jun Chen Lianmin Chen Pubo Chen Tingtao Chen Yan Chen Marc Chevrette Loo Wee Chia Ludmila Chistoserdova Byung-Kwan Cho Ashok Choudhary Felipe Christoff Wouters Yuefeng Chu Camilla Ciolli Mattioli Ousmane H. Cisse Gachon Claire Claudia Claus Friederike Katharina Clever Gitta Coaker Ana G. Cobian-Guemes Marta Cobo Simon Stephen D. Cole Maureen L. Coleman Jacqui Comstock Pablo Conesa-Zamora Sean Conlan Bede Constantinides Bruno Contreras-Moreira Francesca Cordero Paulina Corral Clara Correia-Melo Richard Costa Polveiro Sneha P. Couvillion John V. Cox Jason M. Crawford Douglas J. Creedon Jonas Cremer Alex Crits-Christoph Scott Cunningham Robert Czajkowski Paul M. D'Agostino Jan-Ulrik Dahl Zhongmin Dai Leslie Keiclyn Daille Enriquez Alex Dajkovic Paul Daly Mary E. Davey Lawrence A. David Maude David James J. Davis Robin Dawson Tom Delmont Marcos De Moraes Yijie Deng Yu Deng Nicole J. De Nisco Daniel P. Depledge Damien P. Devos Muhe Diao Patricia Diaz George C. Dicenzo Seth W. Dickey Johan Dicksved Christian Diener Nicholas A. Dillon Alexander Dilthey Demetrius Dimucci Yuanzhao Ding Marcia Dinis Alan Angelo Dispirito Talisa Doering Nadezhda Victoria Doncheva Andrew C. Doxey Daniel Christopher Ducat Lara Dugas Seana Duggan Sylvia Duncan Ashley M. Dungan Anne K. Dunn Sanjucta Dutta Michael L. Dyall-Smith Emily Ebel Martinique Lefevre Edwards Sabine Ehrt Sahar El Aidy Melissa Ellermann Stephen P. Ellner Mostafa S. Elshahed David Emerson Susanne Engelmann Melinda Anne Engevik Hyungjin Eoh Tobias Jurgen Erb A. Murat Eren Eduard Fadeev Camilla Fagorzi Sicun Fan Michael J. Federle Conor Feehily Na Fei Pinghui Feng Youzhi Feng Isabel Fernandez Escapa Fernando Ferreira Kenneth A. Fields Joshua Fierer Steven E. Finkel Sarai Finks J. Ross Fitzgerald Avi I. Flamholz Michelle Flenniken Beverly E. Flood Sarah M. Fortune Iain D. C. Fraser David N. Fredricks Kelle C. Freel Shiri Freilich Nancy E. Freitag Clemence Frioux Ping Fu Songzhe Fu Yunhe Fu Thilo M. Fuchs Jed Fuhrman Erika Ganda Sukirth Ganesan Michael G. Ganzle Gui-Feng Gao Erin C. Garcia Nathan Garcia Sarahi L. Garcia Melanie G. Gareau Josep M. Gasol Julia M. Gauglitz David A. Gaul Asimenia Gavriilidou Ding Gc Micahel Gebhardt Benedikt Geier Paul Bryn Llewellyn George Volker Gerdts Samira Ghaedmohammadi Shokufeh Ghasemian Sorboni Richard J. Giannone Steven R. Gill Osnat Gillor Matthew Gilmour Khyati Girdhar Erin Gloag Joao Vitor Godoy Takashe Alejandro Gomez Mejia Yanhai Gong Victor Gonzalez Antonio Gonzalez Ana Camila Gonzalez-Nayeck Lawrence Goodridge Isabel Gordo Dennis Goss-Souza Sarah M. Gray Todd A. Gray Shermalyn R. Greene Jessica A. Grembi Harald R. Gruber-Vodicka Erwan Gueguen Emily Laura Gulliver Rudiyanto Gunawan Kiran Gurung Asiya Gusa Elaine M. Haase Muhammad Bilal Habib Mehrad Hamidian Trinity L. Hamilton Tobin Hammer Jarrad Hampton-Marcell William Hanage Pamela Hanson Xavier Harrison Roland Hatzenpichler Anna Hayes Yan He Zhili He Brian P. Hedlund Julian Hegemann Marco Hein Jason E. Heindl Almut Heinken John D. Helmann Chris Henry Christopher Henry Michael Henson Marta Hernandez-Garcia Joanna Hicks Caitlin Hicks Pries Megan S. Hill Luke Hillary Kelly Marie Hines Adrian Ho Christopher Hodgkins James F. Holden Erik Holmqvist Elizabeth A. Holzhausen Xiao-Yue Hong Mingsheng Hong Suzie Hoops Alice Hotopp Andrew J. Hryckowian Anyi Hu Yongfei Hu Jinhu Huang Li-Nan Huang Dana E. Hunt Ryan C. Hunter Fatima Hussain Josiah Hutton Kevin Hybiske Keiichi Inaoue Ikbal Agah Ince Jaime Iranzo William R. Jacobs Marie-Agnes Jacques Natalia Jakus Neema Jamshidi Elisabeth M.-L. Janssen Heather B. Jaspan Benjamin Anderschou Holbech Jensen Paul A. Jensen Ederson da Conceicao Jesus Mollie Winfield Jewett Xu Jia Hongchen Jiang Linshu Jiang Xiaofang Jiang Yong Jiang Shuo Jiao Yuan Jin Bradley D. Jones Stuart Jones Peter Jorth Paula Jouhten Igor B. Jouline Tingting Ju David Kaftan Lindsay Kalan Stephan Kamrad Antti Karkman Lisa Karstens Shingo Kato Kathryn Kauffman Jason G. Kay Leonard Kaysser Simon Keely Dr Ian Keesey Scott T. Kelley Eduard J. Kerkhoven Mohammadali Khan Mirzaei Devanshi Khokhani Adam Kim Manuel Kleiner Karl E. Klose Benjamin J. Koestler Steffen Kolb Weidong Kong Yaxian Kong Eugene V. Koonin Tamas Korcsmaros Tal Korem Olivia Kosterlitz Corey Krabbenhoft Karin E. Kram Jens Kreth Yi-Qun Kuang Anand Kumar Deepak Kumaresan Hang Fai Kwok Simon Labarthe Leo Lahti Henry Lam Margaret Lam Richard J. Lamont Lefu Lan Christian Lauber Aonghus Lavelle Simon Lax Sunil Laxman Chih-Ying Lay Sam Leareng Quentin J. Leclerc Jaejin Lee Kyu-Ho Lee Vincent T. Lee Jenni Lehtimaki Danielle G. Lemay Katherine P. Lemon Jay T. Lennon Tiphaine Le Roy Baptiste Leroy Elisabeth Letellier Janina P. Lewis Joseph Lewis Ruth E. Ley Fu-Li Li Jibing Li Juan Li Ruichao Li Xiaoping Li Xinxin Li Yang Li Yanpeng Li Zhipeng Li Yuting Liang Zhikai Liang Xiudong Liao Julia Lienard Chun Shen Lim Xiangping Lin Melody Lindsay Fangqiong Ling Changhong Liu Dawei Liu Hai-Peng Liu Haoyu Liu Jinxin Liu Junhua Liu Mao-Ke Liu Shengen Liu Shuting Liu Xiao Liu Xingyin Liu Ya-Jun Liu Zhaoguo Liu Malgorzata Barbara Lobocka Torey P. Looft Zhiyong Lou Tiffany M. Lowe-Power Gabriel L Lozano Catherine Lozupone Danqi Lu Huijie Lu Junfeng Lu Tillmann Lueders Adela Maria Lujan Piotr Lukasik Jessica K. Lukowski Xiaoping Luo Yuheng Luo Mor Lurie-Weinberger Joshua Mark Lyte Jiaming Ma Li-Jun Ma Zhe Ma Alejandro Eduardo Maass Michael Christopher Macey Daniel Machado Tanmay Majumdar Rex R. Malmstrom Nilusha Malmuthuge Christian Maltecca Lauren Manck Mike Manefield Melissa Manus Sylvie Manuse Shengyong Mao Julia A. Maresca Simone Marini Stephanie Markert Jose Manuel Marti Carlos Martin Laura Martinez Alvarez Manuel Martinez-Garcia Maria Elena Martino Vincent G. Martinson Rasmus Lykke Marvig Shah Masaud Joleen Masschelein Ruth Massey William Joseph Massey Sebastien Matamoros Timothy E. Mattes Mauro Maver Xavier Mayali Luis Mayorga Jessica R. McCann Christopher McCrae Daniel McDonald Diane McDougald Shelby E. McIlroy James B. McKinlay Jeffrey Scott McLean Matthew B. McNeil Marco Enrique Mechan-Llontop Filiatrault Melanie Silvia Melgar Timothy C. Meredith Lauren Messer Michelle M. Meyer Mario Meza Segura Jennifer Middleton Aram Mikaelyan Laura A. Mike Andrew D. Millard Aaron W. Miller Daniel P. Miller Kiwamu Minamisawa Douglas A. Mitchell Sara Mitri Samuel J. Modlin Jose Arturo Molina-Mora Denise M. Monack Tushar More Andrey Morgun Jorge Moura De Sousa Volker Mueller Arunika Mukhopadhaya Biswarup Mukhopadhyay Anne Muller Conrad W. Mullineaux Rafael Munoz-Tamayo Mario E. Muscarella D. Na Girish Nair Tanja Narancic Takashi Narihiro Muhammad Nawaz Stephen Nayfach Daniel R. Neill William C. Nelson Bao-Anh Thi Nguyen Abigail Nieves Delgado Yosuke Nishimura Cecilia Noecker Avery J. C. Noonan Jeanette M. Norton Angela Novais Juliano Novak Eric Nybo Howard Ochman Erkison Ewomazino Odih Joanne O'Donnel Peter Oelschlaeger Tamir Ofek Pierre Offre Thomas Vincent O'Halloran Hugo Oliveira Angela Oliverio Alejandro Olmedo-Velarde Jolien Onsea Daniel Osorio Jay Osvatic Hong-Yu Ou Zihao Ou Zhiming Ouyang Egon Anderson Ozer Bernhard O. Palsson Meichen Pan Ivona Pandrea Sivachandran Parimannan John Parkinson Anastacia Parks Sally R. Partridge Edoardo Pasolli Alessandro Passera Ranjana Pathania Kathryn A. Patras Shyamal Peddada Dale A. Pelletier Jose Penades Rafael Pena-Miller John Penders Ariane L. Peralta Ana Elena Perez-Cobas Veronika K. Pettersen Bernadeta Pietrzak Lars Plate Magdalena Plotka Mircea Podar Claudia Pogoreutz Katherine S. Pollard Olga Ponomarova Andrew W. Pountain Julie D. Pourtois Alexander J. Probst Meng Pu Sandra Pucciarelli Emily Putnam Qi Qu Zhe-Xue Quan Maria Soledad Ramirez Christopher Rao Noa Rappaport Majeeda Rasheed Jayamary Divya Ravichandar Timothy D. Read Maria Rebolleda Gomez Tavis Reed Linta Reji Maria R. Esteban Torres Charlie Rice Luke Richards Christian U. Riedel Raul Riesco Jarrin Richard J. Roberts Nash D. Rochman Dmitry A. Rodionov William Rodriguez Josue A. Rodriguez-Ramos Connie A. Rojas Barry H. Rosen Denis Roy Martin Rumbo Hossam E. Rushdi Joseph Russel David G. Russell Feargal Ryan Claudia P. Saavedra Rajib Saha Ali Salehzadeh-Yazdi Hubert Salvail Scott Samuels Laura M. Sanchez Shengmin Sang Panagiotis Sapountzis Antonia Sargona Guillaume Sarrabayrouse Jimmy H. Saw Till F. Schaberle Joseph Schacherer Matthias Schewe Jonathan E. Schmitz Dirk Schneider Frank Schreiber Lynn Schriml Alison J. Scott Anna Maria Seekatz Daniel Segre Julie A. Segre Adrian Serohijos Shiraz A. Shah Yunlong Shan Yongqi Shao Zongze Shao B. Jesse Shapiro Vineet K. Sharma Virag Sharma Cody Sheik Giyoon Shin Abhishek Shrivastava Natalia Shulzhenko Mark W. Silby Anoop Singh Mangal Singh Ritam Sinha Clayton M. Small Younes Smani Thomas J. Smith Scott D. Soby Bahrad Ali Sokhansanj Evgeni Sokurenko Ahmed M. Soliman Kevin V. Solomon Vincent Somerville Yinglong Song Matthew Sorbara Patrick Sorensen Lauren Speare Apollo Stacy Vanessa Stadlbauer Maggie Ann Stanislawski Christoph Stein-Thoeringer Adi Stern Blaire Steven Ann M. Stevens Michael Strong Reed M. Stubbendieck Fengjie Sun Jian Sun Xiang Sun (Sun) Xin Sun Hoon-Ki Sung Jaeyun Sung Dwi Susanti Y. Suzuki Jason B. Sylvan Jyoti Prakash Tamang Sabrina Tamburini Hongzhi Tang Zhonglin Tang Julien Tap Christoph C. Tebbe Eva Teira Herve Tettelin Bas Teusink Kevin R. Theis Janne Gesine Thoming Luke R. Thompson Mitchell G. Thompson J. Cameron Thrash Kara A. Tinker Anna D. Tischler Alfredo G. Torres Guy Edmund Townsend Patricia Q. Tran Tuan Minh Tran Brian K. Trevelline Cagla Tukel Burkhard Tummler Hidetoshi Urakawa Joseph J. Vallino Daniel Valout Angel Valverde Jan Roelof van der Meer James T. Van Leuven Tommi Vatanen Roberto Vazquez Ben Vezina Peter Vikesland Alejandro J. Vila Luis Vitetta Max von Kleist Maarten Jeroen Voordouw Jay Vornhagen Russ Vreeland Steffen Waldherr Kimberly A. Walker Mark Chalfant Walker Nia Walker David A. Walsh Yu Wan Zheng Wang David Wang Gefei Wang Jianjun Wang Kan Wang Leyao Wang Lu Wang Mingbang Wang Shilei Wang Xian-Wei Wang Yi Wang Yue Wang Silvio Waschina Kenneth Wasmund Eric Webb Tilmann Weber Yunwei Wei Alexandra J. Weisberg Allana Welsh Jeanette Whitaker Thea Whitman Ian Will Claire E. Williams Lashanda Williams Michael R. Wilson Steven S. Witkin Patricia Wolf Alan J. Wolfe Richard Wolff Charles Wolgemuth Giselle Chloe Wong Meike T. Wortel Tanja Woyke Erik Scott Wright Bo Wu Jian-Yong Wu Peng Wu Ruonan Wu Tong Wu Wei-Kai Wu Wei-Li Wu Han Xia Juan Xicohtencatl-Cortes Chao Xiong Xiaofeng Xu Xin Xu Kai Xue Aixin Yan Fuhua Yan Qingyun Yan Qian Yang Shihui Yang Yuyi Yang Min Yap Yuzhen Ye Aaron Yerke Ozlem Yilmaz Huaqun Yin Sukhwan Yoon Yunsong Yu Shuofeng Yuan Maksim Zakhartsev Asier Zaragoza-Solas Anton Zavialov Merve S. Zeden Karsten Zengler Cheng-Cai Zhang Guoliang Zhang Hao Zhang Kai Zhang Quan-Guo Zhang Wanjiang Zhang Wenliang Zhang Yongjun Zhang Shijie Zhao Siyan Zhao Xilin Zhao Yingming Zhao Zhe Zhao Beiwen Zheng Chunfu Zheng Hao Zheng Xuhui Zheng Zhang Zheqingzhang Xiangyun Zhi Yongjia Zhong Bin Zhou Dongsheng Zhou Rongqing Zhou Xi Zhou Lifeng Zhu Qiyun Zhu Yan Zhu Ryan M. Ziels Erik R. Zinser Erwin G. Zoetendal Lingyun Zou Cristal Zuniga |
J Vet Diagn Invest J Vet Diagn Invest VDI spvdi Journal of Veterinary Diagnostic Investigation : Official Publication of the American Association of Veterinary Laboratory Diagnosticians, Inc 1040-6387 1943-4936 SAGE Publications Sage CA: Los Angeles, CA 37919965 10.1177/10406387231204560 10.1177_10406387231204560 Brief Reports Use of a chromogenic medium with and without selective enrichment to screen for carbapenemase-producing Enterobacterales (CPE) from canine and feline fecal specimens during an outbreak of NDM-5-producing Escherichia coli Cole Stephen D. 1 Dietrich Jaclyn Rankin Shelley C. Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA 1 Stephen D. Cole, Department of Pathobiology, University of Pennsylvania, 3900 Delancey St, Philadelphia, PA 19104, USA. [email protected] 2 11 2023 1 2024 2 11 2023 36 1 124127 (c) 2023 The Author(s) 2023 American Association of Veterinary Laboratory Diagnosticians This article is distributed under the terms of the Creative Commons Attribution 4.0 License ) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ). Carbapenemase-producing Enterobacterales (CPE) are one of the most urgent threats to human healthcare globally. Descriptions of CPE outbreaks in veterinary hospitals suggest the need for screening strategies for CPE from companion animals. Our aim was to optimize a chromogenic agar method with and without selective enrichment to isolate CPE from companion animal feces in an ongoing outbreak of New Delhi metallo-b-lactamse-5 Escherichia coli. A limit of detection (LOD) assay for spiked canine and feline feces was performed for both methods using a carbapenamase-producing E. coli (24213-18); the LOD (1.5 x 103 cfu/g of feces) was equivalent to that reported for human fecal specimens. We screened 1,247 companion animal fecal specimens for carriage of CPE by 1) direct plating to chromogenic agar and 2) plating to chromogenic agar following selective enrichment. Twenty-one specimens were positive for CPE by both direct culture and enrichment culture. No specimens were positive with selective enrichment and negative by direct culture. A selective enrichment step did not result in any increased recovery of CPE from companion animals, which suggests that enrichment broth may not be necessary for outbreak surveillance testing. It is important to continue to validate methods for the detection of CPE in companion animals as outbreaks become more common in veterinary facilities. carbapenem-resistant Enterobacterales carbapenemase companion animals screening selective enrichment veterinary infection prevention U.S. Food and Drug Administration 1-U18-FD-006855-01 typesetterts1 pmcThe spread of carbapenemase-producing Enterobacterales (CPE) is one of the most urgent threats that face human healthcare globally.16,18 Carbapenemase enzymes produced by CPE hydrolyze carbapenems and other b-lactam drugs. 6 Additionally, strains of CPE are often resistant to most clinically relevant antimicrobials, which makes infections caused by CPE difficult to treat and life-threatening.6,16,18 The 5 common carbapenemase enzyme families described in Enterobacterales are: Klebsiella pneumoniae carbapenemase (KPC), New Delhi metallo-b-lactamase (NDM), Ve-rona integron metallo-b-lactamase (VIM), imipenemase (IMP), and OXA-48-like. 18 Metallo-b-lactamases NDM, VIM, and IMP are classified as Ambler class B. KPC and OXA-48 use serine ester hydrolysis and are classified as Ambler class A and D, respectively. 18 CPE colonize the gastrointestinal tract of people without producing symptoms of infection, which makes CPE a particular challenge for infection control programs.3,16,18 Silent spread of CPE occurs between patients in hospital settings, particularly among immunosuppressed people and people receiving antimicrobial therapy.1,3 Most reports of CPE isolated from dogs and cats are limited to a single or a few cases, 17 but recent descriptions of CPE outbreaks in veterinary hospitals suggest the need for strategies to respond to CPE quickly and aggressively.2,4,10 Strategies for control of CPE in companion animals have not been well-defined. The accurate and rapid laboratory detection of gastrointestinal colonization has been critical to the control of CPE in human hospitals during outbreaks.1,3,16,18 In human hospitals, rapid identification of colonized individuals allows for instituting strategies such as cohort nursing and appropriate personal protective equipment. 3 The same is likely to be true in veterinary clinical settings; however, no microbiology laboratory methods have been evaluated for the screening of CPE in animal feces for infection control purposes, to our knowledge. A 2020 report suggested that many veterinary laboratories in the United States are underprepared to identify CPE. 20 Veterinary diagnosticians and clinicians must take an aggressive approach to the detection of CPE in animals given that the detection of CPE is reportable in many jurisdictions. It is likely that diagnostic laboratories working with veterinary facilities in which CPE outbreaks occur may need to modify their methodology to balance costs with timely reporting of results. Molecular detection of carbapenemase genes by real-time PCR is the current gold standard for rapid detection of carbapenemase-producing CPE, 8 but the cost and resources to perform molecular tests may limit their utility in veterinary medicine. Chromogenic agars have been evaluated for the detection of CPE in human fecal specimens.11,19 However, such agars are considerably more expensive and often have a shorter shelf-life than other prepared media. Selective enrichment is often used in microbiology laboratories to promote the growth of target organisms and suppress the growth on non-target organisms from complex specimens with diverse bacterial loads such as feces. 15 Selective enrichment is not included in the manufacturer's protocols for the use of chromogenic media in the detection of CPE. However, selective enrichment culture steps are routinely included for the isolation of Salmonella spp. from canine fecal specimens 9 and have been shown to be useful for isolation of other multidrug-resistant organisms from companion animal specimens. 7 Our aim was to assess the use of a chromogenic agar method with and without enrichment culture to isolate CPE from companion animal feces in an ongoing outbreak of NDM-5 Escherichia coli at a veterinary teaching hospital. We performed limit of detection (LOD) assays for canine and feline feces in duplicate using an isolate of blaNDM-5 Escherichia coli (24213-18) previously characterized as part of an ongoing outbreak. 4 A 0.5 McFarland standard (~1.5 x 108 cfu/mL) suspension of E. coli 24213-18 was prepared in saline, and a 1:10 dilution series was performed. A 1-mL aliquot of each dilution (101-107) was mixed thoroughly with 2 samples of feces (1 g each; 1 sample obtained from a dog and the other from a cat, with both animals previously determined to be free of CPE). A sterile swab (Specimen collection device; Cepheid) was dipped once into the spiked feces and used to inoculate a chromogenic agar plate (CHROMID CARBA; bioMerieux). The plates were incubated inverted at 35 +- 2degC for 18 h under atmospheric conditions. Enrichment was performed simultaneously by inoculating a swab with the spiked feces that was placed into 5 mL of trypticase soy broth (TSB; Remel) containing a 10-mg meropenem (MEM) Kirby-Bauer disc (Sensi-Disc; BD-BBL). 11 The inoculated TSB-MEM was incubated 35 +- 2degC for 18 h under atmospheric conditions as a selective enrichment for carbapenem-resistant organisms. A 10-mL loop of the TSB-MEM broth was then streaked to chromogenic agar and incubated as described above. A representative, presumptive positive colony (pink-to-burgundy) from the lowest positive dilution was confirmed to harbor an NDM gene by a commercial PCR (Carba-R assay; Cepheid). 8 We also compared direct and enrichment culture on chromogenic agar. Specimens from dogs and cats were collected as part of a biosecurity program established as part of a public health response to a CPE outbreak. Fecal specimens (collected either by free-catch or rectal swab) were submitted to the clinical microbiology laboratory at the Ryan Veterinary Hospital (RVH) at the University of Pennsylvania's School of Veterinary Medicine (Philadelphia, PA, USA). Submission of diagnostic specimens is considered part of clinical care and does not require institutional approval. For the direct method, feces was inoculated onto the chromogenic agar plate per the manufacturer's instructions. For the enrichment method, feces was inoculated into TSB-MEM broth, incubated, and subcultured to chromogenic agar as described above for the LOD assay. Plates were examined after 18-24 h of incubation for pink-to-burgundy-colored colonies (presumptive E. coli) or blue-gray or purple colonies (presumptive Klebsiella, Enterobacter, Serratia, or Citrobacter spp.). Presumptive CPE were subcultured to MacConkey agar (Remel) and identified with the GN identification card on the Vitek 2 (bioMerieux). Production of a carbapenemase enzyme was confirmed by the modified carbapenem inactivation method (mCIM), 14 the minimum inhibitory concentration for imipenem was determined by E-test (bioMerieux), and the carbapenemase gene was identified with the Carba-R assay on the GeneXpert (Cepheid), which tests for carbapenemase genes (blaKPC, blaNDM, blaVIM, blaIMP, blaOXA-48). 8 The LOD following direct plating to chromogenic agar was 1.5 x 103 cfu/g of feces for both canine and feline feces spiked with the 24213-18 isolate. Following the enrichment culture step (TSB-MEM broth), the LOD was 1.5 x 102 cfu/g of cat feces and 1.5 x 103 cfu/g of dog feces. Between July 2019 and March 2021, we screened 1,247 animal specimens (979 canine and 244 feline) for carriage of CPE by direct plating to chromogenic agar and by plating to chromogenic agar following the selective enrichment culture described above. A total of 21 specimens (1.6%), 18 from dogs and 3 from cats, were positive for CPE by direct culture to a chromogenic agar plate (Table 1). Twenty isolates were identified as E. coli and one as E. cloacae complex. All presumptive isolates were positive for carbapenemase production by mCIM. Twenty isolates (19 E. coli and 1 E. cloacae) were positive for a blaNDM gene and 1 E. coli isolate was positive for a blaKPC gene. All corresponding selective enrichment cultures were also positive, and the same carbapenemase gene was identified. No specimens were positive by selective enrichment and negative by direct culture. Table 1. Summary of carbapenemase-producing Enterobacterales (CPE) isolated on chromogenic agar, with and without selective enrichment, from animal feces. Organism/Host species No. of isolates Imipenem MIC, mg/mL Carbapenemase detected Escherichia coli Cat 1 4 NDM 1 8 NDM 1 16 NDM Dog 2 4 NDM 9 8 NDM 5 16 NDM 1 16 KPC Enterobacter cloacae Dog 1 16 NDM KPC = Klebsiella pneumoniae carbapenemase; NDM = New Delhi metallo-b-lactamase. A direct plate method is consistent with the manufacturer's instructions and has been shown to be a sensitive method (> 90%) compared to the recommended U.S. Centers for Disease Control and Prevention method with TSB-MEM. 11 In some human studies,5,13 the selective enrichment method paired with chromogenic medium has been shown to identify additional positive specimens. However, in our study of over 1,200 animal fecal specimens, we found complete correlation between results of a direct chromogenic agar plate method and chromogenic agar culture following a TSB-MEM enrichment step. This suggests that a selective enrichment step may not be necessary to screen companion animals for carriage of CPE. During this outbreak, presumptive positive isolates were reported to clinicians within 24 h of receipt of the specimen, and appropriate infection control measures were implemented if the specimen was positive. Control measures at the RVH included contact precautions, isolation, enhanced environmental disinfection and monitoring, and repeated testing of positive animals at future times. The improved turnaround time may not hold true for all CPE, and continued evaluation of methodologies is needed if outbreaks of CPE are identified in companion animal facilities in the future. Although the use of the enrichment broth improved the LOD for spiked cat feces by 10-fold (1.5 x 102), both direct and enrichment methods for 244 cat specimens yielded identical results (3 positives, 241 negatives). Hence, although the improved LOD with enrichment did not aid in the detection of additional cases during this outbreak, the utility of enrichment could be considered in future surveillance efforts for cats with lower colonization burdens. It is important to acknowledge that important species differences may exist and, given the lower number of positive cats and screened specimens relative to dogs, additional evaluation of feline specimens may be necessary. Our study was performed during an outbreak of NDM-5-producing E. coli. Therefore, the clonal relationship of many of the isolates is a potential limitation for broader application. However, our study lays a foundation for veterinary laboratories to start when faced with specimens to screen in a CPE outbreak. Our described method detected E. coli with a blaNDM gene from the feces of 18 animals, E. coli with a blaKPC gene from 1 animal, and an E. cloacae isolate with a blaNDM gene from 1 animal. Even though we assessed the method with over 1,200 specimens, the relatively low prevalence of CPE in animals means that more studies on methodology are needed. There are many more possible combinations of bacterial species and carbapenemase genes than those detected in our study population, and this method may not be generalizable to the detection of all types of CPE in fecal specimens from companion animals. For example, it is possible that OXA-48-like-producing CPE were missed given that the tested chromogenic agar is not formulated for isolates that produce Ambler class D carbapenemases. Several other chromogenic media are commercially available, but we did not assess them in our study. Our results should not be extrapolated to all chromogenic agars. The chromogenic agar that we used has been shown to be inferior to a laboratory-formulated medium to detect CPE isolates with a low-carbapenem MIC (imipenem < 4 ug/mL) from food animals. 12 The chosen medium was adequate for our study because all outbreak isolates cultured from clinical specimens prior to our study grew readily on the medium and had an imipenem MIC > 4 mg/mL. 11 If a laboratory is performing surveillance during a companion animal CPE outbreak, it would be prudent to evaluate the need for enrichment culture for the targeted strains with their medium of choice. Future studies should include the development and assessment of additional strategies to detect and respond to outbreaks of CPE in companion animal facilities rapidly and cost-effectively. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Funding: Our study received funding (FOA PAR-18-604) from the U.S. Food and Drug Administration's Veterinary Laboratory Investigation and Response Network (FDA Vet-LIRN) under grant 1-U18-FD-006855-01. ORCID iD: Stephen D. Cole References 1 Bhargava A , et al . Risk factors for colonization due to carbapenem-resistant Enterobacteriaceae among patients exposed to long-term acute care and acute care facilities. Infect Control Hosp Epidemiol 2014;35 :398-405.24602945 2 Brilhante M , et al . Two high-risk clones of carbapenemase-producing Klebsiella pneumoniae that cause infections in pets and are present in the environment of a veterinary referral hospital. J Antimicrob Chemother 2021;76 :1140-1149.33615354 3 Centers for Disease Control and Prevention. Facility guidance for control of carbapenem-resistant Enterobacteriaceae (CRE). 2015 Nov 1. 4 Cole SD , et al . New Delhi metallo-b-lactamase-5-producing Escherichia coli in companion animals, United States. Emerg Infect Dis 2020;26 :381-383.31961309 5 Glaser L , et al . Improved surveillance for carbapenem-resistant Enterobacteriaceae using chromogenic media with a broth enrichment. Diagn Microbiol Infect Dis 2015;82 :284-285.26003468 6 Hammoudi Halat D Ayoub Moubareck C . The current burden of carbapenemases: review of significant properties and dissemination among gram-negative bacteria. Antibiotics (Basel) 2020;9 :186.32316342 7 Hordijk J , et al . High prevalence of fecal carriage of extended spectrum b-lactamase/AmpC-producing Enterobacteriaceae in cats and dogs. Front Microbiol 2013;4 :242.23966992 8 Ko YJ , et al . Diagnostic performance of the Xpert Carba-R assay for active surveillance of rectal carbapenemase-producing organisms in intensive care unit patients. Antimicrob Resist Infect Control 2019;8 :127.31384432 9 Marks SL , et al . Enteropathogenic bacteria in dogs and cats: diagnosis, epidemiology, treatment, and control. J Vet Intern Med 2011;25 :1195-1208.22092607 10 Nigg A , et al . Shedding of OXA-181 carbapenemase-producing Escherichia coli from companion animals after hospitalisation in Switzerland: an outbreak in 2018. Euro Surveill 2019;24 :1900071.31576806 11 Papadimitriou-Olivgeris M , et al . Performance of chromID(r) CARBA medium for carbapenemases-producing Enter-obacteriaceae detection during rectal screening. Eur J Clin Microbiol Infect Dis 2014;33 :35-40.23912722 12 Pauly N , et al . ChromID(r) CARBA agar fails to detect carbapenem-resistant Enterobacteriaceae with slightly reduced susceptibility to carbapenems. Front Microbiol 2020;11 :1678.32849351 13 Peretz A , et al . Efficacy of an enrichment media for increasing threshold for carbapenem-resistant Enterobacteriaceae screening. J Clin Lab Anal 2016;30 :563-566.26666427 14 Pierce VM , et al . Modified carbapenem inactivation method for phenotypic detection of carbapenemase production among Enterobacteriaceae. J Clin Microbiol 2017;55 :2321-2333.28381609 15 Pitout JD . Surveillance cultures of multidrug resistant Enter-obacterales, Pseudomonas aeruginosa and Acinetobacter baumanii. In: Leber AL Burnham CD eds. Clinical Microbiology Procedures Handbook. 5th ed. Vol. 4 . ASM Press, 2023:15.6.3.1-15.6.3.4. 16 Potter RF , et al . The rapid spread of carbapenem-resistant Enterobacteriaceae. Drug Resist Updat 2016;29 :30-46.27912842 17 Sellera FP , et al . Rapid spread of critical priority carbapenemase-producing pathogens in companion animals: a One Health challenge for a post-pandemic world. J Antimicrob Chemother 2021;76 :2225-2229.34109407 18 van Loon K , et al . A systematic review and meta-analyses of the clinical epidemiology of carbapenem-resistantEnterobacteriaceae. Antimicrob Agents Chemother 2017;62 :e01730-e01717. 19 Vrioni G , et al . Comparative evaluation of a prototype chromogenic medium (ChromID CARBA) for detecting carbapenemase-producing Enterobacteriaceae in surveillance rectal swabs. J Clin Microbiol 2012;50 :1841-1846.22461675 20 Waltenburg MA , et al . A survey of current activities and technologies used to detect carbapenem resistance in bacteria isolated from companion animals at veterinary diagnostic laboratories United States, 2020. J Clin Microbiol 2022;60 :e0215421. |
Background Mitral valve diseases are a common medical condition, and surgery is the most used therapeutic approach. The need for less invasive interventions led to the development of transcatheter valve implantation in high-risk patients. However, the treatment to the dysfunctions of these prosthetic valves is still uncertain, and the yield and safety of repeated transcatheter valve implantations remain unclear. Cases summary A 69-year-old Caucasian woman with three previous mitral valve procedures performed due to rheumatic valve disease (currently with a biological prosthetic mitral valve) and a 76-year-old Latin woman with previous liver transplantation (due to metabolic-associated fatty liver disease) and biological mitral prosthesis due to mitral valve prolapse with severe regurgitation underwent mitral valve-in-valve (ViV) transcatheter implantation at the time of dysfunction of their surgical prostheses. Later, these patients developed prosthetic valve dysfunction and clinical worsening, requiring another invasive procedure. Due to maintained high-risk status and unfavourable clinical conditions for surgery, re-valve-in-valve (re-ViV) was performed. Discussion Valve-in-valve transcatheter mitral valve implantation was approved in 2017, and, since then, it has been used in several countries, mainly in high-risk patients. Nevertheless, these prosthetic valves may complicate with stenosis or regurgitation, demanding reinterventions. Although there are favourable data for mitral ViV, re-ViV still lacks robust data to support its performance, with only case reports in the literature so far. It is possible that in high-risk patients, there is a greater benefit from re-ViV when compared with the surgical strategy. However, this hypothesis must be studied in future controlled trials. Mitral valve prosthesis Transcatheter valve implantation Prosthesis failure Case reports pmcLearning points Prosthetic mitral valves may complicate with both stenosis and regurgitation, demanding reinterventions. In high-risk patients, the treatment of prosthetic valve complications with re-valve-in-valve is feasible and secure. Introduction Mitral valve diseases are a common medical condition1 that can lead to structural cardiac complications and have high morbidity. Surgical treatment of the mitral valve has been the most used therapeutic approach. However, technological advances and the need for less invasive interventions enabled the development of transcatheter valve implantation, which has also been applied in the treatment of mitral valve diseases.2 Biological valve prostheses have an average durability of ~15 years. The standard treatment in case of dysfunction is reoperation, despite its association with higher morbidity and mortality.3 In patients with high surgical risk, the mitral valve-in-valve (ViV) has been adopted as a less invasive alternative, with lower incidence of complications.4 The safety and efficacy of this procedure have been demonstrated in previous trials with positive outcomes as acceptable early mortality and improvement in patient symptoms.5,6 However, information about the treatment to the dysfunctions of these new prosthetic valves remains scarce in literature. This article reports two patients who underwent mitral re-valve-in-valve (re-ViV): the transcatheter mitral valve implantation (TMVI) to treat the mechanical dysfunction of a previous transcatheter mitral prosthetic valve. The procedures were performed using the prosthesis Inovare (Braile(r), Sao Jose do Rio Preto, Brazil) with transapical access. Summary figure Patient 1 24 years ago Surgical mitral valve replacement with a mechanical prosthesis. 20 years ago The mechanical prosthesis was replaced by a biological prosthesis. 6 years ago Mitral ViV due to stenosis of the biological prosthesis. Day 0 Patient was admitted with dyspnoea and clinical signs of heart failure due to prosthetic valve stenosis. Day 21 Re-ViV using a transapical access. Day 31 Patient was discharged 10 days after the procedure with improved symptoms and without complications. 4 years later Patient remained asymptomatic with no limitations [New York Heart Association (NYHA) functional Class I]. Patient 2 10 years ago Surgical mitral valve replacement with a biological prosthesis due to mitral regurgitation. 10 months ago Mitral ViV due to prosthetic dysfunction (stenosis). Day 0 Patient was admitted with dyspnoea on minimal exertion associated with clinical signs of heart failure and haemolytic anaemia. Day 8 Sepsis by Klebsiella pneumoniae complex. Day 34 Re-ViV using a transapical access due to displacement of the prosthetic mitral valve with periprosthetic regurgitation. Day 37 Sepsis by Serratia marcescens. Day 47 Infection in the right femoral region. Day 48 Transoesophageal echocardiography showed thrombus in one of the leaflets of the new biological prosthetic valve. Day 115 Patient died of septic shock. Case summary Patient 1 A 65-year-old Caucasian woman was admitted with exertional limiting dyspnoea (NYHA functional Class IV) and clinical signs of decompensated heart failure (central cyanosis, tachypnoea 35 breaths per minute). Her physical examination showed opening snap of the mitral valve and a mid-diastolic rumble. The B-type natriuretic peptide (BNP) was 179 pg/mL. The patient had a record of atrial fibrillation and prior ischaemic stroke of cardioembolic aetiology, with a long-term right-sided hemiparesis. Due to rheumatic mitral valve disease, she previously had three mitral valve procedures. The first one was in 1995, when the mitral valve was replaced by a mechanical prosthesis. The second one was in 1999, this time the first mechanical prosthesis was replaced by a biological one. And the last procedure was in 2013, when a stenosis of the biological prosthesis was diagnosed and the mitral ViV was performed with the implantation of an Inovare prosthetic valve (Braile(r), Number 26). At that time, the patient already had high surgical risk and unfavourable clinical conditions for a new sternotomy. In 2019, at hospital admission, she had functional limitations due to dyspnoea and the sequelae of her previous ischaemic stroke with Katz index of 3 and a Lawton-Brody index of 1.7,8 In transoesophageal echocardiography, there was no mobility of the anterolateral and posterior leaflets of the prosthetic mitral valve (only the anteromedial leaflet presented good mobility). The valve area was 0.6 cm2 by planimetry and 0.7 cm2 by pressure half-time (PHT), with maximum and mean mitral diastolic gradients of 23 and 12 mmHg, respectively . The left ventricle ejection fraction was 64%, the right ventricle had mild systolic dysfunction, the pulmonary artery systolic pressure was 70 mmHg, and the tricuspid valve had moderate regurgitation. Figure 1 Pre-procedural echocardiogram shows prosthetic valve stenosis with a maximum and mean mitral transvalvular diastolic gradient of 24 and 12 mmHg, respectively [60.9 x 148 mm (xDPI)]. After discussing with the heart team the increased surgical risk (EuroSCORE II 5.49%) associated with clinical frailty of the patient, it was decided to perform re-ViV with implantation of an Inovare prosthetic valve (Braile(r), Number 24) using transapical access . Once the patient had already undergone prior transapical ViV and adhesions of the pericardium could be present, a greater caution was required for the dissections and there were no organic lesions. The postoperative echocardiography revealed minimal central regurgitation of the prosthetic valve, with maximum and mean mitral diastolic gradients of 13 and 5 mmHg, respectively, and an estimated valve area of 1.8 cm2 using 3D planimetry . The patient was discharged from the hospital 10 days after the procedure with improved symptoms and without complications. Since her first follow-up visit 1 month after the discharge, the patient remained asymptomatic without limitations (NYHA functional Class I) and still is nowadays, 4 years after the procedure. Figure 2 Fluoroscopy: transcatheter heart valve positioning and implantation [75.4 x 147 mm (xDPI)]. Figure 3 Post-procedural echocardiogram reveals a significant reduction in transprosthetic pressure gradient (from 12 to 5 mmHg) and a well-placed valve [91.5 x 133 mm (xDPI)]. Patient 2 A 76-year-old Latin woman with previous liver transplantation in 2012, systemic arterial hypertension, Parkinson's disease, and chronic obstructive pulmonary disease underwent mitral valve replacement with a biological prosthesis in 2012 (Inovare biological prosthesis, Braile(r), Number 29) due to mitral regurgitation that was caused by mitral valve prolapse. As the patient had high risk for a new cardiac surgery, in 2021, after having diagnosed stenosis of the biological prosthesis, she underwent ViV (Inovare biological prosthesis, Braile(r), Number 26). After ViV, echocardiography showed the prosthesis had normal opening of its leaflets, an effective orifice area of 1.62 cm2, a mean gradient of 7 mmHg, and mild-to-moderate paravalvular leak. The procedure resulted in progressive improvement of her symptoms during the following 8 months, from NYHA functional Class III to I. However, 10 months after ViV, she was admitted with dyspnoea on minimal exertion (NYHA functional Class IV), haemolytic anaemia, and clinical signs of heart failure (tachypnoea 24 breaths per minute, bilateral lung wheezing, prolonged expiration, and oedema of the lower limbs). Her physical examination showed frequent extrasystoles and a regurgitant systolic murmur. Blood tests revealed BNP 135 pg/mL, haemoglobin 7.2 g/dL, indirect bilirubin 1.48 mg/dL, haptoglobin < 0.08 g/L, reticulocyte count 12.1%, and lactate dehydrogenase 2155 UI/L. Transthoracic echocardiography showed a prosthetic mitral valve with a mean diastolic gradient of 6 mmHg and severe periprosthetic regurgitation (between the surgical prosthesis and the first ViV prosthesis) with a regurgitant orifice of 9 x 5 mm and an effective regurgitant orifice area of 0.4 cm2. Transoesophageal echocardiography demonstrated displacement of the prosthetic mitral valve towards the left atrium, with projection of its stem towards the left ventricle outflow tract (LVOT) and a LVOT gradient of 25 mmHg. Such displacement was probably associated with partial recoil of the Inovare biological prosthesis and was responsible for the periprosthetic regurgitation , leading to the signs and symptoms of heart failure and haemolytic anaemia. The left ventricle ejection fraction was 60%, the right ventricle had normal systolic function, the pulmonary artery systolic pressure was 46 mmHg, and the tricuspid valve had moderate regurgitation. At the time of hospital admission, her symptoms were causing functional impairment and the patient needed help for basic activities of daily life, presenting Katz index of 3 and a Lawton-Brody index of 1.7,8 Figure 4 Sequence of pre-procedural echocardiogram images showing displacement of the prosthetic mitral valve towards the left atrium with a significant periprosthetic regurgitation. (A) Transthoracic echocardiogram Doppler colour image. (B and C) 3D echocardiogram [51.0 x 159 mm (xDPI)]. During hospitalization, she developed acute renal failure that required renal replacement therapy and also developed urinary and bloodstream infection by K. pneumoniae complex. After clinical compensation and antibiotic therapy, the heart team decided for mitral re-ViV considering the patient remained with a high surgical risk (EuroSCORE II 16.68%). She underwent re-ViV with Inovare biological prosthesis (Braile(r), Number 28) using transapical access . The possible risk of complete embolization of the previous prosthesis due to the manipulation of the catheters represented a great technical challenge during the procedure. Despite this concern, the surgical team succeeded in the implantation of the new prosthetic valve without immediate complications. The intraoperative echocardiography demonstrated no periprosthetic regurgitation and a decrease in the LVOT gradient from 25 to 18 mmHg immediately after the delivery of the new prosthesis (Supplementary material online, Videos S3 and S4). However, in the first days after the procedure, the patient had an infection in the right femoral region and later in the bloodstream by S. marcescens. She also developed an inguinal lymphatic fistula. These complications developed where the right femoral artery and vein were prepared by dissection as stand-by accesses to perform a possible on-pump cardiac surgery. Two weeks after the procedure, transoesophageal echocardiography showed thickening of one of the leaflets of the new prosthetic valve, suggestive of a thrombus with maximum and mean mitral diastolic gradients of 23 and 12 mmHg, respectively. In this exam, there was no more LVOT gradient and no periprosthetic regurgitation. Anticoagulation with intravenous heparin was started with full reversal of the alterations previously found. However, the patient was debilitated by recurrent infections that were not associated with the preprocedural ones and died of septic shock 81 days after re-ViV. Figure 5 Fluoroscopy (A) shows overlapping of the valve stent struts prior to dilatation. (B) During the procedure, a balloon was used to upsize the stent struts. (C) Final angiographic result [57.5 x 163 mm (xDPI)]. Figure 6 Transoesophageal echocardiogram reveals a dilated left atrium with an isoechoic mass straddling the leaflets of the new biological prosthetic valve [94 x 129 mm (xDPI)]. Discussion Nowadays, there is a great interest in the new percutaneous techniques used for the treatment of valvulopathies. The revolution in the therapeutic approach of aortic stenosis in the elderly due to technological advances and the excellent results obtained with the transcatheter aortic valve implantation (TAVI) paved the way for a less invasive treatment of the mitral and tricuspid valves. In this context, the ViV technique, which consists of the transcatheter implantation of a biological prosthesis, has been used as a therapeutic option for high-risk patients who have dysfunction of the surgical bioprosthesis in the aortic or mitral valve position.2 There are three possible types of TMVI that can be used for high-risk patients: ViV for patients with severe dysfunction of a mitral valve prosthesis, valve-in-ring for a new mitral valve dysfunction after valve repair with a prosthetic ring, and valve-in-mitral annulus calcification (MAC) for the cases of mitral valve dysfunction due to severe MAC. The Food and Drug Administration approved mitral ViV for high-risk patients in 2017, while the possible other indications are still being evaluated by the agency.9 After the promising results with prosthetic aortic valve implantation, the first mitral ViV transcatheter implantation was published in 2009 by the Vancouver group, followed by a series of other publications confirming its technical viability.10 Patients with mitral valve diseases are often younger, with only 10% of people over 75 years old being affected by mitral valve regurgitation in developed countries. Consequently, TMVI treatment occurs in younger subjects than those treated with TAVI.3 A meta-analysis published in 2023 in the American Journal of Cardiology described that mitral ViV was associated with better outcomes than a new surgery, including lower rates of complications and shorter length of hospital stay. However, there was no significant difference in mortality rate.11 The 30-day mortality rate for ViV went from 8.8% back in 2014 to 3.9% in 2019.12 Since 2014, the transapical approach has gradually decreased from 76 to 3.8% of the procedures.9,13 This is because the transseptal approach allows a less invasive procedure with less morbidity during hospitalization. For the treatment of the patients described, the Braile Inovare system was used, once it is the only prosthesis routinely available in our institution for the mitral ViV procedure. As the delivery system of this prosthesis only permits the use of the transapical approach, this was the access route chosen for our patients. To minimize procedural risk during re-ViV, some strategies could be applied, as performing the surgery in a hybrid operation room and having all the material available to perform on-pump surgery if needed, including intraoperative cell savage. Considering that re-ViV is a new procedure, not yet widely performed, any decision in its favour should involve shared decision-making with the patient. In the presented cases, the treatment options were offered for the patients with disclosure of all risks and involved limitations. For example, possible complications of the transcatheter mitral prosthesis implantation are the obstruction of the LVOT and patient-prosthesis mismatch. Therefore, it was extensively explained for the patients the importance of adequate pre-procedure tomographic study for better planning of the procedure and to avoid these complications. The choice of re-ViV was eventually defined as the result of a common agreement between the heart team and the preferences of patients. Although previous studies have indicated favourable results for mitral ViV, the re-ViV still lacks robust data to support its performance. So far, it only has case reports in literature. As an example, Khan et al.12 recently reported a similar case involving a 39-year-old woman with a record of two previous surgeries and a mitral ViV that underwent a successfully re-ViV with a SAPIEN 3 bioprosthesis. In their report, even though the Society of Thoracic Surgeons risk score was not elevated, it was considered that there was an increased surgical risk for the patient because of two prior sternotomy procedures and a complex medical history. Similarly, in our cases, the selection of both patients for the re-ViV procedure was guided by the association of increased surgical risk, clinical frailty, and repeated previous invasive interventions. Alternative approaches were discussed for each patient, such as transcatheter plug placement for Patient 2. However, after an extensive analysis, this approach was considered too risky for this patient due to the possibility of migration of the plug itself once the paravalvular leak was located between the two prostheses (surgical and first ViV). Conclusion It is possible that in high-risk patients such as the ones presented in this study, there is a greater clinical net benefit from re-ViV when compared with surgical strategy. However, this hypothesis must be further studied in interventional randomized controlled trials. Likewise, as illustrated in this paper, this procedure may be useful in stenotic or regurgitant prosthesis dysfunction, and future trials are needed to identify the predictors of success to establish patient candidacy for re-ViV. Supplementary Material ytad579_Supplementary_Data Click here for additional data file. Lead author biography Dr Matheus Dal Piaz is a cardiology resident at the Heart Institute of the University of Sao Paulo Medical School, Sao Paulo. He graduated in 2019, at the medical school of the University of Espirito Santo, and has finished internal medicine at the State University of Campinas, in 2022. He has specific interest in valvular heart diseases and arrhythmias. Supplementary material Supplementary material is available at European Heart Journal - Case Reports online. Consent: Informed consent was obtained from Patient 1 and provided by the daughter of Patient 2 in accordance with COPE guidelines. Funding: None declared. Data availability The data underlying this article will be shared upon reasonable request to the corresponding author. |
Background Masses in the heart and valves have a broad differential diagnosis including infective and rheumatic causes as well as primary or metastatic tumours. Diagnosis involves delineating the location, shape, and origin of the mass/masses and considering the clinical context. This case outlines the work-up and approach to diagnosing a cardiac mass along with imaging findings of a unique secondary metastatic mass in the left ventricle (LV). Case summary A 69-year-old female with past medical history of metastatic lung cancer treated with radiotherapy and breast cancer treated with mastectomy presented with dyspnoea and fever. Due to concern for infective endocarditis, transthoracic echocardiogram (TTE) was performed revealing 2 cm x 0.72 cm finger-like, echo-lucent, mobile mass, appearing to originate from LV lateral wall, protruding into the LV cavity, along with valvular masses on mitral and tricuspid valves. Initial differential diagnosis included benign pathologies, but due to the clinical suspicion of malignancy, cardiac MRI was performed which revealed a broad-based mass with invasion into the LV lateral wall and delayed gadolinium enhancement, suggestive of metastatic tumour. The patient was given Aspirin to prevent embolization and eventually underwent hospice care. Discussion Atypical appearing cardiac masses can be seen on TTE. Cardiac magnetic resonance imaging (MRI) should be used for definite diagnosis in cases where clinical features do not match the echocardiographic findings. Case Report Left ventricular mass Valvular masses Cardiac MRI Echocardiogram pmcLearning points Not all cardiac masses with an echo-lucent core and cystic appearance on an echocardiogram are benign. Cardiac MRI should be pursued to diagnose cardiac masses with conflicting features. A broad range of differentials should be correlated to the patient's medical history and clinical features in order to reach a definitive diagnosis. Introduction Left ventricular and valvular masses can broadly be divided into benign and malignant categories. The first and critical step of diagnosis of cardiac mass is to differentiate whether the mass is a thrombus, vegetation, or tumour,1-3 and multimodality imaging are crucial for this. Transthoracic echocardiogram (TTE) is the initial diagnostic modality of choice for such masses.4 Generally, echocardiographic features of mass with echo-lucent core tend to have a benign aetiology, as seen in haemangiomas.5 However, further imaging may reveal an alternate but more accurate diagnosis. Transoesophageal echocardiography (TEE) is an appropriate next step to characterize valvular masses by providing a more accurate assessment of the anatomical relationships, size, and shape of the mass.6 Cardiac computed tomography (CT) has also been favoured as a diagnostic modality, especially for the evaluation of calcified masses and tumour staging.7 Flurodeoxyglucose positron emission tomography (FDG-PET/CT) imaging can also be used to identify metastatic lesions. Endomyocardial biopsy in the diagnosis of cardiac tumour is a class 2a recommendation, especially if the diagnosis cannot be obtained by a non-invasive modality.8 The non-invasive diagnostic tool that provides the best tissue resolution is cardiac magnetic resonance imaging (CMR), which reveals the morphology and accurately measures the mass.9 The most common modulation of CMR is cine magnetic resonance imaging (MRI) in both long and short-axis views, which provide evaluation of location, morphology, extent, border, and mobility of cardiac masses.9 It also further delineates cardiac contractility, valvular dysfunction, pericardial lesions, and extra-cardiac involvement.9 We present the case of a 69-year-old female who was found to have metastatic cardiac masses with an atypical appearance on TTE, which was then more definitively diagnosed using CMR. Summary figure Case presentation A 69-year-old African American female initially presented to the emergency department for shortness of breath secondary to chronic obstructive pulmonary disease (COPD) exacerbation. She had extensive past medical history of stage four squamous cell lung cancer with bone metastasis for which she completed radiotherapy treatment, and breast cancer treated with mastectomy. She also experienced chronic intermittent fever, chills, and productive cough with green-yellow sputum since her cancer diagnosis two years ago. She had a 40-pack year smoking history, without history of intravenous drug use. On exam, she was found to be cachexic but in no acute distress, with clear lung exam, and normal heart sounds without murmurs. On laboratory tests, the patient was found to be anaemic at baseline, without leukocytosis, and with venous lactate of 2.4 mmol/L. Blood cultures grew gram-positive cocci in clusters. Inflammatory markers were elevated with C-related peptide (CRP) of 104.8 mg/L (normal: < 3 mg/L) and erythrocyte sedimentation rate (ESR) of 115 mm/hr (normal: < 20 mm/hr). Chest x-ray was significant for a left pleural-based metastatic lung mass, without evidence of consolidation or pleural effusion . Electrocardiogram (ECG) showed normal sinus rhythm. Due to concern for endocarditis, TTE was performed, which showed multiple large, irregular, echogenic, highly mobile masses on the tip of the anterior and posterior leaflets of mitral valve that extended to sub-valvular apparatus, involving the papillary muscle. Additionally, a large, papillary-shaped mass was also seen in the inferior right atrial cavity with moderate thickening of the tricuspid leaflets, likely representing vegetation. Patient was also worked-up to rule out non-infective causes of endocarditis; and was found to be positive for rheumatoid factor, anti-citrullinated peptide, and anti-scl-70 antibody, but negative for elevated complement levels. Figure 1 Chest x-ray. 4.6 x 10 cm mass is seen in the left upper lobe. Initial differential diagnosis included non-bacterial thrombotic endocarditis, infective endocarditis (IE), secondary metastasis, cyst (blood or infectious), tumour, abscess, or thrombus. As blood cultures speciated into methicillin-resistant Staphylococcus hominis, another set of blood cultures was obtained before administrating antibiotics and the Department of Infectious Disease (ID) was consulted. The first set of cultures was deemed likely to be contaminants as she had no indwelling catheters or devices and did not spike high-grade fever with leukocytosis, which would make bacteraemia with coagulase negative Staphylococcus unlikely. As repeat cultures came back negative, no further antibiotics were given as per ESC 2015 guidelines, which state that in IE, all blood cultures tend to be positive and a single positive with subsequent negative cultures should be interpreted cautiously.10 Repeat TTE showed a 2 cm x 0.72 cm finger-like, echo-lucent, mobile mass, originating from LV lateral wall, protruding into the left ventricular (LV) cavity, along with similar valvular masses as before . The patient did not experience worsening fever, progressive valvular dysfunction, or leukocytosis going against the diagnosis of an infectious aetiology. Rheumatic disease was ruled out as it is unlikely to be associated with vegetation, which is more common in anti-nuclear antibody (ANA) driven diseases with anti-phospholipid syndrome (APS) overlap. Subsequently, she underwent CMR which showed a mobile, multi-lobulated 3.2 x 2.3 x 1.1 cm mass, attached to the lateral wall of the left mid ventricle with delayed enhancement of the mass on perfusion . It was associated with a broad base, suggestive of invasion into the lateral LV wall. The nodularity of mitral valve and thickening of tricuspid valve were also seen. These findings were attributed to cardiac metastasis secondary to lung cancer. She was not deemed a candidate for in-patient chemotherapy. Due to high risk of embolization, patient was started on low-dose aspirin and recommended for follow-up with oncology; however, a month later she was found to have hypercalcemia and a left frontal mass with vasogenic oedema on head CT. She was started on metoprolol 12.5 mg to minimize LV outflow obstruction and anticoagulation was withheld due to brain metastasis. Patient eventually underwent hospice care. Figure 2 Transthoracic echocardiogram. Parasternal long-axis view showing cystic mass (arrow) with echo-lucent core, protruding into the left ventricular cavity from the basal infero-lateral wall. Figure 3 Transthoracic echocardiogram. Basal parasternal short axis at the mitral valve view showing pedunculated finger-like, cystic mass (2x0.72 cm) protruding into the cavity of the left ventricle. Cross sectional view of mass with echo lucent core. Figure 4 Transthoracic echocardiogram. Apical four chamber view showing cystic mass protruding from the anterolateral wall of the left ventricle into the cavity (cross and circle), along with multiple vegetations (vs. mass) on the mitral valve (arrows) and tricuspid valve (arrow). Figure 5 Cardiac MRI. (A) Long axis view: Mass from lateral wall, (B) Mid Short axis view at the level of papillary muscles: Mass from the lateral wall; same intensity as myocardium itself suggesting a solid mass (as compared to TTE where it had an echo-lucent core as if filled with fluid), (C) Gadolinium enhancement: mass enhances in a similar fashion as the lateral wall -> solid mass. Discussion The frequency of primary cardiac tumours is approximately 0.02%.11 Metastasis from primary malignancies from lung, breast, ovary, kidney, leukaemia, lymphoma, and malignant melanoma are the most common causes.3 Incidence of secondary malignancies is 20 to 40 times higher than that of primary cardiac tumour.3 Therefore, TTE should be performed in all patients with a history of malignancy and cardiac symptoms. It is generally uncommon to find cardiac metastasis on valves due to constant motion of the cusps and absence of vessels in the valvular stroma, making this presentation unique.3 In our case, TTE initially revealed a cystic mass in the LV, along with multiple valvular masses. As per the ESC 2015 guidelines, we first ruled out IE.10 Initial differential diagnosis included benign aetiologies like thrombi, lipoma, and fibroelastoma due to the simultaneous presence on valves. However, given the clinical picture, CMR was pursued and demonstrated that the mass had the same intensity as the myocardium, suggesting a solid mass (in contrast to TTE which showed a seemingly fluid filled echo-lucent core). CMR was also suggestive of invasion of the mass into the free LV lateral wall and showed late gadolinium enhancement, which was attributed to cardiac metastasis secondary to lung cancer. This highlights the importance of pursuing CMR in the setting of a clinical picture contradictory to the TTE findings. Most secondary cardiac tumours are hypointense on T1 weighted image and hyperintense on T2 weighted image with the exception of malignant melanoma.6 However, it is important to note that due to low temporal resolution, CMR is not ideal for diagnosing calcification and small masses, especially those related to valves.6 Mobile vegetation carries a high risk for systemic embolism and anticoagulation should be continued indefinitely unless there are major bleeding complications.12 Low molecular weight heparin (LMWH) and unfractionated heparin have shown superiority in mortality in non-bacterial thrombotic endocarditis in patients with malignancy.12 Some studies have suggested that warfarin is less effective than heparin in preventing thromboembolic events in patients with malignancy.12,13 In general, the prognosis of cardiac metastasis depends on the primary tumour. However, the metastasis itself confers a stage 4 classification, resulting in poor prognosis.6 Treatment of secondary cardiac metastasis is individualized and directed towards the primary tumour. Resection can be performed in select cases where cardiac masses cause haemodynamic compromise.6 Conclusion In a patient with known metastatic cancer, a finger-like, echo lucent, mobile mass originating in the left ventricle (LV) with invasion into the LV lateral wall, with delayed enhancement on perfusion on CMR, in the absence of clinically significant fever or bacteremia, is most likely to be due to secondary metastasis. Such LV tumours tend to be clinically silent and have a high risk of embolization. Hence, high suspicion is required for diagnosis and prophylactic anticoagulation should be offered to eligible patients. Supplementary Material ytad606_Supplementary_Data Acknowledgements None. Lead author biography Amrin Kharawala is an Internal Medicine resident at Jacobi Medical Center/Albert Einstein College of Medicine in Bronx, New York, USA. She is interested in pursuing a career in Cardiology and has worked on Cardiology-based research on topics ranging from heart failure, atrial fibrillation, pulmonary embolism, coronary diseases and imaging. Supplementary material Supplementary material is available at European Heart Journal - Case Reports online. Consent: The authors confirm that written informed consent for submission and publication of this case report including images and associated text has been obtained from the patient's next of kin in line with COPE guidance. Funding: No funding was obtained. Ethics approval statement: Not applicable. Data availability The data underlying this article are available in the article and in its online Supplementary material. |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.49182 Pathology Radiology Orthopedics Missed Diagnosis of a Rare Retropatellar Juxta-Articular Angioleiomyoma: A Case Report Muacevic Alexander Adler John R Ghayyad Kassem 1 Kilic Ali Ihsan 2 1 Orthopedic Surgery, Rothman Orthopaedics Florida at AdventHealth, Orlando, USA 2 Orthopedic Surgery, Izmir Bakircay University, Izmir, TUR Ali Ihsan Kilic [email protected] 21 11 2023 11 2023 15 11 e4918220 11 2023 Copyright (c) 2023, Ghayyad et al. 2023 Ghayyad et al. This is an open access article distributed under the terms of the Creative Commons Attribution License CC-BY 4.0., which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from Angioleiomyomas are benign tumors that originate from smooth muscle cells and most commonly affect organs such as the uterus or gastrointestinal tract. This article presents a case of a rarely reported angioleiomyoma located in the retropatellar juxta-articular region of the knee. The patient is a 42-year-old female who experienced chronic anterior knee pain that led to two unsuccessful arthroscopic surgeries. Magnetic resonance imaging (MRI) revealed a well-defined lesion in the retropatellar area, prompting the decision to proceed with open surgery. The histopathological examination confirmed the diagnosis of angioleiomyoma. This case highlights the challenges in diagnosing angioleiomyomas in the knee and emphasizes the importance of comprehensive MRI evaluation for accurate diagnosis and appropriate surgical intervention. Prompt identification and excision of the soft tissue lesion can lead to the complete resolution of symptoms and effective management of this rare condition. retropatellar surgical case reports arthroscopy angioleiomyoma juxta-articular pmcIntroduction An angioleiomyoma is a benign tumor that develops in the soft tissues and originates from smooth muscle cells . Angioleiomyomas are relatively uncommon among benign tumors in soft tissues, accounting for only 4.4% . Moreover, when excluding those that originate in cutaneous and subcutaneous tissues, angioleiomyomas in the extremities are exceptionally rare . The preoperative diagnosis of angioleiomyoma is often uncommon due to its rarity and limited awareness among orthopedic surgeons in this field. As a result, patients may undergo multiple rounds of conservative or surgical treatments, particularly when the neoplasm is located near the knee joint [4-6]. In cases where these rare tumors are situated in the knee, misdiagnosis with more common pathologies such as meniscus or cartilage diseases can occur as observed in the patient described in this case report. This case report focuses on a patient with angioleiomyoma located in the retropatellar juxta-articular region of the knee. To the best of our knowledge, no similar cases have been reported in the existing literature. Case presentation A 42-year-old female patient presented to our clinic with a history of chronic right anterior knee pain persisting for approximately five years. Initially, the pain was sporadic and nonspecific. However, the patient reported having trouble while climbing stairs and kneeling due to pain. She localized the pain just above the tibial tubercle and described it as being aggravated by light touch. The patient denied any history of trauma. She mentioned that she had undergone arthroscopic knee surgery twice in 2019 and 2021 for the same chief complaint, without resolution of symptoms. Unfortunately, surgical reports from her previous surgeries were unavailable. On physical examination, full extension of the knee joint was observed, but active flexion was limited (-30 degrees) due to pain. No noticeable swelling or redness was observed around the knee joint. Light touch palpation elicited tenderness in the area just above the tibial tuberosity. Furthermore, there were no signs of muscle atrophy, typical indications of meniscus lesions, or any evidence of ligament injuries. The knee MRI image obtained before the patient's initial knee arthroscopy surgery and the current knee MRI image were meticulously examined and compared. In both MRI scans, a distinct and well-circumscribed lesion was identified in the retropatellar juxta-articular region. Plain orthogonal radiographs of the knee did not reveal any abnormalities in the bone or soft tissue . Figure 1 Anteroposterior and lateral X-ray views of the knee. No abnormalities were detected in the bone and soft tissues. The lesion appeared hyperintense on T2-weighted images and hypointense on T1-weighted images . Figure 2 (a, c) MRI scan obtained before the patient's first surgery in 2019; (b, d) patient's current MRI scan in 2021. (a, b) In the sagittal view, T1-weighted MRI scan, the leiomyoma appears as a well-demarcated soft tissue mass with intermediate signal intensity, displaying a homogeneous nature. (c, d) In the axial view, T2-weighted MRI scan, the lesion is observed as hyperintense, indicating a brighter signal, and exhibits a well-circumscribed appearance. Based on these diagnostic findings, the decision was made to proceed with surgery. Due to the previous unsuccessful arthroscopic surgeries and the challenges associated with completely excising the lesion using an arthroscopic approach, the patient underwent open surgery . Figure 3 Intraoperative views revealed a solid mass measuring 2 cm x 1 cm x 0.5 cm As revealed in the pathology report, the specimen appeared as a medium-hard, nodular material with a smooth surface macroscopically. It measured 2 cm x 1 cm x 0.5 cm and had a solid, off-white whorled appearance on the cross-sectional cut. Microscopically, the lesion was well-defined and characterized by intersecting fascicles of spindle cells with uniform cigar-shaped nuclei. Immunohistochemical analysis reveals positive staining of these cells for smooth muscle markers including desmin, smooth muscle actin, caldesmon, and calponin. Microscopic findings reveal that the tumor comprises numerous blood vessels (hematoxylin and eosin, x20, x40). The final diagnosis was a benign angioleiomyoma with clean margins free of cellular atypia . Figure 4 (a) The leiomyoma specimen shows a section composed of intersecting fascicles of spindle cells with uniform cigar-shaped nuclei (H&E, 200x magnification). (b) Immunohistochemical staining demonstrates desmin positivity in the leiomyoma (200x magnification). H&E: Hematoxylin & eosin. Discussion Angioleiomyoma is a benign tumor that typically arises from smooth muscle cells and primarily affects organs containing smooth muscles, such as the uterus or gastrointestinal tract. When it occurs in soft tissues, it usually involves the dermis and subcutaneous layers, with deep soft tissue involvement being extremely rare . Depending on its location, it can be classified as cutaneous leiomyoma, angioleiomyoma, or leiomyoma of the deep soft tissue . The first comprehensive review of this rare lesion was published by Stout in 1937, and it has been well-documented in the literature ever since. While these tumors are observed in the lower extremities, only a few reports are available in the orthopedic literature . Hachisuga et al. conducted a study involving 562 cases of leiomyomas, revealing that these tumors primarily occur in individuals between the fourth and sixth decades of life. Approximately 90% of cases affect the extremities, with the lower extremities accounting for around 80% and displaying a higher prevalence among females. In contrast, head and upper extremity lesions are more common in males. Pain and tenderness are the most frequently reported symptoms, which are observed in 60%-75% of patients. Solid histologic subtype and lower extremity lesions typically present as painful subcutaneous masses, often exhibiting well-localized pain, exquisite tenderness, and temperature sensitivity. These symptoms overlap with glomus tumors, and histologic evaluation is necessary for differentiation. Besides glomus tumors, the differential diagnosis for small painful extremity lesions includes hemangiomas, angiolipomas, ganglions, neurilemomas, traumatic neuromas, and eccrine spiradenoma . Magnetic resonance imaging (MRI) plays a valuable role in the diagnostic process as it is a noninvasive imaging technique that helps localize the tumor and rule out other potential causes of knee pain. The presence of post-gadolinium enhancement on MRI indicates the vascular nature of the lesion . However, the definitive diagnosis can only be confirmed through histopathological examination of the tissue specimen. Anterior knee pain is a common complaint characterized by discomfort in the front of the knee, typically around or behind the patella. It is frequently associated with conditions like patellar chondromalacia, patellar tendinitis, and bursitis . While these are commonly encountered causes, it is important to consider rare cases as well. In the presented case, the patient has been experiencing anterior knee pain for approximately five years and has undergone two previous arthroscopic surgeries for the knee for this reason. However, both the old and current MRI reports lack a diagnosis or description of the lesion. The location of the lesion in the retropatellar juxta-articular region may pose challenges for arthroscopic excision. Despite the operations the patient underwent, it was observed that the retropatellar lesion was present in both old and current MRI images. These findings led us to think that the patient had undergone redundant arthroscopic surgery. Unfortunately, the surgical and pathology reports from the previous arthroscopic surgeries were unavailable. Due to the patient's history of undergoing two previous arthroscopic surgeries and the challenges associated with arthroscopic excision of the lesion, the decision was made to perform open surgery. Conclusions A careful MRI examination for a suspicious mass lesion is crucial for achieving an early and accurate diagnosis of angioleiomyoma, the cause of anterior knee pain in this case. Excision of the well-circumscribed soft tissue lesion not only provides a histopathological diagnosis but also results in the complete resolution of symptoms as demonstrated in the present case. This emphasizes the importance of prompt identification and surgical intervention in managing this condition effectively. Author Contributions Human Ethics Concept and design: Kassem Ghayyad, Ali Ihsan Kilic Drafting of the manuscript: Kassem Ghayyad Critical review of the manuscript for important intellectual content: Kassem Ghayyad, Ali Ihsan Kilic Supervision: Ali Ihsan Kilic Consent was obtained or waived by all participants in this study The authors have declared that no competing interests exist. References 1 Benign tumors of smooth muscle Enzinger and Weiss's Soft Tissue Tumors, 7th Edition Weiss SW Goldblum JR Folpe A 564 590 Amsterdam, Netherlands Elsevier 2020 2 Angioleiomyoma. A clinicopathologic reappraisal of 562 cases Cancer Hachisuga T Hashimoto H Enjoji M 126 130 54 1984 6722737 3 Deep leiomyoma of an extremity J Bone Joint Surg Am Goodman AH Briggs RC 529 532 47 1965 14275173 4 A rare case of angioleiomyoma of the knee: a case report Cases J Al-Jabri T Garg S Rao S 7885 2 2009 19918493 5 Intra-articular angioleiomyoma of the knee: a case report Knee Okahashi K Sugimoto K Iwai M Oshima M Takakura Y 330 332 13 2006 16647261 6 Narrative: review of anterior knee pain differential diagnosis (other than patellofemoral pain) Curr Rev Musculoskelet Med Kuwabara A Fredericson M 232 238 14 2021 33818700 7 Solitary cutaneous and subcutaneous leiomyoma Am J Cancer Stout AP 435 469 29 1937 8 Vascular leiomyoma of an extremity: MR imaging-pathology correlation AJR Am J Roentgenol Hwang JW Ahn JM Kang HS Suh JS Kim SM Seo JW 981 985 171 1998 9762979 |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.49178 Preventive Medicine Internal Medicine Cardiology Obesity-Induced Hyperglycemia and Heart Failure Preserved Ejection Fraction: Uncharted Territories to Remission Muacevic Alexander Adler John R Sawalha Khalid 1 Asad Osama 2 Tadisina Shourya 3 Alalawi Luay 4 Mahmood Maria 5 Alkhatib Deya 6 Alexander Thomas 7 1 Cardiometabolic Medicine, University of Missouri Kansas City School of Medicine, Kansas City, USA 2 Internal Medicine, Jordan University of Science and Technology, Irbid, JOR 3 Endocrinology, Diabetes and Metabolism, University of Missouri Kansas City School of Medicine, Kansas City, USA 4 Cardiology, Corpus Christi Medical Center Bay Area, Corpus Christi, USA 5 Marvin Baker Middle School, N/A, Corpus Christi, USA 6 Cardiology, Yale School of Medicine, New Haven, USA 7 Cardiology, Corpus Christi Medical Center, Corpus Christi, USA Khalid Sawalha [email protected] 21 11 2023 11 2023 15 11 e4917820 11 2023 Copyright (c) 2023, Sawalha et al. 2023 Sawalha et al. This is an open access article distributed under the terms of the Creative Commons Attribution License CC-BY 4.0., which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from Until the end of World War II, food security was a global challenge. Consequently, in 1948, type 2 diabetes was relatively uncommon, with the majority of cases being type 1 diabetes requiring insulin therapy. Since then, food has become increasingly palatable and readily available, leading to a rise in obesity across all age groups. Understanding the impact of obesity on our health has become crucial for optimizing healthcare. In this context, we draw attention to two significant, yet relatively uncharted pathogenic effects associated with obesity: Hyperglycemia and Heart Failure with Preserved Ejection Fraction (HFpEF). Thorough pathophysiologic, hemodynamic, and echocardiographic characterization have revealed the existence of a distinct phenotype known as "obese HFpEF" within the broader HFpEF population, and "obesity-induced hyperglycemia" within the diabetes population. In these phenotypes, patients often present with higher Body Mass Index and experience clinical symptoms decades earlier. Recent insights have enhanced our understanding of the mechanisms underlying obesity-mediated heart failure preserved ejection fraction and hyperglycemia. Early detection offers the potential for reversibility of many pathologies associated with obesity through adequate weight reduction. The objective of this review is to provide a deeper insight into these uncharted territories and explore the potential for improved outcomes by reframing these two narratives toward achieving remission. Such a shift has the potential to positively impact individual engagement with healthier lifestyles. cardiometabolic diseases cardiovascular disease prevention hyperglycemia preventative cardiology reversible heart failure obesity induced heart failure preserved ejection fraction obesity induced hyperglycemia pmcIntroduction and background Over the past few decades, the prevalence of obesity has reached alarming levels and is considered a global health epidemic, particularly in the United States . Obesity is associated with numerous cardiovascular risk factors, including hypertension, type 2 diabetes, and dyslipidemia . However, recent insights have enhanced our understanding of the mechanisms underlying the development of obesity-related complications, suggesting significant interindividual heterogeneity, particularly including obesity-induced hyperglycemia (OH) and obesity-induced heart failure (HF) with preserved ejection fraction . Body mass index (BMI) is a widely used tool for screening for overweight and obesity in adults and children . It is defined as weight in kilograms divided by height in meters squared and is related to the amount of fat in the body . BMI classifies obesity into three classes: class 1 where the BMI is 30 to less than 35 kg/m2, class 2 with a BMI of 35 to less than 40 kg/m2, and class 3 with a BMI of 40 or higher kg/m2, sometimes categorized as "severe" or "morbid" obesity . Although it is widely used as a screening tool, it is worth mentioning that it does not reflect total body composition or body fatness . Having those clear definitions in mind, it is projected that by 2030 in the US, the prevalence of class 2 obesity will likely reach 25% and the diabetes prevalence to 13.9% . This affects individuals of all ages, genders, and socioeconomic statuses. This prevalence not only poses a significant burden on healthcare systems but also increases the risk of various cardiometabolic diseases and certain types of cancer . Therefore, broadening our understanding and changing our approach regarding obesity-related complications could offer significant health benefits. Our future is determined by how we approach things now. Review Obesity-induced hyperglycemia OH is an emerging clinical phenotype characterized by elevated blood glucose levels resulting from excess body fat accumulation . It is a consequence of the intricate relationship between adipose tissue, hormones, and insulin resistance . As we gain excess weight, our body's ability to regulate blood glucose becomes impaired, leading to higher blood glucose levels . It is usually associated with BMI >35 kg/m2 and diabetes. Understanding the mechanisms behind OH is vital for developing effective strategies for prevention and management. The pathophysiology of OH is still not completely understood, but it is thought to result from derangements in insulin signaling pathways, along with other etiological factors . Obesity causes an increase in insulin resistance and beta cell dysfunction through the induction of inflammation, endocrinopathies, and increased circulating free fatty acids (FFA) . It also increases pro-inflammatory macrophages, which are recruited in response to adipocyte apoptosis, leading to an increased release of inflammatory cytokines like tumor necrosis factor-a (TNF-a), interleukin-6, and interleukin-1b, causing a state of chronic inflammation. Peroxisome proliferator-activated receptor gamma (PPAR-g) also plays an important role in regulating insulin sensitivity, adipogenesis, glucose, and lipid homeostasis . TNF-a can decrease PPAR-g, insulin receptors, insulin receptor substrate, glucose transporters, and adipose tissue functionality. It causes an increase in lipolysis, resulting in increased delivery f circulating FFAs to the liver, muscle, and pancreas . This increase in FFA mediates mitochondrial dysfunction and increases reactive oxygen species, decreasing the phosphorylation of insulin receptor substrates and impairing insulin receptor activity . An increase in IL-6 production leads to increased hepatic C-reactive protein (CRP) production. Obesity can also decrease adiponectin, an anti-inflammatory cytokine produced by adipocytes that improves insulin sensitivity . Leptin is a hormone secreted by adipocytes and works on the hypothalamus to suppress hunger [10-12]. Chronic leptin stimulation of the arcuate nucleus of the hypothalamus can, in some cases, promote the protein tyrosine phosphatase 1B (PTB1B), which inhibits insulin activity . Leptin lowers blood glucose levels and has anti-lipogenic effects. Obesity can cause an increase in both leptin and insulin levels, contributing to insulin resistance . Acylation-stimulating protein (ASP) is secreted by adipocytes, acting as a lipogenic factor that promotes triglyceride synthesis and storage in adipocytes. A relative decrease in ASP can occur in obesity, leading to a defect in glucose and lipid metabolism . 11 beta-hydroxysteroid dehydrogenase type-1 (11bOHSD-1) is an enzyme produced by adipose tissue and the liver, which converts inactive cortisone to active cortisol and is increased with obesity . It amplifies the glucocorticoid effects even when the glucocorticoid levels are normal. This can cause increased lipolysis and the release of FFA, an increase in gluconeogenesis, and a decrease in peripheral glucose uptake as well . Lipotoxicity from increased FFA can also cause hyperglycemia and eventually diabetes . Impaired uptake of energy in adipose tissue can lead to an increase in circulating FFAs, resulting in ectopic and pathogenic fat deposition in the visceral, pericardial, perivascular regions, liver, muscles, and pancreas . In the liver and muscles, an increase in intracellular binding of FFAs and sphingolipids forms toxic ceramides and their metabolites, leading to mitochondrial dysfunction, endoplasmic reticulum stress, impaired insulin receptor function, and impaired expression of glucose transporters. In the pancreas, increased delivery of FFAs causes Lipotoxicity, leading to beta cell apoptosis and decreased insulin secretion . By now, we have established the possible pathophysiologies associated with OH. We know that type 1 diabetes is a genuine endocrine disorder that develops as a result of autoimmune beta cell dysfunction, leading to insulin deficiency . On the other hand, type 2 diabetes results from insulin resistance caused by genetic and environmental factors . OH shares similar etiologies with type 2 diabetes, except that it occurs before the development of type 2 diabetes and involves experiencing a state of chronic hyperinsulinemia for decades . Further differences and comparisons between type 1, type 2, and OH can be seen in Table 1. Table 1 Overview of type 1, type 2, and obesity-induced hyperglycemia. Author's own work . Criteria/Type Type 1 diabetes Type 2 diabetes Obesity-Induced Hyperglycemia Definition Insulin deficiency Insulin resistance BMI >35 kg/m2 and hyperglycemia Etiology Autoimmune leading to Insulin deficiency Genetics and environmental leading to Insulin resistance Diet and sedentary lifestyles leading to excess endogenous insulin secretion for decades Prevalence < 5-10% > 95% of all diabetics 30-35% of patients with type 2 diabetes Symptoms onset At diagnosis Delayed by years Delayed by decades Significant weight loss manifested by >20% Will continue to need insulin therapy but probably less amounts Significant reduction in medication requirement and number Often may be able to discontinue all medication Management Insulin Diet, lifestyle, and medications Lifestyle and diet changes Prognosis Lifetime management Variable High remission with possible cure Lifestyle modifications and significant weight loss of more than 20% of body weight have demonstrated a significant impact on treating and reversing OH . The same degree of weight loss can improve insulin sensitivity and reduce medication requirements in patients with type 2 diabetes, although it does not guarantee complete resolution . With appropriate lifestyle modifications, OH can be reversible and potentially curable, thus enhancing life expectancy and reducing healthcare expenses . Obesity-induced HFpEF Over the past two decades, we have witnessed a shift in the paradigm of HFpEF, challenging not only our understanding of its pathophysiology but also our approaches to diagnosis and treatment. HFpEF should no longer be viewed solely as left ventricular diastolic dysfunction . Instead, it should be considered a condition characterized by small and thickened left ventricles, exhibiting abnormal diastolic filling patterns as its primary pathophysiological abnormality. This heterogeneous clinical entity encompasses numerous mechanisms and is associated with multiorgan dysfunction, with hypertension and obesity playing significant roles . Obesity-induced cardiomyopathy (OC) is caused by an increase in total blood volume, cardiac output, left ventricular dilatation, and left ventricular wall stress . It can also induce diastolic dysfunction through compensatory left ventricular hypertrophy . This condition is primarily attributed to the hyperdynamic state and chronic inflammation resulting from OH and Lipotoxicity . In the absence of other comorbidities, young adults with morbid obesity which is defined as a body mass index or BMI of > 40 kg/m2 can develop OC. This condition may be reversible, as significant weight loss achieved through gastric bypass surgery can lead to improvements in cardiac dimensions . Systolic dysfunction is sometimes observed in association with obesity, but it is important to note that other confounding factors such as obstructive sleep apnea, atrial fibrillation, and hypertension cannot be ruled out . The structural changes in cardiomyopathy due to obesity are categorized as stage B HF according to the ACC/AHA classification. Typically, these patients do not present in a decompensated state . The duration of obesity significantly determines the cardiac burden. The likelihood of developing obesity cardiomyopathy increases from 20% at 15 years of obesity duration to 95% at 25 years . However, it is often challenging for patients to accurately recall their weight history over the years, making it difficult to predict the exact burden. "Obesity-years" is a term that has been suggested to estimate the cumulative burden of obesity over a person's lifetime . In a study comparing cohorts of individuals with typical HFpEF, obese HFpEF, and obesity cardiomyopathy, data was charted on a graph with age on the X-axis and BMI on the Y-axis . Interestingly, the line representing Age + BMI = 100 intersects with all these cohorts . This suggests that it might serve as an arbitrary method for assessing the likelihood of developing HF . HF of obesity (HFO) is a relatively other new term used to describe HF in obese individuals, independent of other comorbidities . This includes obese HFpEF patients in stage C HF (decompensated) and patients with obesity cardiomyopathy in stage B HF (structural heart disease or diastolic dysfunction) . HFO is likely to develop by age 30 with a BMI >70 kg/m2 and by age 50 in asymptomatic obese individuals with a BMI of 50 kg/m2 . Clinical diagnosis of HFO is challenging since HF symptoms can be attributed to deconditioning resulting from obesity, the elevation of brain natriuretic peptide (BNP) is blunted, and weight limits cardiac catheterization and evaluation by echocardiography . In HFO, both stage B and stage C fall along a continuum of compensatory cardiac adaptations to the excess workload. The likelihood of stage B increases as age + BMI approaches 100 . Stage C HFO requires signs of decompensation, which include volume overload, pulmonary congestion, or the need for diuretics . Cardiac resilience is the ability to maintain adequate cardiac output despite comorbidities (such as hypertension and valve disease) and acute stressors (such as surgery or infection) . This resilience tends to decline with aging . Lifestyle modifications can improve resilience and reverse biological aging . In HFO, the adaptive cardiac changes are mediated by hemodynamic load and inflammation. Patients who achieve a >20% weight reduction by the age of 60-70 years can experience complete reversal of HF . Therefore, educating patients about "Obesity-years" will benefit from cardiac evaluation. Future studies are in critical need to support a paradigm shift in our approach to obesity-related complications, emphasizing the potential for remission through targeted interventions and lifestyle modifications, ultimately leading to improved health outcomes for affected individuals. Conclusions In summary, OH emerges as a consequence of the intricate interplay between adipose tissue, hormones, and insulin resistance, resulting in elevated blood glucose levels. Understanding its underlying mechanisms is pivotal for effective prevention and management. Importantly, OH presents a unique opportunity for reversal through substantial weight loss and lifestyle modifications, potentially offering a path to remission that can alleviate the burden on healthcare systems and improve the quality of life for affected individuals. On the other hand, recognizing the heterogeneity of HFpEF and its association with obesity underscores the importance of tailored diagnostic and therapeutic approaches. Moreover, early intervention through weight reduction interventions may offer a promising avenue for reversing cardiac changes, thus potentially mitigating the progression of HFpEF. Author Contributions Concept and design: Khalid Sawalha, Osama Asad, Shourya Tadisina, Deya Alkhatib, Luay Alalawi, Maria Mahmood, Thomas Alexander Acquisition, analysis, or interpretation of data: Khalid Sawalha, Osama Asad, Shourya Tadisina, Deya Alkhatib, Luay Alalawi, Maria Mahmood, Thomas Alexander Drafting of the manuscript: Khalid Sawalha, Osama Asad, Shourya Tadisina, Deya Alkhatib, Luay Alalawi, Maria Mahmood, Thomas Alexander Critical review of the manuscript for important intellectual content: Khalid Sawalha, Osama Asad, Shourya Tadisina, Deya Alkhatib, Luay Alalawi, Maria Mahmood, Thomas Alexander Supervision: Khalid Sawalha, Osama Asad, Shourya Tadisina, Deya Alkhatib, Luay Alalawi, Maria Mahmood, Thomas Alexander The authors have declared that no competing interests exist. References 1 Prevalence of obesity and severe obesity among adults: United States, 2017-2018 NCHS Data Brief Hales CM Carroll MD Fryar CD Ogden CL 1 8 2020 2 Trends in the prevalence of metabolically healthy obesity among US adults, 1999-2018 JAMA Netw Open Wang JS Xia PF Ma MN 0 6 2023 3 Early recognition of overweight hyperglycaemia may improve clinical outcomes in type 2 diabetes touchREV Endocrinol Chockalingam A Natarajan P Dorairajan S Khan U 33 37 19 2023 37313244 4 "Obesity-years" burden may predict reversibility in heart failure with preserved ejection fraction Front Cardiovasc Med Chockalingam A 821829 9 2022 35198616 5 BMI classification percentile and cut off points Weir CB Jan A Treasure Island, FL StatPearls Publishing 2023 6 The relative contributions of different levels of overweight and obesity to the increased prevalence of diabetes in the United States: 1976-2004 Prev Med Gregg EW Cheng YJ Narayan KM Thompson TJ Williamson DF 348 352 45 2007 17889292 7 Projection of the future diabetes burden in the United States through 2060 Popul Health Metr Lin J Thompson TJ Cheng YJ Zhuo X Zhang P Gregg E Rolka DB 9 16 2018 29903012 8 Obesity and cancer: A current overview of epidemiology, pathogenesis, outcomes, and Management Cancers (Basel) Pati S Irfan W Jameel A Ahmed S Shahid RK 485 15 2023 36672434 9 Obesity-induced hyperglycemia impairs oral tolerance induction and aggravates food allergy Mucosal Immunol Torres L Camila Goncalves Miranda M Dantas Martins V 513 526 16 2023 37302712 10 Obesity-induced insulin resistance and hyperglycemia: etiologic factors and molecular mechanisms Anesthesiology Martyn JA Kaneki M Yasuhara S 137 148 109 2008 18580184 11 OMA Obesity Algorithm VIII Harold Harold BM FOMA William William MMF MMF Centennial Obesity Medicine Association 2021 12 Mechanism linking diabetes mellitus and obesity Diabetes Metab Syndr Obes Al-Goblan AS Al-Alfi MA Khan MZ 587 591 7 2014 25506234 13 2 years of calorie restriction and cardiometabolic risk (CALERIE): exploratory outcomes of a multicentre, phase 2, randomised controlled trial Lancet Diabetes Endocrinol Kraus WE Bhapkar M Huffman KM 673 683 7 2019 31303390 14 Life expectancy and healthy life expectancy data by country 4 2020 2020 15 Heart failure with preserved left ventricular ejection fraction: a complex conundrum simply not limited to diastolic dysfunction Cardiovasc Ther Lopez-Candales A Asif T Sawalha K Norgard NB 1552826 2023 2023 37496726 16 Obesity and heart failure with preserved ejection fraction: new insights and pathophysiological targets Cardiovasc Res Borlaug BA Jensen MD Kitzman DW Lam CS Obokata M Rider OJ 3434 3450 118 2023 35880317 17 Obesity cardiomyopathy: pathophysiology and evolution of the clinical syndrome Am J Med Sci Alpert MA 225 236 321 2001 11307864 18 Hemodynamic effects of weight loss in obesity: a systematic review and meta-analysis JACC Heart Fail Reddy YN Anantha-Narayanan M Obokata M Koepp KE Erwin P Carter RE Borlaug BA 678 687 7 2019 31302042 19 Reversible cardiomyopathies Clin Med Insights Cardiol Patel H Madanieh R Kosmas CE Vatti SK Vittorio TJ 7 14 9 2015 26052233 20 2021 ACC/AHA key data elements and definitions for heart failure: a report of the American College of Cardiology/American Heart Association Task Force on clinical data standards (writing committee to develop clinical data standards for heart failure) J Am Coll Cardiol Bozkurt B Hershberger RE Butler J 2053 2150 77 2021 33250265 21 Cardiac morphology and left ventricular function in normotensive morbidly obese patients with and without congestive heart failure, and effect of weight loss Am J Cardiol Alpert MA Terry BE Mulekar M 736 740 80 1997 9315579 22 Empagliflozin in heart failure with a preserved ejection fraction N Engl J Med Anker SD Butler J Filippatos G 1451 1461 385 2021 34449189 23 Evidence supporting the existence of a distinct obese phenotype of heart failure with preserved ejection fraction Circulation Obokata M Reddy YN Pislaru SV Melenovsky V Borlaug BA 6 19 136 2017 28381470 24 How obesity affects the cut-points for B-type natriuretic peptide in the diagnosis of acute heart failure. Results from the breathing not properly multinational study Am Heart J Daniels LB Clopton P Bhalla V 999 1005 151 2006 16644321 25 Potential reversal of epigenetic age using a diet and lifestyle intervention: a pilot randomized clinical trial Aging (Albany NY) Fitzgerald KN Hodges R Hanes D 9419 9432 13 2021 33844651 26 Quantifying resilience of humans and other animals Proc Natl Acad Sci U S A Scheffer M Bolhuis JE Borsboom D 11883 11890 115 2018 30373844 27 Epigenetic regulation and its effects on aging and cardiovascular disease Cureus Sawalha K Norgard N Lopez-Candales A 0 15 2023 |
Eur Heart J Acute Cardiovasc Care Eur Heart J Acute Cardiovasc Care ehjacc European Heart Journal. Acute Cardiovascular Care 2048-8726 2048-8734 Oxford University Press US 37880824 10.1093/ehjacc/zuad124 zuad124 Editorial AcademicSubjects/MED00170 AcademicSubjects/MED00200 AcademicSubjects/MED00460 Time to treat the climate and nature crisis as one indivisible global health emergency + Abbasi Kamran Editor-in-Chief, BMJ Ali Parveen Editor-in-Chief, International Nursing Review Barbour Virginia Editor-in-Chief, Medical Journal of Australia Benfield Thomas Editor-in-Chief, Danish Medical Journal Bibbins-Domingo Kirsten Editor-in-Chief, JAMA Hancocks Stephen Editor-in-Chief, British Dental Journal Horton Richard Editor-in-Chief, The Lancet Laybourn-Langton Laurie University of Exeter Mash Robert Editor-in-Chief, African Journal of Primary Health Care & Family Medicine Sahni Peush Editor-in-Chief, National Medical Journal of India Sharief Wadeia Mohammad Editor-in-Chief, Dubai Medical Journal Yonga Paul Editor-in-Chief, East African Medical Journal Zielinski Chris University of Winchester Corresponding author. Email: [email protected] This Comment is being published simultaneously in multiple journals. For the full list of journals see: 12 2023 25 10 2023 25 10 2023 12 12 807808 25 10 2023 (c) The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. 2023 This is an Open Access article distributed under the terms of the Creative Commons Attribution License ), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. pmcOver 200 health journals call on the United Nations, political leaders, and health professionals to recognise that climate change and biodiversity loss are one indivisible crisis and must be tackled together to preserve health and avoid catastrophe. This overall environmental crisis is now so severe as to be a global health emergency. The world is currently responding to the climate crisis and the nature crisis as if they were separate challenges. This is a dangerous mistake. The 28th Conference of the Parties (COP) on climate change is about to be held in Dubai while the 16th COP on biodiversity is due to be held in Turkey in 2024. The research communities that provide the evidence for the two COPs are unfortunately largely separate, but they were brought together for a workshop in 2020 when they concluded that: 'Only by considering climate and biodiversity as parts of the same complex problem ... can solutions be developed that avoid maladaptation and maximize the beneficial outcomes.'1 As the health world has recognised with the development of the concept of planetary health, the natural world is made up of one overall interdependent system. Damage to one subsystem can create feedback that damages another for example, drought, wildfires, floods and the other effects of rising global temperatures destroy plant life, and lead to soil erosion and so inhibit carbon storage, which means more global warming.2 Climate change is set to overtake deforestation and other land-use change as the primary driver of nature loss.3 Nature has a remarkable power to restore. For example, deforested land can revert to forest through natural regeneration, and marine phytoplankton, which act as natural carbon stores, turn over one billion tonnes of photosynthesising biomass every eight days.4 Indigenous land and sea management has a particularly important role to play in regeneration and continuing care.5 Restoring one subsystem can help another for example, replenishing soil could help remove greenhouse gases from the atmosphere on a vast scale.6 But actions that may benefit one subsystem can harm another for example, planting forests with one type of tree can remove carbon dioxide from the air but can damage the biodiversity that is fundamental to healthy ecosystems.7 The impacts on health Human health is damaged directly by both the climate crisis, as the journals have described in previous editorials,8,9 and by the nature crisis.10 This indivisible planetary crisis will have major effects on health as a result of the disruption of social and economic systems shortages of land, shelter, food, and water, exacerbating poverty, which in turn will lead to mass migration and conflict. Rising temperatures, extreme weather events, air pollution, and the spread of infectious diseases are some of the major health threats exacerbated by climate change.11 'Without nature, we have nothing,' was UN Secretary-General Antonio Guterres's blunt summary at the biodiversity COP in Montreal last year.12 Even if we could keep global warming below an increase of 1.5degC over pre-industrial levels, we could still cause catastrophic harm to health by destroying nature. Access to clean water is fundamental to human health, and yet pollution has damaged water quality, causing a rise in water-borne diseases.13 Contamination of water on land can also have far-reaching effects on distant ecosystems when that water runs off into the ocean.14 Good nutrition is underpinned by diversity in the variety of foods, but there has been a striking loss of genetic diversity in the food system. Globally, about a fifth of people rely on wild species for food and their livelihoods.15 Declines in wildlife are a major challenge for these populations, particularly in middle-income countries. Fish provide more than half of dietary protein in many African, South Asian and small island nations, but ocean acidification has reduced the quality and quantity of seafood.16 Changes in land use have forced tens of thousands of species into closer contact, increasing the exchange of pathogens and the emergence of new diseases and pandemics.17 People losing contact with the natural environment and the declining loss in biodiversity have both been linked to increases in noncommunicable, autoimmune, and inflammatory diseases and metabolic, allergic and neuropsychiatric disorders.10,18 For Indigenous people, caring for and connecting with nature is especially important for their health.19 Nature has also been an important source of medicines, and thus reduced diversity also constrains the discovery of new medicines. Communities are healthier if they have access to high-quality green spaces that help filter air pollution, reduce air and ground temperatures, and provide opportunities for physical activity.20 Connection with nature reduces stress, loneliness and depression while promoting social interaction.21 These benefits are threatened by the continuing rise in urbanisation.22 Finally, the health impacts of climate change and biodiversity loss will be experienced unequally between and within countries, with the most vulnerable communities often bearing the highest burden.10 Linked to this, inequality is also arguably fuelling these environmental crises. Environmental challenges and social/health inequities are challenges that share drivers and there are potential co-benefits of addressing them.10 A global health emergency In December 2022 the biodiversity COP agreed on the effective conservation and management of at least 30 percent of the world's land, coastal areas, and oceans by 2030.23 Industrialised countries agreed to mobilise $30 billion per year to support developing nations to do so.23 These agreements echo promises made at climate COPs. Yet many commitments made at COPs have not been met. This has allowed ecosystems to be pushed further to the brink, greatly increasing the risk of arriving at 'tipping points', abrupt breakdowns in the functioning of nature.2,24 If these events were to occur, the impacts on health would be globally catastrophic. This risk, combined with the severe impacts on health already occurring, means that the World Health Organization should declare the indivisible climate and nature crisis as a global health emergency. The three pre-conditions for WHO to declare a situation to be a Public Health Emergency of International Concern25 are that it: 1) is serious, sudden, unusual or unexpected; 2) carries implications for public health beyond the affected State's national border; and 3) may require immediate international action. Climate change would appear to fulfil all of those conditions. While the accelerating climate change and loss of biodiversity are not sudden or unexpected, they are certainly serious and unusual. Hence we call for WHO to make this declaration before or at the Seventy-seventh World Health Assembly in May 2024. Tackling this emergency requires the COP processes to be harmonised. As a first step, the respective conventions must push for better integration of national climate plans with biodiversity equivalents.3 As the 2020 workshop that brought climate and nature scientists together concluded, 'Critical leverage points include exploring alternative visions of good quality of life, rethinking consumption and waste, shifting values related to the human-nature relationship, reducing inequalities, and promoting education and learning.'1 All of these would benefit health. Health professionals must be powerful advocates for both restoring biodiversity and tackling climate change for the good of health. Political leaders must recognise both the severe threats to health from the planetary crisis as well as the benefits that can flow to health from tackling the crisis.26 But first, we must recognise this crisis for what it is: a global health emergency. References 1 Otto-Portner H , ScholesB, AgardJ, ArcherE, ArnethA, BaiX, et al Scientific outcome of the IPBES-IPCC co-sponsored workshop on biodiversity and climate change. 2021. 2 Ripple WJ , WolfC, LentonTM, GreggJW, NataliSM, DuffyPB, et al Many risky feedback loops amplify the need for climate action. One Earth 2023;6 :86-91. 3 European Academies Science Advisory Council . Key Messages from European Science Academies for UNFCCC COP26 and CBD COP15. 2021 August. (1 October 2023). 4 Falkowski P . Ocean science: the power of plankton. Nature 2012;483 :S17-S20.22378122 5 Dawson N , CoolsaetB, SterlingE, LoveridgeR, Gross-CampN, WongbusarakumS, et al The role of Indigenous peoples and local communities in effective and equitable conservation. Ecol Soc 2021;26 :19. 6 Bossio DA , Cook-PattonSC, EllisPW, FargioneJ, SandermanJ, SmithP, et al The role of soil carbon in natural climate solutions. Nat Sustain 2020;3 :391-398. 7 Levia DF , CreedIF, HannahDM, NankoK, BoyerEW, Carlyle-MosesDE, et al Homogenization of the terrestrial water cycle. Nat Geosci 2020;13 :656-658. 8 Atwoli L , BaquiAH, BenfieldT, BosurgiR, GodleeF, HancocksS, et al Call for emergency action to limit global temperature increases, restore biodiversity, and protect health. BMJ 2021;374 :n1734.34483099 9 Atwoli L , ErhaborGE, GbakimaAA, HaileamlakA, NtumbaJ-MK, KigeraJ, et al COP27 Climate Change Conference: urgent action needed for Africa and the world. BMJ 2022;379 :o2459.36257789 10 WHO, UNEP, Convention on Biological Diversity . Connecting global priorities: biodiversity and human health: a state of knowledge review. 2015. (1 October 2023). 11 Magnano San Lio R , FavaraG, MaugeriA, BarchittaM, AgodiA. How antimicrobial resistance is linked to climate change: an overview of two intertwined global challenges. Int J Environ Res Public Health 2023;20 :1681.36767043 12 Jelskov U . "Without nature, we have nothing": UN chief sounds alarm at key UN biodiversity event. UN News (Internet). 6 December 2022 (cited 20 June 2023). (1 October 2023). 13 World Health Organization . State of the world's drinking water: an urgent call to action to accelerate progress on ensuring safe drinking water for all. World Health Organization; 2022 October. (1 October 2023). 14 Comeros-Raynal MT , BrodieJ, BainbridgeZ, ChoatJH, CurtisM, LewisS, et al Catchment to sea connection: impacts of terrestrial run-off on benthic ecosystems in American Samoa. Mar Pollut Bull 2021;169 :112530.34087665 15 IPBES . Assessment report on the sustainable use of wild species. 2022 August. 16 Falkenberg LJ , BellerbyRGJ, ConnellSD, FlemingLE, MaycockB, RussellBD, et al Ocean acidification and human health. Int J Environ Res Public Health 2020;17 :4563.32599924 17 Dunne D . Climate change "already" raising risk of virus spread between mammals. 28 April 2022 (cited 24 March 2023). (1 October 2023). 18 Altves S , YildizHK, VuralHC. Interaction of the microbiota with the human body in health and diseases. Biosci Microbiota Food Health 2020;39 :23-32.32328397 19 Schultz R , CairneyS. Caring for country and the health of Aboriginal and Torres Strait Islander Australians. Med J Aust 2017;207 :8-10.28659102 20 Macguire F , MulcahyE, RossingtonB. The Lancet Countdown on Health and Climate Change policy brief for the UK. 2022. (1 October 2023). 21 Wong FY , YangL, YuenJWM, ChangKKP, WongFKY. Assessing quality of life using WHOQOL-BREF: a cross-sectional study on the association between quality of life and neighborhood environmental satisfaction, and the mediating effect of health-related behaviors. BMC Public Health 2018;18 :1113.30208869 22 Simkin RD , SetoKC, McDonaldRI, JetzW. Biodiversity impacts and conservation implications of urban land expansion projected to 2050. Proc Natl Acad Sci U S A 2022;119 :e2117297119. 23 Secretariat of the Convention on Biological Diversity . COP15: nations adopt four goals, 23 targets for 2030 in landmark UN biodiversity agreement. Convention on Biological Diversity (Internet). 12 December 2022 (cited 21 April 2023). (1 October 2023). 24 Armstrong McKay DI , StaalA, AbramsJF, WinkelmannR, SakschewskiB, LorianiS, et al Exceeding 1.5degC global warming could trigger multiple climate tipping points. Science 2022;377 :eabn7950. 25 WHO guidance for the use of Annex 2 of the International Health Regulations (2005). World Health Organization (Internet). (cited 5 October 2023). (1 October 2023). 26 Australian Government Department of Health and Aged Care . Consultation on Australia's first National Health and Climate Strategy. Australian Government Department of Health and Aged Care (Internet). 26 July 2023 (cited 26 July 2023). (1 October 2023). |
Food waste is an issue of global concern requiring worldwide action. In the UK, PS19 billion worth of food is wasted every year. A variety of initiatives have been developed to redistribute surplus food to those in need. The Birchwood Junk Food Cafe in Skelmersdale combines the reduction of food waste with community and societal benefits. The University of Manchester and the Birchwood Centre conducted an evaluation of the cafe including a customer satisfaction survey, a long-form health and wellbeing survey and qualitative interviews. Each day the cafe produces a three-course menu for the public on a 'pay-as-you-feel' basis. During an 18-month period, the cafe intercepted 32 729 kg of food that would otherwise have gone to waste, served over 1500 people, with 3500 covers, 60 different dishes and 1200 volunteer hours. Customer satisfaction was extremely high with 88% being repeated visitors and 86% rating the cafe as excellent. Volunteers include youth from the local Birchwood Centre, who gain valuable experiences. Customers benefit from social interactions and additional community cohesion. The cafe offers an unique opportunity to impact on the wider community and provides support and structure for the volunteers. food choice food waste public health N8 AgriFood pmcIntroduction Food waste is an issue of global concern requiring worldwide action. In the UK, PS19 billion worth of food is wasted every year.1 The UK government has a five-step framework known as the 'food and drink hierarchy', based on the EU Waste Framework Directive (2008), which prioritizes how you should deal with surplus food and drink.2,3 Preventing production of excess food would reduce food waste, although, most food waste occurs at household-level.4 The Real Junk Food project In response to the amount of household waste, charitable organizations have been set up to redistribute surplus food to those in need. The Real Junk Food project (RJFP) is one of those overarching groups, with a network of over 120 Junk Food cafes5 that take edible food from supermarkets that is often past its 'best before'/'display until' date but still safe to eat and make meals for local people. Some also act as food banks to provide food for people who are unable to make ends meet. They are staffed by trained volunteers and run on a 'pay-as-you-feel' basis. The Birchwood Junk Food Cafe in Skelmersdale combines the reduction of food waste with community and societal benefits. They developed partnerships with local supermarkets who donate food and receive donations. Each day the cafe is open, chefs analyse available food and produce a three-course menu for members of the public on a 'pay-as-you-feel' basis. Volunteer chefs are trained by senior volunteers typically working as (paid employed) chefs elsewhere. Volunteers include youth from local centres, who often go on to mentor others. Accessible pricing allows individuals on low incomes to attend and meet other people, helping reduce social isolation. Volunteers often sit with the elderly, and customers make friends at the cafe, building social cohesion. Skelmersdale Skelmersdale sits in the borough of West Lancashire.6 It consists of seven wards, has higher levels of deprivation at all stages of life than elsewhere in West Lancashire and, nationally, six wards are amongst the top 20% most deprived, with four in the top 5%.7 The population of Skelmersdale is younger than anywhere else in West Lancashire. It has the highest proportion of children aged 0-15 living in income-deprived households and the highest proportion of adults aged 60 or over living in pension credit households.7 People in Skelmersdale die earlier than in other areas of West Lancashire. The lowest life expectancy at birth for males is Tanhouse ward (73.6 years), with the highest 9.4 years longer in Derby (83 years). For females, the lowest life expectancy at birth is in Birch Green (76.1 years) compared with Tarleton, 11.5 years longer (87.6 years).7 There are poorer levels of healthy eating and high levels of obesity among adults and children, higher levels of hospital admissions due to alcohol-related harm, higher infant mortality and higher levels of premature mortality from cancer and circulatory disease than elsewhere within West Lancashire.7 BJFC The Birchwood Centre in Skelmersdale is an independent charity that supports 13-25 year olds, providing a range of services helping young people achieve their potential. Services range from supported accommodation to intervention activities, mediation, counselling, training and development. Birchwood joined RJFP to provide healthy, cooked meals for the community. BJFC intercepts food close to its expiry date and produces healthy meals with the help of volunteers including chefs, members of the public and young people from the Centre. For Birchwood Centre volunteers, this model provides them with the opportunity for further education and training to help enhance their employability, and interact with the community outside of the centre, enhancing life skills. The cafe runs in two locations twice a week. Both centres are in deprived communities, with one located in the 3197th most deprived Lower Super Output Area (LSOA) in England and the other in the 1455th most deprived (out of 32 844 LSOAs). By locating the cafe in these areas, the centre helps tackle food poverty by increasing access to affordable healthy food, providing access to fresh foods and supplying hot meals to those with limited cooking facilities. It has a wide range of customers including the elderly, professionals, asylum seekers, refugees and the homeless. The cafe is an asset (or safety net) within the community. Through the common activity of eating together, it provides a safe space for interaction, where the community can build friendships and networks, get to know their neighbours and feel safe. It encourages customers to learn more about food access, use and waste, and interact with more vulnerable people. The cafe operates the 'pay-as-you-feel' system where customers decide how much to pay for their food. If customers do not have money to pay with, they may offer their services as a volunteer. This allows for inclusivity so that everybody can access the cafe. Food not used is allocated to the 'pay-as-you-feel' shop where customers can take goods home. To serve the diverse community, pay-as-you-feel instructions are provided in four languages English, Arabic, French and Persian. Over a period of 18 months, the Cafe intercepted 32 729 kg of food that would otherwise have gone to waste, served over 1500 people, with 3500 covers, 60 different dishes and 1200 volunteer hours. Processes are designed to ensure health and safety standards are upheld and a coordinator organizes the volunteers. Over 12 months, proceeds totalled PS4820.69. This ranged from PS12.35 to PS224.24. On average, BJFC took in PS51.18 each day it ran, with a monthly average of PS400.89. Customer satisfaction survey The University of Manchester and the Birchwood Centre conducted a customer satisfaction survey with 134 cafe customers. Of those, 118 (88%) were repeat visitors, all stated they would return, and 115 (86%) rated the cafe as excellent. A free text option was provided. All comments were overwhelmingly positive. Comments were coded by two separate researchers, resulting in 23 distinct codes. The 23 codes represent aspects of the cafe that the customers valued, for example, the 'quality of the food', the 'service and staff', 'company', the chance to make 'new friends' and 'healthy/fresh food' that helps to 'reduce food waste'. Codes were grouped into themes and subthemes. Two headline themes were identified and labelled as customer and cafe. Respondents referred either to aspects of the cafe and what the cafe provided, or to themselves and the other customers. The Cafe In the headline theme Cafe, we identified five separate subthemes; quality, venue, service/people/staff, ethos and financial support. The quality, healthiness and freshness of the food provided by the cafe were commented on; 'Excellent food', 'great food', 'lovely fresh food'. Customers valued facilities and atmosphere provided by the venues and the opportunity to have a space to gather; 'wonderful place', 'always made welcome', 'nice community feel'. The volunteers and organizers of the cafe received a great deal of praise; 'lovely volunteers', 'good service', 'staff are all lovely and its really nice place to be'. Several customers made particular mention of how they valued the concept of reducing food waste; 'better to eat food before its thrown', 'It's a fantastic idea. To think that all this food would go to waste otherwise!'. Some were grateful for the pay-as-you-feel concept of the cafe and the opportunity to get food from the onsite shop; 'living below the line this week - PS1 a day for food and drink so it really help!!', 'I am struggling to cope at the minute so coming here with access to a healthy meal and food to take away is amazing', 'I am disabled and under pressure from DWP so the cafe is a welcome respite!'. The customers The success of the cafe is also driven by its customers. We identified three subthemes that demonstrate the value added by those attending the cafe; social benefits, community and supporting a cause. Social benefits were a strong theme throughout. Customers valued the opportunity to meet up with friends and family, make new friends or get out of the house and enjoy the company of others. This has benefits in reducing social isolation, which has been identified as a key issue in Skelmersdale. Comments included, 'Wonderful experience every week bringing the community together', 'The cafe is a good way to meet friends', 'It lovely to meet up once a week with friend I'd lost contact with', 'To get out the house'. A strong community spirit has developed around the cafe with people mentioning, the 'fantastic community spirit', how 'It helps bring the community together' and that the cafe has a 'fab community atmosphere'. Finally, customers of the cafe expressed their desire to help what they see as a good cause and support a community initiative they feel is of great value to the local area; 'The cafe is a good way to ... support the community', describing why they came to the cafe people said to 'support worthy cause', 'To support the cafe', to 'support a brilliant initiative'. Customer telephone interviews Customers were also asked to consent to a telephone interview to discuss their thoughts and experiences. In total, six customers participated in an interview. The most predominant theme to emerge was the social aspect of the cafe. Customers talked about how they value the company of others and the main reason for their attending the cafe was to socialize. They were also interested in the cafe, how it came about, operates, improves knowledge about food waste and changes attitudes to food and healthy eating. Customers also enjoyed feeling as though they were helping others by attending. Interviews with cafe organizers and volunteers Interviews were conducted with organizers and volunteers. Two researchers interviewed the founder of the cafe, the manager and two volunteer chefs. The main themes to emerge were the benefit of the cafe to volunteers, the positive aspect of avoiding food waste and educating people that it is okay to buy and eat food that has passed its sell-by date, the benefit of providing healthy, hot meals and groceries on a pay-as-you-feel basis and the social benefits to volunteers and customers. The strongest theme was the potential of the cafe, how it can be taken forward and expanded. Potential All interviewees mentioned the potential to expand and thrive. One participant highlighted that it is not marketed and if they were to advertise it could be much bigger, but they expressed concern that they may struggle to cope if that happened too quickly. It was mentioned they had worked hard to make sure the cafe was not viewed as a 'soup kitchen for poor people' and one of their ambitions was to have a food van that could travel to community events, and other communities. One barrier to expansion highlighted was the lack of facilities, such as storage and refrigeration. Other ideas were to hold a junk food festival, having the cafe run 5 days a week, going to schools, finding local areas to start growing produce, getting more supermarkets on board and getting more support from local councillors and more volunteers. The organizers were conflicted as they were keen to acquire premises, a base that the cafe could be run out of permanently, while at the same time, acknowledging that one of the main benefits of the cafe was operating within communities and being accessible to people who could not travel. All interviewees were keen to see the cafe eventually operate full time, evenings and weekends. Benefit to volunteers Interviewees mentioned how volunteer numbers had increased, mainly from word-of-mouth and social media, and stressed the benefits to volunteers, including instilling a work ethic, letting people see what life beyond their own restricted environment is like and that they are not the only people with issues and/or facing difficulties. They believe volunteering helps build confidence and self-esteem and helps them be more resilient and improve their skill base. Interviewees felt it was important that volunteers learned from their experience, whether about food waste, cooking, healthy eating, other cultures or life in general. The cafe is seen as a safe, protective space where volunteers could feel supported. Specific support is also offered if needed such as, help with applications, references and interview techniques. The cafe is also seen as somewhere that helps raise the expectations of volunteers and inspires them to believe they have opportunities they may otherwise feel are not available to them and that they can have fun while also working hard. Volunteer success stories were shared, such as those that have gone on to gain employment or reconnect with estranged family. The cafe and volunteers also highlight the work of the Birchwood Centre. Food waste Food waste and the ethos of the cafe were mentioned. The cafe contributing to diverting food that would otherwise be discarded was seen as an important and rewarding part of the work. Being unsure from 1 day to the next what food would be delivered was viewed as an exciting challenge. They were proud that they were educating customers about food waste and that many people would now be more prepared to cook and eat food they may previously have rejected. All interviewees highlighted that the cafe also impacted their own attitude to food and food waste. Healthy eating and hot meals Interviewees mentioned that many customers indicated that they did not really eat vegetables before and that cafe meals had made them realize how nice vegetables can be. As the cafe is provided with more fruit and vegetables than meat or fish, the customers are exposed to them regularly. They also mentioned customers who attend the cafe because it is pay-as-you-feel and how the cafe acts as an important lifeline. Again, interviewees referred to the impact on their eating habits and that now they ate more healthily than before. Social benefits Social benefits featured strongly. Interviewees were keen to highlight that volunteers and customers need the company and the opportunity to make friends that the cafe provides. One interviewee described the cafe as the 'bait-on-the-hook' to get people to come along, interact and feel part of the community. The impact this can have on people's lives was mentioned repeatedly and each interviewee had a story to share illustrating success in increasing people's self-confidence and helping them make friends. It was also pointed out that although people may come to the cafe to meet people, organizers then have the opportunity to discover what other support they may need and signpost them to other services. Customer health and wellbeing questionnaires A long questionnaire was developed to look at themes in more detail. The questions were taken from validated questionnaires and covered demographic information, social cohesion, the environment, food consumption, food waste, wellbeing and loneliness.8-12 A total of 35 customers completed the questionnaires. Of these, 71% (n = 24) were female, 53% (n = 18) gave their highest level of education as secondary compared to 47% (n = 16) university, 66% (n = 23) stated that their general health level was good, 70% (n = 23) felt they had enough money for daily expenses and 70% (n = 24) were not in employment. In terms of social cohesion, 55.9% (n = 27) of respondents agreed that people were willing to help their neighbours, 45.2% (n = 14) disagreed that people do not share the same values and 63.6% (n = 27) agreed that there is always someone to help you. Food consumption Of customers who visit the cafe, 76% (n = 25) usually eat breakfast, 55% (n = 18) lunch, 91% (n = 30) dinner and 42% (n = 14) snacks. Most (80%, n = 27) eat a hot meal at least once a day, but 9% (n = 3) eat a hot meal less than three times a week. At the weekend, 91% (n = 31) eat a hot meal at least once a day. On average, the cafe's customers eat three items of fruit and three items of vegetables a day. When asked to provide details regarding what they had eaten on 2 specific days in the previous week when the customers did not attend the cafe, a wide range of responses were provided with fruit (n = 16), toast (n = 15), porridge (n = 12) and biscuits (n = 12) featuring most frequently. Although customers generally demonstrate signs of a healthy diet, 78% (n = 25) believe they could eat healthier. When asked questions relating to loneliness, 35% (n = 9) of those with a valid score were not lonely, 46% (n = 12) moderately lonely, 8% (n = 2) severely lonely and 12% (n = 3) very severely lonely. All of those that reported some form of loneliness (n = 7) reported a household composition of sole occupancy, whereas 50% (n = 8) reported loneliness in a household occupancy of greater than one person. Of those who recorded a valid score on the Warwick-Edinburgh Mental Wellbeing Scale, 53% (n = 16) showed no signs of depression, 20% (n = 6) possible depression and 27% (n = 8) probable depression. Similarly to loneliness, 88% (7/8) of those in sole occupancy showed signs of depression, compared to 26% (5/19) of those in a household with more than one person. Conclusions The BJFC provides an outlet for food that is no longer able to be sold in supermarkets, contributing to reduction of food waste. The BJFC goes beyond the main goal of the RJFP, which is to 'stop food waste'.13 The cafe offers an unique opportunity to impact on the wider community, promotes work of the Birchwood Centre and provides additional support and structure for the young people in the centre. The cafe offers volunteers from the Birchwood Centre the opportunity to gain social skills, learn more about how other people live within their community and feel a greater sense of belonging. One of the key benefits for the young people is the opportunity to learn new skills, gain experience in a working environment to become better prepared for their future, independent living and gaining employment. Customers that took part in the evaluation see the benefit of the cafe to themselves and also in promoting community cohesion. Customers use the cafe for a variety of reasons, but the increased feeling of community spirit and togetherness is a noticeable additional benefit. Customers state that the key reason they attend is the chance to meet new people and make friends. Additionally, customers indicated reasons such as a reason to leave the house, the food and the opportunity to get a hot and healthy meal when experiencing financial hardship. The customers overwhelmingly enjoy the presence of the cafe in their community. Funding This work was funded by N8 AgriFood. This was a practical evaluation that was conducted for operational intelligence purposes to assist the Centre. Data availability Data summaries will be available upon request, for further information please contact the lead author. Greg Williams, Senior Lecturer in Public Health, University of Manchester Christine Greenhalgh, Lecturer in Public Health, University of Manchester Steph Mitchell, Lecturer in Public Health, University of Manchester Omer Ali, Lecturer in Public Health, University of Manchester Stella Connell, Chief Executive, Birchwood Centre David Scott, Homeless Officer/Coordinator, Birchwood Centre Grace Vella, Birchwood Centre Arpana Verma, Clinical Professor of Public Health and Epidemiology, University of Manchester |
Crohns Colitis 360 Crohns Colitis 360 crohnscolitis360 Crohn's & Colitis 360 2631-827X Oxford University Press US 10.1093/crocol/otad074 otad074 Letter to the Editor AcademicSubjects/MED00260 AcademicSubjects/MED00760 AcademicSubjects/MED00972 Unraveling the Place of Small Molecules in the Treatment of Fistulizing Crohn's Disease A Systematic Review and Network Meta-Analysis Attauabi Mohamed MD Department of Gastroenterology and Hepatology, Copenhagen University Hospital Herlev and Gentofte, Herlev, Denmark Gastrounit, Medical Section, Copenhagen University Hospital Amager and Hvidovre, Hvidovre, Denmark Copenhagen Center for Inflammatory Bowel Disease in Children, Adolescents, and Adults, Hvidovre Hospital, Hvidovre, Denmark Rasmussen Ditlev Nytoft MD, PhD Department of Gastroenterology and Hepatology, Copenhagen University Hospital Herlev and Gentofte, Herlev, Denmark Bergenheim Fredrik Olof MD, PhD Department of Gastroenterology and Hepatology, Copenhagen University Hospital Herlev and Gentofte, Herlev, Denmark Burisch Johan MD, PhD, DMSc Gastrounit, Medical Section, Copenhagen University Hospital Amager and Hvidovre, Hvidovre, Denmark Copenhagen Center for Inflammatory Bowel Disease in Children, Adolescents, and Adults, Hvidovre Hospital, Hvidovre, Denmark Seidelin Jakob Benedict MD, PhD, DMSc Department of Gastroenterology and Hepatology, Copenhagen University Hospital Herlev and Gentofte, Herlev, Denmark Address correspondence to: Mohamed Attauabi, MD, Department of Gastroenterology, Herlev Hospital, University of Copenhagen, Borgmester Ib Juuls Vej 1, DK-2730 Herlev, Denmark, ([email protected]) 10 2023 13 12 2023 13 12 2023 5 4 otad07421 12 2023 (c) The Author(s) 2023. Published by Oxford University Press on behalf of Crohn's & Colitis Foundation. 2023 This is an Open Access article distributed under the terms of the Creative Commons Attribution License ), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. pmcWith interest, we read the review by Dr. Singh et al. outlining the available medical options for perianal fistulizing Crohn's disease (CD).1 We would like to clarify the comparative efficacy and ranking of available interventions, with an emphasis on small molecules, which was not analyzed in the review. We conducted a Bayesian random-effects network meta-analysis (NMA) to account for trial heterogeneity, handling varying follow-ups in each trial as recommended.2 As of July 10, 2023, we identified 21 randomized controlled trials comprising 1452 patients. Compared to another NMA,3 we included 4 studies of stem cells,4-7 and 1 study each of upadacitinib,8 ustekinumab,9 and adalimumab versus ustekinumab.10 Based on CINeMA, confidence in findings was rated high between the active agents and placebo but low between active agents. Regarding induction of fistula remission during Weeks 6-14, defined as closure of all external openings draining at baseline, infliximab 5 mg/kg with ciprofloxacin (surface under the cumulative ranking [SUCRA] 0.895, hazard ratio [HR] = 14.80 [95% credible intervals] 2.83-88.92) or monotherapy (SUCRA 0.670, HR = 5.76 [1.88-21.62]) and adipose-derived stem cells (ASCs)-Cx401 (SUCRA 0.757, HR = 9.41 [1.28-173.76]), ranked highest and superior to placebo. Upadacitinib 45 mg also exceeded placebo significantly (SUCRA 0.516, HR = 3.69 [1.09-17.47]), while ustekinumab 6 mg/kg (SUCRA 0.452, HR = 2.33 [0.91-6.20]) and vedolizumab 300 mg (SUCRA 0.339, HR = 1.05 [0.72-20.50]) did not. Regarding maintaining fistula remission through Weeks 44-56, upadacitinib 30 mg (SUCRA 0.750) or 15 mg (SUCRA 0.721) ranked highest. Despite significant efficacy in the trial (30 mg: 4/19 (21.1) versus 0/25, P = .029; 15 mg: 6/35 (17.1), P = .036),8 upadacitinib did not outperform placebo in the NMA . Adalimumab 80/40 mg (SUCRA 0.542), infliximab 5 mg/kg (SUCRA 0.471), and ASCs-Cx601 (SUCRA 0.403) were superior to placebo , while vedolizumab 300 mg and ustekinumab 6 mg/kg were not. None of the interventions separated significantly from the others in both NMAs. No data on the benefit of adding ciprofloxacin to TNF antagonists for this NMA were retrieved. Limitations include the inclusion of anti-TNFs refractory patients in the study of ASCs-Cx601,4 and heterogeneity in terms of dedicated or post hoc trial analyses. Figure 1. League plot for the comparison of advanced therapies in patients with fistulizing Crohn's disease for maintenance of fistula remission at Weeks 44-56. The values in each cell represent the relative treatment effect (hazard ratio and 95% credible intervals) of the column-defining treatment compared to the row-defining treatment. A double asterisk indicates statistical significance. ASCs, adipose-derived stem cells. In conclusion, infliximab 5 mg/kg, ASCs, or upadacitinib 45 mg may be the best option for achieving fistula remission in patients with CD, despite no significant differentiation from other agents. Dr. Singh et al. are commended for their important endeavor. Nevertheless, the absence of data on upadacitinib or comparative analyses undermines the ability to provide guidance for well-informed treatment choices. Author Contributions J.B.S. and M.A. conceived the study idea. M.A., J.B.S., and J.B. planned and designed the study. M.A. and D.N.R. conducted a systematic literature review. M.A. performed the statistical analyses and drafted the manuscript. All authors interpreted the results and contributed with a critical revision of the manuscript for important intellectual content. All authors had full access to all data in the study. J.B.S. had the final decision to submit for publication. All authors have approved the final draft of the manuscript. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted. Funding None declared. Conflicts of Interest M.A., D.N.R., and F.O.B report no conflicts of interest. J.B. reports grants and personal fees from AbbVie, grants and personal fees from Janssen-Cilag, personal fees from Celgene, grants and personal fees from MSD, personal fees from Pfizer, grants and personal fees from Takeda, grants and personal fees from Tillots Pharma, personal fees from Samsung Bioepis, grants, and personal fees from Bristol Myers Squibb, grants from Novo Nordisk, personal fees from Pharmacosmos, personal fees from Ferring, personal fees from Galapagos, outside the submitted work. J.B.S. has received research grants from Takeda, Janssen and is the national coordinator of studies from AbbVie, Arena Pharmaceuticals, Ely Lilly, and Boehringer Ingelheim. None of these pertain to the research submitted here. Ethical considerations Not relevant for this network meta-analysis. Data Availability Data are presented in the current manuscript, its Supplemental Digital Content, or within the manuscripts or appendices of the included studies. References 1. Singh A , MidhaV, KochharGS, ShenB, SoodA. Management of perianal fistulizing Crohn's disease [published online ahead of print September 6, 2023]. Inflamm Bowel Dis. 2023;izad195. doi:10.1093/ibd/izad195 37672347 2. Dias S , WeltonNJ, SuttonAJ, AdesAE. NICE DSU Technical Support Document 2: A Generalised Linear Modelling Framework for Pairwise and Network Meta-Analysis of Randomised Controlled Trials. 2014. Accessed August 1, 2023. 3. Shehab M , AlrashedF, HeronV, RestelliniS, BessissowT. Comparative efficacy of biologic therapies for inducing response and remission in fistulizing Crohn's disease: systematic review and network meta-analysis of randomized controlled trials. Inflamm Bowel Dis. 2023;29 (3 ):367-375. doi:10.1093/ibd/izac103 35604382 4. Panes J , Garcia-OlmoD, Van AsscheG, et al. ; ADMIRE CD Study Group Collaborators. Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn's disease: a phase 3 randomised, double-blind controlled trial. Collaborators ACDSG, ed. Lancet 2016;388 (10051 ):1281-1290. doi:10.1016/S0140-6736(16)31203-X 27477896 5. Panes J , Garcia-OlmoD, Van AsscheG, et al. ; ADMIRE CD Study Group Collaborators. Long-term efficacy and safety of stem cell therapy (Cx601) for complex perianal fistulas in patients with Crohn's disease. Gastroenterology. 2018;154 (5 ):1334-1342.e4. doi:10.1053/j.gastro.2017.12.020 29277560 6. Molendijk I , BonsingBA, RoelofsH, et al. Allogeneic bone marrow-derived mesenchymal stromal cells promote healing of refractory perianal fistulas in patients with Crohn's disease. Gastroenterology. 2015;149 (4 ):918-27.e6. doi:10.1053/j.gastro.2015.06.014 26116801 7. Garcia-Olmo D , HerrerosD, PascualI, et al. Expanded adipose-derived stem cells for the treatment of complex perianal fistula: a phase II clinical trial. Dis Colon Rectum. 2009;52 (1 ):79-86. doi:10.1007/DCR.0b013e3181973487 19273960 8. Colombel JF , IrvingP, RiederF, et al Efficacy and safety of upadacitinib for the treatment of fistulas and fissures in patients with Crohn's disease. J Crohn's Colitis. 2023;17 (Suppl_1 ):i620-i623. doi:10.1093/ecco-jcc/jjac190.0621 9. Sands BE , KramerB, GasinkC, et al Association of ustekinumab serum concentrations and perianal fistula resolution in the Crohn's disease UNITI program. United Eur Gastroenterol J. 2019;7 (8 ):913. doi:10.1177/205064061985467 10. Peyrin-Biroulet L , PanaccioneR, GasinkC, et al. Perianal fistula closure in patients receiving ustekinumab: results from the SEAVUE and STARDUST trials. J Crohns Colitis. 2022;16 (Supplement_1 ):i460. doi:10.1093/ecco-jcc/jjab232.622 |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.49186 Pathology Oncology Utility of CD34 in Assessing Microvessel Density and Its Correlation With Clinicopathological Parameters in Colorectal Carcinoma Patients Muacevic Alexander Adler John R Pandey Shweta 1 Shukla Samarth 1 Vagha Sunita 1 1 Pathology, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND Shweta Pandey [email protected] 21 11 2023 11 2023 15 11 e4918610 10 2023 21 11 2023 Copyright (c) 2023, Pandey et al. 2023 Pandey et al. This is an open access article distributed under the terms of the Creative Commons Attribution License CC-BY 4.0., which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from Currently, the most commonly practiced method of reporting cases of colorectal carcinoma is done according to guidelines provided by the College of American Pathologists (8th edition) and the Royal College of Pathologists (UK). These guidelines include various histopathological parameters like tumor site, extent, histologic type, grade, margins, tumor budding, lymphovascular invasion, and perineural invasion. However, in the present guidelines, the immunohistochemistry-based marker of mean vessel density (MVD) has not been addressed as an important parameter. The present study gives an overview of the importance of MVD. MVD was statistically significant when correlated with tumor size, lymph node metastasis, grade, and vascular invasion. However, no statistical significance was observed when compared with age, perineural invasion, and stage of the tumor. perineural invasion lymphovascular invasion immunohistochemistry cd34 mean vessel density colorectal carcinoma pmcIntroduction Colorectal carcinoma (CRC) is one of the most common malignancies worldwide. Many developing countries have shown a significant rise in the incidence of colorectal malignancies. This is mainly ascribed to certain changes in modifiable factors like dietary patterns of increased consumption of meat products and also due to various lifestyle misconducts like obesity and lack of exercise . More than 1.9 million new cases of CRC were reported in 2020, and there have been nearly 5,76,858 deaths from colon carcinoma and 3,39,022 deaths from rectal carcinoma, which is almost 9.4% of all cancer-related deaths, third only to breast and lung cancer . Sustained tumor angiogenesis is one of the fundamental steps in tumor growth, invasion, and metastasis. Just like any other normal cell in the body, tumor cells also require the formation of a new vascular supply for nutrition and oxygenation [3-5], and hence an increase in the number of blood vessels in a tumor is significant for tumor growth and its metastatic potential . Mean vessel density (MVD) is a biological parameter that can be utilized to determine angiogenesis and understand tumor behavior and biology [6-10]. MVD can be implied to be associated with a higher grade of tumors, metastasis, and neural invasion. CD34 is a very commonly employed immunohistochemical marker for endothelial cells and hematopoietic progenitor cells. The endothelial cells lining the blood vessels immunolabeled with CD34 can be used to evaluate the MVD [11-17]. The present study would like to propose the significance of MVD as a potential parameter in the reporting guidelines as it can prove to be exceedingly useful in analyzing tumor behavior and morphology. Materials and methods The present study is a retrospective analytical study conducted over a period of one year and performed in the Department of Pathology, Jawaharlal Nehru Medical College, Sawangi (Meghe), Wardha, India, in collaboration with the Department of Oncosurgery, Acharya Vinoba Bhave Rural Hospital, Sawangi (Meghe), Wardha, India. The Institutional Ethics Committee gave their approval for the study (DMIHER(DU)/IEC/2023/650). A total of 100 cases diagnosed with carcinoma of the colon or rectum and had subsequently undergone hemicolectomy, total colectomy, low anterior resection, or abdominoperineal resection were included in the study. The sample size was calculated using Cochran's formula with an incidence rate of CRC of 19.5% and the desired error of margin was 8%. The sampling technique used was purposive sampling. Cases confirmed as colorectal adenocarcinoma on histopathology, all subtypes of adenocarcinoma, were included in the study. Patients of all age groups and both genders were included in the study. Patients with recurrent carcinoma, patients on chemotherapy or radiotherapy, and biopsies were excluded from the study. The effect modifiers like age were controlled through stratification. Histopathological sections of tumor mass, margins, and lymph nodes from these resected specimens were studied, and tumor tissue was graded as well differentiated , moderately differentiated , or poorly differentiated , and lymphovascular invasion , perineural invasion, lymph nodes, margins status, and staging was done according to the pathological TNM staging provided by guidelines from the College of American Pathologists . Figure 1 (a) Well-differentiated adenocarcinoma (H&E, low power view, 10x). (b) Moderately differentiated adenocarcinoma (H&E, 40x). (c) Poorly differentiated adenocarcinoma (H&E, 40x). (d) Section showing lymphovascular invasion in a moderately differentiated adenocarcinoma colon. (e & f) Section stained with IHC stain showing membranous positivity for CD34 in endothelial cells in well-differentiated adenocarcinoma colon (e) and moderately differentiated adenocarcinoma colon (f) (low power view, 100x) IHC: immunohistochemistry Calculation of MVD Immunohistochemistry (IHC) staining was performed on these paraffin-embedded sections with vascular hot spots using CD34 . Sections with no or less necrosis, inflammation, or ulceration and the presence of angiogenesis were taken as vascular hot spots. CD34 expression was mainly detected on the cell membrane, in the cytoplasm, or in the tumor stroma. Immunolabeled vessels in at least three hot spots were counted under 400x magnification, and the average was considered the microvessel count/Hpf. Even in the absence of a vessel lumen, any staining in endothelial cells or cell clusters was considered one vessel. Statistical tests Statistical analysis was done by using descriptive and inferential statistics using Student's unpaired t-test, one-way ANOVA, and Pearson correlation coefficient, and the software used in the analysis was SPSS Statistics version 27.0 (IBM Corp. Released 2020. IBM SPSS Statistics for Windows, Version 27.0. Armonk, NY: IBM Corp.), and p<0.05 is considered as the level of significance. Results In the present study, the mean age was 54.35+-12.98, and the maximum cases were seen in age groups above 50 years (62/100). The age of the patients when correlated with CD34 mean vessel count/Hpf was nonsignificant (0.341, NS) (Table 1). A slight male predominance of 53% was seen in cases of CRC, whereas 47% of affected patients were females. The maximum CD34-stained microvessel count observed was 42 and the minimum was 7 with the mean being 23.98 (Table 2). In the present study, the maximum cases were seen in the T3 category (38%), closely followed by 34% cases in the T2 category, and the least number of cases was observed in the T1 category with 8% cases. The maximum mean CD34 count was seen in T3 tumors (25.71). The study observed a significant correlation between the tumor extent (0.008, S), the grade of the tumor (0.0001, S), and the mean CD34 count. Table 1 Correlation between CD34-stained microvessel count and parameters of tumor (Pearson correlation coefficient) NS: nonsignificant, S: significant Variables r-value p-value Age in years -0.096 0.341, NS Tumor extent 0.209 0.037, S Lymph node involvement 0.633 0.0001, S Vascular invasion -0.658 0.0001, S Perineural invasion -0.451 0.25, NS Grade of tumor 0.482 0.0001, S Stage of tumor 0.419 0.057, NS Table 2 Distribution of patients according to CD34-stained microvessel count N Minimum Maximum Mean Std. deviation CD34 count 100 7.00 42.00 23.98 8.12 About 44% of cases showed no involvement of lymph nodes by the tumor cells and 66% of cases showed lymph nodes with positive tumor deposits on microscopy. The correlation between lymph node metastasis and CD34 count was significant (0.0001, S). In the present study, vascular invasion was identified in 39% of cases and vascular invasion was absent in 61% of cases. A significant correlation was observed between CD34 count and vascular invasion (0.0001, S). Tumor cells surrounding a nerve fiber are considered positive perineural invasions and are often associated with poor prognosis. In this study, perineural invasion was identified in 22/100 cases, and it was absent in 78/100 cases. The present study observed no significant correlation between perineural invasion and CD34 count (0.25, NS). The mean CD34 count in cases with perineural invasion was only slightly higher than in cases with absent perineural invasion. The correlation between the stage of tumor in the patients and their CD34 count was not significant (0.057, NS) (Table 1). Discussion CRC ranks third with respect to incidence (29 per 100,000) and is second in terms of mortality in countries with higher human development indexes . More than 9,35,000 deaths and more than 1.9 million new cases were reported in 2020 . Like most other neoplasias, the diagnosis of CRC is also based on clinical, radiological, and pathological assessment. The risk of CRC is higher in first-degree relatives with CRC which increases with age. The most commonly inherited CRC syndrome is Lynch syndrome, also known as hereditary non-polyposis colorectal cancer and familial adenomatous polyposis. Mainly, the mutations observed in Lynch syndrome are in the DNA mismatch repair genes MLH1, MSH2, MSH6, and PMS2. Tumor angiogenesis is one of the hallmarks of cancer and a parameter that can be utilized in providing targeted therapy with respect to the proliferating vessels. Hence, the present study was carried out with the objective of assessing angiogenesis by calculating MVD (mean vessel count/Hpf) using the immunohistochemical marker CD34. The microvessel count was calculated by IHC using the CD34 marker. The CD34 values in the present study ranged from 7 to 42 microvessel/Hpf with the mean being 23.98/Hpf. The mean microvessel count of various studies is given in Table 3. Table 3 Mean microvessel count in various studies S. No. Study and year Mean microvessel count 01 Sharifi et al. 2008 28.5/Hpf 02 Svagzdys et al. 2009 193 + 11.2/mm2 03 Moreira et al. 2011 35.75/Hpf 04 Deliu et al. 2015 351.85/mm2 05 Toma et al. 2018 304.6/mm2 06 Chabowski et al. 2018 64.69 + 33.07/Hpf 07 Present study 23.98/Hpf The present study observed no significant correlation between CD34 and the age of the patients (p-value=0.341). This is in agreement with the studies of Sheikh et al. (0.291, NS), Deliu et al. (0.704, NS), Sharifi et al. (0.127, NS), Behebani et al. (0.20, NS), and Qasim et al. (NS). The present study showed a significant correlation between CD34 expression and the extent of the tumor (0.008, S). This is in concordance with the study of Behebani et al. (0.03, S) but contrary to the study of Sheikh et al. (0.927, NS). The present study observed metastasis of CRC to lymph nodes in 54% of cases. The distribution of CD34 with lymph node metastasis in the present study showed a significant correlation (p-value=0.0001, S) which is in concordance with the study of Behebani et al. (0.03, S) and discordant with the study of Sheikh et al. (0.464, NS). Studies conducted by Sharifi et al. (0.00, S) and Behebani et al. (0.03, S) showed a significant correlation between CD34 expression and the grade of the tumor which is in agreement with the present study (0.0001, S). However, studies by Deliu et al. (0.436, NS) and Sheikh et al. (0.173, NS) are in disagreement with the present study. Lymphovascular invasion was identified in 39 cases of CRC. The correlation between lymphovascular invasion and CD34 expression was significant (0.00001, S) in the present study which is in concordance with the study of Behebani et al. (0.01, S). Perineural invasion was identified in 22 cases of CRC. The present study observed no statistical significance with CD34 expression (0.25, NS) which is in disagreement with Behebani et al. (0.03, S). In the present study, staging was done according to the American Joint Committee on Cancer guidelines (8th edition). The majority of cases were seen in Stage III. The study observed no correlation between the stage of tumor of the CRC cases and CD34 expression (0.057, NS) which is similar to the study of Sharifi et al. (0.544, NS), Qasim et al. (NS), and Chabowski et al. (0.4822, NS). However, it was contrary to the study of Deliu et al. (p-value <0.01, S). The limitations of the present study were technical as well as subjective. IHC is a technique that requires technical expertise and can be very expensive, and improper tissue sampling and tissue heterogenicity can lead to altered staining of CD34 immunohistochemical marker. Apart from IHC, one of the major restraints of this study is that the CD34 biomarker does not have a cut-off value and hence can affect the results. The duration of the study and the small sample size are also major limitations of the present study. Therefore, more follow-up studies are needed to document the correlation between MVD and clinicopathological parameters of CRC. Conclusions The prognosis of colorectal cancer is associated with several clinical and pathological parameters. Age, sex, tumor size, tumor location, tumor multiplicity, tumor edge, tumor budding, margins, vascular invasion, perineural invasion, lymph node involvement, microscopic type, and tumor angiogenesis are a few of them. Microvessel density as a parameter suggests the blood vessel proliferation in a tumor. It can be useful for intratumoral quantification in CRC and also reflect on the tumor size, grade, lymph node involvement, and lymphovascular invasion. The present study gave an overview of the importance of MVD. When correlated with clinicopathological parameters, MVD was statistically significant with tumor size, lymph node metastasis, grade, and vascular invasion. However, it showed no statistical significance when compared with age, perineural invasion, and stage of the tumor. The study suggested that when it comes to blood vessel proliferation and the metastatic tendency of a tumor, CD34 can prove to be a useful tool and provide better diagnosis and patient care in cases of CRC. I wish to express my gratitude to my guiding professor, Dr. Samarth Shukla from the Department of Pathology, for his invaluable guidance throughout this research work. I would also like to extend my thanks to Dr. Sunita Vagha, Professor in the Department of Pathology, for her tremendous support in this research. Finally, I am grateful to my institute, Datta Meghe Institute of Higher Education and Research, for their financial support for this research work. Author Contributions Human Ethics Animal Ethics Concept and design: Shweta Pandey, Samarth Shukla, Sunita Vagha Acquisition, analysis, or interpretation of data: Shweta Pandey Drafting of the manuscript: Shweta Pandey Critical review of the manuscript for important intellectual content: Shweta Pandey, Samarth Shukla, Sunita Vagha Supervision: Shweta Pandey, Samarth Shukla, Sunita Vagha Consent was obtained or waived by all participants in this study. Institutional Ethics Committee issued approval DMIHER(DU)/IEC/2023/650. The Institutional Ethics Committee approved the research proposal to be carried out at Jawaharlal Nehru Medical College. The committee granted the approval on the assumption that the current study would follow the ethical guidelines. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. The authors have declared that no competing interests exist. References 1 Colorectal carcinoma: A general overview and future perspectives in colorectal cancer Int J Mol Sci Marmol I Sanchez-de-Diego C Pradilla Dieste A Cerrada E Rodriguez Yoldi MJ 197 18 2017 28106826 2 Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries CA Cancer J Clin Sung H Ferlay J Siegel RL Laversanne M Soerjomataram I Jemal A Bray F 209 249 71 2021 33538338 3 Lymphangiogenic and angiogenic microvessel density in human primary sporadic colorectal carcinoma World J Gastroenterol Yan G Zhou XY Cai SJ Zhang GH Peng JJ Du X 101 107 14 2008 18176970 4 Angiogenesis in colorectal cancer: prognostic and therapeutic implications Am J Clin Oncol Giatromanolaki A Sivridis E Koukourakis MI 408 417 29 2006 16891872 5 Evaluation of angiogenesis in colorectal cancer Curr Health Sci J Deliu IC Ciurea P Neagoe D 145 151 41 2015 30364821 6 The role of microvessel density, lymph node metastasis, and tumor size as prognostic factors of distant metastasis in colorectal cancer Oncol Lett Cho T Shiozawa E Urushibara F 4327 4333 13 2017 28599434 7 Prognostic value of microvessel density in stage II and III colon cancer patients: a retrospective cohort study BMC Gastroenterol den Uil SH van den Broek E Coupe VM 146 19 2019 31420015 8 Microvessel density as new prognostic marker after radiotherapy in rectal cancer BMC Cancer Svagzdys S Lesauskaite V Pavalkis D Nedzelskiene I Pranys D Tamelis A 95 9 2009 19323831 9 Correlation between tumor budding, MVD in colorectal carcinoma Academic J Cancer Res El Sheikh SA Darweesh MF Bassam AM Ibrahim HA 19 25 9 2016 16/2.pdf 10 Correlations between endothelial cell markers CD31, CD34 and CD105 in colorectal carcinoma Rom J Morphol Embryol Deliu IC Neagoe CD Bezna M 1025 1030 57 2016 28002519 11 Evaluation of angiogenesis in colorectal carcinoma by CD34 immunohistochemistry method and its correlation with clinicopathologic parameters Acta medica Iranica Sharifi N Ghaffarzadegan K Ayatollahi H Shakeri M 161 164 47 2012 12 Evaluating the expression of CD34 marker in colorectal adenocarcinoma and its relationship with clinicopathologic factors Asian J Cell Biol Behbehani A Ranjbari N Rahim F Jazayeri N 80 86 10 2015 13 Differential expression of CD34 in normal colorectal tissue, peritumoral inflammatory tissue, and tumour stroma J Clin Pathol Nakayama H Enzan H Miyazaki E Kuroda N Naruse K Hiroi M 626 629 53 2000 11002768 14 Correlations between CD34 immunolabelled blood vessels and CD34 mRNA expression in colorectal cancer Curr Health Sci J Toma SC Uscatu CD Ungureanu BS 60 63 44 2018 30622757 15 Immunohistochemical expression of PCNA and CD34 in colorectal adenomas and carcinomas using specified automated cellular image analysis system: a clinicopathologic study Saudi J Gastroenterol Qasim BJ Ali HH Hussein AG 268 276 18 2012 22824771 16 Immunohistochemical analysis of vascular density and area in colorectal carcinoma using different markers and comparison with clinicopathologic prognostic factors Tumour Biol Moreira LR Schenka AA Latuf-Filho P 527 534 32 2011 21222066 17 Comparison of microvessel density using nestin and CD34 in colorectal cancer Anticancer Res Chabowski M Nowak A Grzegrzolka J Piotrowska A Janczak D Dziegiel P 3889 3895 38 2018 29970509 |
Biol Lett Biol Lett RSBL roybiolett Biology Letters 1744-9561 1744-957X The Royal Society 37788713 10.1098/rsbl.2023.0251 rsbl20230251 10016070Genome Biology Opinion Piece iNaturalist is an open science resource for ecological genomics by enabling rapid and tractable records of initial observations of sequenced biological samples iNaturalist is an open science resource for ecological genomics by enabling rapid and tractable records of initial observations of sequenced biological samples Goldberg Jay Keche Conceptualization Writing - original draft Writing - review & editing [email protected] Department of Ecology and Evolutionary Biology, University of Arizona, Tucson, AZ 85721, USA 4 10 2023 October 4, 2023 10 2023 4 10 2023 October 4, 2023 19 10 202302511 6 2023 June 1, 2023 12 9 2023 September 12, 2023 (c) 2023 The Authors. 2023 Published by the Royal Society under the terms of the Creative Commons Attribution License which permits unrestricted use, provided the original author and source are credited. The rapidly growing body of publicly available sequencing data for rare species and/or wild-caught samples is accelerating the need for detailed records of the samples used to generate datasets. Many already published datasets are unlikely to ever be reused, not due to problems with the data themselves, but due to their questionable or unverifiable origins. In this paper, I present iNaturalist a pre-existing citizen science platform that allows people to post photo observations of organisms in nature as a tool that allows genomics researchers to rapidly publish observations of samples used to generate sequencing datasets. This practice aligns with the values of the open science movement, and I also discuss how iNaturalist, along with other online resources, can be used to create an open genomics pipeline that enables future replication studies and ensures the value of genomics datasets to future research. genomics , iNaturalist , open science , natural history pmc1. Introduction The number of high-quality published genomes has increased rapidly in recent years , and the feasibility of sequencing multiple individuals of species with large heterozygous genomes has enabled pan-genomics with eukaryotic organisms . Once restricted to prokaryotes with small genomes , there are now several plant and animal species with publicly available pangenome databases . Evolutionary biologists are routinely using whole-genome sequencing to observe responses to climate change and experimental manipulation in real time. Many laboratories and consortia are publishing genomes as fast as possible to make them available to the broader scientific community , but often publish their data in minimalist reports that sometimes lack even basic descriptions of the data itself . The explosion of genomic data, while scientifically exciting, presents a dilemma if details regarding the collection of source sample(s) are not properly recorded and made available to the broader scientific community. Datasets originating from wild samples require more rigorous documentation of the originating samples to ensure their long-term value especially when they are rare or cryptic species, or members of poorly resolved clades. Current best practice is to submit voucher specimens to museums/herbaria, but many researchers fail to do so and when they do the degradation of preserved samples can create issues for later validation, as natural pigmentation fades over time or fine-scale structures important for identification are inadvertently damaged during transport or long-term storage. Travelling to consult collections in person is also difficult or impossible for many researchers. Many museums have begun digitizing their collections to alleviate this burden and make their specimens open access, but this practice is not yet universal and requires resources that are unavailable to underfunded institutions . The ethics of collecting samples from natural populations are hotly debated, considering widespread ecological degradation , and it is of critical importance that biologists minimize the environmental impact of their research. When extra samples for museum deposition cannot be collected due to ethical concerns, it creates a significant gap for open genomics research. iNaturalist a platform where users post observations of wildlife and experts identify them could be a valuable tool for researchers who wish to improve the reusability of their data while minimizing the environmental impact of sample collection. Observations posted on iNaturalist can represent the whole organism in cases where a small non-lethal sample is sufficient for sequencing studies, and the precise individual sampled in cases where an entire organism is required, thereby eliminating the need for additional sampling for record-keeping purposes. Furthermore, the publicly accessible nature of iNaturalist observations (one can access them without an account on the platform) makes it ideal for tackling the lack of robust, easily accessible, information regarding the originating samples used to generate publicly available sequencing datasets and help create a fully open genomics data pipeline (figure 1). This practice is not mutually exclusive with the use of formally curated museum specimens especially when there are no ethical concerns surrounding the collection of study species and can be used in combination with established practices to expand the availability of information surrounding sample/specimen collection. Figure 1. A flowchart outlining an example 'open genomics pipeline' with seven key steps and their corresponding open science platform. The second step in this pipeline, publicly recording the initial field observations/collection associated with a study, is the aspect that iNaturalist fulfils. The precise steps, and platforms used to carry them out, necessary for the best open science practices will vary, given the wealth of system-specific databases such as FlyBase or the Sol Genomics Network. 2. What is iNaturalist? iNaturalist is a citizen science platform that allows users to upload photos from an internet-connected device (smartphone, computer, etc.). It is not the first or only citizen science platform to accomplish this many region-specific databases also exist but its global scope and large user-base makes it the best suited for use in genomics research. Knowledgeable identifiers, often actively publishing researchers or museum curators, identify observations added to the database. These photo observations are also accompanied by metadata the date/time and location at which the photo was taken and sometimes include specific notes regarding the sex, life stage, etc. of the observed organism (these are often filled in by identifiers). Any discussion of the observations by the observer and identifiers is also recorded and associated with it. iNaturalist has already proven its value to ecologists and provided data for studies regarding invasion dynamics and animal behaviour . 3. An open genomics pipeline Open-access journals have become commonplace and many funding agencies mandate that results be published in them. Public repositories for various forms of data (GenBank, Dryad, etc.) and the code needed to analyse them (Github) exist and are often free to contribute to. Some model species and popular study clades even have their own dedicated repositories (e.g. Flybase, Sol Genomics Network). Resources for publishing step-by-step methodologies (protocols.io) also exist. Yet, until the advent of iNaturalist (and other citizen science platforms), there was no way to freely publish open-access natural history observations other than within peer-reviewed publications. Now, however, it is possible to instantly upload photos from the field, have them automatically associated with key metadata (time and location), and make them freely available to both the scientific community and the broader public using iNaturalist. This makes it a valuable tool for ecological and evolutionary geneticists to improve their data pipelines and better align with open science practices. iNaturalist's utility lies in how it allows researchers to associate publications with field observations via their unique URLs (example user profile and observation can be found in Web resources) that provide an easy-to-follow paper trail. This allows future researchers to verify the identity of the initial sample and collection details. This is critical for species that are likely to have their taxonomy revised as their identity can be followed through disagreements between systematists based on their observable traits. The iNaturalist taxon framework generally follows the Catalogue of Life but is manually updated by a global team of curators, many of whom are also curators of physical herbarium/museum collections and formally trained taxonomists. Knowledgeable users can flag species or taxa for curation and the platform records these notes, alongside curators' responses and/or changes. This detailed digital paper trail allows for minor identification errors (e.g. those that do not meaningfully alter the outcome of a study) or post-publication taxonomic revisions to be recorded and linked to the final dataset and/or publication without the need for formal corrections. To maximize the utility of iNaturalist for producing digital vouchers, researchers should provide as much detail as possible when submitting observations. At a bare minimum, all metadata fields (location, date/time, life stage, sex, etc.) should be completed. Multiple clear and descriptive photographs showing any/all traits necessary for identification should be submitted. When necessary, microscopy images of fine-scale morphology to aid with expert identification should be submitted. Depending on the study in question, further details (text annotations and/or photographic evidence) regarding local habitat or environmental conditions should also be provided; this information could be valuable for interpreting the outcomes of transcriptomic or population genetic studies examining organismal responses to local environments or rapid anthropogenic change. If observed samples are submitted to physical museum/herbarium collections, the voucher code and information about the specimen should also be provided in the notes section. If/when sequencing data are available, database information (e.g. GenBank accession numbers) should be provided. Researchers could also describe the purpose of sample collection (experimental design, extraction procedure, etc.), but it may be preferable to record this information with a hypothesis registry service instead. Ultimately, iNaturalist observations for research purposes should include all the information necessary for the scientific community to validate and replicate study findings. When accessed in bulk through the Global Biodiversity Information Facility (GBIF), sets of iNaturalist observations can be given digital object identifiers (DOIs) that enable replication studies , and, within the iNaturalist platform, observations can be collected into projects. Since it is now common to find genomics studies that include hundreds or thousands of samples collected from multiple species across broad geographical or long temporal scales , the collation of collection records into tractable projects/datasets will enable researchers to keep track of the samples used in a study that they may be planning, carrying out, or have already published. Any projects that an observation is a part of are shown underneath the observation, thus making it easy to track how researchers have used, or are planning to use, a sample/dataset. In addition to tracking important metadata regarding the use of scientific samples for open and repeatable science, this gives the public deeper insight into the science of the species they see in daily life and a direct line to the researchers conducting it. 4. Future directions While it is a powerful tool, iNaturalist is not perfect. Like all centralized services there is a risk of data loss should their infrastructure be compromised by natural disaster, malicious actors or financial setbacks. Much like private data storage, all important resources should be backed up and archived in other trusted databases. This could be accomplished by depositing datasets in other locations, be it a system-specific repository, regional database, or general-purpose repository (e.g. Zenodo). This process could likely be automated using computational tools that access iNaturalist via their application programming interface (API). Their API could also be used to automate the process of bulk observation uploads and/or modifying their descriptions to include links to resulting datasets (e.g. GenBank submissions) as they become available. API use is currently subject to strict rate limits (100 requests per minute; 5 GB per hour), which could prove to be a bottleneck for large high-throughput studies, but this will likely increase as they continue to develop and improve their digital infrastructure. It is also important to consider how iNaturalist observations will be referenced in other databases, ideally they should be referenced reciprocally such that observations reference subsequent datasets and these datasets reference back to the initial observations. Ultimately, propagating and eventually standardizing this process will require further discussion about and development of data management practices, but iNaturalist in its current form is already a valuable tool for creating open ecological genomics research. 5. Conclusion As the genomics revolution continues to open doors to research on the ecology and evolution of previously impossible-to-study species, the need for better documentation of data origins will increase dramatically. While online photo observations are not a full-fledged replacement for formally curated museum specimens, iNaturalist is a platform that researchers can use to rapidly publish field observations of samples that are eventually used in sequencing projects. When combined with other open science resources, it creates an open genomics data pipeline that allows both the scientific community and public-at-large to have better insight into the process behind genomics research. 6. Web resources iNaturalist Homepage: GBIF homepage: iNaturalist user profile: Example observation: Public information repositories protocols.io: Dryad: Github: GenBank: European Nucleotide Archive (ENA): FlyBase: WormBase: The Arabidopsis Information Resource (TAIR): Sol Genomics Network: Saccharomyces Genome Database: Catalogue of Life: Center for Open Science Preregistration Portal: International Nucleotide Sequence Database Collaboration: Biology focused pre-print servers bioRxiv: EcoEvoRxiv: medRxiv: Zenodo: Acknowledgements I would like to acknowledge the California Academy of Sciences and National Geographic Society for enabling the iNaturalist initiative and all developers who have worked on the project in any way. I would also like to thank Margaret Wilch for introducing me to iNaturalist and Judith Bronstein for encouraging me to write this manuscript, as well as helpful comments on an early draft. I also appreciate the comments from three anonymous reviewers that have greatly improved this manuscript. Data accessibility This article has no additional data. Declaration of AI use I have not used AI-assisted technologies in creating this article. Conflict of interest declaration I declare that I have no conflict of interest associated with the contents of this manuscript, and that I am not affiliated with iNaturalist (or its parent organizations) in any way beyond that of other enthusiastic users. Funding This work was supported by an NSF postdoctoral research fellowship in biology to J.K.G. (grant no. 2010772). References 1. Kress WJ, Soltis DE, Kersey PJ, Wegrzyn JL, Leebens-Mack JH, Gostel MR, Liu X, Soltis PS. 2022 Green plant genomes: what we know in an era of rapidly expanding opportunities. Proc. Natl Acad. Sci. USA 119 , e2115640118. (10.1073/pnas.2115640118)35042803 2. Golicz AA, Bayer PE, Bhalla PL, Batley J, Edwards D. 2020 Pangenomics comes of age: from bacteria to plant and animal applications. Trends Genet. 36 , 132-145. (10.1016/j.tig.2019.11.006)31882191 3. Rasko DA et al. 2008 The pangenome structure of Escherichia coli: comparative genomic analysis of E. coli commensal and pathogenic isolates. J. Bacteriol. 190 , 6881-6893. (10.1128/JB.00619-08)18676672 4. Gao L et al. 2019 The tomato pan-genome uncovers new genes and a rare allele regulating fruit flavor. Nat. Genet. 51 , 1044-1051. (10.1038/s41588-019-0410-2)31086351 5. Tong X et al. 2022 High-resolution silkworm pan-genome provides genetic insights into artificial selection and ecological adaptation. Nat. Commun. 13 , 5619. (10.1038/s41467-022-33366-x)36153338 6. Waldvogel AM et al. 2020 Evolutionary genomics can improve prediction of species' responses to climate change. Evol. Lett. 4 , 4-18. (10.1002/evl3.154)32055407 7. Kovacs AT, Dragos A. 2019 Evolved biofilm: review on the experimental evolution studies of Bacillus subtilis pellicles. J. Mol. Biol. 431 , 4749-4759. (10.1016/j.jmb.2019.02.005) 8. Mathers TC, Mugford ST, Wouters RHM, Heavens D, Botha AM, Swarbreck D, Van Oosterhout C, Hogenhout SA. 2022 Aphidinae comparative genomics resource. Zenodo (10.5281/zenodo.5908005) 9. Smith DR. 2017 Goodbye genome paper, hello genome report: the increasing popularity of 'genome announcements' and their impact on science. Brief Funct. Genomics 16 , 156-162. (10.1093/bfgp/elw026)27339634 10. Hains T, O'Neill K, Velez J, Speed N, Clubb S, Oleksyk T, Pirro S. 2020 The complete genome sequences of 22 parrot species (Psittaciformes, Aves). F1000Res. 9 , 1318. (10.12688/f1000research.25560.1) 11. Ong SQ, Julaluddin NSM, Yong KT, Ong SP, Lim KF, Azhar S. 2023 Digitization of natural history collections: a guideline and nationwide capacity building workshop in Malaysia. Ecol. Evol. 13 , e10212. (10.1002/ece3.10212)37325726 12. Byrne AQ. 2023 Reimagining the future of natural history museums with compassionate collection. PLoS Biol. 21 , e3002101. (10.1371/journal.pbio.3002101)37141192 13. Serniak LT, Chan SS, Lajtha K. 2023 Predicting habitat suitability for Amynthas spp. in the United States: a retrospective analysis using citizen science data from iNaturalist. Biol. Invasions 25 , 817-825. (10.1007/s10530-022-02947-8) 14. Vardi R, Berger-Tal O, Roll U. 2021 iNaturalist insights illuminate COVID-19 effects on large mammals in urban centers. Biol. Conserv. 254 , 108953. (10.1016/j.biocon.2021.108953)33424027 15. Forti LR, Hepp F, de Souza JM, Protazio A, Szabo JK. 2022 Climate drives anuran breeding phenology in a continental perspective as revealed by citizen-collected data. Divers. Distrib. 28 , 2094-2109. (10.1111/ddi.13610) 16. Forti LR, Hepp F, de Souza JM, Protazio A, Szabo JK. 2022 Climate drives anuran breeding phenology in a continental perspective as revealed by citizen-collected data. Zenodo (10.5281/zenodo.6811407) 17. Lange JD, Bastide H, Lack JB, Pool JE. 2022 A population genomic assessment of three decades of evolution in a natural drosophila population. Mol. Biol. Evol. 39 , msab368. (10.1093/molbev/msab368)34971382 18. Shaffer HB et al. 2022 Landscape genomics to enable conservation actions: the California conservation genomics project. J. Hered. 113 , 577-588. (10.1093/jhered/esac020)35395669 |
Crit Care Sci Crit Care Sci ccsci Critical Care Science 2965-2774 Associacao de Medicina Intensiva Brasileira - AMIB 10.5935/2965-2774.20230132-en Letter to the Editor Trauma induced coagulopathy and fibrinogen levels: why do we need to measure them, and what are the supplementation strategies? Savioli Felicio 1 1 Department of Critical Care Medicine, Hospital Sirio-Libanes - Sao Paulo, Brazil Corresponding author: Felicio Savioli, Hospital Sirio-Libanes, Rua Adma Jaffet, 91, Zip code: 01308-050 - Sao Paulo, Brazil, E-mail: [email protected] Jul-Sep 2023 Jul-Sep 2023 35 3 328330 27 5 2023 03 6 2023 This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. pmcINTRODUCTION Fibrinogen is a large glycoprotein produced in the liver. With a normal plasma concentration of 1.5 - 3.5g/L, fibrinogen is the most abundant blood coagulation factor. The final stage of blood clot formation is the conversion of soluble fibrinogen to insoluble fibrin, leading to a stable clot.(1) In cases of severe bleeding, fibrinogen reaches critically low plasma concentrations at an earlier stage than other coagulation factors.(2) Fibrinogen also binds to glycoprotein IIb/IIIa receptors on the platelet membrane, promoting platelet aggregation and clot stabilization.(3) The importance of fibrinogen in clot firmness can be better illustrated by an analogy to a wall, as proposed by Lang and von Depka.(4) If we consider the platelets as bricks and fibrinogen as cement, a balanced ratio allows us to build a stable wall or a stable clot. On the other hand, if the number of bricks is reduced (thrombocytopenia) and the amount of cement is increased (hyperfibrinogenemia), the wall will not break, and the clot will be stable due to the higher levels of fibrinogen. However, if there are bricks but no cement (hypofibrinogenemia), the risk of wall collapse is high or, analogously, the risk of bleeding is high as well. TRAUMA-INDUCED COAGULOPATHY Trauma is one of the 10 leading causes of death and disability in the world and is the leading cause of death in the young population. Moreover, hemorrhage is responsible for at least 40% of deaths after trauma.(5) In a Brazilian hospital, a retrospective study including 467 trauma patients was conducted. Sixty percent of deaths occurred in 24 hours. Of these patients, 18% died from hemorrhage.(6) Trauma-induced coagulopathy (TIC) is a consequence of tissue hypoperfusion and tissue injury. The coagulation system balance changes rapidly during injury and resuscitation, and consequently, the TIC phenotype can quickly change over time from primarily an anticoagulant to a procoagulant state within hours to days if the patient survives. Several processes, including dysfunction of natural anticoagulants, platelet dysfunction, hyperfibrinolysis and fibrinogen consumption, have been identified as primary components of TICs.(7) In major trauma, key contributors to low levels of fibrinogen include hemodilution (due to fluid resuscitation), blood loss, consumption in clot formation at the wound sites, hypothermia, and acidosis.(8) In addition, upon admission, hypofibrinogenemia in major trauma is independently associated with an increase in injury severity and shock and is a predictor of mortality.(9) Currently, the sixth edition of the European guidelines on the management of major trauma following coagulopathy recommends fibrinogen supplementation for patients with bleeding and fibrinogen levels below 1.5g/L.(10) FIBRINOGEN SUPPLEMENTATION STRATEGIES There are three possible sources of fibrinogen: fresh frozen plasma (FFP), cryoprecipitate and fibrinogen concentrate (FC). Fresh frozen plasma contains a variable amount of fibrinogen and other coagulation factors. A prospective cohort study found no consistent correction of clot function or increases in procoagulant factor concentrations following FFP transfusion during the acute phase of ongoing bleeding.(11) Furthermore, the RETIC trial showed that FFP was insufficient to correct hypofibrinogenemia or significantly improve the clot strength versus the fibrinogen concentrate in adult trauma patients. In addition, the study was terminated early for futility and safety reasons because of the high proportion of patients in the FFP group who required rescue therapy compared with those in the FC group.(12) Additionally, the panel of experts from the European Guidelines of Trauma do not recommend fibrinogen supplementation with FFP to correct hypofibrinogenemia if cryoprecipitate or FC are available. According to the guidelines,(10) the evidence was grade 1C. Cryoprecipitate is derived from FFP and consists of factor VIII, fibrinogen, von Willebrand factor, factor XIII, fibronectin, and other plasma proteins, such as alpha-2 antiplasmin, which decreases fibrinolysis. Variability of the clotting factor levels in blood donors means that the fibrinogen concentration in cryoprecipitate varies as well.(13) CRYOSTAT-1 was a feasibility study for a multicenter, randomized controlled trial evaluating the effects of early administration of high-dose cryoprecipitate in adult trauma patients. This 1-year study recruited 43 patients, with all completing a subsequent 3-month follow-up visit. The authors concluded that early cryoprecipitate therapy maintained acceptable blood fibrinogen levels during active bleeding, with a signal for reduced mortality in the treatment arm of the study.(14) CRYOSTAT-1 facilitated CRYOSTAT-2 trial development. In the CRYOSTAT-2 trial, the effect of early cryoprecipitate (within 90 minutes of admission) compared to standard blood transfusion therapy on 1,605 bleeding trauma patients from 26 major trauma centers has been tested. Data analysis is now underway. This study will provide the answer as to whether early cryoprecipitate transfused for major trauma improves mortality.(15) Currently, the most widespread form of fibrinogen replacement in the UK, Canada and Australia is through the delivery of cryoprecipitate, contrasting with most of Europe, where FC is the preferred method of replacement.(16) In most European countries, FC is the main product for replacing fibrinogen because of its increased viral safety profile, standardized concentration of fibrinogen, lower risk of TRALI and TACO, benefits of room temperature and faster administration.(17) The FiiRST trial described a pilot feasibility study to evaluate the effect on clinical and laboratory outcomes and complications of early infusion of FC in trauma cases. Fifty hypotensive adult patients requiring blood transfusion were randomly assigned to receive either 6g of FC or placebo. The authors observed that early infusion of FC was feasible and led to an increased plasma fibrinogen concentration during trauma resuscitation.(18) Recently, the FlinTIC trial(19) assessed whether FC in the prehospital setting could improve blood clot stability in TICs. Patients were allocated to receive either FC or placebo at the trauma scene or during transportation. A dose of 3g of the study drug was given to patients with bodyweights of 30 to 60kg, 4.5g to patients with bodyweights of 60 to 90kg and 6g to patients with bodyweights of 90 to 120kg. The median between-group difference in the change in FIBTEM MCF was 5mm. The authors concluded that early FC administration was feasible for prehospital trauma care. Additionally, they mentioned that FC supplementation protects against early fibrinogen depletion and promotes rapid blood clot initiation and clot stability. CONCLUSION Hypofibrinogenemia is an important cause of bleeding in trauma patients. The treatment remains fibrinogen replacement with cryoprecipitate or fibrinogen concentrate. However, there is no evidence showing that fibrinogen concentrate is superior to cryoprecipitate in cases of trauma-induced coagulopathy. Larger multicenter trials are necessary to elucidate the best fibrinogen supplementation strategy in trauma patients. REFERENCES 1 Litvinov RI Pieters M de Lange-Loots Z Weisel JW. Fibrinogen and fibrin Subcell Biochem 2021 96 471 501 33252741 2 Grottke O Mallaiah S Karkouti K Saner F Haas T. Fibrinogen supplementation and its indications Semin Thromb Hemost 2020 46 1 38 49 31574543 3 Fullard JF. The role of the platelet glycoprotein IIb/IIIa in thrombosis and haemostasis Curr Pharm Des 2004 10 14 1567 1576 15134555 4 Lang T von Depka M. [Possibilities and limitations of thrombelastometry/-graphy] Hamostaseologie 2006 26 3 Suppl 1 S20 9 German 16953288 5 Faria I Thivalapill N Makin J Puyana JC Raykar N. Bleeding, hemorrhagic shock, and the global blood supply Crit Care Clin 2022 38 4 775 793 36162910 6 Trajano AD Pereira BM Fraga GP. Epidemiology of in-hospital trauma deaths in a Brazilian university hospital BMC Emerg Med 2014 14 22 25361609 7 White NJ. Mechanisms of trauma-induced coagulopathy Hematology Am Soc Hematol Educ Program 2013 2013 660 663 24319248 8 Moore EE Moore HB Kornblith LZ Neal MD Hoffman M Mutch NJ Trauma-induced coagulopathy Nat Rev Dis Primers 2021 7 1 30 33927200 9 Rourke C Curry N Khan S Taylor R Raza I Davenport R Fibrinogen levels during trauma hemorrhage, response to replacement therapy, and association with patient outcomes J Thromb Haemost 2012 10 7 1342 1351 22519961 10 Rossaint R Afshari A Bouillon B Cerny V Cimpoesu D Curry N The European guideline on management of major bleeding and coagulopathy following trauma: sixth edition Crit Care 2023 27 1 80 36859355 11 Khan S Davenport R Raza I Glasgow S De'Ath HD Johansson PI Damage control resuscitation using blood component therapy in standard doses has a limited effect on coagulopathy during trauma hemorrhage Intensive Care Med 2015 41 2 239 247 25447807 12 Innerhofer P Fries D Mittermayr M Innerhofer N von Langen D Hell T Reversal of trauma-induced coagulopathy using first-line coagulation factor concentrates or fresh frozen plasma (RETIC): a single-centre, parallel-group, open-label, randomised trial Lancet Haematol 2017 4 6 e258 71 28457980 13 Callum JL Karkouti K Lin Y. Cryoprecipitate: the current state of knowledge Transfus Med Rev 2009 23 3 177 188 19539873 14 Curry N Rourke C Davenport R Beer S Pankhurst L Deary A Early cryoprecipitate for major haemorrhage in trauma: a randomised controlled feasibility trial Br J Anaesth 2015 115 1 76 83 25991760 15 Curry N Davenport R Lucas J Deary A Benger J Edwards A The CRYOSTAT2 trial: the rationale and study protocol for a multi-centre, randomised, controlled trial evaluating the effects of early high-dose cryoprecipitate in adult patients with major trauma haemorrhage requiring major haemorrhage protocol activation Transfus Med 2023 33 2 123 131 36321753 16 Novak A Stanworth SJ Curry N. Do we still need cryoprecipitate? Cryoprecipitate and fibrinogen concentrate as treatments for major hemorrhage - how do they compare? Expert Rev Hematol 2018 11 5 351 360 29584463 17 Jensen NH Stensballe J Afshari A. Comparing efficacy and safety of fibrinogen concentrate to cryoprecipitate in bleeding patients: a systematic review Acta Anaesthesiol Scand 2016 60 8 1033 1042 27109179 18 Nascimento B Callum J Tien H Peng H Rizoli S Karanicolas P Fibrinogen in the initial resuscitation of severe trauma (FiiRST): a randomized feasibility trial Br J Anaesth 2016 117 6 775 782 27956676 19 Ziegler B Bachler M Haberfellner H Niederwanger C Innerhofer P Hell T Kaufmann M Maegele M Martinowitz U Nebl C Oswald E Schochl H Schenk B Thaler M Treichl B Voelckel W Zykova I Wimmer C Fries D FIinTIC study group Efficacy of prehospital administration of fibrinogen concentrate in trauma patients bleeding or presumed to bleed (FIinTIC): A multicentre, double-blind, placebo-controlled, randomised pilot study Eur J Anaesthesiol 2021 38 4 348 357 33109923 |
Turk J Med Sci Turk J Med Sci Turkish Journal of Medical Sciences 1300-0144 1303-6165 Scientific and Technological Research Council of Turkey (TUBITAK) 33890447 10.3906/sag-2012-268 turkjmedsci-51-6-2822 Research Article The analysis of pleural complications of COVID-19 pneumonia TURK Merve Satir * AKARSU Irmak TOMBUL Ismail KANKOC Aykut OZKAN Nur Dilvin VALIYEV Elgun SAYAN Muhammet CELIK Ali KURUL Ismail Cuneyt ARIBAS Olgun Kadir TASTEPE Abdullah Irfan Department of Thoracic Surgery, Faculty of Medicine, Gazi University, Ankara, Turkey * Correspondence: [email protected] 2021 21 4 2021 51 6 28222826 23 12 2020 13 12 2021 21 4 2021 (c) TUBITAK 2021 This work is licensed under a Creative Commons Attribution 4.0 International License. Background/aim As the number of case reports related to the new type of coronavirus (COVID-19) increases, knowledge of and experience with the virus and its complications also increase. Pleural complications are one relevant issue. We aimed in this study to analyze pleural complications, such as pneumothorax, pneumomediastinum, and empyema, in patients hospitalized with the diagnosis of COVID-19 pneumonia. Materials and methods The files of patients who have pleural complications of COVID-19 pneumonia and were consulted about thoracic surgery between March 2020 and December 2020 were retrospectively reviewed. The data of the patients were analyzed according to age, sex, length of stay, treatment method for pleural complications, mortality, severity of COVID-19 pneumonia, tube thoracostomy duration, and presence of a mechanical ventilator. Results A total of 31 patients fulfilling the inclusion criteria were included in the study. There were 11 female (35.5%) and 20 male (65.5%) patients. The most common complication was pneumothorax in 20 patients (65%). The median duration of hospitalization was 22 days and the mortality rate was 71%. Mortality was significantly higher in patients on mechanical ventilation (p = 0.04). Conclusion The mortality rate is very high in patients with pleural complications of COVID-19 pneumonia. Pneumothorax is a fatal complication in critically ill patients with COVID-19 pneumonia. Pneumothorax pneumomediastinum COVID-19 empyema pandemic pmc1. Introduction As the number of case reports related to the new type of coronavirus (COVID-19) that emerged at the end of 2019 and caused the pandemic increases, the knowledge about its clinical conditions and complications also increases. Patients with COVID-19 pneumonia may experience a wide range of clinical conditions, from being asymptomatic to dying due to respiratory failure. COVID-19 pneumonia may be complicated by some pleural complications such as pneumothorax (PT), pneumomediastinum (PM), pleural effusion and empyema [1-4]. In the physiopathology of PM in COVID-19 pneumonia, the Macklin effect, in which alveolar ruptures form due to increased intrathoracic pressure caused by coughing, resulting in free alveolar air moving from the hilus to the mediastinum through the bronchovascular sheaths are blamed . PT can occur spontaneously due to pneumonia, or it can be barotraumatic with positive airway pressure in patients on mechanical ventilators . Empyema due to COVID-19 pneumonia is very rare in the literature and is explained by the secondary infection of the pleural effusion occurring via the inflammatory effect . Here, we aimed to analyze the data of patients with pleural complications of COVID-19 pneumonia, including PT, PM, and pleural effusion, in this retrospective study. 2. Materials and methods 2.1. Patient selection After approval by the Republic of Turkey Ministry of Health Ethics Committee (2020-10-16T13_53_24), we retrospectively reviewed the files of patients with pleural complication of COVID-19 pneumonia and who consulted with the Department of Thoracic Surgery in our hospital between March 2020 and December 2020. COVID-19 diagnoses were made via thorax computed tomography (CT), swab polymerase chain reaction (PCR) tests, or antigen-antibody tests. The patients whose follow-up records were not available, whose pleural complications were not confirmed radiologically, and whose complications occurred for iatrogenic reasons, such as central venous catheterization or thoracentesis, were not included in this study. Analyses were performed according to age, sex, length of stay, treatment methods for complications, mortality, severity of COVID-19 pneumonia, duration of tube thoracostomy and the presence of a mechanical ventilator. 2.2. Statistical analysis Analyses were made using the SPSS (IBM, version 20, NY, USA) program. Descriptive data were given as mean +- standard deviation, median (minimum-maximum) or number and frequency. The chi-squared test was used for categorical variables and the log rank test was used for continuous variables. Distribution normalization was evaluated by histogram. Mean values were used for normal distribution and median values were used for asymmetrical distribution. Overall survival was investigated using the Kaplan-Meier method and survival differences between groups were investigated using the log-rank and Cox-regression methods. Studies were conducted at a 95% confidence interval; p <0.05 was considered significant. 3. Results A total of 31 patients who met inclusion criteria were included in the study. There were 11 female (35.5%) and 20 male (65.5%) patients. The characteristics of the patients are given in Table. The median age was 67 (range: 31-90). The most common pleural complication was PT in 20 patients (64.5%) followed by isolated PM in 7 patients (22.5%) and pleural effusion in 4 patients . Pleural complications occurred in right side in 13 patients, left side in 9 patients, and bilaterally in 2 patients . The number of patients who need the mechanical ventilators was 22 (3 of them with noninvasive mechanical ventilator). Tube thoracostomy was performed in 20 patients (2 of them bilaterally). The treatment of 8 (40%) patients with pneumothorax was completed successfully and their tube thoracostomies were removed. The median hospitalization time was 22 days (range: 1-64) and the median duration of tube thoracostomy was 9 (0-38) days. A total of 22 (71%) patients died. During the 60-day follow-up, the mean survival of patients with pleural complications was 31.3 days . The mean survival day was significantly better in nonintubated patients than in intubated patients . There were no significant correlations between survival, and age (p = 0.7), etiology (p = 0.09), and being older than 70 years (p = 0.2). Sixteen of (80%) of 20 patients with pneumothorax needed mechanical ventilation. Surgical treatments such as bullae excision, primary repair, or pulmonary resection were not performed for pneumothorax in any of the patients due to their very poor general medical condition or the adequacy of tube thoracostomy treatment. The most common comorbidity of our series was hypertension in 12 (38.7%) patients, followed by malignancy in 8 (25.8%) patients. Other comorbidities were given in Table. Mortality occurred in 3 of 6 patients who had no comorbidity and 20 of 25 patients with comorbidity. The mean survival time in comorbidity-positive and -negative group were 18 and 29 days, respectively, but survival differences was not statistically significant (p = 0.1). Our series included one empyema case. The staphylococcus aureus strains were isolated in the pleural fluid culture and she was treated with tube thoracostomy, intrapleural lavage, and intravenous antibiotics for 31 days. The patient was discharged without surgical intervention. 4. Discussion In this study, pleural complications occurring due to COVID-19 pneumonia were analyzed. Pleural complications occurring in COVID-19 pneumonia cases increase mortality, morbidity, interventional procedures and patient costs. PM occurs via the Macklin effect, as explained above. Due to the continuity of the mediastinal and neck fascia, free air can move to the subcutaneous area or peripheral to the subpleural region, causing PM-subcutaneous emphysema and PT, respectively . Sometimes the coexistence of these three entities can be detected. In our study, there were isolated PT in 17 patients, isolated PM in 7 patients, and coexistence of PM-PT and subcutaneous emphysema in 3 patients. Mallick et al. claimed that pleural complications in COVID-19 pneumonia occurred due to parenchymal degeneration as a result of prolonged disease and severe inflammation . Similarly, Oye et al. reported that the PM and PT in COVID-19 pneumonia emerged due to damaging the lung parenchyma with ischemic and inflammatory effects. They also reported that the risk of complications was increased with the severity of the disease . Additionally, there are studies in the literature reporting that PT is related to positive air pressure . Hameed et al. concluded in their series including 3 patients that tube thoracostomy was required for 2 patients and the mean duration of the tube thoracostomy was 11 days . The median tube thoracostomy duration was 9 days in our study. Udi et al. indicated in their study including patients with respiratory failure requiring mechanical ventilators that barotrauma was significantly higher in the COVID-19 pneumonia group compared to other, and they explained that this was due to the excess parenchymal restriction . In our study, the spontaneous PT-PM/barotraumatic PT-PM ratio was 0.25 and it supported the inference by Udi et al.. Through the literature review, we have seen that the severity of pneumonia is excessive in patients who had pleural complications of COVID-19 pneumonia . In our series, 80% of the patients had severe pneumonia in accordance with the literature. In general, there is no specific treatment for isolated PM, and treatment is based on symptoms. If severe mediastinal emphysema and subcutaneous emphysema are present, free air can be drained . In our study, patients who developed isolated PM were followed up with daily chest X-ray and the mediastinal emphysema resolved in the following days spontaneously. It has been reported that the mortality of pleural complication occurring in COVID-19 pneumonia is quite high. It is not clear whether this is related to the severity of the underlying pneumonia or whether pleural complications contribute to mortality. Mortality rate in our study was over 70% and only 9 patients (29%) were discharged successfully. Cases of effusion/empyema developing after COVID-19 pneumonia are rarely reported in the literature. Tessitore et al. published a case series including 3 patients with empyema treated with surgical decortication. They reported that a strong inflammatory response and added vasculitis and microvascular thrombosis in response to infection in the lower respiratory tract caused reactive pleural effusion and empyema developed with bacterial superinfection . On the other hand, Yarlagadda et al. reported that empyema occurred via aspiration pneumonia in their case report . In our study, there were 3 pleural effusion and 1 empyema cases. We thought that the etiology was bacterial superinfection of the reactive fluid in our patient who had a long duration of hospitalization and had some comorbidities, such as hemodialysis for renal failure, diabetes, and hypertension. The patient was discharged without surgical intervention. The limitations of our study were as follows; it is a retrospective and single-centered study and included small number cases. In addition, we could not make a comparison with patient groups who did not have any pleural complication of COVID-19 pneumonia or those who were hospitalized for other viral pneumonia because only patients who were consulted with our department were included in the study. Another limitation of our study was that we wanted to investigate the relationship between inflammation parameters and survival. However, these parameters were high in almost all of the patients included the study since our study group was on the hospitalized patients with COVID-19 pneumonia. In addition, we did not decide on which blood value was taken on which day of hospitalization. Additionally, the number of patients included in our study was insufficient for any analysis which determines cut-off value for inflammation markers such as receiver operating characteristics (ROC) analysis. 5. Conclusion Pleural complications due to COVID-19 pneumonia can be seen rarely. Mortality is very high in patients with this complication. However, multicenter studies with more patients and long-term follow-ups are needed to clarify whether the mortality is due to complications or whether the complications develop in patients with severe pneumonia. Figure 1 a) Thorax CT shows left-sided pneumothorax in a patient with COVID-19 pneumonia; b) Coexistence of pneumomediastinum and diffuse ground glass opacities are seen in tomography scan; c) Tomographic view of right-sided pleural effusion and mild COVID-19 pneumonia; d) Thorax CT scan shows pneumomediastinum and bilateral pneumothorax. Figure 2 Overall survival of patients in the time of hospitalization. Figure 3 There was a statistically significant survival difference between intubated and nonintubated patients (p = 0.04). Table Characteristics of patients. n % Age, Med., Range: 67 years (30-90 years) Duration of H, Med, Range (Days): 2 (1-64) Duration of TT, Med, Range (Days): 9 (1-38) Sex F 11 35.5 M 20 65.5 Pleural complications PT 17 54.8 PM 7 22.6 PT + PM 3 9.7 PE 3 9.7 Empyema 1 3.2 MV Spontaneous 19 61.3 NIMV 3 9.7 IMV 9 29 Mortality Exitus 22 71 Alive 9 29 Treatment Conservative 10 32.2 TT 21 67.8 Side of PT, PE Right 13 54.2 Left 9 37.5 Bilaterally 2 8.3 Comorbidities Bronchial asthma 3 9.6 COPD 4 12.9 Hypertension 12 38.7 DM 1 3.2 Malignancy 8 25.8 CAD 5 16.1 CVD 3 9.6 CRF 1 3.2 Cirrhosis 1 3.2 None 6 19.3 Abbreviations: CAD: coronary artery disease; COPD: chronic obstructive pulmonary disease; CRF: chronic renal failure; CVD: cerebro-vascular disease; DM: diabetes mellitus; F: female, IMV: invasive mechanical ventilation, H: hospitalization, M: male; Med: median; MV: mechanical ventilation; NIMV: noninvasive mechanical ventilation; PE: pleural effusion; PM: pneumomediastinum; PT: pneumothorax, TT: tube thoracostomy. Conflict of interest The authors declare that there are no conflicts of interest. Informed consent Informed consent is not required for this study because it is a retrospective study and it does not include any personal data of patients. References 1 Shan S Guangming L Wei L Xuedong Y Spontaneous pneumomediastinum, pneumothorax and subcutaneous emphysema in COVID-19: case report and literature review Revista do Instituto de Medicina Tropical de Sao Paulo 2020 62 e76 10.1590/S1678-9946202062076 33053145 2 Mallick T Dinesh A Engdahl R Sabado M COVID-19 Complicated by spontaneous pneumothorax Cureus 2020 12 7 e9104 10.7759/cureus.9104 32789049 3 Manna S Maron SZ Cedillo MA Voutsinas N Toussie D Spontaneous subcutaneous emphysema and pneumomediastinum in non-intubated patients with COVID-19 Clinical Imaging 2020 67 207 213 10.1016/j.clinimag.2020.08.013 32871424 4 Yarlagadda K Mi K Sendil S Koons CL Komanduri S A 31-year-old man with COVID-19-associated empyema and lupus anticoagulant American Journal of Case Report 2020 21 e926623 10.12659/AJCR.926623 5 Gillespie M Dincher N Fazio P Okorji O Finkle J Coronavirus disease 2019 (COVID-19) complicated by spontaneous pneumomediastinum and pneumothorax Respiratory Medicine Case Reports 2020 31 101232 10.1016/j.rmcr.2020.101232 32989414 6 Udi J Lang CN Zotzmann V Krueger K Fluegler A Incidence of barotrauma in patients with COVID-19 pneumonia during prolonged invasive mechanical ventilation - a case-control study Journal of Intensive Care Medicine 2021 36 4 477 483 10.1177/0885066620954364 32959730 7 Sonia F Kumar M A Complication of pneumothorax and pneumomediastinum in a non-intubated patient with COVID-19: a case report Cureus 2020 12 8 e10044 10.7759/cureus.10044 32983734 8 Tessitore A Patella M Giuliani M Theologou T Freguia S Surgical treatment of pleural empyema in Coronavirus disease 19 patients: the Southern Switzerland experience Interactive Cardiovascular and Thoracic Surgery 2021 32 3 367 370 10.1093/icvts/ivaa269 33221888 9 Vecchio R Intagliata E Basile F Spataro C Giulia G Subcutaneous cervical emphysema and pneumomediastinum due to a diastatic rupture of the cecum Giornale di chirurgia 2015 36 6 272 275 10.11138/gchir/2015.36.6.272 26888704 10 Oye M Ali A Kandah F Chowdhury N Two cases of spontaneous pneumomediastinum with pneumothorax in patients with COVID-19 associated pneumonia Respiratory Medicine Case Reports 2020 31 101308 10.1016/j.rmcr.2020.101308 33262929 11 Toquica Gahona CC Raj K Bhandari K Nuguru S Bukhari A Subcutaneous emphysema in patients with COVID-19 infection: a report of three cases Cureus 2020 12 9 e10559 10.7759/cureus.10559 33101806 12 Wang XH Duan J Han X Liu X Zhou J High incidence and mortality of pneumothorax in critically Ill patients with COVID-19 Heart Lung 2021 50 1 37 43 10.1016/j.hrtlng.2020.10.002 33138976 13 Hameed M Jamal W Yousaf M Thomas M Haq IU Pneumothorax in Covid-19 pneumonia: a case series Respiratory Medicine Case Reports 2020 31 101265 10.1016/j.rmcr.2020.101265 33101895 14 Zayet S Klopfenstein T Mezher C Gendrin V Conrozier T Coronavirus disease 2019 with spontaneous pneumothorax, pneumomediastinum and subcutaneous emphysema, France New Microbes New Infect 2020 38 100785 10.1016/j.nmni.2020.100785 33072337 15 Newcomb AE Clarke CP Spontaneous pneumomediastinum: a benign curiosity or a significant problem? Chest 2005 128 5 3298 3302 10.1378/chest.128.5.3298 16304275 |
Turk J Med Sci Turk J Med Sci Turkish Journal of Medical Sciences 1300-0144 1303-6165 Scientific and Technological Research Council of Turkey (TUBITAK) 10.3906/sag-2107-24 turkjmedsci-52-1-276 Letter to the Editor Antimicrobial activities of Ankaferd BloodStopper, hypochlorous acid, and chlorhexidine against specific organisms KOLUMAN Ahmet 1 AKTAS Alper 2 ADILOGLU Selen 2* 1 Department of Biomedical Engineering, Faculty of Technology, Pamukkale University, Denizli, Turkey 2 Department of Oral Maxillofacial Surgery, Faculty of Dentistry, Hacettepe University, Ankara, Turkey * Correspondence: [email protected] 2022 17 10 2021 52 1 276278 04 7 2021 22 2 2022 17 10 2021 (c) TUBITAK 2022 This work is licensed under a Creative Commons Attribution 4.0 International License. pmcTo the Editor, Many antimicrobial agents can be used for the control of bacterial colonization, plaque accumulation, inflammation, and postoperative infection after the oral surgery . It had been hypothesized to compare the effects of Ankaferd BloodStopper (ABS), hypochlorous acid (HOCl), and chlorhexidine gluconate (CHG) on specific microorganisms such as Streptococcus mutans, Staphylococcus aureus, Actinomyces israelii, and Lactobacillus casei to find ideal antimicrobial agent. In this hypothesis, it was seen that higher concentration and long exposure time of all agents are more impressive at all of the microorganisms. In the long-term exposure, it was found that HOCl and CHG affect faster than ABS for Lactobacillus casei. For A. israelli, the effect of CHG is more than ABS and HOCl (CHG > HOCl > ABS) for all organisms at short-term exposure. However, in long-term exposure, HCOl is more effective for L. casei and S. aureus than ABS but for A. israelli and S. mutans, there was not a significant difference. Although the effect of CHG on S. mutans started in 120 s, ABS and HOCl needed more time to affect. Coleghon et al. showed that CHG had a larger inhibition zone than ABS at both short-term exposure similar to our study . In the long-term, effectiveness of CHG continued for all microorganisms in this study (Table 1) . In disc diffusion, lower concentrations of all agents were more effective for microorganisms. ABS had better results for A. israelli and L. casei than other agents. At disc diffusion, CHG was worse than ABS and HOCl (Table 2). Barry et al. applied CHG on 1100 strains of gram-positive and gram-negative bacteria and the resistance to CHG is seen low . Sensitivity of Streptococcus mutans to CHG is more than sensitivity of Lactobasillus species to CHG dealing with pH level . In this study, pH was not examined but a significant difference was not seen between L. casei and S. mutans according to the concentration and duration. Only the concentration of CHG is found as important for the efficiency on S. mutans group. Cinar et al. showed that ABS had a smaller inhibition zone but at long-term exposure, the results of ABS do not differ from those of the other antimicrobial agents . ABS has an additional hemostatic and antiinflamation effect, beside antimicrobial effect . In this study, the time needed for the effectiveness of ABS is observed to be more than CHG and HOCl. On the other hand, ABS disc diffusion form can be preferred due to its superiority to CHG and HOCl. ABS has pleiotropic effects on blood cells, vascular endothelium, angiogenesis, and cellular proliferation that can help the tissue regeneration and wound healing . In the literature, it was shown that ABS deactivates the proliferation of the cell lines and cancer cells . Therefore, the combined effect (antimicrobial, hemostatic, and improving wound accelerator) makes ABS more valuable than its equivalents. A possible advantageous use of ABS for human health was seen on Helicobacter pylori, an antibiotic resistant species shown in the literature . If ABS is so effective on a resistant microorganism like H. pylori at high concentration without any damage to the living tissues, this antibacterial agent can be a good choice for precaution of the other resistant microorganisms. Cinar et al. observed that Lactobasillus species have a resistance to ABS . In our study, L. casei was resistant to ABS in short term exposure, but it was seen that in long-term exposure and at high concentration, the effect of the ABS did not differ from that of CHG and HOCl. ABS had the same effect with CHG and HOCl for A. israelli in long-term exposure with high concentration but there is not sufficient research in the literature about the effect of ABS on Actinomyces species. HOCl is an important antimicrobial agent that is synthesized with acidification of H2O2. In this research, it was seen that HOCl is effective on S. aureus more than ABS, less than CHG. Also, when the concentration (200 ppm) is higher, the efficiency of HOCl is better. Ishihara et al. showed that when applying 100 ppm HOCl, chlorine levels can reduce by the presence of organic compounds. Therefore, if concentration is higher, chlorine level and effectiveness can be higher . As a result, in long-term exposure, 3 of the agents have similar antimicrobial effects and can be preferred successfully during oral surgery. Clinician should keep in mind the tissue-friendly character of HOCl, wound healing effect of ABS, and antiplaque activity of CHX while choosing the agent to prefer for the oral surgery patients. Figure The graphic of the effects of antimicrobial agents on bacterial species. Table 1 The effect of ABS, CHX, and HOCl on different bacterial species in long-term. Control population Ankaferd (%) CHG (%) HOCl (ppm) Time 100 50 0.2 0.12 200 100 Streptococcus mutans ATCC 25175 5th min 7.819544 5.255273 6.60206 3.963788 4.30103 4.579784 4.944483 10th. min 3.748188 4.78533 2.963788 3.623249 3.832509 3.812913 Staphylococcus aureus ATCC 23235 5th min 7.880814 5.892095 6.986772 3.934498 3.724276 4.662758 4.447158 10th min 3.857332 4.826075 2.939519 2.991226 2.462398 3.863323 Actinomyces israelii (Kruse) Lachner-Sandoval ATCC 10049 5th min 7.431364 5.70757 6.832509 3.431364 4.732394 4.623249 4.778151 10th min 3.39794 4.70757 2.792392 3.869232 3.230449 3.845098 Lactobacillus casei ATCC 334 5th min 7.653213 5.838849 6.431364 3.770852 3 3.973128 4.78533 10th minute 3.929419 5.94939 2.944483 2.963788 2.819544 3.544068 Green = Active biocidal applications decrease at least 3 log according to CLSI and EUCAST Yellow = Insufficient applications defined by CLSI and EUCAS. Table 2 The effect of disc diffusion of ABS, CHX, and HOCl on bacterial species. Ankaferd (%) CHX (%) HCLO (ppm) 100 50 0.2 0.12 200 100 Streptococcus mutans ATCC 25175 18 13 19 15 17 14 Staphylococcus aureus ATCC 23235 19 11 19 14 13 11 Actinomyces israelii (Kruse) Lachner-Sandoval ATCC 10049 11 5 16 14 12 8 Lactobacillus casei ATCC 334 9 6 15 13 11 10 Yellow = Resistant or intermittent Green = Sensitive Conflict of interest The author declares no financial or other conflicts of interest related to this paper. References 1 Zambon JJ Ciancio SG Mather ML Charles CH The effect of an antimicrobial mouthrinse on early healing of gingival flap surgery wounds Journal of Periodontology 1989 60 1 31 4 10.1902/jop.1989.60.1.31 2921710 2 Cinar C Odabas ME Akca G Isik B Antibacterial effect of a new haemostatic agent on oral microorganisms Journal of Clinical and Experimental Dentistry 2012 4 3 e151 5 10.4317/jced.50750 24558546 3 Barry AL Fuchs PC Brown SD Lack of effect of antibiotic resistance on susceptibility of microorganisms to chlorhexidine gluconate or povidone iodine European Journal of Clinical Microbiology & Infectious Diseases 1999 18 12 920 1 10.1007/s100960050434 10691210 4 Cleghorn B Bowden GH The effect of pH on the sensitivity of species of Lactobacillus to chlorhexidine and the antibiotics minocycline and spiramycin Journal of Dental Research 1989 68 7 1146 50 10.1177/00220345890680070201 2632598 5 Gul M Gunay A Tanik A An evaluation of the effects of caffeic acid phenethyl ester and Ankaferd blood stopper on secondary wound healing of oral mucosal tissue Turkish Journal of Medical Science 2020 50 1 248 57 10.3906/sag-1908-114 6 Turk S Malkan UY Ghasemi M Hocaoglu H Mutlu D Growth inhibitory activity of Ankaferd hemostat on primary melanoma cells and cell lines SAGE Open Medicine 2017 5 2050312116689519 10.1177/2050312116689519 28293423 7 Ghasemi M Okay M Malkan UY Turk S Jabbar J Ankaferd Hemostat Affects Etoposide Resistance of the Malignant Melanoma Cells International Journal of Hematology and Oncology 2020 30 1 43 53 10.4999/uhod.203965 8 Ciftciler R Koluman A Haznedaroglu IC Akar N Effects of Ankaferd Hemostat on Helicobacter pylori strains and antibiotic resistance Turkish Journal of Medical Science 2019 49 1 347 55 10.3906/sag-1807-206 9 Ishihara M Murakami K Fukuda K Nakamura S Kuwabara M Stability of Weakly Acidic Hypochlorous Acid Solution with Microbicidal Activity Biocontrol Science 2017 22 4 223 7 10.4265/bio.22.223 29279579 |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.49189 Obstetrics/Gynecology Allergy/Immunology Hematology Refractory Thrombocytopenia in a 29-Year-Old Pregnant Woman With Autoimmune Hepatitis: A Case Report and Literature Review Muacevic Alexander Adler John R Al-Sum Hythem A 1 Alsurori Suhad M 1 Alkhlassi Maha N 2 Alanazi Albandari A 3 Alkhlassi Ibtisam N 4 Alkhlassi Salma N 3 1 Department of Obstetrics and Gynaecology, Division of Maternal Fetal Medicine, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Riyadh, SAU 2 College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, SAU 3 College of Medicine, King Saud University, Riyadh , SAU 4 College of Medicine, King Saud University, Riyadh, SAU Ibtisam N. Alkhlassi [email protected] 21 11 2023 11 2023 15 11 e4918919 11 2023 Copyright (c) 2023, Al-Sum et al. 2023 Al-Sum et al. This is an open access article distributed under the terms of the Creative Commons Attribution License CC-BY 4.0., which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from Autoimmune hepatitis (AIH) is a rare autoimmune liver disease that mostly affects women in their reproductive years, leading to impaired fertility. Nonetheless, the majority of women with well-controlled AIH have a favorable prognosis for pregnancy. This case report describes a 29-year-old pregnant woman with cirrhosis secondary to AIH who presented with severe thrombocytopenia. Her labs showed a decline in her platelet counts from 28 x 109/L before pregnancy to 20 x 109/L during pregnancy. Her abdominal ultrasound showed liver cirrhosis secondary to AIH and splenomegaly. Throughout pregnancy, various scans were performed to monitor the fetal well-being, which showed normal results. She was on a medication regimen that included nadolol of 80 mg/kg/day, prednisolone of 5 mg/kg/day, and azathioprine of 50 mg/kg/day. Due to a breech presentation, the patient was scheduled for a cesarean section. She received two courses of dexamethasone at 20 mg/day for four days within two weeks of delivery. On the day of her scheduled C-section, tranexamic acid of 1 g TID for two days was administered, and she received platelet transfusions of 12 units both before and after the procedure, with an additional 6 units administered during the procedure. Despite proper management, her platelet count remained consistently low. However, she successfully delivered a healthy baby, and the overall condition of the patient was stable. aih autoimmune hepatitis in pregnancy thrombocytopenia in pregnancy refractory thrombocytopenia aih -autoimmune hepatitis autoimmune hepatitis with cirrhosis pmcIntroduction Autoimmune hepatitis (AIH) is a rare autoimmune liver disease that primarily affects women during their reproductive years, leading to amenorrhea and infertility. However, when the disease is well-controlled, most women with AIH have a positive prognosis for pregnancy . The underlying pathology of AIH involves a gradual inflammation of hepatocytes, which cannot be attributed to common causes of chronic liver disease such as alcohol-related liver disease, viral hepatitis, exposure to hepatotoxic substances, or hereditary liver disorders [2-6]. Various clinical studies have examined pregnancy outcomes in AIH patients [6-11]. Some studies suggest that flares of the disease are more common in the postpartum period compared to during pregnancy , while others report remission of the disease during pregnancy . Here, we describe a case of severe and refractory thrombocytopenia in a pregnant woman with autoimmune hepatitis despite receiving proper treatment and present the outcomes and management of AIH in pregnancy. Case presentation A 29-year-old pregnant woman is in the 38th week of gestation. She is identified as gravida 2 para 1 plus 0, with a history of liver cirrhosis secondary to AIH. Throughout her pregnancy, her hemoglobin level remained stable at 97 g/L, both before and during pregnancy. However, her platelet count exhibited a decrease from 28 x 109/L before pregnancy to 20 x 109/L during pregnancy. To manage her medical condition and support her pregnancy, the patient was prescribed a medication regimen that included nadolol at a dosage of 80 mg taken once daily, prednisolone at a dosage of 5 mg taken once daily, and azathioprine at a dosage of 50 mg taken once daily. During pregnancy, abdominal ultrasound was done, showing liver cirrhosis , splenomegaly , and normal portal vein doppler . Figure 1 Right and left lower lobe of the liver showing cirrhosis without clear focal lesion. Figure 2 Splenomegaly measuring 29 cm x 11 cm. Figure 3 Patent portal vein with normal waveform, velocity, and direction. Various scans were performed to monitor the well-being of the fetus. A nuchal translucency scan (NT) was conducted, which revealed normal thickness. A fetal anatomy scan was conducted at 21 weeks, showing normal results. Growth scans were also performed at 29 weeks and 34 weeks, respectively, indicating normal growth. Within two weeks before delivery, she received two courses of dexamethasone, with a dosage of 20 mg taken once daily for four doses. In preparation for the delivery, tranexamic acid was administered on the morning of her scheduled C-section, with a dosage of 1 g taken three times a day for 48 hours, and she received 12 units of platelets both before and after the operation, with an additional 6 units administered during the operation. However, her platelet count remained persistently low despite receiving proper treatment and multiple platelet transfusions. Eventually, the patient underwent a C-section due to a breech presentation, resulting in an estimated blood loss of 900 ml. The fetal weight at birth was recorded as 2.520 kg, and the APGAR score was 5 at one minute and 9 at five minutes after birth. The patient was followed for weeks after a c-section, and her surgical wound has healed well with no complaints. She will be receiving ongoing follow-up care from both hematology and hepatology specialists and will also be provided with appropriate instructions for emergency room (ER) visits. During her previous pregnancy, which ended at the 37th gestational week, the patient experienced significant changes in her hematological parameters. Her hemoglobin level before pregnancy measured 13.2 g/L. However, her hemoglobin level improved to 110 g/L during pregnancy. Conversely, her platelet count showed a decline from 42 x 109/L before pregnancy to 29 x 109/L during pregnancy. The patient was on nadolol at 80 mg/kg/day, prednisolone at 5 mg/kg/day, and azathioprine at 50 mg/kg/day. Additionally, she received a stress dose of hydrocortisone at 100 mg TID. A series of scans were performed to monitor the overall health and development of the fetus throughout pregnancy. An anatomy scan was conducted at 31 weeks of gestation, and a growth scan was performed at 36 weeks of gestational age, which yielded normal results. Before delivery, the patient received 6 units of platelets, and the baby was born through a vaginal delivery with a cephalic presentation and an estimated blood loss of 400 ml. The newborn weighed 2.820 kg and had APGAR scores of 9/9 at the first and fifth minutes, respectively, indicating a healthy condition. Discussion AIH is a chronic liver condition characterized by immune system dysfunction, and its exact cause is unknown . Numerous studies have extensively investigated the outcomes of AIH during pregnancy. A recent systematic review conducted in Portugal found that AIH flares occur in 7-33% of pregnancies and in 11-86% of cases during the postpartum period. Additionally, the occurrence of fetal growth restriction or newborns that are small for gestational age appears to be higher in patients with AIH. However, the incidence of fetal malformations is similar to that of the general population, and no correlation has been found with the medication used during pregnancy. Despite these risks, studies show that the rate of live births among AIH patients is similar to that of the general population . Furthermore, another study reported by Westbrook et al. analyzed 81 pregnancies in AIH patients and found a live birth rate of 73% . A retrospective study conducted in the Netherlands found that 6% of AIH patients experienced a relapse, while the relapse rate for postpartum episodes was 27%. However, pregnancies among AIH patients had a success rate of 98.5%, with 72% resulting in childbirth . According to Schramn et al., approximately 20% of individuals with AIH experience a flare during pregnancy, with flares being more frequent during the postpartum period compared to during pregnancy. The exact immune mechanisms triggering these postpartum flares remain unclear . It is worth mentioning that fetal mortality is also a concern in AIH pregnancies. Candia et al. discovered that 19% of women with AIH experienced fetal deaths before the 20th week of pregnancy, while Schramn et al. found a higher percentage of fetal mortality, reaching 24% in their analysis of a limited number of pregnant women with AIH . In terms of medication use and efficacy during pregnancy in AIH, comprehensive studies have been conducted. In a retrospective study examining the management of AIH, 17 patients (37%) were identified as receiving immunosuppression monotherapy, with 14 patients on prednisone and 3 patients on azathioprine. Interestingly, no significant differences were observed between patients who experienced flares and those who did not. However, the study revealed that women who experienced a flare were more inclined to require combined therapy to sustain remission. Moreover, these women were found to be more susceptible to necessitating second-line treatment due to an inadequate response to the combined therapy. In addition, a single reported case of an unknown congenital malformation was observed in a pregnancy where azathioprine monotherapy was used. However, the outcome of the fetus exposed to mycophenolate mofetil (MMF) during the first two months of gestation was significantly positive . Another case involved a 33-year-old female diagnosed with AIH type I who discontinued prednisolone treatment, resulting in elevated transaminase levels. Subsequently, budesonide at a dosage of 9 mg/day was initiated, proving to be effective in improving the patient's laboratory results. The patient opted not to pursue azathioprine, and approximately six months later she became pregnant. After five months of pregnancy, budesonide was gradually tapered and eventually discontinued upon confirmation of the pregnancy. At this stage, the patient's AIH condition appeared stable, and she successfully delivered a healthy child without experiencing any complications or disease flares . In Turkey, a case report of a pregnant woman who had cirrhosis as a result of AIH was studied. Upon her hospitalization, it was found that she had severe thrombocytopenia with a platelet count of 27 x 103/ml. As part of her treatment, she was prescribed a daily dose of 4 mg of prednisolone. The woman underwent a cesarean section at 36 weeks, 4 days after receiving immunoglobulin and platelet transfusions. The administration of low-molecular-weight heparin (LMWH) was temporarily halted until 12 hours after the operation. Unfortunately, she passed away due to a massive thromboembolism that occurred 24 hours after delivery . In a study investigating the use of TPO-RAs for thrombocytopenia, a patient with severe chronic refractory ITP experienced successful treatment with Romiplostim during her first pregnancy . Unintentionally, a second pregnancy occurred while she was receiving Eltrombopag. Despite this, she decided to continue taking eltrombopag for the entire duration of the pregnancy, which lasted 39 weeks, as she was determined not to interrupt the pregnancy. Remarkably, she gave birth to a healthy baby at full term, weighing 2 kg. The median duration of exposure to Tpo-RAs during pregnancy was 4.4 weeks, ranging from 1 to 39. Also In 17 pregnancies, thrombopoietin receptor agonists (Tpo-RAs) were initiated beyond week 32 of gestation to prepare for delivery. This decision was based on a platelet count of <= 20 x 109/L in 10 cases (58%). Among the patients, four had preexisting chronic immune thrombocytopenic purpura (ITP) and were already receiving Tpo-RAs when they became pregnant, while in three cases, Tpo-RAs were initiated early in the third trimester due to symptomatic ITP that did not respond to standard therapy. The median platelet count at the time of Tpo-RA initiation was 10 x 109/L (range: 1 x 109/L to 20 x 109/L). Ten patients (77%) demonstrated an initial positive response. However, three patients with longstanding chronic ITP, including two who had undergone splenectomy, did not exhibit any response to Tpo-RAs. Among the 10 respondents, 7 received additional concurrent ITP medication, primarily corticosteroids. At the time of delivery, the median platelet count was 94 x 109/L (range: 6 x 109/L to 250 x 109/L). A platelet count below 50 x 109/L was observed in only 5 out of the 17 pregnancies (29%), and no cases of severe maternal bleeding were observed . The randomized placebo-controlled trials ADAPT-1 and ADAPT-2 demonstrated that Avatrombopag, a thrombopoietin receptor agonist, significantly increased platelet count and reduced the need for platelet transfusion in 435 patients with liver disease and severe thrombocytopenia who required an elective procedure. Notably, Avatrombopag effectively elevated platelet counts by 37,000 to 45,000/mL in patients with initial platelet counts ranging from 40,000 to 50,000/mL, with 87% of patients achieving a platelet count above 50,000/mL, which was the primary goal. Similarly, the L-PLUS-1 and L-PLUS-2 trials evaluated the efficacy of Lusutrombopag, another thrombopoietin receptor agonist, in 311 patients with liver disease and a platelet count less than 50,000/mL who required an invasive procedure. The trials demonstrated that Lusutrombopag significantly reduced the percentage of patients who required platelet transfusions compared to placebo (22-35% vs. 71-87%). Based on the positive results from the ADAPT and L-PLUS trials, both Avatrombopag and Lusutrombopag have received approval from the US Food and Drug Administration for use in augmenting the platelet count prior to elective procedures in patients with chronic liver disease-associated thrombocytopenia . Conclusions In conclusion, pregnant women with autoimmune hepatitis require specialized antenatal care and close perinatal surveillance. A multidisciplinary approach is necessary to ensure comprehensive follow-up of these patients, and, with effective management, a successful pregnancy outcome is possible. However, clinicians should provide thorough counseling to patients about the potential complications associated with AIH even before conception to promote informed decision-making. Lastly, our study is limited due to the few reported cases, which can be attributed to the relative rarity of AIH. Future research studies and more cases need to be included to further explore the effects of medications and the disease course during pregnancy in patients with AIH. Author Contributions Human Ethics Acquisition, analysis, or interpretation of data: Ibtisam N. Alkhlassi, Albandari A. Alanazi, Maha N. Alkhlassi, Suhad M. Alsurori, Hythem A. Al-Sum, Salma N. Alkhlassi Drafting of the manuscript: Ibtisam N. Alkhlassi, Albandari A. Alanazi, Maha N. Alkhlassi, Suhad M. Alsurori, Hythem A. Al-Sum, Salma N. Alkhlassi Critical review of the manuscript for important intellectual content: Ibtisam N. Alkhlassi, Albandari A. Alanazi, Maha N. Alkhlassi, Suhad M. Alsurori, Hythem A. Al-Sum, Salma N. Alkhlassi Supervision: Ibtisam N. Alkhlassi, Maha N. Alkhlassi, Suhad M. Alsurori, Hythem A. Al-Sum, Salma N. Alkhlassi Concept and design: Albandari A. Alanazi, Maha N. Alkhlassi, Suhad M. Alsurori, Hythem A. Al-Sum Consent was obtained or waived by all participants in this study The authors have declared that no competing interests exist. References 1 Creasy and Resnik's Maternal-Fetal Medicine: Principles and Practice Resnik R Philadelphia Elsevier 2018 2 Autoimmune hepatitis N Engl J Med Krawitt EL 54 66 354 2006 16394302 3 Diagnosis and treatment of autoimmune hepatitis Hepatology Czaja AJ Freese DK 479 497 36 2002 12143059 4 Simplified criteria for the diagnosis of autoimmune hepatitis Hepatology Hennes EM Zeniya M Czaja AJ 169 176 48 2008 18537184 5 Autoimmune hepatitis: diagnostic criteria, subclassifications, and clinical features Clin Liver Dis McFarlane IG 605 621 6 2002 12362570 6 Autoimmune hepatitis and pregnancy Best Pract Res Clin Obstet Gynaecol Braga A Vasconcelos C Braga J 23 31 68 2020 32376296 7 Outcomes of pregnancy in autoimmune hepatitis: a population-based study Hepatology Wang CW Grab J Tana MM Irani RA Sarkar M 5 12 75 2022 34455632 8 Importance of complete response for outcomes of pregnancy in patients with autoimmune hepatitis Liver Int Fischer SE de Vries ES Tushuizen ME 855 864 43 2023 36594353 9 Autoimmune hepatitis: tolerogenic immunological state during pregnancy and immune escape in post-partum Front Immunol Bozward AG Wootton GE Podstawka O Oo YH 591380 11 2020 33072138 10 Pre-existing liver disease in pregnancy: cirrhosis, autoimmune hepatitis and liver transplantation Best Pract Res Clin Gastroenterol Milic S Tatalovic T Mikolasevic I 101668 44-45 2020 32359683 11 Presentation and outcomes of pregnancy in patients with autoimmune hepatitis Clin Gastroenterol Hepatol Llovet LP Horta D Eliz MG 2819 2821 17 2019 30616023 12 Outcomes of pregnancy in women with autoimmune hepatitis J Autoimmun Westbrook RH Yeoman AD Kriese S Heneghan MA 0 44 38 2012 13 Pregnancy in autoimmune hepatitis: outcome and risk factors Am J Gastroenterol Schramm C Herkel J Beuers U Kanzler S Galle PR Lohse AW 556 560 101 2006 16464221 14 Autoimmune hepatitis and pregnancy: a rheumatologist's dilemma Semin Arthritis Rheum Candia L Marquez J Espinoza LR 49 56 35 2005 16084224 15 Safety and efficacy of budesonide during pregnancy in women with autoimmune hepatitis J Gastrointestin Liver Dis Wiest I Roig A Antoni C Ebert M Teufel A 256 257 31 2022 35694989 16 Autoimmune hepatitis and pregnancy: report of two cases with different maternal outcomes Clin Exp Hepatol Orgul G Ozkan EU Celik HT Beksac MS 212 214 3 2017 29255809 17 Use of thrombopoietin receptor agonists for immune thrombocytopenia in pregnancy: results from a multicenter study Blood Michel M Ruggeri M Gonzalez-Lopez TJ 3056 3061 136 2020 32814348 18 Thrombocytopenia and liver disease: pathophysiology and periprocedural management Hematology Am Soc Hematol Educ Program Lim HI Cuker A 296 302 2022 2022 36485111 |
Today, many epidemiological studies and biobanks are offering to disclose individual genetic results to their participants, including the National Institutes of Health's All of Us Research Program. Returning hereditary disease risks and pharmacogenetic test results to study participants from racial/ethnic groups that are historically underrepresented in biomedical research poses specific challenges to those participants and the health system writ large. For example, individuals of African descent are underrepresented in research about drug-gene interactions and have a relatively higher proportion of variants of unknown significance, affecting their ability to take clinical action following return of results. In this brief report, we summarize studies published to date concerning the perspectives and/or attitudes of African Americans engaged in genetic research programs to anticipate factors in disclosure protocols that would minimize risks and maximize benefits. A thematic analysis of studies identified (n = 6) lends to themes centered on motivations to engage or disengage in the return of results and integrating research and care. Actionable strategies determined in reaction to these themes center on ensuring adequate system and health education support for participants and personalizing the process for participants engaging in return of results. Overall, we offer these themes and actionable strategies as early guidance to research programs, and provide recommendations to policy makers focused on fair and equitable return of genetic research results to underrepresented research participants. precision medicine genetic research return of results health equity health policy National Institutes of Health 10.13039/100000002 1OT2OD031925-01 pmcIntroduction An increasing number of epidemiological studies and biobanks are offering to disclose individual genetic results to their participants.1-4 While such efforts satisfy ethical mandates to respect the needs and interest of participants, the impact of returning genetic research results in large-scale population-based studies, where participants are often unselected for disease and participant-investigator relationships may be remote, is not well understood.5 Data on the real-world impact of the return of genomic research results among racial/ethnic groups that are historically underrepresented in biomedical research are especially limited. These knowledge gaps compound concerns that, without a thoughtful approach to implementation, the return of genomic research results could exacerbate existing disparities in genomic medicine.6 Addressing the needs of participants of African descent/ancestry or heritage in the United States (ie, African Americans), in particular, is critical for both scientific and social reasons. Genetics has frequently been used to stigmatize and marginalize the individuals identified (either by self or society) as Black populations, making them wary about genomics research and precision medicine.7-9 In addition, genetic testing typically provides less utility for individuals of African descent/ancestry, providing molecular explanations for disease less often, perhaps partially due to health system factors that may include, but not be limited to, low clinician electronic health record engagement for historically marginalized groups and thus lesser amounts of phenotype data that are required to accurately interpret the genetic basis of disease among such groups.10 Moreover, as data on the influence of pharmacogenetic variants in individuals of African descent/ancestry emerge, it is unclear whether pharmacogenetic research reports provided to such individuals are consistent across genetic research programs to help address health disparities. Considering these issues, it is critical to offer early, evidence-based guidance to research programs seeking to develop or contemplate policies focused on the fair and equitable return of genetic research results. In this brief report, we provide such an offering through a review of studies published to date about the perspectives and/or attitudes of African Americans engaged in the return of genetic research results to anticipate factors in disclosure protocols that would minimize risks and maximize benefits. Data and methods Literature review Two authors (N.E. and M.N.) conducted a literature search in the National Institute of Health's (NIH's) PubMed database from November through December 2022 using the following search terms: African American, African, Black, and "return of results." Original articles published at any time reporting perspectives, attitudes, and/or experiences among individuals of African descent/ancestry with return of genetic results were assessed for inclusion in the review. We extracted the following information from included articles: study population, purpose, approach, key findings, and authors' policy and practice recommendations regarding return of results. Given the dearth of studies on return of research results with a specific focus on Black individuals of African descent/ancestry, we sought studies that examined disclosure of both clinical and research-grade genetic findings. Thematic analysis Two authors (R.M.H.-S. and K.C.) conducted a thematic analysis of literature review results and their respective authors' recommendations using deductive data coding (to identify and develop emerging categorical themes and actionable strategies) in Microsoft Word and Excel (Microsoft Corporation), using constant comparative analysis in accordance with the grounded theory approach.11 The resulting codes were built into categorical and actionable themes that were deliberated upon and discussed among all members of the research team until strong (>95%) agreement was reached. Results Literature review We identified only 6 studies that met our inclusion criteria and are indexed to date in PubMed, all of which were published between the years 2012 and 2021 and focused on return of research vs clinical results (see Table 1). Three studies in our scoping review were from a single study in 2012 involving a total of 45 participants. Across all studies, the number (n) of participants of African ancestry/descent ranged from 41 to 48. Four of the 6 studies were conducted between 2012 and 2014 and 2 were conducted in 2021, prior to the All of Us program's return of results announcement in December 2022. Five of the 6 studies were qualitative, and only 1 study focused on return of results in adult vs pediatric populations of African descent/ancestry. Only 1 study enrolled a racial/ethnic subset of participants from another study where return of genetic results would occur.16 Table 1. Summary of key findings and recommendations across studies reporting Black or African-American participant attitudes and perspectives around return of genetic results. Author (year) Study population, purpose, and approach Key findings and recommendations Halverson and Ross (2012)12 Population: African-American parents (n = 45) of children receiving medical care from 2 facilities in Chicago, IL Purpose: Assess perspectives of parents regarding biobank participation and return of results for themselves and their children Approach: post-engagement surveys and focus groups After discussing the design of biobanks to allow/not allow return of results, most participants agreed that they would enroll themselves and their children. Participants advocated for return of their results. Opinions about the return of their own results vs results of their children were similar. Halverson and Ross (2012)13 Population: Same as above Purpose: Assess changes in attitudes about biobank research, governance, and the return of results before and after deliberative engagement Approach: post-engagement surveys and focus groups Engagement did not change attitudes. Most participants expressed moderate to strong concern regarding genetic information privacy in research. Most participants from both health care facilities expressed interest in receiving actionable results. Participants from the federally qualified health center opposed return of non-actionable results, while participants from the university-based practice were more interested. Researchers need to consider the diversity within African-American populations when developing return-of-results protocols. Halverson and Ross (2012)14 Population: Same as above Purpose: Evaluate therapeutic misconceptions of participants about participating in biobank-based research with the potential for return of results Approach: Focus groups conducted during 4 participant engagement sessions Several participants believed that they could receive clinical care by participating in biobank research. Return of results plans may contribute to perceptions that biobank participation provides clinical utility. Yu et al (2013)15 Population: African-American (n = 41) and non-African-American (n = 35) adults in Seattle/King County, WA Purpose: Evaluate attitudes regarding return of results from exome and whole-genome sequencing Approach: Focus groups African-American participants were less willing to participate themselves or to allow their children to participate in hypothetical studies of genomic sequencing than non-African-American participants. African Americans were more likely than non-African-American adults to discuss (1) how results may inform management of current, rather than future, health; (2) concerns with law enforcement access to their identifiable genetic information; (3) the psychological impacts of accessing their results; (4) lack of access to health care, which might hinder their ability to follow up on actionable results; (5) the importance of faith and church communities in decision making; (6) the potential for people to believe they are sick based on test results; (7) desire for control of one's own results; and (8) benefits to future generations. Lewis et al (2021)16 Population: African-American participants of the ClinSeq project (n = 49) Purpose: Assess participant perspectives on optimal engagement strategies and priorities for return of results Approach: Focus groups Participants had clear preferences for certain types of results (eg, life-threatening results) over others (eg, ancestry-related results). Development of return of results protocols would benefit from community engagement that includes the following: (1) large numbers of participants to provide a diversity of opinions, (2) longitudinal engagement, and (3) reciprocal flow of information between researchers and participants. West et al (2022)17 Population: Professional, personal, family, and/or community stakeholders (n = 76, 48 of whom are African American) Purpose: Assess stakeholders' perspectives on returning nonactionable apolipoprotein L1 (APOL1) genetic results to African-American research participants Approach: In-depth interviews Most interviewees supported the return of APOL1 results. Few interviewees presenting professional perspectives expressed concern for potentially harming individuals or limited benefits. Emergent themes of benefits included (1) personal value, (2) expectations of future actionability, (3) respect and reciprocity, and (4) community/scientific benefit. Participants also perceived risks that included psychological burdens. Thematic analysis Emerging categorical and actionable themes across these studies that may inform the development and implementation of earnest and equitable policy solutions and support are listed in Table 2. Emerging categorical themes centered largely on motivations to engage or disengage in return of results and integrating research and care. Themes captured as actionable strategies moving forward centered largely on ensuring adequate system and health education support for participants and personalizing the process for participants engaging in return of results. Table 2. Emerging categorical themes and actionable strategies: returning genetic test results to individuals of African descent/ancestry. Emerging categorical themes Motivations to engage or disengage Participants hold general interest in engaging in the return of results process. Engagement in return of results likely depends on the clinical nature or actionability of the results being conveyed. Adults may equally engage themselves and their children in return of results. Integrating research and care The return of genetic research results may contribute to misconceptions around clinical utility of the studies, especially if return of results occurs in usual care (vs research) settings. Lack of access to follow-up health care may hinder participants' ability to address actionable genetic testing results. Actionable strategies Support the system and educate Provide system support to address psychological impacts or burdens following return of results. Discuss community, generational, and/or scientific benefits and other implications with participants. Create and implement system guidelines and policies that support educated decision making among participants. Personalize the process Discuss religious and/or spiritual beliefs that exist around disease manifestation. Address participants' concerns about and desires for genetic information privacy and control of test results. Demonstrate respect for and reciprocity with participants. Discussion Very few studies have been published and indexed in PubMed to date about the return of genetic research results to African-American individuals as an underrepresented population. Our work highlights specific challenges facing large-scale population-based studies, including but not limited to the National Institute of Health's (NIH's) All of Us Research Program, that are enrolling large numbers of participants from minoritized populations and returning individual genomic research results.18-20 Developing protocols and policies that are evidence-based and sensitive to the needs and preferences of groups whose perspectives and health genetic data are underrepresented in the scientific literature (ie, African Americans) will be challenging without further research and engagement that could build on the present themes and actionable strategies presented. All of Us is a high-profile example of population-based research that is pioneering the return of genomic research results and facing these challenges. All of Us has been returning results derived from genetic analyses as part of its commitment to core values that include giving participants access to their information.18-20 All of Us entered a new phase at the end of 2022 when it started returning personalized health reports that contain information about genetic variants that may increase risks for disease (hereditary disease risks) and genetic variants associated with drug/medication metabolism (pharmacogenetic results).18 Because over 75% of All of Us participants to date are from populations that are traditionally underrepresented in biomedical research, protocols for the return of hereditary disease risks and pharmacogenetic results will need to be sensitive to the special opportunities and challenges of disclosing genomic research results to members of these populations.18-20 For example, the All of Us Public Data Browser does not stratify survey data about social determinants of health by race/ethnicity.21 The All of Us program should address these query limitations, as they can create barriers to communities being able to understand factors that may disproportionally affect marginalized populations' ability to appreciate the diversity of the community. Our findings do highlight a number of both common themes and instructive points that may improve the likelihood that return of genetic results programs in population-based studies, including but not limited to programs like All of Us, will improve outcomes in African-American participants. First and foremost, return of genetic research results is desired by African Americans not only for themselves but to also benefit their children and community as a whole. There are also expectations that African Americans will be engaged in a bidirectional process when protocols are developed, including decisions about the types of information that would be disclosed and withheld. Articles also emphasized how the communication of information needs to appreciate the diversity of perspectives within the African-American community, and how decision making about study participation and post-disclosure follow-up is often made after consultation with trusted others, including spiritual leaders. Our work also identifies potential misunderstandings that research programs will need to address. Therapeutic misperceptions that engagement in programs like All of Us will provide clinical care need to be proactively addressed, including given the potential for participants to be informed about important genetic information that participants will need to manage themselves. Frame effects, where messages are framed according to individuals' attitudes and behaviors, might drive misconceptions around the intent of research participation. Protocol designs need to consider and avoid such misconceptions, particularly for the return of results in usual care settings, where the line between research and care may be blurred.22 While these challenges are not unique to African Americans, they are likely to be more problematic for the community. For example, genetic testing typically identifies more variants of uncertain significance,23 and the importance of pharmacogenetic variants in individuals of African descent/ancestry (vs others) is poorly understood, raising questions about whether they accurately identify drug-gene interactions.24 In addition, even when genetic conditions are identified in patients of African descent, they may be at risk of receiving care that is inferior to the care received by patients of European descent because of systemic biases that presently exist in health care settings.10,25,26 Materials that proactively address these complications should be disseminated through NIH-supported communication routes to help members of the African-American community fully understand the intent and processes for the return of results. The All of Us program may benefit African Americans by engaging in the development of community-driven solutions that address challenges. A return of results process that educates and supports participants in their attempts to navigate subsequent and necessary follow-up screening and care may be particularly beneficial. Such efforts are likely to be appreciated, and may improve the recruitment and sustained involvement of study participants. not just in the African-American community but from many underrepresented subgroups facing similar challenges. Importantly, the gene list that research programs consider for return of results potentially has important implications for health inequities. Diagnostic genetic testing often provides molecular explanations for disease less often in individuals of African descent, and early evidence suggests that the yield from genetic-screening programs will be lower for groups such as African Americans than for other groups.27,28 Selection of genes associated with conditions that disproportionately affect African Americans may help mitigate these disparities. For example, a specific protein change (Val142Ile) in the tetrameric thyroxine transport protein transthyretin (TTR) gene is implicated in hereditary transthyretin-related amyloidosis (hATTR), a potentially fatal autosomal dominant disorder that disproportionately affects individuals of African descent/ancestry.29 TTR corresponds to the use of tafamidis (ie, Vyndaqel, manufactured by Pfizer) as a pharmacogenetic biomarker with a US Food and Drug Administration clinical pharmacology and clinical study labeling section, and is listed in the American College of Medical Genetics and Genetics' (ACMG) current recommendations (v3.2) for reporting secondary findings in clinical exome and genome sequencing.30-32 Programs such as All of Us that plan to screen genes and return results based on earlier versions of curated lists (eg, v2.0 of the ACMG's recommendations for secondary findings disclosure) would omit TTR/hATTR.33 Expanding gene lists to address current recommendations for secondary findings disclosure, including TTR/hATTR, may help ensure a more equitable distribution of benefits from return of results. Last, questions remain regarding whether programs like All of Us should provide participants with personalized reports containing details about genetic variants of unknown or undefined significance (VUS).34 Well-meaning policies that discourage the disclosure of VUS to minimize the risk of returning false-positive results could disproportionally minimize the potential benefits of return of results. This is especially true for participants of African descent/ancestry, given that they are more likely to receive VUS findings during diagnostic testing. Therefore, if and/or whenever information relating to VUS is provided to individuals of African descent/ancestry, it will be important to (1) develop and implement processes and policies that appropriately convey new information about genetic health risk through timely reanalysis of variants of unknown significance and (2) ensure that research participants and their children have pathways within the health system to receive any necessary health education and receive necessary follow-up screening and care upon receiving such results. There are some limitations to our literature review. First, our literature search was conducted in only 1 database (PubMed). Second, the studies in our review relied exclusively on hypothetical research scenarios (vs actual experiences) to examine issues related to return of genetic research results to individuals of African descent/ancestry and included relatively small numbers of participants. These factors limit the generalizability of our findings and potential utility of our recommendations. Nonetheless, our findings are helpful to stimulate further research, engagement, and discussions involving patients/study participants, researchers, clinicians, policy makers, and other health care system stakeholders who face the challenges noted herein with the hopeful mission to leverage precision medicine research and care to reduce racial/ethnic health disparities. Conclusion To date, limited studies report perspectives about return of genetic results to individuals of African descent/ancestry. Nonetheless, stakeholders engaged in the advancement of health equity and precision medicine should consider these thematic findings to address system-level challenges that accompany returning genetic testing results to members of distinct racial/ethnic subgroups, including individuals of African descent/ancestry. More research is needed to validate and/or enrich themes highlighted herein noting privacy concerns, actionability of results, and psychological impacts/burdens upon receiving information about their genetic health risks and pharmacogenetic treatment implications/considerations. Our recommended strategies along these themes may help ensure, as a starting point, that participants and their children are supported in their attempts to learn about their genetic status, including VUSs, and navigate follow-up care upon return of clinically actionable results through supportive study protocols and policies. Supplementary Material qxad066_Supplementary_Data Supplementary material Supplementary material is available at Health Affairs Scholar online. Funding This work is funded by the National Institutes of Health's All of Us Research Program, agreement no. 1OT2OD031925-01. |
: Authors need to include the total deliveries in the results. The use of percentage where n<30 is not recommended. Main manuscript: The introduction is well written giving a clear context to the reader. Materials and methods: Line 105 The authors should be consistent in the use of the comma i.e., 1,800 and 2000 deliveries. How does seasonality affect the results? Could the results have been different if the study was conducted for a full year? Line 153 to 159 How did the authors define univariate logistic regression analysis? Is this not a bivariate analysis after which they enter variables with a p-value less than 0.20 into the multivariate logistic regression model. Results: Table 1 and 2 The title is not informative. Should show who/what, where and when. The use of percentages when n<30 is not recommended. Correct this throughout the manuscript. Line 260 Is this univariate or bivariate analysis. Univariate analysis does not generate odds ratios. Table 3 Include the values for the 2xn table for us to see where the CORs came from Reviewer #2: Abstract: basic demographic information would have helped to appreciate who the study population were. The univariate analysis is also clearly missing here Sample size determination Why was the sample size not determined? Data collection tool and procedures Was any validation done for this questionnaire based on the fact that there was translation from English to other languages? ********** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose "no", your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: Yes: Christian Obirikorang ********** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at [email protected]. Please note that Supporting Information files do not need this step. 10.1371/journal.pone.0296076.r002 Author response to Decision Letter 0 Submission Version1 14 Nov 2023 RESPONSE TO REVIEWERS' COMMENTS REVIEWER #1 1. Authors need to include the total deliveries in the results (Abstract). The use of percentage where n<30 is not recommended. Response: Both comments have been addressed. The first two sentences of the results section under the abstract now reads as; "A total of 687 women and their 702 newborns contributed data for analysis. Overall stillbirth incidence was 31.3 per 1000 births. Of the 22 stillbirths, 17 were antepartum." 2. The introduction is well written giving a clear context to the reader Response: The authors are thankful to the reviewer for such kind and encouraging remarks. 3. Line 105. The authors should be consistent in the use of the comma i.e., 1,800 and 2000 deliveries. Response: This has been noted and addressed. The sentence in question now reads as; "Approximately 1,800 to 2,000 deliveries are conducted annually at the facility (Biostatistics Unit, HTH, 2022)." 4. How does seasonality affect the results? Could the results have been different if the study was conducted for a full year? Response: The results could have been different if the study had been conducted for a full year. However, the 'seasonality' element has been taken off. 5. Line 153 to 159 How did the authors define univariate logistic regression analysis? Is this not a bivariate analysis after which they enter variables with a p-value less than 0.20 into the multivariate logistic regression model. Response: 'Univariate' was used to mean one exposure variable was under consideration at a time. However, the authors have changed to 'Bivariate' as suggested 'Univariate' has been changed to "Bivariate" throughout the manuscript. Covariates that were statistically significant at p < 0.1 were entered into multivariate analysis in a backward stepwise regression. Under Methods, Data Management and Analysis, the relevant sentence has been revised to read as; "A backward stepwise regression with p<0.1 was done in the multivariate analysis" 6. Table 1 and 2....The title is not informative. Should show who/what, where and when. Response: The authors agree with the reviewer on this and have reviewed the titles accordingly as shown below; Table 1 is now titled as; "Demographic characteristics of mothers included in the determination of stillbirth incidence at Ho Teaching Hospital" Table 2 is now titled as; "Obstetric factors of index pregnancy and characteristics of newborns assessed in the study" The authors opine that these titles suffice and that the other elements pointed out can be teased from the body of the manuscript. We also wish to guard against excessively long titles. 7. The use of percentages when n<30 is not recommended. Correct this throughout the manuscript. Response: The authors thank the reviewer for this comment as it was not known to us. The correction has been done throughout the manuscript 8. Line 260 Is this univariate or bivariate analysis. Univariate analysis does not generate odds ratios. Response: It has been changed to 'bivariate' 9. Table 3... Include the values for the 2xn table for us to see where the CORs came from Response: Table 3 has been revised to include the values (and percentages) for the 2 x n table to show where the CORs came from as suggested. REVIEWER #2 1. Abstract: basic demographic information would have helped to appreciate who the study population were. The univariate analysis is also clearly missing here Response: The suggested findings have been incorporated. The results (Abstract) now reads as; "A total of 687 women and their 702 newborns contributed data for analysis. The mean age (SD) was 29.3 (6.3) years and close to two-thirds had had at least one delivery previously. Overall stillbirth incidence was 31.3 per 1000 births. Of the 22 stillbirths, 17 were antepartum. Pre-eclampsia was the most common hypertensive disorder of pregnancy observed (49.3%, 33/67). Among others, less than 3 antenatal visits and low birthweight increased the odds of stillbirths in the bivariate analysis. In the final multivariate model, pregnancy and delivery at 28-34 weeks gestation [AOR 9.37(95% CI 1.18 - 74.53); p=0.034] and induction of labour [AOR 11.06 (95% CI 3.10 - 39.42); p < 0.001] remained significantly associated with stillbirths." 2. Why was the sample size not determined? Response: There were very few studies and none at all in our regional setting reporting current stillbirth incidence. The only published study from our regional setting was in Hohoe and it reported stillbirth prevalence among singletons in a retrospective study. This baseline was not deemed appropriate to use in sample size determination. We emphasize 'regional setting' because we desired to be able to speak to our local context in this assessment. Hence, we chose the permitted alternative of gathering data in a prospective study over a 6-month period to enable us report stillbirth incidence in our setting. Secondly, this prospective study was meant to give a preliminary insight into the problem of stillbirth in the facility and the findings thereof will inform larger and more comprehensive future studies into stillbirths in our setting. 3. Was any validation done for this questionnaire based on the fact that there was translation from English to other languages? Response: Pretesting the questionnaire was the only validation mechanism employed. Though the interviewers were Ewe and Twi speakers, they were still trained to standardize how the questions were framed during the interviews to minimize response bias and to improve internal validity. The pretesting of the questionnaire has been reported. Attachment Submitted filename: RESPONSE TO REVIEWERS COMMENTS ON STILLBIRTH WORK.docx Click here for additional data file. 10.1371/journal.pone.0296076.r003 Decision Letter 1 Kananura Rornald Muhumuza Academic Editor (c) 2023 Rornald Muhumuza Kananura 2023 Rornald Muhumuza Kananura This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Submission Version1 6 Dec 2023 Stillbirth incidence and determinants in a tertiary health facility in the Volta Region of Ghana. PONE-D-23-17720R1 Dear Dr. Osarfo, We're pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you'll receive an e-mail detailing the required amendments. When these have been addressed, you'll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at [email protected]. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they'll be preparing press materials, please inform our press team as soon as possible no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact [email protected]. Kind regards, Rornald Muhumuza Kananura, PhD Academic Editor PLOS ONE Additional Editor Comments (optional): This statement in the abstract needs to be revised to have it aligned with how the study contributes to the current literature of understanding the consistent high stillbirths in low-resource settings of SSA or Ghana. "Published data on stillbirths and their associating factors in the Volta Region of Ghana is limited and adversely affects a good understanding of local factors that must be considered in designing appropriate interventions." Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the "Comments to the Author" section, enter your conflict of interest statement in the "Confidential to Editor" section, and submit your "Accept" recommendation. Reviewer #1: All comments have been addressed Reviewer #2: All comments have been addressed ********** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Yes ********** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ********** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data e.g. participant privacy or use of data from a third party those must be specified. Reviewer #1: Yes Reviewer #2: Yes ********** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ********** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: The authors have satisfactorily attended to comments from the initial review. I have no further comments Reviewer #2: based in the responses received, the authors have answered all queries that were raised. The paper is not acceptable in the current form ********** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose "no", your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: Yes: Addmore Chadambuka Reviewer #2: Yes: Christian Obirikorang ********** 10.1371/journal.pone.0296076.r004 Acceptance letter Kananura Rornald Muhumuza Academic Editor (c) 2023 Rornald Muhumuza Kananura 2023 Rornald Muhumuza Kananura This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 11 Dec 2023 PONE-D-23-17720R1 Stillbirth incidence and determinants in a tertiary health facility in the Volta Region of Ghana. Dear Dr. Osarfo: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact [email protected]. If we can help with anything else, please email us at [email protected]. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Rornald Muhumuza Kananura Academic Editor PLOS ONE |
: Conclusion: PR may appear to be an effective and safe treatment for patients with IPF, but the results of this overview should be interpreted dialectically and with caution. Further high-quality, rigorous studies are urgently needed to draw definitive conclusions and provide scientific evidence. (The revision is on page 3, lines 50-54 of the manuscript.) Conclusion: What is the precise role of PR in the treatment of IPF? Based on the trials we included, definitive conclusions to this question are difficult to draw. It is unclear whether this is related to the quality of the original studies and the variable quality of the evidence on the results (ranging from very low to moderate). Therefore, considering the limitations of the overview, further scientific research is warranted to investigate the efficacy of PR in IPF, for providing a more robust, scientifically rigorous, and accurate foundation for clinical decision-making. (The revision is on pages 20-21, lines 438-445.) 2. Having created a sensitivity analysis based not least on the most prevalent types of PR would have been helpful. Response: Many thanks to the reviewer for the invaluable and professional advice, this comment is significantly valuable in verifying the robustness of the study findings. We have made our best efforts to correlate prevalent types of PR. Unfortunately, this seems to be challenging given the study type of our article. The main focus of our study was to assess the risk of bias and evidence quality of the original studies we included using assessment tools to obtain clinical evidence of interest. Presenting a sensitivity analysis based on PR proved difficult as we could not analyze the obtained data quantitatively. And, to our knowledge, there do not appear to be any published overview of systematic reviews-type articles that have used this type of analysis. We would like to thank the reviewer once again for this comment. This suggestion may have been due to our unclear description of the data synthesis in the article, so we have revised the manuscript (Pages 6-7, lines 145-150, and Page 13, lines 276-277). We have described the data synthesis in the method portion more clearly in the article hoping that this will improve the methodological adequacy and rigor of the article, and we also hope that we can avoid the possibility of misinterpretation by the readers due to the unclear description of the data synthesis methodology. 3. Please specify in every case who has been the reviewers that conducted the literature search, by providing their capital letters. Response: We apologize for neglecting to detail the researchers who participated in the literature search, and the correction is below. Revised portion: Two researchers (SY Song and WR Liu) independently conducted the literature search (The revision is on page 6, line 134 of the manuscript). Other changes: 1. Page 1, line 3 and lines 16-17, We have removed the current address of one of the authors. 2. Page 21, lines 457-464, We changed this section to make it more concise and clear, the details of the revision are in the manuscript. 3. We reformatted the references according to the journal's requirements but did not add or remove any references. We did our best to improve the manuscript and ensure that our manuscript met the style requirements of PLOS ONE, so we made some changes to the manuscript. These changes do not affect the content of the paper or the framework. And here we listed the changes and marked them in red in the revised paper. We appreciate the diligent work of the editor and reviewers. Thank you for your commitment to improving the quality of our academic writing. We hope that all these changes fulfill the requirements to make the manuscript acceptable for publication. Looking forward to hearing from you soon. Sincerely, Jiansheng Li Attachment Submitted filename: Response to Reviewers.docx Click here for additional data file. 10.1371/journal.pone.0295367.r003 Decision Letter 1 Bongomin Felix Academic Editor (c) 2023 Felix Bongomin 2023 Felix Bongomin This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Submission Version1 9 Nov 2023 PONE-D-23-30793R1The role of pulmonary rehabilitation in idiopathic pulmonary fibrosis: an overview of systematic reviewsPLOS ONE Dear Dr. Li, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE's publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Please submit your revised manuscript by Dec 24 2023 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at [email protected]. When you're ready to submit your revision, log on to and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript:A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at We look forward to receiving your revised manuscript. Kind regards, Felix Bongomin, MB ChB, MSc, MMed, FECMM Academic Editor PLOS ONE Journal Requirements: Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article's retracted status in the References list and also include a citation and full reference for the retraction notice. Additional Editor Comments: Dear authors, Thank you for revising this work. However, the results section of the abstract doesn't summarise the goal of these umbrella review. Are you looking at the quality of the systematic reviews or you want to answer the question on "The role of pulmonary rehabilitation in idiopathic pulmonary fibrosis"? Kindly extensively revise the abstract. [Note: HTML markup is below. Please do not edit.] [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at [email protected]. Please note that Supporting Information files do not need this step. 10.1371/journal.pone.0295367.r004 Author response to Decision Letter 1 Submission Version2 18 Nov 2023 Dear Felix Bongomin, Thank you so much for your letter and the comments on our manuscript entitled "The role of pulmonary rehabilitation in idiopathic pulmonary fibrosis: an overview of systematic reviews" (ID: PONE-D-23-30793R1). Thank you for your dedication and valuable suggestions on our revised manuscript. We all agree that these comments are essential to strengthen the rigor and readability of our article. Therefore, we have extensively revised the abstract of our article based on your suggestions. Revised sections are highlighted in red in the manuscript. The main corrections in the manuscript are as follows. Responses to Editor Comments: 1.Additional Editor Comments: The results section of the abstract doesn't summarise the goal of these umbrella review. ......Kindly extensively revise the abstract. Response: We have thought deeply about your comments, and we all agree that it is a highly valuable and helpful comment. We apologize for the lack of clarity in the abstract, which may prevent the editor and readers from quickly understanding the main objective of our article through the abstract. Thus, our modifications of the abstract are the following. Revised portion: (1) Background: The role of pulmonary rehabilitation (PR) in idiopathic pulmonary fibrosis (IPF) has been studied in several systematic reviews (SRs), but no definitive conclusions have been drawn due to the wide variation in the quality and outcomes of the studies. And there are no studies to assess the quality of relevant published SRs. This overview aims to determine the effectiveness of PR in patients with IPF and to summarize and critically evaluate the risk of bias, methodological, and evidence quality of SRs on this related topic. (The revision is on page 2, lines 24-30 of the manuscript.) (2) Results: Seven SRs from 2018-2023 (including 1836 participants) on PR for the treatment of IPF were selected, all of which included patients with a definitive diagnosis of IPF. After strict evaluation by the ROBIS tool and AMSTAR-2 tool, 42.86% of the SRs had a high risk of bias and 85.71% of the SRs had critically low methodological quality in this overview. PR might be effective for patients with IPF on exercise capacity, quality of life, and pulmonary function-related outcomes, but we did not find high quality evidence to confirm the effectiveness. (The revision is on page 2, lines 38-45 of the manuscript.) (3) We reformatted the references according to the journal's requirements but did not add or remove any references. We appreciate your efforts again and hope that the revisions we made will be in line with PLOS ONE's publication criteria. Looking forward to hearing from you soon. Sincerely, Jiansheng Li Attachment Submitted filename: Response to Reviewers.docx Click here for additional data file. 10.1371/journal.pone.0295367.r005 Decision Letter 2 Bongomin Felix Academic Editor (c) 2023 Felix Bongomin 2023 Felix Bongomin This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Submission Version2 21 Nov 2023 The role of pulmonary rehabilitation in idiopathic pulmonary fibrosis: an overview of systematic reviews PONE-D-23-30793R2 Dear Dr. Li, We're pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you'll receive an e-mail detailing the required amendments. When these have been addressed, you'll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at [email protected]. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they'll be preparing press materials, please inform our press team as soon as possible no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact [email protected]. Kind regards, Felix Bongomin, MB ChB, MSc, MMed, FECMM Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: 10.1371/journal.pone.0295367.r006 Acceptance letter Bongomin Felix Academic Editor (c) 2023 Felix Bongomin 2023 Felix Bongomin This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 13 Dec 2023 PONE-D-23-30793R2 PLOS ONE Dear Dr. Li, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset If revisions are needed, the production department will contact you directly to resolve them. If no revisions are needed, you will receive an email when the publication date has been set. At this time, we do not offer pre-publication proofs to authors during production of the accepted work. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few weeks to review your paper and let you know the next and final steps. Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact [email protected]. If we can help with anything else, please email us at [email protected]. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Felix Bongomin Academic Editor PLOS ONE |
PLoS Comput Biol PLoS Comput Biol plos PLOS Computational Biology 1553-734X 1553-7358 Public Library of Science San Francisco, CA USA 10.1371/journal.pcbi.1011689 PCOMPBIOL-D-23-01471 Education Biology and Life Sciences Neuroscience Cognitive Science Cognitive Psychology Learning Human Learning Biology and Life Sciences Psychology Cognitive Psychology Learning Human Learning Social Sciences Psychology Cognitive Psychology Learning Human Learning Biology and Life Sciences Neuroscience Learning and Memory Learning Human Learning Medicine and Health Sciences Ophthalmology Visual Impairments Biology and Life Sciences Neuroscience Cognitive Science Cognitive Psychology Perception Sensory Perception Vision Biology and Life Sciences Psychology Cognitive Psychology Perception Sensory Perception Vision Social Sciences Psychology Cognitive Psychology Perception Sensory Perception Vision Biology and Life Sciences Neuroscience Sensory Perception Vision People and Places Population Groupings Professions Instructors Biology and Life Sciences Computational Biology Genome Analysis Gene Ontologies Biology and Life Sciences Genetics Genomics Genome Analysis Gene Ontologies Social Sciences Economics Labor Economics Employment Careers People and Places Population Groupings Professions Teachers Social Sciences Sociology Communications Social Communication Social Media Computer and Information Sciences Network Analysis Social Networks Social Media Social Sciences Sociology Social Networks Social Media Ten simple rules for writing a PLOS Computational Biology quick tips article Palagi Patricia M. Conceptualization Visualization Writing - original draft Writing - review & editing 1 Schwartz Russell Conceptualization Writing - review & editing 2 Markel Scott Conceptualization Writing - review & editing 3 Ouellette B. F. Francis Conceptualization Visualization Writing - original draft Writing - review & editing 4 * 1 SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland 2 Carnegie Mellon University, Pittsburgh, Pennsylvania, United States of America 3 Dassault Systemes BIOVIA, San Diego, California, United States of America 4 Bioinformatics.ca, Montreal, Quebec, Canada Mac Gabhann Feilim Editor Johns Hopkins University, UNITED STATES I have read the journal's policy and the authors of this manuscript have the following competing interests: All authors are currently PLOS Computational Biology Section Editors. * E-mail: [email protected] 21 12 2023 12 2023 19 12 e1011689(c) 2023 Palagi et al 2023 Palagi et al This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The authors received no specific funding for this work. pmcIntroduction Seventeen years have passed since Phil Bourne inaugurated the Ten Simple Rule (TSR) collection in PLOS Computational Biology (PLOS CB) with a paper entitled "Ten Simple Rules for Getting Published" . At that time, the change in how we communicate sciences had already begun : social media was blooming, the information deluge was ongoing, and the fear of missing information was anchored in each of us. The Ten Simple Rules collection filled a space in scientific publications where researchers eager to share their experiences, wisdom, and doubts could quickly do it using a colloquial narrative. The topics covered were broad themes in scientific practice, such as soft skills and career development, captured in a concise and quick-to-read format, something between a blog post and a scientific article. This type of article attracted much interest from readers. In 2018, the collection reached the milestone of 1,000 Rules , and today this figure is above 250 papers (2,500 Rules!) . With the increase of technical and scientific topics, in 2013, PLOS Computational Biology tried a new experience with a similar format we introduced "Quick Tips" (QT) articles with the attempt to make a clear distinction between the more specific and focused scientific activities and skills presented with resources, databases, and other tools in Quick Tips versus the broader themes presented in a Ten Simple Rules article. "Ten Simple Rules for Writing a PLOS Ten Simple Rules Article" explains the Ten Simple Rules concept, format, and reasoning very well and is still relevant today. Inspired by that article, we wrote this Ten Simple Rules paper intending to accomplish a similar task: explaining to our community what a Quick Tips article is about and how a Quick Tips article differs from a Ten Simple Rules article. The authors are the Section Editors of the Education Collection (PP and BFFO), which encompasses the Quick Tips, and the Section Editors of the Ten Simple Rules Collection (RS and SM). In our work at PLOS CB, we are routinely deliberating the merits of a submission being a Ten Simple Rules or a Quick Tips, and for this reason, we decided to put these Ten Simple Rules about Quick Tips together. Historically, several papers were submitted as Ten Simple Rules that should have been Quick Tips. Still, we will refrain from commiserating about things not done but rather present what we hope will be a clear distinction that will make it obvious in the future why articles are best considered as Quick Tips versus Ten Simple Rules (or vice-versa). We hope and plan for this present article to be helpful for future writers willing to contribute to this collection and to help clarify the differences between Ten Simple Rules and Quick Tips. Why is this not a Quick Tips article but a Ten Simple Rules article, and why are we not as endearing as Dashnow, Lonsdale, and Bourne were in doing a "Ten Quick Tips for Writing a PLOS Quick Tips Article"? The reason is simple. As stated in Rule 1, this is a soft-skills article: it aims to explain how best to write a particular type of manuscript for PLOS. Thus, it is not a Quick Tips but a Ten Simple Rules article. In Fig 1, we summarize the Ten Simple Rules we are presenting. 10.1371/journal.pcbi.1011689.g001 Fig 1 Summary of the Ten Simple Rules presented in this manuscript. Rule 1: Give tips, not rules Quick Tips are for guiding readers on developing scientific and technical skills on using databases, resources, computational or data analysis methods and tools. Quick Tips can teach how to analyze network data , use the Gene Ontology (GO) , or use deep learning in biology . They have a specific educational perspective. With a Quick Tips article, you drive the reader towards learning and applying what they are learning. They are quick tips, not simple rules. As such, each tip needs to inform the reader about a different aspect of the overall problem (computational) biologists want to get better at. Ten Simple Rules are more to develop soft skills, career promotion/advancement (how to organize a scientific conference , write your cover letter , write a literature review , etc.), or other broad issues in scientific practice (e.g., models for successful collaboration , developing scientific communities , or practicing inclusive science ). Rule 2: Minimize overlap and amplify new insights When putting together a Quick Tips article, ensure there is no redundancy with other Quick Tips or other educational articles. The Quick Tips articles have yet to become as famous as its sister collection, Ten Simple Rules, which counts 255 articles so far . Still, plenty of valuable Quick Tips and education articles in PLOS and other journals may have treated the same topic as yours. But if you think you have a different or unique perspective on the same topic, do not forget to reference all those relevant to your Quick Tips in your manuscript and explain what makes yours unique. Paraphrasing Dashnow, Lonsdale, and Bourne's wise advice in Rules 7 and 9: summarize, cite, and write well . Rule 3: Make each tip a declarative statement, not simply a passing thought The title of the tip is essential, and it needs to state a tip. At a glance, the reader must understand your main key message, which must simultaneously be persuasive and noteworthy. When you declare a tip, make sure it is a statement and to the point. You are providing a unit of advice to your readers to perform (or not) specific tasks, and as such, you want to avoid misinterpretations. By making your tips declarative statements, you can ensure they are unambiguous and leave no room for interpretation or confusion. If you provide an opinion, provide evidence to sustain your point of view and convince your readers of your argument. Rule 4: Be concise and to the point Less is more. Quick Tips papers are currently part of the PLOS Computational Biology Education collection , and as for any article in this collection, a Quick Tips article is about 2,000 to 2,500 words . From a pedagogical perspective, some educational models support the value of being concise (e.g., Miller) , which we support in the PLOS Education collection. However, there is some flexibility here. The story of your manuscript may be more important than the length of the manuscript you are submitting. Word limits provide boundaries and are a great tool to make you reflect on the primary key messages you want to deliver. You cannot neglect good writing practices because Quick Tips papers are short. Make sure to read and apply the excellent rules provided by Ehrhart and Evelo in to your manuscript. Rule 5: Be creative on the number of tips Another important difference between the Quick Tips articles and Ten Simple Rules articles is that you are not restricted to 10 tips, as opposed to Ten Simple Rules, where 10 is one of the rules . Please feel free to do so if it makes sense to have 8, 9, or 13 tips. As we see in Fig 2, the number of tips we have seen in Quick Tips articles ranges from 7 to 15. 10.1371/journal.pcbi.1011689.g002 Fig 2 Distribution of the number of tips presented in the 36 Quick Tips articles from 2020-09 to 2023-10 . Rule 6: Make sure your tips are presented logically and that there are no gaps Quick Tips are like recipes, like a procedural order of execution of tasks for a given topic. They should follow at least a logical order. Consider them a "sorted checklist" that your readers will follow and apply. As for a recipe, you can't miss any ingredients or procedures, as the result may not be as expected. Rule 7: Be visual Using images in a manuscript can help to make the content more accessible, engaging, and visually appealing to readers, and as the adage says: "an image is worth a thousand words." Images can help visualize or clarify a concept or idea you are discussing in the text and provide evidence for your claims in the tips. As Weinstein and Sumeracki, two cognitive scientists, say "Pictures are usually remembered better than words, and can provide additional memory cues" and thus help learning and understanding . Thus, we recommend Quick Tips authors incorporate a figure summarizing and illustrating their tips (Fig 1). By the way, we recommend the same for Ten Simple Rules authors. Alternatively, suppose you do not use a figure. In that case, we recommend including a table in the introduction that declares the tips in a summarized way and allows the reader to get an overview of the text to follow. For all images presented on the web or within a publication, it is important to have some alternative text (Alt-Txt) for visually impaired readers and also to consider a color palette that color blind people will be able to interpret . Rule 8: Be an empathic instructor Quick Tips are educational articles and thus serve to teach scientific or technical skills to your readers. Be mindful of your language (avoid jargon, define terms), and be specific, clear, and concise. Quick Tips need to be written as a tutorial used by a classroom teacher or a reader to learn from you. Your ambition: be the reference article about teaching that topic. You can write a Quick Tips article alone, but collaborating is better. Seven of the 10 most cited PLOS CB Quick Tips articles have three or more authors . Your tips should be messages from a community of instructors you represent for a community of readers. When you write a Quick Tips article, you (singular, but hopefully plural) speak as experts with an aura of knowledge, authority, and empathy for your readers. Rule 9: Ask for feedback before writing the manuscript Well ahead of starting to work on that manuscript, outline the tips, and send this together with a summary to [email protected]. We will happily comment and guide you before you spend too much time writing a full manuscript. One common question where people still need clarification: should it be a Ten Simple Rules or a Quick Tips submission? If you are unsure after reading this publication, please contact the section editors or PLOS Computational Biology directly ([email protected]). As always, it is also a good idea to consult and share with colleagues before you submit any article. Rule 10: Help the editors do a great job As for all PLOS Computational Biology articles, we send the submissions for peer review, so don't forget to include many suggestions for potential reviewers (5 or 6 is ideal) from which the section editors may select. Identify experts within your field who can serve as independent, objective reviewers and are free from competing interests. At the same time, since Quick Tips are for educational purposes and have a particular format (not to be confused with usual research papers), these experts should be aware of the Quick Tips format. They should also have an open and teaching mindset. Remember that suggesting recent collaborators or other researchers at your institution is inappropriate, as it would be for any other manuscript submission. Conclusions Ten Simple Rules and Quick Tips are fundamentally similar types of articles. Except for Rules 1 and 5, all the other rules in this manuscript can also apply to the Ten Simple Rules papers. If we were to give you extra and particular advice, it would be: never underestimate Rule 2. Minimize overlap and amplify new insights. Ten Simple Rules, Quick Tips, and the Education collections already have plenty of exciting and insightful manuscripts, which are excellent resources for teaching and learning. But there is always a place for your preferred topic; we welcome and look forward to your new ideas. We endeavor to get back to you in a timely way. As a way to say "thank you," we want to remind new potential authors of the Quick Tips and Ten Simple Rules articles that these articles (which also include all in the PLOS CB Education collection) are what is referred to as "Front Matter," and PLOS has no publication charges (no APC) on Front Matter papers. Like all PLOS articles, Quick Tips articles are fully Open Access (Gold) and are free to you as the author (Open Access Diamond). Front matter is like the author and PLOS giving to the community, so there are no charges. The authors acknowledge the help of Patrick Graf for the graphic design of Fig 1. References 1 Bourne PE . Ten Simple Rules for Getting Published. PLoS Comput Biol. 2005;1 :e57. doi: 10.1371/journal.pcbi.0010057 16261197 2 The History of Communications. [cited 2023 Aug 28]. Available from: 3 Bourne PE , Lewitter F , Markel S , Papin JA . One thousand simple rules. PLoS Comput Biol. 2018;14 :e1006670. doi: 10.1371/journal.pcbi.1006670 30571692 4 PLOS Comp. Bio. Ten Simples Rules collection. [cited 2023 Aug 28]. Available from: 5 Dashnow H , Lonsdale A , Bourne PE . Ten Simple Rules for Writing a PLOS Ten Simple Rules Article. PLoS Comput Biol. 2014;10 :e1003858. doi: 10.1371/journal.pcbi.1003858 25340653 6 Miele V , Matias C , Robin S , Dray S . Nine quick tips for analyzing network data. PLoS Comput Biol. 2019;15 :e1007434. doi: 10.1371/journal.pcbi.1007434 31856181 7 Blake JA . Ten Quick Tips for Using the Gene Ontology. PLoS Comput Biol. 2013;9 :e1003343. doi: 10.1371/journal.pcbi.1003343 24244145 8 Lee BD , Gitter A , Greene CS , Raschka S , Maguire F , Titus AJ , et al . Ten quick tips for deep learning in biology. PLoS Comput Biol. 2022;18 :e1009803. doi: 10.1371/journal.pcbi.1009803 35324884 9 Corpas M , Gehlenborg N , Janga SC , Bourne PE . Ten Simple Rules for Organizing a Scientific Meeting. PLoS Comput Biol. 2008;4 :e1000080. doi: 10.1371/journal.pcbi.1000080 18584020 10 Tomaska L , Nosek J . Ten simple rules for writing a cover letter to accompany a job application for an academic position. PLoS Comput Biol. 2018;14 :e1006132. doi: 10.1371/journal.pcbi.1006132 29851981 11 Pautasso M. Ten Simple Rules for Writing a Literature Review. PLoS Comput Biol. 2013;9 :e1003149. doi: 10.1371/journal.pcbi.1003149 23874189 12 Knapp B , Bardenet R , Bernabeu MO , Bordas R , Bruna M , Calderhead B , et al . Ten Simple Rules for a Successful Cross-Disciplinary Collaboration. PLoS Comput Biol. 2015;11 :e1004214. doi: 10.1371/journal.pcbi.1004214 25928184 13 Maestre FT . Ten simple rules towards healthier research labs. PLoS Comput Biol. 2019;15 :e1006914. doi: 10.1371/journal.pcbi.1006914 30973866 14 Michaut M. Ten Simple Rules for Getting Involved in Your Scientific Community. PLoS Comput Biol. 2011;7 :e1002232. doi: 10.1371/journal.pcbi.1002232 22046114 15 Perez-Lopez E , Gavrilova L , Disla J , Goodlad M , Ngo D , Seshappan A , et al . Ten simple rules for creating and sustaining antiracist graduate programs. PLoS Comput Biol. 2022;18 :e1010516. doi: 10.1371/journal.pcbi.1010516 36227841 16 Guevara-Ramirez P , Ruiz-Pozo VA , Cadena-Ullauri S , Salazar-Navas G , Bedon AA , V-Vazquez JF , et al . Ten simple rules for empowering women in STEM. PLoS Comput Biol. 2022;18 :e1010731. doi: 10.1371/journal.pcbi.1010731 36548242 17 Lewitter F. Welcome to PLoS Computational Biology "Education". PLoS Comput Biol. 2006;2 :e7. doi: 10.1371/journal.pcbi.0020007 18 Fox JA , Ouellette BFF . Education in Computational Biology Today and Tomorrow. PLoS Comput Biol. 2013;9 :e1003391. doi: 10.1371/journal.pcbi.1003391 24348234 19 PLOS Computational Biology Other article types. [cited 2023 Oct 29]. Available from: 20 Miller GA . The magical number seven, plus or minus two: some limits on our capacity for processing information. 1956. Psychol Rev. 1994;101 :343-352. doi: 10.1037/0033-295x.101.2.343 8022966 21 Ehrhart F , Evelo CT . Ten simple rules to make your publication look better. PLoS Comput Biol. 2021;17 :e1008938. doi: 10.1371/journal.pcbi.1008938 34014916 22 PLOS Comp. Bio. Quick Tips collection. [cited 2023 Oct 29]. Available from: 23 Weinstein Y , Sumeracki M , Caviglioli O . Understanding How We Learn: A Visual Guide. Routledge, Taylor & Francis Group. 2018. 24 Guide to image descriptions. [cited 2023 Oct 29]. Available from: 25 How to Write Alt Text and Image Descriptions for the visually impaired. [cited 2023 Oct 29]. Available from: 26 Okabe M , Ito K . Color Universal Design (CUD) How to make figures and presentations that are friendly to Colorblind people -. 2008. Available from: |
: Write down the aims of study. 4. Line 55: change as "The Human Microbiome Project (HMP) under National Institute of Health (NIH) 5. Line 63-68: These could be better representative for the discussion section. 6. Introduction: At the end of this section, mention about the study rationale and objectives. 7. Line 88: change "NIH Human Microbiome Project" to NIH's HMP". 8. Line 137-144: Mention here about the p value, what p value was considered as significant? what parameter they used to calculate the p value. 9. Line 188: The authors are suggested to write "spp." Instead of "sp." 10. Line 239 and others: remove space between number and %. Reviewer #3: In the present study, L'Heureux et. al. and colleagues investigated the localisation of nitrate-reducing and highly abundant microbial communities in the oral cavity. The topic explored in this article is interesting, however, there are several points in this manuscript that need to be addressed in more detail and are listed below. 1. the authors did not provide clinical information on the study participants, e.g. healthy/disease status. Several systemic diseases are known to affect the oral microbiome and lead to dysbiosis. Please discuss this point in more details 2. The authors mention several well-established NO3-reducing bacteria, but not all reduce NO3 with the same efficiency. Please provide more information about the bacterial taxa with the highest NO3 reducing power and rank the taxa by their efficiency from top to bottom. 3.Please add a new paragraph explaining the limitations of the study in more detail. 4.In Figure 2, please italicize all bacterial names. 5. Did the authors examine the differences between males and females for each sample? Please create a new MDS figure showing the sex differences within the samples. ********** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose "no", your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: No Reviewer #3: Yes: Mohamed Abdelbary ********** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at [email protected]. Please note that Supporting Information files do not need this step. 10.1371/journal.pone.0295058.r002 Author response to Decision Letter 0 Submission Version1 3 Nov 2023 When submitting your revision, we need you to address these additional requirements. 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. RESPONSE: Thank you for providing the style requirements. We have revised the manuscript accordingly. 2. In your Data Availability statement, you have not specified where the minimal data set underlying the results described in your manuscript can be found. PLOS defines a study's minimal data set as the underlying data used to reach the conclusions drawn in the manuscript and any additional data required to replicate the reported study findings in their entirety. All PLOS journals require that the minimal data set be made fully available. For more information about our data policy, please see RESPONSE: The data are currently publicly available in the Human Microbiome Project repository that is referenced in the manuscript. The data will be available with a DOI provided through the University of Exeter ORE once the article has been accepted for publication. Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: No ________________________________________ 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: No ________________________________________ 5. Review Comments to the Author Reviewer #1: The manuscript describes the localization of nitrate-reducing and microbial communities in the oral sites such as attached gingiva, buccal mucosa, hard palate, saliva, supra- & subgingival plaque, and tongue dorsum. The contents (data) of the manuscript seem suitable for the publication of the PLoS One. The specific points are as follows; RESPONSE: We thank the reviewer for helpful comments that have improved the manuscripts. [Suggestions] >> "Resuls" and Figure 3: (P. 14, L. 236-237) "Haemophilus sp. and Streptococcus sp. were found in high percentage median relative abundance in all oral sites." The referee feels that "Haemophilus sp. in the supragingival plaque" and "Streptococcus sp.in the tongue dorsum" were not so high in the Figure 3. RESPONSE: Lines 236-237 have been revised accordingly ('Haemophilus sp. and Streptococcus sp. were found in all oral sites'). >> "Discussiom" (P. 17, L. 301-305) "Furthermore, it is important to note that variation between samples of the same site may also occur due to differences in sampling techniques, for example, the pressure used to sample bacteria caught within the tongue crypt. Further understanding of how sampling techniques could influence the recording of bacterial abundance may be useful for future studies." For the authors; The referee has an experience of reading literature as follows, 1) Kikutani et al: A novel rapid oral bacteria detection apparatus for effective oral care to prevent pneumonia. Gerodontology 2012; 29(2): e560-e565), it says "The collection pressure was about 20 g, and a 1-cm distance was rubbed back and forth three times with a swab." And additionally, 2) Sato-Suzuki et al: Nitrite-producing oral microbiome in adults and children. Sci Rep 10: 16652 (11 pages), 2020. RESPONSE: Thank you for drawing our attention to these articles that support our statement. We have revised referencing accordingly. Reviewer #2: I have reviewed the manuscript entitled "Localisation of nitrate-reducing and highly abundant microbial communities in the oral cavity" submitted for possible publication in the journal "PLOS ONE". The authors have done great efforts in compiling the results and describing the material and methods used in their study. The topic of manuscript is of interest of the reader and belongs to one of the most emerging issues in healthcare systems. The paper can significantly contribute to the field. As the authors have described very well, I didn't notice any major flaw or suggestions for further improvement in the manuscript. Although some minor changes have to be done before proceeding it further rocedure. My specific comments are: RESPONSE: We thank the reviewer for a constructive and positive review of our submission. 1. I suggest to write full forms for NO etc at it's first appearance in the abstract and then at introduction. RESPONSE: This has been corrected in the abstract and introduction. 2. Line 16-17: The sentence needs to be rephrased. RESPONSE: This sentence now reads "NO3 reducing oral bacteria reduce inorganic dietary nitrite (NO2-) via the NO3 NO2 NO pathway." 3. Abstract: Write down the aims of study. RESPONSE: We have revised the abstract to include the study aim ("The aim of this study was to assess whether other areas in the mouth could contain a physiologically more relevant abundance of bacteria, which may be important for sampling in clinical studies.") 4. Line 55: change as "The Human Microbiome Project (HMP) under National Institute of Health (NIH) RESPONSE: This has been revised as suggested. 5. Line 63-68: These could be better representative for the discussion section. RESPONSE: Thank you for this suggestion. However, we feel that this section forms a key part of the study rationale and ask the reviewer's discretion to maintain it in the introduction. 6. Introduction: At the end of this section, mention about the study rationale and objectives. RESPONSE: We have revised lines 80-85 accordingly. ("The aim of this study was, therefore, to determine the site(s) in the mouth where the highest abundance of NO3 reducing bacteria reside in a larger human population, such as those found in the HMP, in order to inform methodology for future studies investigating the relationships between oral NO3 reducing bacteria and human health.") 7. Line 88: change "NIH Human Microbiome Project" to NIH's HMP". RESPONSE: We do not feel that the use of genitive case is necessary here and ask the reviewer's discretion in maintaining the commonly used terminology (e.g. ). 8. Line 137-144: Mention here about the p value, what p value was considered as significant? what parameter they used to calculate the p value. RESPONSE: We have clarified that P<0.05 was considered statistically significant in line 147. 9. Line 188: The authors are suggested to write "spp." Instead of "sp." RESPONSE: Thank you. We have remover "sp." from this narrative given that only genus level data were presented for analysis. 10. Line 239 and others: remove space between number and %. RESPONSE: This has been revised throughout the manuscript. Reviewer #3: In the present study, L'Heureux et. al. and colleagues investigated the localisation of nitrate-reducing and highly abundant microbial communities in the oral cavity. The topic explored in this article is interesting, however, there are several points in this manuscript that need to be addressed in more detail and are listed below. 1.The authors did not provide clinical information on the study participants, e.g. healthy/disease status. Several systemic diseases are known to affect the oral microbiome and lead to dysbiosis. Please discuss this point in more details RESPONSE: The HMP participants were healthy 40-yr-old adults, who were screened using exclusion criteria based on health history, including the presence of systemic diseases (e.g., hypertension, cancer, or immunodeficiency or autoimmune disorders), use of potential immunomodulators, and recent use of antibiotics or probiotics. We have added this information in the methods section (line 96-100). 2. The authors mention several well-established NO3-reducing bacteria, but not all reduce NO3 with the same efficiency. Please provide more information about the bacterial taxa with the highest NO3 reducing power and rank the taxa by their efficiency from top to bottom. RESPONSE: We thank the reviewer for raising this consideration and we have added reference to previous research (Doel et al. 2005, Hyde et al. 2014) that has assessed efficiency of given species for nitrate reduction in vitro (lines 74-81). 3.Please add a new paragraph explaining the limitations of the study in more detail. RESPONSE: We have revised the paragraph highlighting study limitations as suggested (line 305-320). 4.In Figure 2, please italicize all bacterial names. RESPONSE: This genera names have been italicized. 5. Did the authors examine the differences between males and females for each sample? Please create a new MDS figure showing the sex differences within the samples. RESPONSE: We checked for sex differences within each oral site before proceeding with further analysis. There were no sex differences, therefore, the male and female samples were grouped together. This information has been added in lines 130-134. ________________________________________ 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose "no", your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: No Reviewer #3: Yes: Mohamed Abdelbary ________________________________________ Attachment Submitted filename: Rebuttal Letter.docx Click here for additional data file. 10.1371/journal.pone.0295058.r003 Decision Letter 1 Heboyan Artak Academic Editor (c) 2023 Artak Heboyan 2023 Artak Heboyan This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Submission Version1 15 Nov 2023 Localisation of nitrate-reducing and highly abundant microbial communities in the oral cavity PONE-D-23-17952R1 Dear Dr. L'Heureux, We're pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you'll receive an e-mail detailing the required amendments. When these have been addressed, you'll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at [email protected]. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they'll be preparing press materials, please inform our press team as soon as possible no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact [email protected]. Kind regards, Artak Heboyan, Ph.D. Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the "Comments to the Author" section, enter your conflict of interest statement in the "Confidential to Editor" section, and submit your "Accept" recommendation. Reviewer #1: All comments have been addressed Reviewer #2: All comments have been addressed ********** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Yes ********** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ********** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data e.g. participant privacy or use of data from a third party those must be specified. Reviewer #1: Yes Reviewer #2: Yes ********** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ********** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: (No Response) Reviewer #2: (No Response) ********** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose "no", your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: Yes: Naveed Ahmed ********** 10.1371/journal.pone.0295058.r004 Acceptance letter Heboyan Artak Academic Editor (c) 2023 Artak Heboyan 2023 Artak Heboyan This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 13 Dec 2023 PONE-D-23-17952R1 PLOS ONE Dear Dr. L'Heureux, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset If revisions are needed, the production department will contact you directly to resolve them. If no revisions are needed, you will receive an email when the publication date has been set. At this time, we do not offer pre-publication proofs to authors during production of the accepted work. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few weeks to review your paper and let you know the next and final steps. Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact [email protected]. If we can help with anything else, please email us at [email protected]. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Artak Heboyan Academic Editor PLOS ONE |
: In conclusion part : Our investigation furnished a more comprehensive analytical framework encompassing metabolites and oxykinase. what do you mean by oxykinase? 3-Introduction: Both non-volatile targeted metabolites and volatile non-targeted metabolites have been employed on an MS platform to differentiate the RSA and healthy groups (6). The LC platform's extensive coverage and board dynamic range of metabolites are its primary advantages Please explain what these terms' abbreviation means. 4-How did you calculate the sample size for this work? criteria must the patients meet in order to be selected? In terms of age, race, and chronic illnesses like diabetes or other immunological dysfunctions? Metabolomics may be impacted by the factors listed above. pretreatment and statistical analysis To confirm the statistical significance of the differential metabolites, a student's t-test was conducted between groups, with a p-value less than 0.05 based on OPLS-DA. Please explain what these terms' abbreviation means. identification AI database ?? Please explain what these terms' abbreviation means. participants: You mentioned that: ''The limited sample size precluded the statistical analysis of adverse factors to determine their association with disease'' Please elaborate. because a greater sample size provides more useful information and lowers odds ratios. Also, RSA is a prevalent situation that aids in gathering big sample sizes, hence further explanation of the causes of small sample sizes is required. of significantly altered metabolites and pathways ''Notably, approximately 200 of these metabolites were associated with drug treatment, likely stemming from prior interventions for pregnant women with RSA. As our investigation did not account for the influence of pharmaceuticals, these metabolites were excluded from our analysis'' Clarify that please - you mentioned that RSA, an autoimmune disease with multifaceted etiology I disagree that RSA is a disease because it is a disruption of a natural physiological function, possibly caused by an autoimmune condition, during pregnancy. -The sample size of the cohort (17 patients and 11 healthy controls) was conducted, dynamic changes were captured, resulting in the extraction of dependable e differential information I think this is a mistake -Additionally, research has demonstrated that lipid mediators are not only a consequence of oxidative stress but also an inducement for modulating processes (17) Old information and reference - The biosynthesis of leukotrienes (LTs), which are derived from AA, involves a two-step process mediated by 5-lipoxygenase. LTs serve important roles in immune regulation, self-defense, and the maintenance of homeostasis in living systems. -Old data with no reference -of change in response to the perturbation of RSA. Notably, glutamine assumes a crucial role in energy metabolism by replenishing TCA cycle intermediates through a mitochondrial metabolic pathway known as "glutaminolysis". In the presence of glutaminase (GIs), glutamine undergoes conversion to glutamate, which subsequently yields aketoglutarate (aKG) that enters the TCA cycle and undergoes catabolism to lactate. The onset of RSA elicits body's oxidative stress response, which promptly triggers biochemical reaction and amplifies the energy demand where is the references for all of that? -which stimulates fatty acid oxidation. M1 macrophages, characterized by classical activation, exhibit reduced susceptibility to glutamate metabolism. Upon activation, these macrophages promptly initiate a proinflammatory response to the occurrence of reproductive system associated events by detecting microbial components, including signaling lipoprotein, and damaged-associated molecular patterns that are released from shed abortive material resulting from sudden symptoms of miscarriage. References?? you elaborate on the clinical implications of your findings and how it can assist in treating people who have RSA. 12-What is the limitations of your work in frank words 13-Refrences: -No 2 please check -Many old references e.g:7,8,9,10 references should be updated I believe that those comments should be reviewed and corrected before any publication decisions are made. ********** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose "no", your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: Yes: Entsar Rashad Abd-Allah Reviewer #2: Yes: Fatma EL Zharaa Abdelhakam ********** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at [email protected]. Please note that Supporting Information files do not need this step. Attachment Submitted filename: Review.docx Click here for additional data file. 10.1371/journal.pone.0296122.r002 Author response to Decision Letter 0 Submission Version1 25 Oct 2023 Response to Reviewers Journal Requirements: Q: 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at and A: We have revised the file naming and table naming based on the PLOS ONE templates. Q:2. We note that the grant information you provided in the 'Funding Information' and 'Financial Disclosure' sections do not match. When you resubmit, please ensure that you provide the correct grant numbers for the awards you received for your study in the 'Funding Information' section. A: I have corrected the Funding Information. Reviewer #1: Q: It is important to determine gene expression and discuss the RSA at the molecular level. I suggest joining these findings with the abnormal expression of some specific immunoregulatory genes involved in T-cell activation and differentiation. According to psychophysiological interaction (PPI) analysis, TLR2, CXCL8, IFNG, IL2RA, and ITGAX were among the top five immunoregulatory hub genes of differentially expressed genes in unexplained recurrent spontaneous abortion (URSA). Among the identified differentially expressed genes (DEGs) in URSA, IFNG may play a key role in regulating maternal immune response. AS the key genes and functional pathways identified will provide new insights into the molecular mechanisms involved in RSA pathogenesis and provide potential diagnostic and therapeutic targets. A: Thank you for your suggestions. As suggested by reviewer, we have added the suggested content to the discussion section on page 20. Reviewer #2: Q:1. Title:What does the term "dysimmunity" mean? Is it actibation or suppression? It is redundant, in my opinion, and needs to be clarified. A: Thank you for your suggestions. The title of the manuscript has been revised to "Untargeted metabolomics analysis reveals the metabolic disturbances and exacerbation of oxidative stress in recurrent spontaneous abortion". Q:2. Abstract: In conclusion part: our investigation furnished a more comprehensive analytical framework encompassing metabolites and "oxykinase". What do you mean by oxykinase? A: The term of "oxykinase" has been revised to "enzymes associated with oxidative stress". Q:3. Introduction: Both non-volatile targeted metabolites and volatile non-targeted metabolites have been employed on an MS platform to differentiate the RSA and healthy groups. The LC platform's extensive coverage and board dynamic range of metabolites are its primary advantages. Please explain what these terms' abbreviation means. A: The "LC" and "MS" abbreviation have been revised to "liquid chromatogram" and "mass spectrometer" respectively. Q:4. How did you calculate the sample size for this work? A: For metabolomics research, there are the following requirements: the number of experimental samples is larger than that of control samples, and at least 30 human samples are required. However, the number of patients with recurrent fluency is still relatively small in our hospital, which is not specialized in obstetrics. We have done our best to preserve the collection of samples. Q:5. What criteria must the patients meet in order to be selected? In terms of age, race, and chronic illnesses like diabetes or other immunological dysfunctions? Metabolomics may be impacted by the factors listed above. A: More detailed information about the exclusion criteria was added in the manuscript on page 5. Statistical analysis has been performed for the age of the enrolled population. Q:6. Data pretreatment and statistical analysis To confirm the statistical significance of the differential metabolites, a student's t-test was conducted between groups, with a p-value less than 0.05 based on OPLS-DA. Please explain what these terms' abbreviation means. A: The abbreviation "OPLS-DA" in this sentence has been deleted. Q:7. Metabolites identification AI database ?? Please explain what these terms' abbreviation means. A:The illustration about "AI database" has been added in the manuscript. Q:8. Study participants You mentioned that: "The limited sample size precluded the statistical analysis of adverse factors to determine their association with disease'' Please elaborate. because a greater sample size provides more useful information and lowers odds ratios. Also, RSA is a prevalent situation that aids in gathering big sample sizes, hence further explanation of the causes of small sample sizes is required. A: The information about the limited sample size was added in the manuscript. Q:9. Identification of significantly altered metabolites and pathways "Notably, approximately 200 of these metabolites were associated with drug treatment, likely stemming from prior interventions for pregnant women with RSA. As our investigation did not account for the influence of pharmaceuticals, these metabolites were excluded from our analysis'' Clarify that please A: The detailed information has been clarified in the manuscript on page 12. Q:10. Discussion You mentioned that RSA, an autoimmune disease with multifaceted etiology I disagree that RSA is a disease because it is a disruption of a natural physiological function, possibly caused by an autoimmune condition, during pregnancy. A: Thank you for your suggestions. The term disease has been revised to complication Q:11 The sample size of the cohort (17 patients and 11 healthy controls) was conducted, dynamic changes were captured, resulting in the extraction of dependable e differential information I think this is a mistake A: We agree with the comment and re-wrote the sentences in the revised manuscript as the following " 17 RSA women patients and 11 healthy pregnant women". Q:12 Additionally, research has demonstrated that lipid mediators are not only a consequence of oxidative stress but also an inducement for modulating processes (17) Old information and reference A: The old reference has been replaced with the latest reference in the article. Q: 13 The biosynthesis of leukotrienes (LTs), which are derived from AA, involves a two-step process mediated by 5-lipoxygenase. LTs serve important roles in immune regulation, self-defense, and the maintenance of homeostasis in living systems. -Old data with no reference A: The old reference has been replaced with the latest reference in the article. Q:14 of change in response to the perturbation of RSA. Notably, glutamine assumes a crucial role in energy metabolism by replenishing TCA cycle intermediates through a mitochondrial metabolic pathway known as "glutaminolysis". In the presence of glutaminase (GIs), glutamine undergoes conversion to glutamate, which subsequently yields aketoglutarate (aKG) that enters the TCA cycle and undergoes catabolism to lactate. The onset of RSA elicits body's oxidative stress response, which promptly triggers biochemical reaction and amplifies the energy demand where is the references for all of that? A: The relevant reference has been inserted into the manuscript. Q:15 which stimulates fatty acid oxidation. M1 macrophages, characterized by classical activation, exhibit reduced susceptibility to glutamate metabolism. Upon activation, these macrophages promptly initiate a proinflammatory response to the occurrence of reproductive system associated events by detecting microbial components, including signaling lipoprotein, and damaged-associated molecular patterns that are released from shed abortive material resulting from sudden symptoms of miscarriage. References?? A: The supported reference has been added into the manuscript (reference 32, reference 33). Q:16 Could you elaborate on the clinical implications of your findings and how it can assist in treating people who have RSA. A: We are grateful for the suggestion. To be more clearly and in accordance with the reviewer concerns, we have added a more detailed interpretation regarding RSA treating on page 21. Q:17 What is the limitations of your work in frank words A: Thank you for your suggestions. As suggested by reviewer, we have added the suggested content to the conclusion section on page 21. Q:18 Refrences: -No 2 please check -Many old references e.g:7,8,9,10 references should be updated A: The old reference 7, 8, 9, 10 are old reference to the traditional authority detection method, so we did not update the reference, but we updated other older documents in the full paper. Attachment Submitted filename: Response to Reviewers.docx Click here for additional data file. 10.1371/journal.pone.0296122.r003 Decision Letter 1 Farouk Mohammed Hamdy Academic Editor (c) 2023 Mohammed Hamdy Farouk 2023 Mohammed Hamdy Farouk This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Submission Version1 7 Dec 2023 Untargeted metabolomics analysis reveals the metabolic disturbances and exacerbation of oxidative stress in recurrent spontaneous abortion PONE-D-23-19156R1 Dear Dr. Tuo, We're pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you'll receive an e-mail detailing the required amendments. When these have been addressed, you'll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at [email protected]. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they'll be preparing press materials, please inform our press team as soon as possible no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact [email protected]. Kind regards, Mohammed Hamdy Farouk, PhD Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the "Comments to the Author" section, enter your conflict of interest statement in the "Confidential to Editor" section, and submit your "Accept" recommendation. Reviewer #1: All comments have been addressed Reviewer #2: All comments have been addressed ********** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Yes ********** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ********** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data e.g. participant privacy or use of data from a third party those must be specified. Reviewer #1: Yes Reviewer #2: Yes ********** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ********** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: the article can be accepted , but i hope to complete this study involving immunoregulatory genetic parameters. Reviewer #2: The authors develop a unique theoretical framework, and I believe that they should highlight their originality much more. ********** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose "no", your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: Yes: Entsar Rashad Abd-Allah Reviewer #2: Yes: Fatma EL Zahraa Abd EL Hakam ********** Attachment Submitted filename: Review 2.docx Click here for additional data file. 10.1371/journal.pone.0296122.r004 Acceptance letter Farouk Mohammed Hamdy Academic Editor (c) 2023 Mohammed Hamdy Farouk 2023 Mohammed Hamdy Farouk This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 13 Dec 2023 PONE-D-23-19156R1 PLOS ONE Dear Dr. Tuo, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset If revisions are needed, the production department will contact you directly to resolve them. If no revisions are needed, you will receive an email when the publication date has been set. At this time, we do not offer pre-publication proofs to authors during production of the accepted work. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few weeks to review your paper and let you know the next and final steps. Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact [email protected]. If we can help with anything else, please email us at [email protected]. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Prof. Mohammed Hamdy Farouk Academic Editor PLOS ONE |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.49190 Internal Medicine Otolaryngology Pulmonology Tracheomalacia in Adults: An Uncommon Cause of Dyspnea Muacevic Alexander Adler John R Alsalihi Yusur 1 Yousef Natalie M 1 Grewal Sundeep 2 Teitelbaum Benjamin 3 1 Clinical Education Department, California Health Sciences University College of Osteopathic Medicine, Clovis, USA 2 Clinical Education Department, Internal Medicine, California Health Sciences University College of Osteopathic Medicine, Clovis, USA 3 Surgery Department, Clovis Community, Clovis, USA Natalie M. Yousef [email protected] 21 11 2023 11 2023 15 11 e4919020 11 2023 Copyright (c) 2023, Alsalihi et al. 2023 Alsalihi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License CC-BY 4.0., which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from Tracheomalacia (TM), the most common congenital tracheal defect, is due to compromised cartilage integrity, manifesting in the narrowing of expiratory airways and various respiratory symptoms. While TM is common in infants and toddlers, it is rarely found in adults, often due to acquired injuries or chronic lung diseases. We present a unique case of a 67-year-old man with persistent dyspnea and hoarseness for two years. Despite a history of smoking, he had no signs of pulmonary disease and had a consistently high oxygen saturation during episodes of dyspnea. His dyspnea was of unknown etiology until a diagnostic bronchoscopy revealed tracheal stenosis and flaccidity of cartilaginous structures, with pronounced collapse during expiration. This atypical presentation highlights the complexity of TM in adults. It underscores the importance of considering it as a differential diagnosis, particularly in male smokers with gradual, persistent dyspnea and a minimal history of pulmonary disease. cartilaginous disorders general internal medicine dyspnea of unknown origin tracheomalacia otolaryngology ear nose throat (ent) pmcIntroduction The normal intrathoracic trachea is compliant, dilating with inspiration and narrowing with expiration due to the difference between intrathoracic and intraluminal pressures [1-3]. However, in tracheomalacia (TM), the tracheal cartilage is compromised, leading to loss of structural integrity and an inability to prevent airway collapse due to increased intrathoracic pressure during exhalation. Most cases of TM are expiratory, indicating excessive tracheal narrowing when intrathoracic pressure is substantially greater than intraluminal pressure such as during forced expiration, cough, or the Valsalva maneuver . Furthermore, various respiratory symptoms, such as chronic cough, wheezing, shortness of breath (dyspnea), noisy breathing (stridor), and recurrent respiratory infections, are common. Although TM occurs in 1 in 2,100 infants and toddlers , such a presentation is increasingly rare in the adult population that has fully developed tracheal cartilages, so much so that specific incidence rates in adults (without underlying conditions or predisposing factors) have not been widely reported in the medical literature. TM in the adult population is typically due to an acquired injury from previous surgery involving the airway, intubation, or chronic lung disease. Additionally, chronic compression due to goiter or tumors and masses, which occur most commonly in the middle-aged and elderly, may predispose to the development of TM in adults. The most affected adult demographic with TM is men >40 years of age . This article was previously presented as a poster at the American College of Osteopathic Internists conference in Tampa, Florida, in October 2023. Case presentation We present a case of a 67-year-old Caucasian man who presented to the outpatient ENT clinic with a primary complaint of dyspnea for two years. The patient also complained of hoarseness but felt no changes in the strength of his voice. He was afebrile and stated that he has been healthy for the past two years with no significant illness to report. Furthermore, the onset of dyspnea has been gradual, with no pulmonary or constitutional symptoms. He noticed that shortness of breath occurs randomly without direct association with exercise or exertion. His medical history was negative for pulmonary disease and seasonal allergies. After ruling out cardiac and pulmonary causes, the patient was referred to an otolaryngologist. On physical examination, the patient was found to have an expiratory stridor. His vitals were within the normal range, and his oxygen saturation was 98%, with no use of accessory muscles or significant respiratory effort. Social history was positive for tobacco use of one pack/week for 30 years, and no significant use of alcohol or drugs was reported. Under suspicion of growth along the oropharyngeal pathway, in-office laryngoscopy was performed. The scope did not show masses or abnormal structural findings. Speech therapy and voice rest were recommended, and the patient was referred for a thorax CT scan that showed transverse tracheal narrowing at level T3 and tracheal stenosis. Under suspicion of compressive structure, the patient underwent a diagnostic endoscopy and bronchoscopy. No masses or growths were observed but rather, an overall flaccidity of cartilaginous structures within the trachea. The flaccidity was more pronounced distal to the carina. The cartilaginous structure was observed to be open during the inspiratory phase but had a collapse of the lateral wall during the expiratory phase . Figure 1 Patent tracheal expansion during the inspiratory phase Figure 2 Lateral wall trapezoidal collapse during the expiratory phase Discussion Our case presents atypical symptoms with no identifiable direct cause. In the adult population, TM is most often due to an acquired disease process. Tracheostomy or endotracheal tube intubation is the most common cause of secondary TM . Traumatic tracheal injury that causes cartilage loss, including external trauma and surgery, can also cause TM. Our patient had no pulmonary disease or direct trauma to the chest or surrounding structures. Some research suggests that chronic inflammation and irritants, such as cigarette smoke, contribute to the development of TM . Weakening of the tracheal wall may be related to recurrent injury from irritants. This association is most closely related to the development of COPD due to smoking and, subsequently, tracheal irritation and collapse. Also, it may be due to irritation that causes excessive coughing or increased gag reflex, increasing intrathoracic pressure, and increasing collapsibility. Although our patient is a smoker, there has been no direct explanation of how smoking causes TM, and he did not have signs of COPD or excessive lung damage. While smoking is a contributing factor, it is rare to see isolated TM due to tobacco use . Studies show that smoking is linked with mucosal and cartilaginous irritation and inflammation . Increased inflammation causes an aberrant activation of the immune system and recruitment of inflammatory biomarkers. Some of these biomarkers are tasked with cleaning up the debris, including healthy and unhealthy cells. The process can lead to synechiae and collagenous band formation. These bands can lead to structural reformation of the known cartilaginous-heavy cartilaginous structure. Interestingly, our patient has not been a life-long smoker, and we suspect that his smoking is a contributing factor to his tracheomalacia diagnosis but not the only factor. We hypothesize that while smoking is the source of the irritation, this patient may be more predisposed to aberrant immune response due to his old age and possibly, a genetic component. While he denied any pathological concerns about his musculoskeletal system and joint health, we recognize that such an unusual response may have a multi-factorial origin. Most interestingly, while our patient felt short of breath, his oxygen saturation remained well above 92% for the duration of the history intake. Furthermore, even when conversing, his oxygenation levels did not drop. It is important to note that the patient's trachea does not collapse on breathing in, but rather on breathing out, indicating that appropriate tidal volume is reaching the lungs, but the expiratory phase is difficult. Akin to breathing out of a straw, we hypothesize that the presumed reduction in expiratory volume due to tracheal collapse leads to increased carbon dioxide within the lungs, increasing respiratory drive in the brain. The increased respiratory drive within the brain and the increased carbon dioxide concentration within the lungs give a sensation of shortness of breath. Another unique feature of his dyspnea was the constant nature of his symptoms. Typically, pulmonary or cardiac dyspnea worsens with exertion and is relieved by rest, unless in advanced disease processes. This patient felt short of breath even at rest and felt his dyspnea was constant. The stable and gradual nature of this presentation led him to defer going to the doctor for two years. Typically, the presentation of TM in adults requires intubation until a source is identified and corrected or until a tracheoplasty is performed. Management of this case included smoking cessation and a trial of respiratory exercises. We also recommended humidified air due to some studies that show that it leads to a reduction in the inflammatory response. Currently, the patient is under observation and continued management if his symptoms worsen or improve . Conclusions In conclusion, our case presents an unusual constellation of symptoms with no apparent cause. Tracheomalacia (TM) in adults is typically acquired, often resulting from tracheostomy or intubation. However, our patient did not have a history of such incidents. Chronic inflammation and irritants, such as cigarette smoke, may contribute to TM, but the patient showed no signs of related conditions. In particular, his oxygen saturation remained above 92% during dyspneic episodes, and his symptoms were constant, unlike typical pulmonary or cardiac-related dyspnea. Clinicians should note the nature of dyspnea, constant versus exerted, and keep TM in their differential diagnosis, especially in men with a positive history of smoking, insignificant pulmonary disease, and gradual, constant symptomatic dyspnea. Careful evaluation and follow-up are necessary to determine the best course of treatment for this rare presentation. Author Contributions Human Ethics Concept and design: Natalie M. Yousef, Yusur Alsalihi, Sundeep Grewal Acquisition, analysis, or interpretation of data: Natalie M. Yousef, Yusur Alsalihi, Benjamin Teitelbaum Drafting of the manuscript: Natalie M. Yousef, Yusur Alsalihi Critical review of the manuscript for important intellectual content: Natalie M. Yousef, Yusur Alsalihi, Benjamin Teitelbaum, Sundeep Grewal Supervision: Yusur Alsalihi, Benjamin Teitelbaum, Sundeep Grewal Consent was obtained or waived by all participants in this study The authors have declared that no competing interests exist. References 1 Tracheomalacia and tracheobronchomalacia in pediatrics: an overview of evaluation, medical management, and surgical treatment Front Pediatr Kamran A Jennings RW 512 7 2019 31921725 2 Tracheal dynamics in infants with respiratory distress, stridor, and collapsing trachea Radiology Wittenborg MH Gyepes MT Crocker D 653 662 88 1967 6020927 3 A method for the demonstration of calibre changes in the bronchi in normal respiration J Clin Invest Heinbecker P 459 469 4 1927 16693767 4 Acquired tracheomalacia: etiology and differential diagnosis Chest Feist JH Johnson TH Wilson RJ 340 345 68 1975 169105 5 Acquired tracheobronchomalacia Ann Clin Res Jokinen K Palva T Sutinen S Nuutinen J 52 57 9 1977 883758 6 Tracheomalacia Yang D Cascella M Treasure Island (FL) StatPearls [Internet] 2023 7 Tracheomalacia and bronchomalacia in children: incidence and patient characteristics Chest Boogaard R Huijsmans SH Pijnenburg MW Tiddens HA de Jongste JC Merkus PJ 3391 3397 128 2005 16304290 8 Cigarette smoking and inflammation revisited Respir Physiol Neurobiol Rom O Avezov K Aizenbud D Reznick AZ 5 10 187 2013 23376061 9 Airway humidification reduces the inflammatory response during mechanical ventilation Respir Care Jiang M Song JJ Guo XL Tang YL Li HB 1720 1728 60 2015 26329357 |
Medicine (Baltimore) Medicine (Baltimore) MD Medicine 0025-7974 1536-5964 Lippincott Williams & Wilkins Hagerstown, MD 00020 10.1097/MD.0000000000036735 3 4800 Research Article Clinical Case Report Unveiling the hidden clues: Dohle body-like inclusions as morphological markers for MYH9-related disorders: A case report Zhang Yan MM [email protected] a Zuo Zhongbao MM [email protected] a Yu Wenyan MM [email protected] a Xu Aifang MM a* a Department of Clinical Laboratory, Xixi Hospital of Hangzhou, Hangzhou, Zhejiang, China. * Correspondence: Aifang Xu, Department of Clinical Laboratory, Xixi Hospital of Hangzhou, Hengbu Street No. 2, Hangzhou, Zhejiang 310023, China (e-mail: [email protected]). 22 12 2023 22 12 2023 102 51 e3673528 9 2023 30 11 2023 Copyright (c) 2023 the Author(s). Published by Wolters Kluwer Health, Inc. 2023 This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Rationale: This study aimed to address the diagnostic challenges associated with MYH9-related disorders (MYH9-RDs) and highlight the importance of recognizing Dohle body-like inclusions as crucial diagnostic markers for this condition. Patient concerns: Patients with MYH9-RDs often present with mild and diverse clinical characteristics, leading to misdiagnosis, delayed diagnosis, and inappropriate treatments, such as hormonal therapy and splenectomy. This section highlights the significance of understanding atypical clinical presentations and their impact on patients' well-being. Diagnoses: This section emphasizes the misdiagnosis of MYH9-RDs as immune thrombocytopenia due to overlapping clinical features. This highlights the need for a comprehensive approach, including detailed personal and family history, careful review of peripheral blood smears, and identification of Dohle body-like inclusions to differentiate MYH9-RDs from other conditions. Intervention: This study advocates for a shift in the diagnostic approach, urging physicians to pay closer attention to the morphological features observed in peripheral blood smears, particularly the presence of Dohle body-like inclusions and large platelets. This emphasizes the importance of avoiding unnecessary diagnostic studies through effective utilization of this simple and reliable method. Outcomes: By adopting a comprehensive approach that combines gene sequencing with morphological analysis, an accurate diagnosis of MYH9-RDs can be achieved. Early identification of MYH9-RDs allows for appropriate management strategies, genetic counseling, and prevention of complications associated with the condition. Lessons: This section highlights the lessons learned from this study, emphasizing the need for increased awareness among healthcare professionals about MYH9-RDs and the importance of incorporating peripheral blood smear evaluations into the diagnostic process. This emphasizes the significance of accurate diagnosis to prevent unnecessary treatments and ensure appropriate patient care. Dohle body-like inclusions giant platelet MYH9-RDs thrombocytopenia OPEN-ACCESSTRUE pmc1. Introduction MYH9-related disorders (MYH9-RDs) encompass a spectrum of rare genetic conditions characterized by diverse clinical presentations and isolated thrombocytopenia. These disorders are caused by mutations in MYH9, which encodes the non-muscle myosin heavy chain IIA protein. The clinical manifestations of MYH9-RDs vary widely, ranging from mild cases of isolated thrombocytopenia to more severe forms associated with progressive nephropathy, hearing loss, and cataracts. The diagnostic journey for patients with MYH9-RDs can be challenging due to overlapping features with other thrombocytopenic disorders, particularly immune thrombocytopenia (ITP). Misdiagnosis of MYH9-RDs as ITP is common, leading to inappropriate treatments and delayed identification of the underlying condition. Moreover, the lack of awareness and limited understanding of MYH9-RDs among healthcare professionals further contributes to the diagnostic complexities. In recent years, the identification of morphological clues in peripheral blood smears has emerged as a valuable diagnostic strategy for identifying MYH9-RDs. Notably, the presence of Dohle body-like inclusions and large platelets has been observed in patients with MYH9-RDs, providing important morphological markers for differentiating these disorders from other thrombocytopenic conditions. This article aims to shed light on the diagnostic challenges associated with MYH9-RDs and to emphasize the significance of recognizing Dohle body-like inclusions as crucial diagnostic markers for this condition. We explored the clinical complexities, consequences of misdiagnosis, and implications for patient care. Additionally, we discuss the importance of adopting a comprehensive approach that combines gene sequencing with morphological analysis, highlighting the role of peripheral blood smear evaluation in achieving accurate diagnoses and facilitating appropriate management strategies. By enhancing the understanding of MYH9-RDs and promoting awareness among healthcare professionals, we aimed to improve diagnostic accuracy, minimize misdiagnosis, and enhance patient outcomes. 2. Case presentation Based on the information provided, a 26-year-old man presented with frequent ecchymosis (bruising) and was found to have thrombocytopenia (platelet count = 22 x 109/L). Further laboratory investigations confirmed macrothrombocytopenia (presence of abnormally large platelets) and Dohle body-like inclusions in the blood smear (Fig. 1). These findings strongly suggest a diagnosis of MYH9-RDs. Figure 1. Peripheral smear containing a gaint platelet (A) and Dohle-like body (B). The patient's clinic1al history reveals a long-standing history of frequent nasal bleeding and bruising since childhood. Previous visits to multiple hospitals failed to identify the exact cause of the thrombocytopenia. Additionally, the patient has been experiencing hematuria (blood in urine) since the age of 20 years. Laboratory tests revealed unremarkable results for coagulation function, clotting factors, blood urea nitrogen, creatinine, alanine aminotransferase, and aspartate aminotransferase levels. The maximum amplitude value, indicative of platelet aggregation, was within the normal range. A platelet antibody IgG test yielded a negative outcome. Serum measurements indicated total bilirubin and unconjugated bilirubin concentrations of 26.33 mmol/L (reference range: 0-23 mmol/L) and 15.7 mmol/L (reference range: 0-13.7 mmol/L), respectively. The detailed family history sheds more light on the hereditary nature of thrombocytopenia in this family and further supports the diagnosis of MYH9-RDs. The following are some key points regarding family history and the implications for the diagnosis: Multigenerational inheritance (Fig. 2): The presence of thrombocytopenia or bleeding episodes in the patient's grandmother, father, 4 aunts, younger brother, and 1 cousin strongly suggested a hereditary pattern of thrombocytopenia within the family. This pattern of inheritance is consistent with that of MYH9-RDs, which are known to be inherited in an autosomal dominant manner. Figure 2. Family pedigree. The arrow indicates the proband. #, *: without history of thrombocytopenia. , *: with history of thrombocytopenia. Clinical features in family members: The father had thrombocytopenia and exhibited a higher mean platelet volume and platelet distribution width than normal, indicating larger platelets. This is in line with the macrothrombocytopenia observed in MYH9-RDs. The father also presented with isolated proteinuria, which can be associated with MYH9-RDs, suggesting potential kidney involvement. Clinical features in the younger brother: The younger brother experienced severe nosebleeds and persistent bleeding, requiring platelet transfusions. The fluctuating platelet count (brief increase followed by a decrease) was consistent with the characteristic variability observed in MYH9-RDs. This highlights the variable expressivity of disorders within the same family. Cousin's bleeding episode: One of the cousins experienced bleeding related to childbirth, although the specific treatment measures are unknown. This highlights the potential bleeding tendency of individuals with MYH9-RDs, which can pose challenges during pregnancy and childbirth. Genetic testing results (Fig. 3): The patient's genetic testing revealed a mutation in exon 41 of the MYH9 gene (c.5797C>T, p.R1933*), providing a definitive confirmation of the diagnosis of MYH9-RDs in the patient. This result further supports the hereditary nature of the disorder in the family. Figure 3. Patient's gene sequencing results (the red arrow indicates genetic variation sites). Deafness and MYH9-RDs: The patient's grandmother had mild deafness, and there is a suspicion that it may be related to MYH9-RDs. However, distinguishing whether deafness in older individuals with MYH9-RDs is directly caused by gene mutation or is a separate age-related condition can be challenging. Although deafness can occur in MYH9-RDs, further evaluation and genetic studies are needed to establish a clear association. 3. Discussion MYH9-RDs encompass an autosomal dominant inherited condition characterized by thrombocytopenia, giant platelets, and Dohle body-like inclusions. These Dohle body-like inclusions can be observed in the cytoplasm of neutrophils, monocytes, eosinophils, and basophils in peripheral blood smears. However, clinical misdiagnosis and oversight are common because of the tendency to overlook these inclusions, especially when they are faintly stained, and when laboratory personnel lack attentiveness and thoroughness, leading to missed diagnoses. Additionally, MYH9-RDs are rare disorders in real-life scenarios, which has resulted in some laboratory staff confusing the Dohle body-like inclusions with true Dohle bodies. Morphologically, true Dohle bodies are small, often round or oval structures with indistinct cloud-like borders. In contrast, the Dohle body-like inclusions in MYH9-RDs were distributed along the cellular periphery, exhibiting clear features and well-defined, tangible boundaries. It is important to note that while true Dohle bodies manifest during infections and are typically accompanied by granulocyte toxic granules, vacuolar degeneration, nuclear condensation, and other signs of granulocyte poisoning, they generally do not coincide with the presence of giant platelets. Furthermore, true Dohle bodies tend to disappear as the infection is brought under control, whereas Dohle body-like inclusions persist throughout an affected individual's lifetime. Therefore, a meticulous examination of blood smears is valuable and straightforward for evaluating suspected cases of thrombocytopenia. Genetic analysis of MYH9 confirmed the presence of a heterozygous mutation (c.5797C>T, p.R1933*) in exon 41 of the patient. These clinical and laboratory findings were consistent with a diagnosis of MYH9-RDs. When clinical assessments and laboratory tests indicate hereditary thrombocytopenia in patients and their families, genetic testing becomes an indispensable tool for confirming diagnosis. Bleeding symptoms in patients with MYH9-RDs exhibit heterogeneity. While some patients do not experience significant bleeding tendencies, others may present with mild to moderate symptoms such as easy bruising, recurrent epistaxis, gingival bleeding, and increased menstrual bleeding. The bleeding tendency of MYH9-RDs is primarily associated with the degree of thrombocytopenia rather than platelet dysfunction. Notably, our patient's platelet aggregation was within the normal range, consistent with the findings reported by Jiang et al. In addition to hematological changes, MYH9-RDs commonly present with various non-hematological disorders, and the severity and manifestation of these conditions can vary over time. Approximately 50% of patients experience hearing impairment, nephropathy or proteinuria in 25% of cases, and bilateral cataracts are observed in approximately 20% of cases. It is important to recognize that different individuals within the same family may exhibit varying phenotypes at different ages, as observed in our patient's family. Furthermore, the phenotype of a patient with an MYH9 mutation can evolve over time, as supported by previous research. Progressive manifestations that can develop over time include neurological deafness, senile cataracts, and nephritis, which may ultimately progress to end-stage renal disease. In the case of our patient and his father, persistent hematuria and proteinuria were observed, necessitating regular monitoring of the kidney function. The patient in this family study presented with subtle and diverse clinical characteristics that were easily overlooked, particularly when historical platelet counts and a complete family history were not readily available. The patient's isolated thrombocytopenia necessitated a prolonged search for the underlying cause. ITP, a common condition characterized by isolated thrombocytopenia, can often lead to the misdiagnosis of relatively rare MYH9-RDs. The negative result for platelet antibody IgG suggests the absence of specific antibodies against platelets, which is important in ruling out certain conditions, such as immune thrombocytopenia. In fact, many patients with MYH9-RDs have been misdiagnosed with ITP, resulting in inappropriate treatments such as hormonal therapy and splenectomy. A study based on the Italian registry reported that 60% of cases were initially diagnosed as ITP, with 30% of patients receiving inappropriate treatments. Therefore, physicians should pay close attention to detailed personal and family histories and conduct a thorough review of peripheral blood smears, especially when Dohle body-like inclusions are observed alongside large platelets, as this strongly indicates the presence of MYH9-RDs. Due to the rarity of this condition and lack of awareness, MYH9-RDs are often misdiagnosed, leading to unnecessary diagnostic procedures. Evaluation of a peripheral blood smear is a simple and effective method for accurate diagnosis. This case highlights the importance of a comprehensive approach that combines gene sequencing with morphological analysis (thrombocytopenia, giant platelets, and Dohle-like bodies), particularly in identifying Dohle body-like inclusions and true Dohle bodies, which helps differentiate the underlying causes of long-standing thrombocytopenia. 4. Conclusion The diagnosis of inherited thrombocytopenias with nonspecific clinical presentations poses a significant challenge. A comprehensive approach involving clinical evaluation, careful examination of blood smears, and genetic testing is crucial for the diagnosis of MYH9-RDs. We emphasize the importance of recognizing the morphological characteristics of the Dohle body-like inclusions as a valuable diagnostic clue. Acquiring the ability to identify laboratory indicators of inherited thrombocytopenia is crucial for preventing misdiagnosis. Author contributions Conceptualization: Yan Zhang, Aifang Xu. Data curation: Yan Zhang, Zhongbao Zuo, Wenyan Yu. Investigation: Wenyan Yu. Writing - original draft: Yan Zhang. Writing - review & editing: Zhongbao Zuo, Aifang Xu. Abbreviations: ITP immune thrombocytopenia MYH9-RDs MYH9-related disorders This research was funded by 2022 Medical Science and Technology Project of Zhejiang Province (2022KY1028). Written informed consent has been obtained from the patient to have the case details for publication. This study was approved by the Xixi Hospital of Hangzhou. The authors have no conflicts of interest to disclose. Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. How to cite this article: Zhang Y, Zuo Z, Yu W, Xu A. Unveiling the hidden clues: Dohle body-like inclusions as morphological markers for MYH9-related disorders: A case report. Medicine 2023;102:51(e36735). References Pecci A Ma X Savoia A . MYH9: structure, functions and role of non-muscle myosin IIA in human disease. Gene. 2018;664 :152-67.29679756 Rabbolini DJ Chun Y Latimer M . Diagnosis and treatment of MYH9-RD in an Australasian cohort with thrombocytopenia. Platelets. 2018;29 :793-800.29090586 Cherif H Greinacher A Lubenow N . Patient was wrongly diagnosed and repeatedly treated for immune thrombocytopenia for 50 years. Lakartidningen. 2018;115 :EY3I. Huang YC Shih YH Lin CY . A family with an MYH9-related disorder with different phenotypes masquerading as immune thrombocytopaenia: an underreported disorder in Taiwan. Int J Hematol. 2020;112 :878-82.32712863 Cheng W Zhao J Dai W . Light blue inclusion bodies in neutrophils, eosinophils, basophils, monocytes, and macrothrombocytopaenia suggestive of MYH9-RD. Int J Lab Hematol. 2023;45 :407-8.36945139 Iqbal NT Li W . Pay attention to neutrophil inclusions in pediatric patients with thrombocytopenia. Blood. 2019;134 :907.31515229 Pecci A Klersy C Gresele P . MYH9-related disease: a novel prognostic model to predict the clinical evolution of the disease based on genotype-phenotype correlations. Hum Mutat. 2014;35 :236-47.24186861 Jiang B Hartzell M Yu S . Venous thromboembolism prophylaxis of a patient with MYH-9 related disease and COVID-19 infection: a case report. World J Hematol. 2023;10 :1-8. Chang TH Hwang DY Chiou PF . Novel identification of a sporadic MYH9-related disease with Uremia in Taiwanese: a case report and literature review. Acta Nephrolog. 2017;31 :26-30. Ban BH Shah V . MYH9-related thrombocytopenia. Mayo Clin Proc. 2017;92 :1169-70.28688473 Yan S Jinlin L . Long-lasting thrombocytopenia and senile cataract. J Appl Lab Med. 2020;5 :1391-4.32542376 Noris P Biino G Pecci A . Platelet diameters in inherited thrombocytopenias: analysis of 376 patients with all known disorders. Blood. 2014;124 :e4-e10.24990887 Reddy P Kollipara R Shammo JM . The May-Hegglin anomaly: a rare cause of a common complaint. BMJ Case Rep. 2021;14 :e235432. |
Medicine (Baltimore) Medicine (Baltimore) MD Medicine 0025-7974 1536-5964 Lippincott Williams & Wilkins Hagerstown, MD 00045 10.1097/MD.0000000000036333 3 4900 Research Article Clinical Case Report Campylobacter fetus-induced primary psoas abscess in patient with gouty arthritis: A case report and literature review Luo Xiaodong BS [email protected] a He Yanfang BS [email protected] a Zha Daogang MD, PhD [email protected] a Kang Chunyu BS [email protected] a Sijie Yuan MD, PhD a* a Department of General Practice, Nanfang Hospital, Southern Medical University, Guangzhou, China. * Correspondence: Yuan Sijie, Department of General Practice, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China (e-mail: [email protected]). 22 12 2023 22 12 2023 102 51 e3633312 9 2023 06 11 2023 Copyright (c) 2023 the Author(s). Published by Wolters Kluwer Health, Inc. 2023 This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Rationale: Campylobacter fetus is rare pathogen with high mortality rate in immunosuppressive hosts. This study aimed to summarize clinical and pathological presentation of C fetus induced psoas abscess. Patient concerns: A 66-year-old male patient with long medical history of poorly-controlled gouty arthritis and steroid intake complained of a severe low back pain. Physical examination showed tenderness in his psoas. Diagnoses: The patient underwent puncture biopsy to the lesion in the psoas under ultrasound guidance. The lesion was indicated as abscess by pathological examination, and its pathogen was indicated as C fetus by the next generation sequencing. Interventions: Meropenem 1 g q8.h were administered intravenously for 10 days. Then the antibiotic treatment was switched to amoxicillin/clavulanate potassium 0.375g q.8.h and levofloxacin 0.5g q.d oral administration when discharge. Outcomes: The patient's fever and low back pain improved and infectious parameters declined. He was discharged in good general condition with advice for further monitoring and therapy. In the first month follow-up, the patient did not report recurrence or aggravation of his symptoms. Lessons: C fetus should be noticed in immunosuppressive patient with exposure to livestock who present with rare systematic or local invasive infection. We advocated the meropenem for the first-line treatment against C fetus. Campylobacter fetus case report eosinophils meropenem psoas abscess OPEN-ACCESSTRUE pmc1. Introduction Psoas abscess is an infection-invasive condition rarely reported worldwide. It is traditionally classified into primary and secondary according to its origin and spreading distance. Individuals with immunosuppression or underlying diseases are susceptible to developing psoas abscess. The common pathogens are Staphylococcus aureus, Escherichia coli, Bacteroides species, and Mycobacterium tuberculosis. Besides, some rare pathogens may also induce the psoas abscess, including Campylobacter fetus. Till recent, only 2 cases reported C fetus-induced secondary psoas abscess associating with spondylitis, while no primary case is reported. Although the clinical outcomes were favorable, it may become fatal if invasive C fetus infection could not be diagnosed and treated in time. In the past decades, C fetus infection was difficult to diagnose due to low positive culture, and the number of cases was probably underestimated. Owning to the rare cases, the development in early diagnosis and treatment of C fetus-induced secondary psoas abscess is limited. Herein, we reported a case of C fetus-induced primary psoas abscess in a Chinese rural male with long medical history of gouty arthritis and oral steroids intake. Blood cultures did not grow any pathogenic bacteria. He was treated initially with a combination of ceftriaxone and levofloxacin then meropenem along for 2 weeks. The clinical response was favorable, and the inflammatory parameters significantly declined when the patient was discharged. The present case report provides experiments in diagnosis and treatment toward primary C fetus infection in psoas. 2. Case report A 66-year-old Chinese rural male with a past medical history of gouty arthritis presented to the spine surgery department of Nanfang Hospital, Southern Medical University for paralysis in left upper and lower limbs. The patient reported it started approximately 1 year ago. He endorsed associated symptoms of worsening neck and low back pain for the past 1 month. On initial presentation, the patient's blood pressure, heart rate and temperature were normal. The spinal physical examination revealed limitation in neck and waist motion, positive Hoffmann symptoms, tenderness in several lumbar intervertebral discs, and amyotrophy in 2 lower limbs. Magnetic resonance imaging (MRI) and Computerized tomography scan revealed multiple cervical and lumbar intervertebral discs herniation combined with secondary stenosis, and fresh vertebral compression fractures in T12 and L1 (Fig. 1A-D). Given the urgent operation indications in cervical spinal, the orthopedists planned to perform cervical decompression next day. However, initial laboratory exam reported mild leukocytosis of 10.00 x 109/L combined with elevated C-reactive protein (CRP) of 59.29mg/L and ProCT of 1.040 ng/mL, hinting potential infectious risks. The orthopedists had to postpone the operation and transmit the patient to the department of general practice. Figure 1. Imaging examination of cervical and lumbar vertebras. (A) MRI of cervical in sagittal view. (B) CT of cervical in sagittal view. (C) MRI of lumbar in sagittal view. (D) CT of cervical in sagittal view. CT = computerized tomography scan, MRI = magnetic resonance imaging. After admission, the patient complained of suffering from a severe low back pain, enforcing him bedridden, and to require tramadol 0.1 g q.d i.m. to resolve. He also reported the acute gouty arthritis usually relapsed in the past 3 years, during which he was prescribed plenty of metacortandracin as analgetic. The general physical examination revealed thickening of fat around the face (moon face), telangiectasias, muscle wasting and weakness in 4 limbs, thinning of the skin and slight violet rashes on abdomen. Besides, a peculiar tenderness on the left psoas, which could not be well explained by the lumbar intervertebral discs herniation or compressive fracture, caught our attention. As the cortisol and adrenocorticotropic were normal, the metacortandracin was stopped immediately. According to the infectious disease consultation, the patient was initialed on empiric intravenous (i.v.) antibiotic treatment of ceftriaxone sodium 2g q.d. Two days after, the mycoplasma pneumoniae condensing set test reported positive result of 1:160, and oral azithromycin 0.5g q.d administration was added into treatment. The patient reported emerging anaphylactic rashes on his chest, and the antibiotic treatment was stopped in case of aggravated allergies. Owning to the complicated condition, the hospitalized disease symposium was performed. The suspected lesions in the psoas were found in the lumbar MRI and computerized tomography (Fig. 2A and B). The puncture biopsy guided by ultrasound was performed to yield the tissue for pathogen next generation sequencing (NGS) (RNA and DNA), and pathological examination (Fig. 3A). In the total 129,414,630 sequences of RNA and 121,331,807 sequences of DNA, the NGS reported 177 RNA sequences with 0.52% abundance and 426 DNA sequences with 11.03% abundance, which were all belonged to the bacteria, C fetus. Subsequently, the pathological examination reported chronic abscess associated with lytic necrosis, fibroplasia, calcification and eosinophilia infiltration in the lesion (Fig. 3B-D). Immediately, the antibiotic treatment was escalated to ceftriaxone sodium 2 g q.d and levofloxacin 0.5 g q.d intravenous administration. During the treatment, the patient appeared fever associated with arthritis in his left ankle and knee joints, which he reported was similar to the pervious acute gouty arthritis. Emergent tests of complete blood count, CRP, Procalcitonin (PCT), uric acid and 2 sets of blood culture were performed, and results reported the leukocyte, CRP, and PCT elevated to 15.00 x 109/L, 228.42 mg/mL, and 0.864 ng/mL, while the uric acid remained normal as previous (<420 mmol/L). The fever and arthritis were ameliorated after oral ibuprofen and colchicine administrations. In consideration of antibiotic resistance, the antibiotic treatment was escalated to meropenem 1g i.v. q.8.h. The oral ibuprofen and colchicine administrations were performed when needed. After 10-day treatment, patient reported the fever, severe low back pain and psoas tenderness significant improved, and did not need tramadol injection anymore. His leukocyte, CRP, PCT declined to 12.00 x 109/L, 66.12 mg/mL, 0.184 ng/mL, and the blood culture was negative. Antibiotic treatment was switched to amoxicillin/clavulanate potassium 0.375g q.8.h and levofloxacin 0.5g q.d oral administration when discharge. In the first month follow-up, the patient reported the fever and low back pain did not recurrent or aggravated, which permit him to stand and walk slowly. We seriously suggested the patient to strictly follow our orders of oral medicine treatment and return visit. Figure 2. Imaging examination of lumbar vertebras. (A) MRI of cervical in horizontal view. (B) CT of cervical in horizontal view. (C) CT of cervical in coronal view. Red arrows indicated the psoas lesions. CT = computerized tomography scan, MRI = magnetic resonance imaging. Figure 3. Biopsy of psoas lesion. (A) Ultrasound image of lesion for puncture biopsy. (B-D) Pathological examination of psoas lesion (1000x). Red arrows indicated the eosinophils. 3. Discussion C fetus is a slender, curved microaerophilic gram-negative bacterium inhabiting commensally in the intestines of livestock, such as cattle and sheep, and the newly reported reptile: turtle. It probably infected human through intake of contaminated food or water. Invasive C fetus has been reported to cause pericarditis, endocarditis, pneumonia with empyema, septic arthritis and septic thrombophlebitis. Likewise, Cypierre et al reported the secondary C fetus septic sites in lung, joint, skin, periton, and renal. It was believed that, C fetus more often caused bacteremia in elder patients (mean aged 68.4 ) with immunosuppression or underlying diseases. The 66-year-old patient in our case admitted that he had contacted livestock when he was a slaughter, and nowadays he has raised many turtles in his residence. The C fetus from the reservoirs probably infected his gastrointestine asymptomatically. Then, owning to the gouty arthritis, the patient has taken plenty of metacortandracin as analgetic, which suppressed the immunity leading to asymptomatic bacteremia and varied systematic complications, such as spondylodiscitis. Within the 12 C fetus-induced spondylodiscitis cases, only 2 reported secondary psoas abscess which were similar to our case (Table 1). Compared with these 2 cases, only psoas was infected without lumbar and intervertebral discs involvement in our case. We checked the patient's lumbar and intervertebral discs in the MRI, there was no spondylitis sign including irregular boundary, erosion or abscesses (low signal intensity in T1 and high signal intensity in T2), and the fracture lines of the compressive T12 and L1 were clear. The MRI was considered the most superior imaging modalities for early diagnosis of spondylitis with advantages of high sensitivity (96%) and specificity (92%-94%). However, it was reported that whether MRI shows spondylitis signal may depend on the phase of disease. Tanaka et al reported MRI did not showed spondylitis signal in 13 days after onset of fever and low back pain, but showed in 26 days after. The patient in our case recalled his low back pain started several years ago, then significantly aggravated in 1 month. Hence, his MRI should have shown spondylitis sign if his lumbar and intervertebral discs were infected. Yet, our radiologists and orthopedists did not agree with any spondylitis in the MRI. Meanwhile we noticed the abnormal tenderness combined with "unknown suborbicular lesions" described in MRI report in the patient's psoas, and subsequently performed ultrasound-guided puncture biopsy followed with pathogen NGS to indicate the C fetus-induced abscess in the psoas. However, it was unclear how the C fetus merely infected the psoas but not the lumbar or intervertebral discs. The reason may be that, the patient recalled he had received multiple local injection, probably contained steroids, in the psoas to resolve the severe low back pain, which damaged the immunological barrier of psoas. Within the abscess, pathological examination revealed eosinophils which was probably related to C fetus infection, for Campylobacter were indicated associating with neutrophilic to eosinophilic switches, and contributing mostly to the eosinophil-associated antimicrobial resistance genes. These hinted the difficulty in treatment toward the C fetus-induced primary psoas abscess in our case. Table 1 Case reports of Campylobacter fetus spondylitis combined with psoitis. Date Author Age Sex Symptom Comorbidity Positive culture Treatment Outcome 2018 Laenens et al 53 Male Low back pain HIV Intervertebral disc Oral ciprofloxacin 0.5 g b.i.d Recovery 2010 Chaillon et al 91 Female Fever, lower back pain None Intervertebral disc Oral amoxicillin, 6 g q.d Recovery With regard to treatment and prognosis, even if the 2 reported cases had full recovery, up to 15% fatality rate was reported in patient with Campylobacter infection receiving inappropriate antibiotic treatment. Due to the rare case, the consensus of C fetus infection treatment has not been established till present. As blood cultures were negative for 3 times, which was accordance with the low positive rate reported previously, no susceptibility testing could be performed. On initiation, empiric ceftriaxone and levofloxacin i.v. treatment was performed according to the consultation of infectious disease specialist. The patient appeared acute gouty arthritis as previous, with fever and elevated WBC, CRP and PCT, but the puncture induced bacteremia could not be ruled out. Besides, the risk of antibiotic resistance could not be ignored, for C fetus was probably resistant to the third generation cephalosporins and fluoroquinolones ; additionally the eosinophils closely related with antibiotic resistance of C fetus were observed in the abscess. Thus, we escalated the antibiotic treatment to meropenem, and the clinical outcome was favorable. 4. Conclusion To sum up, we reported the first case of C fetus-induced primary psoas abscess in human worldwide to the best of our knowledge. Although C fetus infection was still rare, physicians should notice any patient who had contacted with reservoirs and suffered from immunosuppression and underlying diseases. Diagnosis could be indicated according to the NGS, or other pathogen gene sequencing examination, of the lesion if the culture was negative. Pathological examination is necessary. If the eosinophils were observed, the C fetus may have antibiotic resistance, and we recommend the carbapenem antibiotic as the first-line treatment. Acknowledgments The authors would like to thank all additional people, including nurses and specialists for consultation, involved in the patient care at department of general practice. Author contributions Conceptualization: Yuan Sijie. Data curation: Xiaodong Luo, Daogang Zha, Yuan Sijie. Formal analysis: Yanfang He, Chunyu Kang, Yuan Sijie. Abbreviations: CBC complete blood count CRP C-reactive protein MRI magnetic resonance imaging PCT = Procalcitonin NGS next generation sequencing The authors have no conflicts of interest to disclose. Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. How to cite this article: Luo X, He Y, Zha D, Kang C, Sijie Y. Campylobacter fetus-induced primary psoas abscess in patient with gouty arthritis: A case report and literature review. Medicine 2023;102:51(e36333). References Garner JP Meiring PD Ravi K . Psoas abscess - not as rare as we think? Colorectal Dis. 2007;9 :269-74.17298628 Lopez VN Ramos JM Meseguer V . Microbiology and outcome of iliopsoas abscess in 124 patients. Medicine (Baltim). 2009;88 :120-30. Chaillon A Baty G Lauvin MA . Campylobacter fetus subspecies fetus spondylodiscitis. J Med Microbiol. 2010;59 :1505-8.20705728 Laenens D Plazier M van der Hilst J . Campylobacter fetus spondylodiscitis in a patient with HIV infection and restored CD4 count. BMJ Case Rep. 2018;2018 :bcr2018225272. Tappe D Schulze MH Oesterlein A . Molecular detection of Campylobacter jejuni as a cause of culture-negative spondylodiscitis. J Clin Microbiol. 2012;50 :1499-500.22259199 Wagenaar JA van Bergen MA Blaser MJ . Campylobacter fetus infections in humans: exposure and disease. Clin Infect Dis. 2014;58 :1579-86.24550377 Wang CM Shia WY Jhou YJ . Occurrence and molecular characterization of reptilian campylobacter fetus strains isolated in Taiwan. Vet Microbiol. 2013;164 :67-76.23466328 Kanj SS Araj GF Taher A . Campylobacter fetus pericarditis in a patient with beta-thalassemia: case report and review of the literature. Clin Microbiol Infect. 2001;7 :510-3.11678937 Loeb H Bettag JL Yung NK . Vibrio fetus endocarditis. Report of 2 cases. Am Heart J. 1966;71 :381-6.5905454 Targan SR Chow AW Guze LB . Campylobacter fetus associated with pulmonary abscess and empyema. Chest. 1977;71 :105-8.830489 Kilo C Hagemann PO Marzi J . Septic arthritis and bacteremia due to vibrio fetus: report of an unusual case and review of the literature. Am J Med. 1965;38 :962-71.14310014 Vesely D MacIntyre S Ratzan KR . Bilateral deep brachial vein thrombophlebitis due to vibrio fetus. Arch Intern Med. 1975;135 :994-5.1041482 Cypierre A Denes E Barraud O . Campylobacter fetus infections. Med Mal Infect. 2014;44 :167-73.24637053 Bessede E Lehours P Labadi L . Comparison of characteristics of patients infected by Campylobacter jejuni, campylobacter coli, and campylobacter fetus. J Clin Microbiol. 2014;52 :328-30.24197884 Pigrau C Bartolome R Almirante B . Bacteremia due to Campylobacter species: clinical findings and antimicrobial susceptibility patterns. Clin Infect Dis. 1997;25 :1414-20.9431389 Awada B Hindy J Chalfoun M . Cervical osteomyelitis potentially caused by campylobacter fetus. J Infect Public Health. 2021;14 :1233-6.34454173 Butler JS Shelly MJ Timlin M . Nontuberculous pyogenic spinal infection in adults: a 12-year experience from a tertiary referral center. Spine (Phila Pa 1976). 2006;31 :2695-700.17077738 Takafumi Y Masami M Yurito U . Magnetic resonance imaging in the early phase of pyogenic spondylitis: a report of four cases. J Orthop Sci. 1997;2 :16-23. Tanaka A Takahashi J Hirabayashi H . A case of pyogenic spondylodiscitis caused by campylobacter fetus for which early diagnosis by magnetic resonance imaging was difficult. Asian Spine J. 2012;6 :274-8.23275811 Wang Z Locantore N Haldar K . Inflammatory endotype-associated airway microbiome in chronic obstructive pulmonary disease clinical stability and exacerbations: a multicohort longitudinal analysis. Am J Respir Crit Care Med. 2021;203 :1488-502.33332995 Yi X Li Y Liu H . Inflammatory endotype-associated airway resistome in chronic obstructive pulmonary disease. Microbiol Spectr. 2022;10 :e0259321.35311590 Pacanowski J Lalande V Lacombe K . Campylobacter bacteremia: clinical features and factors associated with fatal outcome. Clin Infect Dis. 2008;47 :790-6.18699745 Sprenger H Zechner EL Gorkiewicz G . So close and yet so far - molecular microbiology of campylobacter fetus subspecies. Eur J Microbiol Immunol (Bp). 2012;2 :66-75.24611123 Gazaigne L Legrand P Renaud B . Campylobacter fetus bloodstream infection: risk factors and clinical features. Eur J Clin Microbiol Infect Dis. 2008;27 :185-9.17999095 |
Medicine (Baltimore) Medicine (Baltimore) MD Medicine 0025-7974 1536-5964 Lippincott Williams & Wilkins Hagerstown, MD 00070 10.1097/MD.0000000000036589 3 5800 Research Article Clinical Case Report Application of intravitreal aflibercept to treat bilateral exudative retinal detachment secondary to retinitis pigmentosa: Case report and review of literature Kao Chia-Chen MD [email protected] ab Chen Kuo-Jen MD [email protected] c Cheng Kai-Chun PhD abc* a Department of Ophthalmology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan b Department of Ophthalmology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan c Department of Ophthalmology, Kaohsiung Municipal Siaogang Hospital, Kaohsiung, Taiwan. * Correspondence: Kai-Chun Cheng, Department of Ophthalmology, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan, R.O.C. (e-mail: [email protected]). 22 12 2023 22 12 2023 102 51 e3658907 6 2023 21 9 2023 Copyright (c) 2023 the Author(s). Published by Wolters Kluwer Health, Inc. 2023 This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Rationale: Exudative retinal detachment with macular edema is one of the complications of retinitis pigmentosa (RP). In this report, we present a case who treated with intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) in RP-related exudative retinal detachment and subsequently improved with favorable outcome. Patient Concern: A 49-year-old man, with a history of RP, had persistent blurred vision and was newly diagnosed with bilateral shallow exudative retinal detachment and macular edema. Diagnosis: Fluorescein angiography showed bilateral diffuse dye leakage with macular pooling, and systemic survey excluded the possibility of infection or autoimmune disease. Interventions: The patient was treated with intravitreal injection of aflibercept, one of the anti-VEGF agents, for bilateral eyes. Recurrent exudative retinal detachment and macular edema were noted, and repeated intravitreal injections of aflibercept in bilateral eyes were then arranged. Subsequently, bilateral macular edema and exudative retinal detachment subsided again, and the treatment course lasted for approximately 1 year. Outcomes: After 1 year, the exudative retinal detachment with macular edema was much improved. In the meanwhile, visual functional improvement was also achieved. Lessons: This case illustrated the possibility of intravitreal injection of anti-VEGF therapy for the treatment of this rare complication of RP, and it may be a newly explored alternative treatment. aflibercept anti-VEGF agents exudative retinal detachment intravitreal injection retinitis pigmentosa (RP) OPEN-ACCESSTRUE pmc1. Introduction In recent literature of retinitis pigmentosa (RP), cryotherapy and laser photocoagulation were reported as treatment for Coats'-like serous retinal detachment. However, we presented a case with RP-related bilateral shallow exudative retinal detachment and macular edema, which showed different fundus pattern from previous reports. In addition, in our case, anti-VEGF (vascular endothelial growth factor) therapy was an effective treatment in this rare complication of RP. 2. Case report The 49-year-old man had a history of RP. He received cataract surgery for the right eye due to progressive blurred vision. In the following 2 months, he still felt persistent bilateral blurred vision. Visual acuity (VA) was counting fingers 30cm in the right eye and 20/400 in the left eye. Slit lamp examination showed silent anterior chamber in bilateral eyes, posterior chamber intraocular lens with mild after-cataract in the right eye, and nuclear sclerosis with posterior subcapsular opacity in the left eye. The fundus examination showed bilateral mid-peripheral retinal pigmentary change and newly appeared diffuse shallow exudative retinal detachment with posterior pole and peripheral retinal involvement (Fig. 1). Optical Coherence Tomography revealed marked macular edema with shallow exudative retinal detachment in bilateral eyes (Fig. 2), and fluorescein angiography showed bilateral diffuse dye leakage with macular pooling (Fig. 1). Systemic survey excluded the possibility of infection, and autoimmune disease was not favored due to normal limits for rheumatoid factor, antinuclear antibody and HLA-B27. Figure 1. Color fundus revealed shallow exudative retinal detachment with macular edema in bilateral eyes. FAG showed bilateral diffuse dye leakage with macular pooling. FAG = fluorescein angiography. Figure 2. OCT showed resolution of bilateral macular edema and exudative retinal detachment after repeated intravitreal injection of aflibercept. OCT = optical coherence tomography. Afterwards, intravitreal injection of 2 mg aflibercept was performed for bilateral eyes, and macular edema resolution with decreased exudative retinal detachment was found. The patient subjectively felt improving vision, and his VA also improved to 20/600 in the right eye and 20/200 in the left eye. However, recurrent macular edema and exudative retinal detachment were then noted in the following months. Repeated intravitreal injections of aflibercept in bilateral eyes were then arranged, and subsequently, bilateral macular edema and exudative retinal detachment subsided again (Fig. 2). The treatment course lasted for approximately 1 year, and the final VA was 20/600 in the right eye and 20/40 in the left eye. Both eyes achieved visual functional improvement, and the condition was stable until now. 3. Discussion RP may be complicated with choroidal neovascularization (CNV), cystoid macular edema, or exudative retinal detachment in the late stage in rare circumstances. VA may also gradually worsen due to RP-related macular atrophic degeneration or optic neuropathy, and some patients might develop neovascular glaucoma with progression to ocular phthisis. As for RP-related retinal detachment, it is associated with a spectrum of exudative, tractional, and rhegmatogenous retinal detachment. Exudative retinal detachment does not usually require surgical repair, although cryotherapy or laser are reported occasionally necessary in sight-threatened patients in certain condition. In previous literature reports, RP with exudative subretinal fluid might present with bilateral Coats'-like serous retinal detachment, including telangiectasia and prominent lipid deposition, and such lesions often localize inferiorly and require laser photocoagulation. In comparison, our patient had bilateral diffuse shallow exudative retinal detachment and macular edema, without appearance of telangiectasia or lipid deposits, and the lesion was located from macula to peripheral retina. The mechanism of conventional laser photocoagulation and cryotherapy is possibly to damage the retinal pigment epithelium and choriocapillaris, and this can result in permanent choroidal and retinal atrophy. Laser photocoagulation may also transiently worsen macula edema and exudative subretinal fluid. Therefore, in our case with diffuse retina detachment, it would be difficult to do laser photocoagulation for the diffuse subretinal fluid, and it could be unsafe to perform cryotherapy for retinal lesions in posterior pole. In addition, topical dorzolamide was demonstrated to be effective for the treatment of cystoid macular edema in patients with RP, but there was no reported of positive treatment effect for RP related exudative retinal detachment. Apart from the above consideration, the pathophysiology and mechanism of exudative retinal detachment in our patient might be different from the previous reports of Coats'-like pattern serous retinal detachment. In our case, there could be the possibility of occult neovascular lesions or vascular permeability increase, leading to diffuse fluorescein leakage and dye pooling in fluorescein angiography. Intravitreal injection of anti-VEGF is considered to reduce the choroidal and retinal vascular permeability, to stabilize the blood-retinal barrier and thereby to inhibit exudation into retinal space. Thus, intravitreal injection of aflibercept was effective for our patient, and exudative retinal detachment and macular edema subsided after repeated anti-VEGF injection; however, only one paper mentioned this treatment strategy in Coats'-like exudative vitreoretinopathy in RP, so further reports are required to help ophthalmologists deal with this rare situation. Although there were previously concerns regarding long-term inhibition of VEGF, leading to inhibited neuro-protective effect, anti-VEGF agent is recently viewed as a safe management for neovascularization and macular edema secondary to RP. Occasionally, CNV may be successfully managed with a single intravitreal anti-VEGF injection, but most cases require more than a one-year period to achieve stabilization in RP-related CNV. In our case, anti-VEGF agents were also effective in exudative RD and macular edema, but there might be recurrence in the following months. Our patient received repeated intravitreal injections of aflibercept in both eyes for 3 times during 1 year, and the exudative retinal detachment with macular edema subsided and maintained stable condition. In the meanwhile, the patient also achieved improvement of VA. In conclusion, heightened awareness of potential complications of RP might assist earlier diagnosis, thus facilitating timely intervention leading to better prognosis. Consequently, detailed fundus examination should be performed in RP patients with deteriorated vision; additionally, RP related exudative retinal detachment and macular edema could indicate occult neovascular lesions or increased vascular permeability, and anti-VEGF therapy could be considered as an alternative therapeutic option in this rare condition. Author contributions Conceptualization: Chia-Chen Kao. Investigation: Chia-Chen Kao. Methodology: Chia-Chen Kao. Software: Kuo-Jen Chen. Supervision: Kai-Chun Cheng. Validation: Chia-Chen Kao, Kuo-Jen Chen. Writing - original draft: Chia-Chen Kao. Writing - review & editing: Kai-Chun Cheng. Abbreviations: CNV choroidal neovascularization RP retinitis pigmentosa VA visual acuity VEGF vascular endothelial growth factor This study was financially supported by grants KMHK-109-035 and H-110-004 from Kaohsiung Municipal Siaogang Hospital, Taiwan; grant KMUH111-1M38 from Kaohsiung Medical University Hospital, Taiwan and grants MOST 108-2314-B-037-088; 110-2314-B-037-112 from the Ministry of Science and Technology, Taiwan and grant NSTC 112-2314-B-037-024 from the National Science and Technology Council, Taiwan. The authors certify that they have obtained all appropriate patient consent form. In the form, the patient has given his consent for the images and other clinical information to be reported in the journal. The patient understands his name and initials will not be published and due efforts will be made to conceal identity. The authors have no conflicts of interest to disclose. All data generated or analyzed during this study are included in this published article [and its supplementary information files]. How to cite this article: Kao C-C, Chen K-J, Cheng K-C. Application of intravitreal aflibercept to treat bilateral exudative retinal detachment secondary to retinitis pigmentosa: Case report and review of literature. Medicine 2023;102:51(e36589). References Chan WO Brennan N Webster AR . Retinal detachment in retinitis pigmentosa. BMJ Open Ophthalmol. 2020;5 :e000454. Kan E Yilmaz T Aydemir O . Coats-like retinitis pigmentosa: reports of three cases. Clin Ophthalmol. 2007;1 :193-8.19668510 Ikeda Y Hisatomi T Yoshida N . The clinical efficacy of a topical dorzolamide in the management of cystoid macular edema in patients with retinitis pigmentosa. Graefes Arch Clin Exp Ophthalmol. 2012;250 :809-14.22215259 Moinuddin O Sathrasala S Jayasundera KT . Coats-like exudative vitreoretinopathy in retinitis pigmentosa: ocular manifestations and treatment outcomes. Ophthalmol Retina. 2021;5 :86-96.32507488 Manabu M Akio O Maho O . Long-term efficacy and safety of anti-VEGF therapy in retinitis pigmentosa: a case report. BMC Ophthalmol. 2018;18 :248.30217183 Sayadi J Miere A Souied EH . Type 3 neovascularization associated with retinitis pigmentosa. Case Rep Ophthalmol. 2017;8 :245-9.28512428 |
Medicine (Baltimore) Medicine (Baltimore) MD Medicine 0025-7974 1536-5964 Lippincott Williams & Wilkins Hagerstown, MD 00027 10.1097/MD.0000000000036617 3 7100 Research Article Clinical Case Report The niche of dermal graft to reconstruct a complex pressure injury wound in sacral region: A case report Cheng Te-Wei MD [email protected] a Lin Yun-Nan MD bc* Lee Su-Shin MD [email protected] b Kuo Yur-Ren MD, PhD [email protected] b a Department of General Medicine, Taipei Medical University Hospital, Taipei, Taiwan b Division of Plastic Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan c School of Post-Baccalaureate Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. * Correspondence: Yun-Nan Lin, Division of Plastic Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80756, Taiwan (e-mail: [email protected]). 22 12 2023 22 12 2023 102 51 e3661705 9 2023 13 11 2023 22 11 2023 Copyright (c) 2023 the Author(s). Published by Wolters Kluwer Health, Inc. 2023 This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Rationale: Pressure ulcers are a common health issue, particularly among elderly and bedridden patients who are vulnerable to pressure injuries in the sacral region. Currently, free flap and local flap surgeries are the gold standard procedures for the reconstruction of such injuries. However, the recurrence rate of flap surgery appears to be high. In this context, we presented a case involving a sacral pressure ulcer reconstructed with dermal grafting. Patient concerns: A 59-year-old male with a medical history of hepatitis C, brain hemorrhage, hydrocephalus, and multiple fractures presented with a sacral ulcer. Owing to the patient's history of recurrent pressure injuries and the challenges associated with postoperative wound care, the patient and his family were hesitant to proceed with flap surgery. Diagnoses: The patient was diagnosed with a stage IV pressure ulcer measuring 4 cm x 4 cm in size in the sacral region, according to the National Pressure Ulcer Advisory Panel staging system. Interventions: Before surgery, the patient received standard wound care with dressing for 4 months, along with short-term oral antibiotics due to a positive wound culture for Pseudomonas aeruginosa. During the surgery, a dermal graft with a size of 35 cm2 and a thickness of 0.014 inches was harvested from the patient's left thigh. The graft was then secured to the wound bed. Outcomes: Although the dermal graft failed with sloughing after 1 week, the wound bed showed improvement with granulation. After 1.5 months, the wound area had decreased to half of its original size, and the wound eventually healed after 3.5 months. Lessons: Dermal grafts have a niche in reconstructing pressure injury wounds in the sacral region, because of the relative ease of wound care and additional benefits even in cases where the graft fails. dermal grafting pressure-induced injury pressure ulcer OPEN-ACCESSTRUE pmc1. Introduction Pressure ulcers, also known as pressure sores, are a global health concern. This pressure-induced injury is a consequence of prolonged external force and ischemia. Besides the elderly, populations who are bedridden or dependent on wheelchairs usually suffer from bedsores due to immobilization, impaired sensation, or malnutrition. According to international pressure ulcer prevalence surveys conducted between 1989 and 2005, the overall prevalence of pressure ulcers was approximately 15% in healthcare facilities. Moreover, the sacrum was the most common region, accounting for about 30% of cases. For patients with stage III and IV injuries, the reconstructive ladder includes primary wound closure, skin grafting, regional flaps, and free flaps. Currently, flaps are the gold standard for sacral pressure sores. On the other hand, for lesions on the lower limbs, skin grafts such as split-thickness skin grafting are recommended. These clinical approaches were supported by Schryvers et al whose 20-year retrospective study found that flaps could tolerate pressure for pressure injury wound on pelvic region including sacral, ischial, and trochanteric sites. However, according to Keys et al, the recurrence rate of pressure ulcers after flap surgery is up to 39%, with an average follow-up period of 4.4 years. Therefore, in this case, we presented an innovative method of dermal grafting to reconstruct a complex and ulcerative wound in the sacral region in a patient with pressure injury. 2. Case report This was a 59-year-old male with underlying hepatitis C without medication and a history of intracranial hemorrhage, subdural hemorrhage, hydrocephalus treated with ventriculoperitoneal shunt and lumbar peritoneal shunt, left 5th and 6th rib fractures, right distal radius fracture treated with open reduction and internal fixation and short arm splint, and L1 compression fracture under vertebroplasty. Substance use in alcoholism and amphetamine abuse was noted. He had been bedridden for years and presented to our plastic surgery outpatient department due to ulcers in the sacral region for 4 months. According to the National Pressure Ulcer Advisory Panel system, the patient was diagnosed with stage IV pressure ulcers in the sacral region, measuring 4 cm x 4 cm in size (Fig. 1). Standard wound care was provided using Biodyne ointment (China Chemical & Pharmaceutical Co., Ltd., Taiwan), Purilon gel (Coloplast Co., Ltd., UK), and AQUACEL Foam (ConvaTec Inc., NC). The patient underwent routine outpatient department follow-up and was prescribed oral antibiotics because of a positive wound culture for Pseudomonas aeruginosa. In addition, bedside debridement was performed following the recommendations of the plastic surgeons. The preoperative wound was a stage III pressure ulcer with granulation tissue in the sacral region. Figure 1. The pressure ulcer at the first visit was stage IV, as there was full-thickness skin and tissue loss with exposed fascia. It measured 4 cm x 4 cm in size and was located in the sacral region. The study was conducted in accordance with the Declaration of Helsinki. Informed consent statement was obtained from the patient for publication of this study. Our study is a case report, and data sharing is not applicable to this article since no datasets were generated or analyzed during the current study. 3. Operation technique An epidermal flap with a thickness of 0.012 inches was elevated using a Zimmer dermatome. A dermal graft measuring 35 cm2 and 0.014 inches in size was harvested from the left thigh and transplanted into the marked area (Fig. 2A). Anchoring sutures were performed using pledgets with SI-AID (ALCARE CO., Ltd, Japan) (Fig. 2B). The epidermal flap was then reattached to the underlying tissue at the donor site (Fig. 3A). After the operation, wound care was provided using Biodyne ointment and AQUACEL Foam. The patient was discharged from the hospital after receiving prophylactic antibiotics for 3 days. He continued to receive follow-up care at the plastic surgery outpatient department on a weekly basis. The donor site healed well without any complications (Fig. 3B). Although the graft failed with slough after 1 week, the wound bed improved with granulation tissue, and the wound area decreased by half in size after 2 months (Fig. 2C). The wound healed completely after 3.5 months (Fig. 2D). Figure 2. (A) The recipient site of the pressure ulcers in the sacral region, stage III, with granulation tissue on the day of the operation, after debridement. (B) The recipient site on the day of the operation after dermal grafting with anchoring sutures and pledgets with SI-AID ( dermal graft; SI-AID). (C) A picture taken at the 2-month follow-up revealed that the sloughing graft improved the wound bed. (D) A picture taken at the 3.5-month follow-up showed that the wound had healed. Figure 3. (A) The dermal graft was harvested after the epidermal flap was elevated, with a thickness of 0.012 inches. A dermal graft with a size of 35 cm2 and thickness of 0.014 inches was harvested from the left thigh. (B) A picture taken at the 2-month follow-up showed that the donor site was healing well. 4. Discussion The pathophysiology of pressure ulcers is related to sustained external force on body prominence. It has been reported that a pressure of approximately 32 mm Hg over the arterial capillary or around 8 to 12 mm Hg over the venous capillary would cause occlusion of blood flow, which results in hypoxia in local tissue. Those who were bedridden, chair-bound, had impaired nutrition, or had a history of cerebrovascular accident were vulnerable to such pressure-induced injury. Conservative treatment is suitable for low grade pressure ulcers (stages I to II), while reconstructive surgery is indicated to the patient with wound deep or hard to heal (stages III to IV). The recurrence rate seemed to be higher in patients undergoing skin grafting, which accounted for 75% of the total recurrence, compared to that of patients receiving flaps, if not avoiding weight bearing or no neurologic or functional recovery. However, even with the flap procedure, the recurrence rate was around 16.8% to 42% (Table 1). Bamba et al reported that the complication rate after flap reconstruction was 58.7% in a study of patients who underwent surgery between 1997 and 2015. Major complications include wound dehiscence, postoperative infection, and ulcer recurrence. Table 1 Overview of the recurrence rate in literature for flap surgery. Authors, published year Patient no. No. of sores Recurrence rate (%) Average period of follow-up (yr) Average time to recurrence (d) Keys et al 2010 135 227 39 4.4 365 (48% in 1st year) Larson et al 2012 101 179 16.8 1.7 435.9 Grassetti et al 2014 143 143 22.4 2 NA Bamba et al 2017 276 347 28.6 NA 357.9 Wurzer et al 2018 55 63 27 NA 728 Firriolo et al 2018 24 30 42 4.9 (median) NA Morel et al 2019 85 85 30.6 NA 277 (median) NA = not available. Therefore, preoperative assessment should be comprehensive. Nutritional supplements such as sufficient albumin (>3 g/dL) are associated with less ulcer recurrence, as described by Sirimaharaj et al. Exudate management also maintains the quality of skin. Besides, postoperative wound care, such as pressure relief, nutritional supplements, and multidisciplinary approaches also matter. Josvay et al took advantage of the fluidization bed and prone position to protect surgical sites from pressure loading to reduce the recurrence rate. The dermal components of the harvested skin graft prevented wound contraction. In 1990, Brown et al first described "deepithelialized full-thickness" grafts and pronounced that the amount of intact dermal collagen matrix was the key to the inhibition of contraction. The dermal matrix plays a role in wound healing by providing a scaffold for granulation tissue, stimulating angiogenesis, containing growth factors, and regulating fibroblast behavior. Han et al reported that dermal graft is another type of skin graft that is different from a split-thickness skin graft or full-thickness skin graft owing to superiority in its scar quality on both the recipient and donor sites when it comes to wound coverage. Besides, in acute burn injury, it plays a role. In our previous experience, with the same thickness harvested by the Zimmer dermatome, the dermal layer in the dermal graft was thicker than that in the skin graft. Dermal grafts have a pure dermis, whereas skin grafts also contain epidermal components. Moreover, the technique used to obtain dermal grafts results in lower morbidity at the donor site than skin grafts. In this case, the decision to use a dermal graft was made because of the patient's tendency to recurrent pressure injuries and multiple medical histories. In our experience, postoperative wound care is less challenging with a dermal graft than with flap surgery, as the recipient and donor sites are smaller and there is less tension on the wound. The use of dermal grafts has several benefits over other reconstructive methods. In addition to allowing for a second skin graft reconstruction and providing a favorable condition for subsequent grafting procedures, the dermal graft also has a smaller wound size and less tension force on the wound, making postoperative wound care less challenging. These benefits are particularly important for bedridden patients, who are at a higher risk of wound dehiscence and require a shorter healing process. Despite the favorable preoperative parameters of our patient, including an albumin level of 3.93 g/dL and wound size of 9 cm2, we observed graft failure with slough formation after 1 week. This could potentially be due to poor wound conditions such as secondary infection and long-term ulceration. However, we noticed that the wound bed improved with granulation, and the wound area shrank by half of its original size after 2 months. Eventually, the wound healed after 3.5 months. The sloughing graft functioned as a wound dressing and provided beneficial effects, as described by Lee et al. We anticipated a simple procedure using dermal grafts would be beneficial for treating these complex wounds. However, it is important to note that this study had some limitations. First, we do not suggest that the dermal graft technique can completely replace flap surgery for the treatment of all pressure ulcers. In our case, the reconstruction with dermal grafts was applied to pressure ulcers in sacral region. Nevertheless, ischial regions, trochanters, and heels are also areas susceptible to pressure ulcers. Second, to provide further evidence for the effectiveness of dermal grafts, larger case numbers are required in future studies. Moreover, long-term follow-up monitoring of wound healing outcomes is essential. 5. Conclusion In this particular case, we employed dermal grafts as an innovative method for reconstructing pressure ulcer wound sites, which has not been previously reported. Our observations indicated that the use of dermal grafts led to improved wound bed conditions and eventually resulted in wound healing, even in instances where the graft may have failed. Author contributions Conceptualization: Yun-Nan Lin. Data curation: Te-Wei Cheng. Investigation: Yun-Nan Lin. Methodology: Yun-Nan Lin. Project administration: Yun-Nan Lin. Supervision: Su-Shin Lee, Yur-Ren Kuo. Writing - original draft: Te-Wei Cheng. Writing - review & editing: Te-Wei Cheng, Yun-Nan Lin. The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. This study received grants from KMUH-111-1T03, MOST111-2314-B-037-090, KMUH109-9M28, KMUH110-OR33, and MOST110-2314-B-037-108. The authors have no conflicts of interest to disclose. How to cite this article: Cheng T-W, Lin Y-N, Lee S-S, Kuo Y-R. The niche of dermal graft to reconstruct a complex pressure injury wound in sacral region: A case report. Medicine 2023;102:51(e36617). References Reuler JB Cooney TG . The pressure sore: pathophysiology and principles of management. Ann Intern Med. 1981;94 :661-6.7235399 Mervis JS Phillips TJ . Pressure ulcers: pathophysiology, epidemiology, risk factors, and presentation. J Am Acad Dermatol. 2019;81 :881-90.30664905 VanGilder C MacFarlane GD Meyer S . Results of nine international pressure ulcer prevalence surveys: 1989 to 2005. Ostomy Wound Manage. 2008;54 :40-54.18382042 Wong JK Amin K Dumville JC . Reconstructive surgery for treating pressure ulcers. Cochrane Database Syst Rev. 2016;12 :CD012032.27919120 Cushing CA Phillips LG . Evidence-based medicine: pressure sores. Plast Reconstr Surg. 2013;132 :1720-32.24281597 Schryvers OI Stranc MF Nance PW . Surgical treatment of pressure ulcers: 20-year experience. Arch Phys Med Rehabil. 2000;81 :1556-62.11128889 Keys KA Daniali LN Warner KJ . Multivariate predictors of failure after flap coverage of pressure ulcers. Plast Reconstr Surg. 2010;125 :1725-34.20517098 Lindan O . Etiology of decubitus ulcers: an experimental study. Arch Phys Med Rehabil. 1961;42 :774-83.14465389 Berlowitz DR Wilking SV . Risk factors for pressure sores: a comparison of cross-sectional and cohort-derived data. J Am Geriatr Soc. 1989;37 :1043-50.2809051 Srivastava A Gupta A Taly AB . Surgical management of pressure ulcers during inpatient neurologic rehabilitation: outcomes for patients with spinal cord disease. J Spinal Cord Med. 2009;32 :125-31.19569459 Larson DL Hudak KA Waring WP . Protocol management of late-stage pressure ulcers: a 5-year retrospective study of 101 consecutive patients with 179 ulcers. Plast Reconstr Surg. 2012;129 :897-904.22183500 Grassetti L Scalise A Lazzeri D . Perforator flaps in late-stage pressure sore treatment: outcome analysis of 11-year-long experience with 143 patients. Ann Plast Surg. 2014;73 :679-85.23759968 Bamba R Madden JJ Hoffman AN . Flap reconstruction for pressure ulcers: an outcomes analysis. Plast Reconstr Surg Glob Open. 2017;5 :e1187.28203494 Wurzer P Winter R Stemmer SO . Risk factors for recurrence of pressure ulcers after defect reconstruction. Wound Repair Regen. 2018;26 :64-8.29381242 Firriolo JM Ganske IM Pike CM . Long-term outcomes after flap reconstruction in pediatric pressure ulcers. Ann Plast Surg. 2018;80 :159-63.28984658 Morel J Herlin C Amara B . Risk factors of pelvic pressure ulcer recurrence after primary skin flap surgery in people with spinal cord injury. Ann Phys Rehabil Med. 2019;62 :77-83.30273680 Sirimaharaj W Charoenvicha C . Pressure ulcers: risk stratification and prognostic factors that promote recurrence after reconstructive surgery. Int J Low Extrem Wounds. 2018;17 :94-101.30012070 Mervis JS Phillips TJ . Pressure ulcers: prevention and management. J Am Acad Dermatol. 2019;81 :893-902.30664906 Josvay J Klauber A Both B . The operative treatment of pressure sores in the pelvic region: a 10-year period overview. J Spinal Cord Med. 2015;38 :432-8.25299238 Tchanque-Fossuo CN Kuzon Jr WM . An evidence-based approach to pressure sores. Plast Reconstr Surg. 2011;127 :932-9.21285799 Brown D Garner W Young V . Skin grafting: dermal components in inhibition of wound contraction. South Med J. 1990;83 :789-95.2371603 Lee JH Kim J-W Lee J-H . Wound healing effects of paste type acellular dermal matrix subcutaneous injection. Arch Plast Surg. 2018;45 :504-11.30466229 Han S-K Yoon T-H Kim J-B . Dermis graft for wound coverage. Plast Reconstr Surg. 2007;120 :166-72.17572559 Lindford AJ Kaartinen IS Virolainen S . The dermis graft: another autologous option for acute burn wound coverage. Burns. 2012;38 :274-82.21903331 |
Medicine (Baltimore) Medicine (Baltimore) MD Medicine 0025-7974 1536-5964 Lippincott Williams & Wilkins Hagerstown, MD 00038 10.1097/MD.0000000000036620 3 6800 Research Article Clinical Case Report Primary pulmonary synovial sarcoma with delayed diagnosis in a 69-year-old man: A case report Kim Chan Seop MD [email protected] a Cho Hye Soo MD [email protected] b Lee Ok Jun MD, PhD [email protected] c Ahn Su Yeon MD [email protected] d Yoo Jin Young MD, PhD e* a Department of Radiology, Chungbuk National University Hospital, Cheongju, Korea b Department of Radiology, Seoul National University Hospital, Seoul, Korea c Department of Pathology, Chungbuk National University College of Medicine, Cheongju, Korea d Department of Radiology, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea e Department of Radiology, Chungbuk National University College of Medicine and Hospital, Cheongju, Korea. * Correspondence: Jin Young Yoo, Department of Radiology, Chungbuk National University College of Medicine and Hospital, Cheongju 28644, Korea (e-mail: [email protected]). 22 12 2023 22 12 2023 102 51 e3662012 9 2023 18 11 2023 22 11 2023 Copyright (c) 2023 the Author(s). Published by Wolters Kluwer Health, Inc. 2023 This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Rationale: Primary pulmonary synovial sarcoma is a rare malignant pulmonary tumor accompanied by calcifications in approximately 15% of cases. These calcifications usually have a fine, stippled appearance; coarse shapes have seldom been reported. Moreover, the presence of coarse calcifications often suggests benign tumors, which vastly differ in treatment. We present a rare case of primary pulmonary sarcoma with coarse intratumoral calcifications, the diagnosis of which was delayed because of its radiologic appearance. Patient concerns: A computed tomography (CT) scan of a 69-year-old man with right upper quadrant (RUQ) pain revealed an incidental mass at the base of the right lower lobe, the margin of which was not well described with respect to the liver, and intratumoral coarse calcification was noted. Initially, the lesion was believed to be hepatic, and magnetic resonance imaging (MRI) was performed. Based on its imaging features, the mass was thought to be a pulmonary lesion, and a preliminary diagnosis of a benign lesion, such as a hamartoma or granuloma, was made. Four months after the initial CT scan, the patient's RUQ pain had aggravated; however, no change in the mass was observed on follow-up CT. Diagnosis: The final diagnosis was primary pulmonary sarcoma, proven by surgical biopsy. Interventions: Wedge resection of the right lower lobe was performed, and the patient received adjuvant chemotherapy. Outcomes: The patient's RUQ pain improved, and no recurrence or metastasis has been reported to date. Lessons: This case describes a rare presentation of a primary pulmonary synovial sarcoma with coarse intratumoral calcifications and the MRI features of the lesion. Intratumoral coarse calcifications often suggest benign lesions, such as hamartomas or post-inflammatory granulomas; however, as malignant lesions cannot be completely excluded, other radiologic and clinical features should be considered carefully. Focal areas of enhancement and eccentric calcification distribution might suggest malignant lesions such as primary pulmonary synovial sarcoma. Furthermore, despite not being used routinely, MRI scans might be helpful because advanced MRI techniques, such as diffusion-weighted imaging, can help distinguish malignant lesions from benign lesions. If the clinical course of a patient suggests malignancy, a more aggressive biopsy strategy should be considered. coarse intratumoral calcifications delayed diagnosis primary pulmonary synovial sarcoma radiologic features OPEN-ACCESSTRUE pmc1. Introduction Synovial sarcoma, which accounts for 5% to 10% of all soft tissue sarcomas, is a malignant soft-tissue tumor that usually arises near the articular structure. However, "synovial sarcoma" is a misnomer because this type of sarcoma originates from primitive mesenchymal cells rather than from the intra-articular synovium. It can occur anywhere in the body, with the most common site being the extremities. Most pulmonary synovial sarcomas are metastases from extrathoracic synovial sarcomas, and primary sarcomas are rare, accounting for <0.5% of all pulmonary malignancies. A synovial sarcoma is accompanied by calcifications in approximately 30% of cases, but in primary pulmonary synovial sarcoma, its frequency is reported to be approximately 15%. These calcifications mostly appear as fine, stippled calcifications; coarse calcifications are seldom reported. In terms of evaluating intratumoral calcifications on computed tomography (CT), stippled and punctate calcifications suggest a tumor's malignant potential, while the presence of intratumoral coarse, popcorn-like, or laminated calcifications suggests benign tumors such as hamartoma or inflammatory granuloma. Thus, diagnosis of primary pulmonary synovial sarcoma can be delayed because of a lack of early symptoms and indolent growth. We herein report a case of primary pulmonary synovial sarcoma presenting with large coarse calcifications, which was initially believed to be a benign lesion but was later diagnosed as primary pulmonary synovial sarcoma via surgical biopsy. 2. Case presentation This study was approved by the Institutional Review Board of Chungbuk National University Hospital (CBNUH 2023-09-024) and was CARE-compliant. Written informed consent was obtained from the patient for the publication of this report and any accompanying images. A 69-year-old man with right upper quadrant pain was referred to our hepatology department. A CT scan performed outside the facility revealed a 4.5-cm circumscribed mass at the base of the right lower lobe, abutting the right diaphragm, with heterogeneous enhancement and intratumoral eccentric coarse calcification (Fig. 1). No mediastinal lymphadenopathy was observed. The mass was at an acute angle with the diaphragm, suggesting a pulmonary parenchymal origin rather than a hepatic, diaphragmatic, or pleural origin. However, some of its margins were not well described with respect to the liver and diaphragm, and magnetic resonance imaging (MRI) of the liver was performed. On MRI, its margins with the liver and diaphragm were well described, and the possibility of it being a hepatic mass was excluded. The mass showed heterogeneous but overall intermediate signal intensity on T2-weighted imaging and foci of high signal intensity within the mass on T2-weighted imaging. On post-contrast T1-weighted imaging, the mass showed heterogeneous enhancement, consistent with the previous CT image. There was no evidence of microscopic fat on the in-phase and out-of-phase T1-weighted images. Notably, on diffusion-weighted imaging, the tumor showed remarkable diffusion restriction, with an apparent diffusion coefficient value of 972 (Fig. 2). Laboratory studies were unremarkable other than serum carcinoembryonic antigen, which was minimally increased (5.13 ng/mL). However, this finding was also considered unremarkable because of the minimal increase. The patient's medical or familial history of cancer was unremarkable. Considering these radiological features and laboratory results, the tumor was considered likely to be a benign lesion, such as a hamartoma or a post-inflammatory granuloma. However, as some portions of the tumor showed enhancement and the calcifications were eccentric, the possibility of malignancy could not be excluded. The patient was transferred to the thoracic surgery department, and the surgeon, based on the report of the radiologic department, opted to perform a follow-up CT scan after 6 months. Figure 1. Initial computed tomography (CT) scan of the mass. Axial post-contrast mediastinal setting CT images (slice thickness, 3 mm) show a 45-mm, well-defined mass at the right lower lobe, abutting the diaphragm. The nodule has well-defined coarse calcifications and heterogeneous enhancement. Figure 2. Magnetic resonance imaging (MRI) scan during workup. (A) T2-weighted MRI (slice thickness, 5 mm) shows a 45-mm lesion with a heterogeneous, intermediate-intensity signal with internal foci of high signal intensity. In-phase (B) and out-of-phase (C) T1-weighted images show no signal drop in the out-of-phase image, suggesting the absence of a microscopic fat component. Pre-contrast (D), arterial-phase post-contrast (E), and portal-phase post-contrast (F) T1-weighted images show heterogeneous enhancement consistent with previously scanned post-contrast CT images. (G) b800 diffusion-weighted MRI. (H) The apparent diffusion coefficient (ADC) map shows a mean ADC value of 972, suggesting diffusion restriction within the mass. Four months after the initial CT scan, the patient revisited the outpatient thoracic surgery clinic, complaining of aggravated pain in the right upper quadrant. Follow-up CT did not show any significant interval change in the mass, and wedge resection of the right lower lobe was performed for surgical biopsy. Grossly, the cut surface of the resected, well-circumscribed mass showed a whitish-gray tumor with calcifications measuring 5.5 cm in diameter. The tumor was confined to the lung parenchyma, and its pleural surface was smooth (Fig. 3). Histopathologically, the tumor was composed of densely populated short spindle cells with internal calcification foci and collagen deposits. Immunohistochemically, the tumor cells tested positive for CD99 and BCL2. Based on these findings, the tumor was diagnosed as a monophasic synovial sarcoma (Fig. 4). As pathologic findings cannot differentiate metastatic pulmonary synovial sarcoma from extrathoracic synovial sarcoma or primary pulmonary synovial sarcoma, a whole-body fluorodeoxyglucose-positron emission tomography (FDG-PET)/CT scan was performed, which showed no evidence of extrathoracic lesions; thus, the diagnosis of primary pulmonary synovial sarcoma was confirmed. After surgery, the patient's symptoms improved, and he received adjuvant chemotherapy. Figure 3. Macroscopic findings. The cut surface of the resected well-circumscribed mass shows a whitish-gray tumor with calcifications, measuring 5.5 cm in the largest diameter. The tumor was confined to the lung parenchyma, and its pleural surface was smooth. Figure 4. Histological findings after surgical biopsy. (A-C) Hematoxylin and eosin-stained microscopic images show a well-defined margin between the mass and normal lung parenchyma (original magnification x 40) (A), internal foci of calcifications (original magnification x 100) (B), and densely populated short spindle cells and collagen deposits between tumor cells (original magnification x 400) (C). (D) Immunochemistry stain for BCL2 was positive. These findings are consistent with synovial sarcoma. 3. Discussion Primary pulmonary synovial sarcoma is an aggressive tumor with a 5-year survival rate of 50%. In most cases, it lacks early symptoms. When symptomatic, it presents as a large, heterogeneous thoracic mass with pleuritic chest pain, cough, dyspnea, hemoptysis, or pleural effusion. On CT, it appears as a circumscribed mass with heterogeneous enhancement and occasional calcifications. These radiologic features are nonspecific, and differential diagnosis from other tumors such as intrathoracic sarcoma other than synovial sarcoma, solitary fibrous tumor of the pleura, thymic neoplasm, or lung cancer is needed. Even if synovial sarcoma is confirmed by surgical biopsy, it is not immunohistopathologically distinguishable from metastatic and primary synovial sarcomas. Furthermore, the lungs are the most common sites of metastasis from extrathoracic synovial sarcoma. Therefore, the diagnosis of primary pulmonary synovial sarcoma requires systematic investigation to exclude other possible diagnoses. Primary pulmonary synovial sarcoma rarely accompanies lymphadenopathy ; thus, if a large circumscribed mass is present in young adults without lymphadenopathy, not only lung cancer but also primary pulmonary synovial sarcoma should be considered. Whole-body FDG-PET/CT may be useful for excluding metastatic synovial sarcomas because synovial sarcomas tend to show avid FDG uptake. Synovial sarcomas are classified into 3 histologic subtypes: biphasic, monophasic, and poorly differentiated. Among these, biphasic synovial sarcoma is the most common type ; however, the monophasic type is much more common in the respiratory system. The histopathologic features in our case showed densely populated short spindle cells with areas of collagen fibers and focal calcifications consistent with synovial sarcoma. When a pulmonary nodule contains intranodal calcification, it is known as a central location, and a large coarse morphology such as popcorn-like or laminated calcification can virtually exclude malignancy; however, eccentric, punctate, or amorphous calcification suggests the potential for malignancy. A wide variety of entities can appear as nodules with calcification, from benign nodules such as hamartomas or granulomas to malignant conditions such as primary lung cancer and primary intrathoracic or metastatic sarcomas. Considering the broad spectrum of these entities, the possibility of malignancy should be evaluated when the calcification pattern does not exactly fit the benign pattern but the location of the nodule correlates with the patient's symptoms. Our case appeared as a circumscribed, heterogeneous, enhancing mass with intratumoral calcification, which is known as a primary pulmonary synovial sarcoma. However, calcifications in primary pulmonary sarcomas tend to be punctate or amorphous, which did not occur in our case, as calcifications appeared well-defined and coarse. Because of the nonspecific radiologic features of primary pulmonary synovial sarcoma and the discrepancy with its known calcification pattern, it could be misdiagnosed as a benign condition, such as hamartoma or post-inflammatory granuloma. However, on account of the diffusion-weighted MRI scan, we decided not to exclude the possibility of malignancy, which helped in an accurate diagnosis. Although MRI is not routinely used for the diagnosis of lung nodules, in this case, it was performed incidentally, and the tumor showed diffusion restriction, as previously reported. However, the generalizability of these MRI findings in primary pulmonary sarcoma is limited because of the small sample size. Further studies are needed to verify the MRI findings of primary pulmonary synovial sarcoma. 4. Conclusion The case presented here shows a radiologic picture of a rare primary pulmonary sarcoma with large coarse calcifications. Because of its slow-growing nature and calcification, it can be easily overlooked as a benign lesion. Active clinical and radiologic surveillance could help in the accurate diagnosis, and the use of nonroutine diagnostic modalities, such as diffusion-weighted MRI, can also be helpful in ambiguous lesions. Author contributions Conceptualization: Jin Young Yoo. Data curation: Chan Seop Kim, Ok Jun Lee. Investigation: Chan Seop Kim, Ok Jun Lee. Visualization: Chan Seop Kim, Jin Young Yoo. Writing - original draft: Chan Seop Kim, Jin Young Yoo. Writing - review & editing: Chan Seop Kim, Hye Soo Cho, Su Yeon Ahn, Jin Young Yoo. Abbreviations: CT computed tomography FDG-PET fluorodeoxyglucose-positron emission tomography MRI magnetic resonance imaging RUQ right upper quadrant The authors have no conflicts of interest to disclose. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. How to cite this article: Kim CS, Cho HS, Lee OJ, Ahn SY, Yoo JY. Primary pulmonary synovial sarcoma with delayed diagnosis in a 69-year-old man: A case report. Medicine 2023;102:51(e36620). References Gazendam AM Popovic S Munir S . Synovial sarcoma: a clinical review. Curr Oncol. 2021;28 :1909-20.34069748 Wilkerson BW Crim JR Hung M . Characterization of synovial sarcoma calcification. AJR Am J Roentgenol. 2012;199 :W730-4.23169746 Begueret H Galateau-Salle F Guillou L . Primary intrathoracic synovial sarcoma. Am J Surg Pathol. 2005;29 :339-46.15725802 Park JH Kang CH Kim CH . Highly malignant soft tissue sarcoma of the extremity with a delayed diagnosis. World J Surg Oncol. 2010;8 :84.20863406 Kim GH Kim MY Koo HJ . Primary pulmonary synovial sarcoma in a tertiary referral center. Medicine (Baltimore). 2015;94 :e1392.26313782 Bakri A Shinagare AB Krajewski KM . Synovial sarcoma: imaging features of common and uncommon primary sites, metastatic patterns, and treatment response. AJR Am J Roentgenol. 2012;199 :W208-15.22826423 Khan AN Al-Jahdali HH Allen CM . The calcified lung nodule: what does it mean? Ann Thorac Med. 2010;5 :67-79.20582171 Hong JH Jee W-H Jung C-K . Soft tissue sarcoma: adding diffusion-weighted imaging improves MR imaging evaluation of tumor margin infiltration. Eur Radiol. 2019;29 :2589-97.30413958 |
Medicine (Baltimore) Medicine (Baltimore) MD Medicine 0025-7974 1536-5964 Lippincott Williams & Wilkins Hagerstown, MD 00063 10.1097/MD.0000000000036676 3 5300 Research Article Clinical Case Report A case report of near-missed heat stroke Yeoh Cheng Wooi MD, MRCPI ab* Law Wan Chung MBBS, MRCP(UK) [email protected] b a Department of Medicine, Faculty of Medicine and Health Sciences, University of Malaysia Sarawak, Jalan Datuk Mohammad Musa, Kota Samarahan, Sarawak, Malaysia b Department of Medicine, Sarawak General Hospital, Jalan Hospital, Kuching, Sarawak, Malaysia. * Correspondence: Cheng Wooi Yeoh, Department of Medicine, Faculty of Medicine and Health Sciences, University of Malaysia Sarawak, Jalan Datuk Mohammad Musa, Kota Samarahan 94300, Sarawak, Malaysia (e-mail: [email protected]). 22 12 2023 22 12 2023 102 51 e3667620 9 2023 24 11 2023 Copyright (c) 2023 the Author(s). Published by Wolters Kluwer Health, Inc. 2023 This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Rationale: Heat-related illnesses have protean manifestations that can mimic other life-threatening conditions. The diagnosis of heat stroke requires a high index of suspicion if the patient has been exposed to a high-temperature environment. Central nervous system dysfunction is a cardinal feature. Strict adherence to temperature criteria can potentially lead to misdiagnosis. Patient concerns: A 37-year-old construction worker was brought in by his wife and coworker due to a sudden loss of consciousness while resting after completing his work. Diagnoses: Due to challenges faced during the coronavirus disease 2019 pandemic, as well as language barriers, a detailed history from the coworker who witnessed the patient's altered sensorium was not available. He was initially suspected of having encephalitis and brainstem stroke. However, subsequent investigations revealed multiorgan dysfunction with a normal brain computed tomography and cerebral computed tomography angiogram. In view of the multiple risk factors for heat stroke, pupillary constriction, and urine color suggestive of rhabdomyolysis, a diagnosis of heat stroke was made. Interventions: Despite delayed diagnosis, the patient's multiorgan dysfunction recovered within days with basic supportive care. Outcomes: There were no noticeable complications on follow-up 14 months later. Lessons: Heat stroke can be easily confused with other neurological pathologies, particularly if no history can be obtained from the patient or informant. When approaching a comatose patient, we propose that serum creatinine kinase should be considered as an initial biochemical screening test. coma creatine kinase heat stroke heat-related illness rhabdomyolysis unconsciousness OPEN-ACCESSTRUE pmc1. Introduction Heat-related illnesses consist of a spectrum of clinical conditions of varying severity. The heat stroke is at the extreme end of the continuum. Heat stroke is defined as a core body temperature of more than 40 0C associated with central nervous system dysfunction. The temperature criteria was arbitrarily determined, and different studies in the past years used different cutoff values. Clinicians should recognize that the core body temperature of heat stroke casualties may vary with the timing of measurement or after cooling measures have been attempted. Furthermore, it is not a routine practice to measure rectal temperature without specific indications. Heat stroke is a medical emergency. Prompt diagnosis, rapid cooling, and efficient supportive care are important elements in reducing morbidity and mortality. Most authors recommend cooling measures to be applied first in the field for heat stroke patients, then only transfer to the hospital. 2. Case description In January 2022, a 37-year-old male construction worker suddenly lost consciousness at his workplace at around 3.30 PM The day before, he had headache, back pain, and generalized weakness, but no fever. On the morning of the incident, he experienced a premonitory feeling of vague, indescribable discomfort. However, he still went to work. At noon, he experienced dizziness, but continued his piling work. He suddenly fell unconscious while resting after finishing his work for the day. His coworkers noted that he had a seizure. He was brought to a nearby clinic but was advised to visit the hospital. Due to the fear of contracting coronavirus disease 2019 (COVID-19), the coworker decided to send him back to his quarters and call for an ambulance. A wet towel was applied to his forehead while waiting for the ambulance. During the active waves of the COVID-19 pandemic, our hospital implemented an infection control policy that permitted only one person to accompany the patient at any point in time. The wife was the person who accompanied him. On arrival at the hospital, the patient was restless and uncooperative. His blood pressure was 132/82 mm Hg, pulse rate was 154 beats per minute, temperature was 36.8 0C (taken from scanning forehead by an infrared thermometer). Figure 1 shows the electrocardiography on arrival at the Emergency Department. He could move all his limbs. The patient was empirically treated for encephalitis by the attending team of doctors with intravenous Cephalosporin. He received intravenous diazepam 10 mg at 5.00 PM. An urgent plain computed tomography scan of the brain did not show any significant abnormalities. Due to his delirious state, the attending doctor administered intravenous midazolam 2 mg, followed by another intramuscular midazolam 2 mg, together with a dose of intramuscular haloperidol 5 mg at 7.25 PM. In view of the limited Intensive Care Unit bed and his stable condition, he was admitted to a General Medical Ward. The on-call team that reviewed him subsequently suspected the patient had a brainstem stroke. Figure 1. ECG on arrival at emergency department. (GRAYSCALE). ECG = electrocardiography. During our review, his wife's history revealed that he had been working as a construction worker for many years and had recently restarted his job 3 days prior, after being unemployed for more than 6 months during the COVID-19 pandemic. Usually, he wore a hat and 2 layers of clothing. His face fully covered with only the eyes exposed. The working hours were 6.00 am to 3.00 PM. Upon examination, his Glasgow Coma Scale (GCS) score was 9/15 (eye - 2; verbal - 1; and motor - 5). The pupils were 2 mm and equal. The neck was supple. The patient had bilateral flaccid limbs and flexor plantar responses. His urine was orange-brown in color. We suspected severe heat-related illness and immediately performed a serum creatine kinase assay. His intravenous hydration was optimized. Cooling measures, including the removal of clothing and fanning were applied. The patient was then transferred to a ward with air conditioning several hours later. His GCS improved after 4 hours but was only able to tell his name. The brain magnetic resonance imaging scan was canceled. His sensorium returned to normal, and pupillary constriction resolved more than 36 hours after the last dose of parenteral benzodiazepine. There was retrograde amnesia. He was able to ambulate with support on day 4 of admission. His body temperature was normal throughout the hospital stay. He was discharged on day 7 of admission and required another week to regain full muscle strength. Table 1 shows the serial investigation results during admission, which depict the affected organ systems. Table 1 Serial investigation results. Investigation On admission Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Reference range Hemoglobin 14.6 14.4 12.9 12 11.8 15.2 13.9 12.5-16.5 g/dL Total white cell 17.9 14.78 15.06 4.92 8.52 11.14 10.79 4-11 x 103/mL Platelet 244 89 58 53 83 191 158 142-424 x 103/mL PT 12.5 15.3 19.9 13.3 10.1-12.6 s APTT 33.8 30.5 31.2 30 28.2-39.8 s Sodium 141 140 137 138 136 137 137 135-145 mmol/L Urea 8.6 12 7.2 3.81 3.4 3.3 3.5 1.7-8.3 mmol/L Creatinine 255 242 108 76 67 80 63 60-120 mmol/L Total bilirubin 14.4 13 22.2 56.2 34.8 31.1 20.4 3-18 mmol/L AST 186 678 939 484 377 197 1-31 U/L ALT 69 109 491 1494 1067 977 691 1-31 U/L Albumin 38 30 28 28 26 29 35-52 g/L Calcium 2.42 2.27 1.97 2.20-2.55 mmol/L Phosphate 0.25 0.95 0.87 0.66-0.99 mmol/L Creatine kinase 10,566 14,334 9589 4723 39-108 U/L CK-MB 149 <25 U/L Troponin T 96 <10 ng/L Other investigation results: Venous blood gas (on arrival): pH: 7.322; pO2:44.7 mm Hg; pCO2: 33.8 mm Hg; HCO3-: 17.1; base excess: -7.9 mmol/L. Urine toxicology screen (post-IV diazepam): benzodiazepine detected. Peripheral blood film: no hemolysis, no platelet clump/fibrin seen. Blood culture: no growth. Blood film for malaria parasite: negative in three consecutive samples. Leptospira IgM: negative. Dengue serology: NS1 antigen/Ig M: negative; Ig G: positive. CT cerebral angiogram: no evidence of large vessel occlusion. ALT = alanine aminotransferase, APTT = activated partial thromboplastin time, AST = aspartate aminotransferase, CK-MB = creatine kinase-myocardial band, CT = computed tomography, HCO3- = bicarbonate, IgG = immunoglobulin G, IgM = immunoglobulin M, NS1 = nonstructural protein 1, pCO2 = partial pressure of carbon dioxide, pO2 = partial pressure of oxygen oxygen, PT = prothrombin time. The patient was followed up until 14 months later. He was able to do farming work and return to usual self. 3. Discussion Many conditions may present with high body temperatures and central nervous system dysfunction. Although our patient had a normal body temperature, the differential diagnoses of encephalitis or encephalopathy, brainstem stroke, cerebral malaria, severe dengue fever, thrombotic thrombocytopenic purpura, severe sepsis and drug intoxication had been considered. Anyway, subsequent investigations did not support the alternative diagnosis. Early recognition of heat-related illnesses could prevent unnecessary and costly investigations. As illustrated in this case, brain magnetic resonance imaging was called off upon diagnosis. The patient was admitted during the COVID-19 pandemic whereby strict infection control measures were implemented. During this period, the noncontact infrared forehead temperature was recorded on arrival at the emergency department and throughout the hospital stay. No rectal temperature measurements were performed. However, an infrared thermometer is not reliable for assessing body temperature. Moreover, 2 hours had passed since his symptom onset until he had a documented temperature upon arrival at the Emergency Department. Rigid adherence to the temperature cutoff value without considering factors that could have affected the body temperature would lead to missing the diagnosis of heat stroke. Our patient had several predisposing factors for exertional heat stroke. Borneo has a tropical rainforest climate, characterized by high temperatures and high humidity. His job as a construction worker has subjected him to prolonged exposure to a high-temperature environment. Besides, the lack of acclimatization following a 6-month cessation of the job of a similar nature made him susceptible to heat-related illness. Furthermore, his thick clothing may protect him from direct sunlight, but limits heat dissipation via convection and sweat evaporation. Exertional heat stroke has a lower mortality rate than classic heat stroke. However, the actual mortality rate in the general population is unknown, mainly because of misdiagnosis and incomplete data. The reported mortality rate of exertional heat illness varies widely between studies, ranging from 0% to 33%. Although the majority of the patients survived the acute episode of heat stroke, some survivors developed long-term neurologic and renal complications. Fortunately, our patient recovered without lasting sequelae despite delayed diagnosis, and no immediate cooling attempt was performed in the field. It is possible that both general supportive care and individual factors play important roles in the prognosis of severe heat-related illnesses. It is likely that timely removal of this patient from the environment and management of his delirious state with sedative drugs stopped further exertion, thereby reducing further heat production. In addition, the Emergency Department was air conditioned. Changing his clothing to thin hospital attire and intravenous hydration promoted heat dissipation. It is well recognized that pupillary constriction can occur in heat stroke. In fact, this patient's constricted pupils without upper motor neuron signs or cranial nerve palsies led to the suspicion of heat stroke upon transfer under our care. Intuitively, his pupillary constriction may be attributable to the administration of multiple doses of parenteral benzodiazepines (10 mg diazepam and 4 mg midazolam in total) at the Emergency Department. However, the pupil constriction lasted more than 36 hours. Midazolam has a short half-life. On the other hand, the sedative effect of diazepam is not associated with pupil constriction. Nevertheless, it is uncertain whether transient acute liver dysfunction has any effect on benzodiazepine metabolism. Most of the patient's history was obtained only after regaining consciousness. Additional details were gathered from a coworker who had witnessed his collapse. During admission, only a limited history could be obtained from the wife, as she was the only informant available. His wife spoke local dialect and slang, which contributed to a communication barrier for us. We only managed to contact the patient's coworker, who witnessed his sudden loss of consciousness during that day, more than one year after his discharge. According to the coworker, he saw the patient suddenly fell down while sitting in a pavilion. Upon approaching him, the patient was drooling bubbly saliva and the limbs were stiff and jerking. He was unresponsive with the eyes closed. There was no urinary incontinence or tongue biting noted. This description suggested that the patient had a generalized tonic-clonic seizure. Assessment of patients who are unable to provide a history can be a challenging task for clinicians. In a culturally diverse society and with the increasing popularity of international travel, clinicians may occasionally encounter patients with altered sensorium or language barriers. This could pose a diagnostic challenge, especially when a reliable informant or interpreter is unavailable. The importance of information about the timing, condition of the patient, and environment in which the patient was found could not be overemphasized. Careful systematic and targeted clinical examinations from head to toe are essential. In view of the broad differential diagnoses for unconsciousness, some basic initial screening blood investigations may be useful to guide further investigation or management. Rhabdomyolysis can result from prolonged coma; conversely, certain conditions that can cause rhabdomyolysis may result in coma.[13-15] Thus, we suggest that serum creatine kinase should be included as part of the initial workup for acutely unconscious patients when a reliable history cannot be obtained from the patient or any informant. To illustrate the relationship between elevated serum creatine kinase levels and coma, we created a diagram, as shown in Figure 2. Although creatinine kinase is not a specific biomarker, it is relatively cheap and readily accessible in resource-limited settings. It can be used to screen for many conditions associated with an altered sensorium. Figure 2. Conditions that may present with coma and associated with raised serum creatine kinase. (RGB); Black arrows: conditions that may lead to rhabdomyolysis; blue arrows: conditions that can present as coma; purple arrows: conditions that can manifest as raised serum creatine kinase. 4. Patient perspective In retrospect, the patient felt that the degree of exertion was not particularly high before he lost consciousness. It took him by surprise upon regaining consciousness in the hospital. He found that physiotherapy was helpful in regaining muscle strength. Acknowledgments We are indebted to Dr Huong Nai Law for reviewing and editing the manuscript. We would like to thank the University of Malaysia Sarawak for providing the necessary support for this publication. The authors would also like to thank the patient and Director General of Health, Ministry of Health, Malaysia, for permitting access to the patient's medical records for publication. Author contributions Conceptualization: Cheng Wooi Yeoh. Data curation: Cheng Wooi Yeoh. Formal analysis: Cheng Wooi Yeoh, Wan Chung Law. Investigation: Cheng Wooi Yeoh, Wan Chung Law. Software: Cheng Wooi Yeoh. Supervision: Cheng Wooi Yeoh, Wan Chung Law. Validation: Cheng Wooi Yeoh, Wan Chung Law. Visualization: Cheng Wooi Yeoh. Writing - original draft: Cheng Wooi Yeoh. Writing - review & editing: Cheng Wooi Yeoh, Wan Chung Law. Abbreviation: COVID-19 coronavirus disease 2019 The patient provided written informed consent for his personal or clinical details along with any identifying images to be published in an online, open-access journal. CARE guidelines for case reports were followed. The datasets generated during and/or analyzed during the current study are not publicly available, but are available from the corresponding author on reasonable request. The authors have no conflicts of interest to disclose. How to cite this article: Yeoh CW, Law WC. A case report of near-missed heat stroke. Medicine 2023;102:51(e36676). References Sorensen C Hess J . Treatment and prevention of heat-related illness. N Engl J Med. 2022;387 :1404-13.36170473 Yezli S Yassin Y Ghallab S . Classic heat stroke in a desert climate: a systematic review of 2632 cases. J Intern Med. 2023;294 :7-20.36951097 Rublee C Dresser C Giudice C . Evidence-based heatstroke management in the emergency department. West J Emerg Med. 2021;22 :186-95.33856299 Epstein Y Yanovich R . Heatstroke. N Engl J Med. 2019;380 :2449-59.31216400 Leon LR Bouchama A . Heat stroke. Compr Physiol. 2015;5 :611-47.25880507 Sullivan SJL Rinaldi JE Hariharan P . Clinical evaluation of non-contact infrared thermometers. Sci Rep. 2021;11 :22079.34764438 Westwood CS Fallowfield JL Delves SK . Individual risk factors associated with exertional heat illness: a systematic review. Exp Physiol. 2021;106 :191-9.32249985 Demartini JK Casa DJ Stearns R . Effectiveness of cold water immersion in the treatment of exertional heat stroke at the Falmouth Road Race. Med Sci Sports Exerc. 2015;47 :240-5.24983342 Knoll JM Knight LR Quiroz D . Variation in clinical presentations and outcomes of heat stroke victims in the mass-casualty setting. J Emerg Med. 2019;57 :866-70.31606230 Liu S Xing L Wang Q . Association between early stage-related factors and mortality in patients with exertional heat stroke: a retrospective study of 214 cases. Int J General Med. 2021;14 :4629-38. Walter EJ Carraretto M . The neurological and cognitive consequences of hyperthermia. Crit Care. 2016;20 :199.27411704 Szabadi E . Functional organization of the sympathetic pathways controlling the pupil: light-inhibited and light-stimulated pathways. Front Neurol. 2018;9 :1069.30619035 Cooksley T Rose S Holland M . A systematic approach to the unconscious patient. Clin Med (Lond). 2018;18 :88-92.29436445 May R Hunt K . Clinical approach to comatose patients. Anaesth Intensive Care Med. 2019;21 :16-9. Fernandes PM Davenport RJ . How to do it: investigate exertional rhabdomyolysis (or not). Pract Neurol. 2019;19 :43-8.30305378 |
Medicine (Baltimore) Medicine (Baltimore) MD Medicine 0025-7974 1536-5964 Lippincott Williams & Wilkins Hagerstown, MD 00021 10.1097/MD.0000000000036734 3 4500 Research Article Clinical Case Report Upside-down stomach in paraesophageal hernia: A case report Zhu Xiuliang MD [email protected] a Hu Chengyu MM [email protected] b Gong Weihua MD c* a Department of Radiology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China b Department of Surgery, Second Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou, China c Department of Gastrointestinal Surgery, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China. * Correspondence: Weihua Gong, Department of Gastrointestinal Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, No. 88 Jiefang Road, Hangzhou, 310009, China (e-mail: [email protected]). 22 12 2023 22 12 2023 102 51 e3673428 9 2023 30 11 2023 Copyright (c) 2023 the Author(s). Published by Wolters Kluwer Health, Inc. 2023 This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Rationale: Paraesophageal hernias, accounting for a mere 5% to 10% of all hiatal hernias, occasionally present an exceedingly uncommon yet gravely consequential complication characterized by the inversion of the stomach. Delving into the clinical manifestations and optimal therapeutic approaches for patients afflicted by this condition merits substantial exploration. Patient concerns: A 60-year-old man was referred to our hospital with acute onset of severe epigastric pain, abdominal distension, and vomiting. A chest radiograph unveiled an elevated left diaphragmatic dome accompanied by a pronounced rightward shift of the mediastinum. Subsequent abdominal computed tomography imaging delineated the migration of the stomach, spleen, and colon into the left hemithorax, facilitated by a significant diaphragmatic defect. Diagnoses: The diagnosis of a giant paraesophageal hernia with complete gastric inversion was established through a comprehensive evaluation of the patient's clinical manifestations and imaging findings. Interventions: Surgical intervention was performed on the patient. During the procedure, a left diaphragmatic defect measuring approximately 10 x 8 cm was identified and meticulously repositioned, followed by the repair of the diaphragmatic hernia. The herniated contents comprised the pancreas, stomach, spleen, a segment of the colon, and a portion of the greater omentum. Outcomes: The patient experienced a smooth postoperative recuperation and was discharged 12 days following the surgical procedure. Subsequently, during a 7-month follow-up period, the patient continued to exhibit favorable progress and recovery. Lessons: Paraesophageal hernias are rare, and the presence of an inverted stomach in a giant paraesophageal hernia is exceptionally uncommon. Clinical presentation lacks distinct features and can lead to misdiagnosis. This case emphasizes the importance of timely surgical intervention guided by imaging, offering valuable clinical insights. hiatal hernia paraesophageal hernia upside-down stomach OPEN-ACCESSTRUE pmc1. Introduction Upside-down stomach anomaly is an infrequent manifestation of paraesophageal hernia, constituting a minority subset within the realm of diaphragmatic hernias. Among the spectrum of hiatal hernias, paraesophageal herniation comprises a mere 5% to 10%. The presence of an upside-down stomach is exceptionally rare, and the prompt identification of this anomaly in its incipient stages holds substantial clinical significance, contributing significantly to the formulation of effective treatment strategies. When a large paraesophageal hernia occurs, the abdominal organs protrude into the thoracic cavity through the hiatal hernia. The condition known as upside down stomach is considered a severe manifestation of gastric volvulus, which was first documented by Berti in 1886. Gastric volvulus can occur along the organ and mesenteric axes, with the latter being relatively uncommon. In the acute phase, upside down stomach primarily presents with gastrointestinal symptoms. It is crucial to promptly and accurately diagnose this condition, as ischemia, necrosis, and perforation may be observed in cases of incarcerated stomach with gastric volvulus. Timely surgical intervention significantly mitigates mortality and associated complications. This case report contributes substantial clinical evidence to enhance treatment and diagnostic approaches. 2. Case presentation A 60-year-old man was referred to hospital due to an acute episode of severe epigastric pain, abdominal distension, and vomiting that lasted tens of hours. This patient has no previous gastrointestinal or cardiovascular disease, and no history of abdominal and thoracic trauma was evident in anamnesis. While patient has a history of high blood pressure and takes medication regularly. The patient exhibited mild tenderness of the epigastrium and left upper quadrant with guarding and no rebound tenderness on physical examination. Cardiovascular and respiratory examinations were unremarkable. The routine laboratory studies were unremarkable. Hence, chest radiography (Fig. 1A), upper gastrointestinal barium study (Fig. 1B), and abdominal computed tomography (CT) scanning (Fig. 1C) was performed. Chest radiograph showed a high left diaphragmatic dome and the mediastinum has shifted to the right. Upper gastrointestinal barium study showed that the stomach was completely upside-down. Abdominal CT reconstructed sagittal image revealed large diaphragmatic defect which allowed passage of the stomach, colon, and spleen in the left hemithorax. Based on the patient's clinical symptoms and imaging manifestations, the diagnosis of diaphragmatic hernia was made. Emergency laparotomy was performed and a left diaphragmatic defect measuring about 10 x 8 cm was identified. Hernia contents involving the pancreas, stomach, spleen, part of the colon, and the greater omentum were reduced. A splenectomy and gastropexy were performed and primary repair of diaphragm with mesh was done. Postoperative upper gastrointestinal barium study was normal (Fig. 1D). The postoperative course was uneventful, and the patient was discharged 12 days after surgery and was well at 7 months' follow-up. Although the incidence is low, when it occurs there is a high risk of life-threatening complications. By describing the clinical profile and treatment options for this rare disease, it provides direction and experience for clinicians in diagnosis and treatment. This case will also enhance our knowledge and understanding of the disease and avoid misdiagnosis. Figure 1. (A) Chest radiograph shows elevated left diaphragmatic dome with rightward shift of mediastinum. (B) Upper gastrointestinal barium study shows stomach was upside-down. (C) Abdominal CT reconstructed sagittal image shows stomach, spleen, and colon passing through left hemithorax via large diaphragmatic defect. (D) Postoperative barium meal imaging indicates stomach's return to normal position. 3. Discussion Diaphragmatic hernia is categorized into congenital and acquired. Among the acquired types, esophageal hiatal hernia is prevalent. There exist 4 categories of esophageal hiatal hernias: sliding, paraesophageal, mixed, and giant paraesophageal. However, a standardized definition for giant paraesophageal hernias is lacking. Some assert that when at least 30% of the stomach translocates into the thoracic cavity, it qualifies, while others posit a threshold of over 50% stomach hernia. In this presented case, the paraesophageal hernia displayed as an upside-down stomach, or even herniation of the spleen, colon, small intestine, or pancreas into the thoracic cavity. This signifies a comprehensive stomach prolapse, warranting the diagnosis of a type IV giant paraesophageal hernia. Upside-down stomach occurrence within paraesophageal hernias is exceptionally rare, prompting discussion on potential pathogenesis and clinical manifestations. Diaphragmatic hiatus and relaxation of the phrenoesophageal membrane stand as primary culprits for diaphragmatic herniation. The presence of a pressure gradient between thoracic and abdominal cavities facilitates herniation of the stomach and other abdominal organs into the thoracic region. The stomach and other organs rotate into the thoracic cavity along the axis of the diaphragmatic membrane organ from the esophageal hiatus. As this progression unfolds, the stomach undergoes a 180-degree rotation, culminating in gastric inversion. Research has demonstrated that with age, the diaphragmatic esophageal ligament's resilience and tension decline, primarily attributed to decreased collagen levels. Consequently, the incidence of esophageal hiatal hernia significantly rises in elder patients harboring concurrent ailments and degenerative conditions. Further investigations have suggested the potential role of genetic factors as etiological contributors. In a clinical context, symptoms associated with gastroesophageal reflux disease might manifest in type I and type II hiatal hernias. Type III hernias usually present with epigastric pain, nausea, and dysphagia. Notably, type IV giant paraesophageal hernias can induce dyspnea, abdominal pain, bloating, and vomiting, although certain patients remain asymptomatic. The clinical portrayal of an upside-down stomach hinges upon disease progression, stomach location, gastric torsion, and the extent of obstruction. The acute phase is typified by gastrointestinal obstruction, which underlines the urgency of diagnosis and intervention. With the stomach twisted and inverted within the thoracic cavity, bleeding of the gastric mucosa ensues, representing a significant pathological consequence. The gravest complications involve gastric perforation or necrosis. Furthermore, gastric herniation has been linked to the onset of iron deficiency anemia. This condition arises due to chronic blood loss attributed to mucosal lesions stemming from the stomach's twisting process, an aspect often underestimated, ultimately culminating in iron deficiency anemia. Hernia sacs that protrude into the chest cavity can result in the constriction of the thoracic dimensions. This occurrence compromises both the respiratory and circulatory systems due to the resultant compression exerted on the heart and lungs. Chest X-ray, CT, and upper gastrointestinal barium studies serve as diagnostic aids to corroborate the diagnosis. Among these, CT is hailed as the diagnostic gold standard for hernias. It affords clinicians the precision to delineate hernia location, dimensions, and contents. Recent series of cases have reported a mortality rate of approximately 15% to 20% for paraesophageal hernias, with a noteworthy surge in mortality when severe complications arise. This underscores the criticality of emergent surgical hernia repair as the chosen course of action. The transition from traditional open surgery to laparoscopic treatment represents a substantial advancement, bearing significant implications for hiatal hernia treatment. Presently, laparoscopic fundoplication stands as a prevalent strategy for addressing paraesophageal hernias. The utilization of laparoscopic techniques boasts favorable attributes including a high success rate, expedited recovery, and fewer postoperative complications.[18-20] Previously, nonabsorbable suture repair was the norm for most paraesophageal hernia surgical interventions. Despite ongoing debates concerning complications arising from mesh repair, biological meshes have garnered increased attention due to their merits, including reduced recurrence rates and heightened resistance to infection. In contrast to earlier case reports, this patient's clinical presentation centered solely around severe epigastric pain, abdominal distension, and vomiting. Interestingly, the absence of prominent symptoms like cardiac compression and dyspnea indicates that during the acute phase of a giant paraesophageal hernia, gastrointestinal symptoms could assume a primary role. This underscores the immediate need to accurately confirm acute giant paraesophageal hernia cases, averting any potential misdiagnoses that might compromise effective treatment strategies. Age-related factors should be considered, as diminished diaphragmatic tone and ligament laxity likely contributed to the abrupt onset of acute paraesophageal hernia. A noteworthy observation is that the patient exhibited a complete inversion of the stomach within the thoracic cavity, accompanied by concurrent herniation involving the pancreas, spleen, colon, and greater omentum. Fortunately, swift intervention through laparoscopic repair surgery culminated in a positive prognosis for the patient. Distinguishing this case from previous reports is the exceptional rarity of the patient's giant paraesophageal hernia, positioning it as a valuable model for shaping future diagnostic and therapeutic frameworks. Given the infrequent occurrence and increased risk associated with upside-down stomach in paraesophageal hernias, the main focus is on swift and timely diagnosis, coupled with surgical intervention. This approach significantly reduces patient mortality rates and improves overall prognoses. The underlying mechanisms causing inverted stomach in paraesophageal hernias need thorough exploration in subsequent research efforts. This can lead to proactive strategies to prevent upside-down stomach from emerging in this clinical context. Furthermore, establishing standardized protocols for clinical diagnosis and treatment is crucial. This ensures consistency and accuracy in patient care. The ongoing exploration of various treatment methods not only represents optimism but also instills renewed hope among those affected by this condition. Author contributions Conceptualization: Xiuliang Zhu. Supervision: Weihua Gong. Writing - original draft: Xiuliang Zhu. Writing - review & editing: Chengyu Hu. Abbreviation: CT computed tomography XZ and CH contributed equally to this work. All data generated or analyzed during this study are included in this published article [and its supplementary information files]. The patient gave written consent for publication. The authors have no conflicts of interest to disclose. How to cite this article: Zhu X, Hu C, Gong W. Upside-down stomach in paraesophageal hernia: A case report. Medicine 2023;102:51(e36734). References Caruso G Caramma S Zappala A . Acute intrathoracic gastric volvulus with retrograde gastric intussusception: a case report of a rare surgical emergency with review of the literature. Int J Surg Case Rep. 2020;72 :381-5.32563826 Lainez Ramos-Bossini AJ Ruiz Carazo E Rabadan Caravaca MD . 'Back-and-Forth Stomach' CT imaging findings of a pathophysiologic entity causing acute gastric volvulus. Tomography. 2022;8 :245-56.35202185 Lesinski J Zielonka TM Wajtryt O . Giant hiatal hernias. Adv Respir Med. 2019;87 :54-62.30830959 Dean C Etienne D Carpentier B . Hiatal hernias. Surg Radiol Anat. 2012;34 :291-9.22105688 Mitiek MO Andrade RS . Giant hiatal hernia. Ann Thorac Surg. 2010;89 :S2168-2173.20494004 Li J Guo C Shao X . Another type of diaphragmatic hernia to remember: parahiatal hernia. ANZ J Surg. 2020;90 :2180-6.32356615 Apaydin N Uz A Evirgen O . The phrenico-esophageal ligament: an anatomical study. Surg Radiol Anat. 2008;30 :29-36.18058057 Carre IJ . Familial hiatal hernia. West J Med. 1985;143 :251-2. McDowell BC Horst KK Klinkner DB . Congenital paraesophageal hernia with gastric outlet obstruction in a neonate with Cornelia de Lange Syndrome. Radiol Case Rep. 2022;17 :1478-82.35265244 Callaway JP Vaezi MF . Hiatal and paraesophageal hernias. Clin Gastroenterol Hepatol. 2018;16 :810-3.29306040 Umemura A Suto T Fujiwara H . Cardiopulmonary impairments caused by a large hiatal hernia with organoaxial gastric volvulus showing upside-down stomach: a case report. Am J Case Rep. 2019;20 :1530-5.31624225 Dietrich CG Hubner D Heise JW . Paraesophageal hernia and iron deficiency anemia: mechanisms, diagnostics and therapy. World J Gastrointest Surg. 2021;13 :222-30.33796212 Ohira S Okada Y Ishida Y . Cardiopulmonary arrest secondary to compression of the heart owing to esophageal hiatal hernia: a case report. Acute Med Surg. 2020;7 :e615.33364036 Humble AG Sample CB . Morgagni's hernia in a hypoxaemic adult. Lancet. 2016;388 :705.26831471 Sfara A Dumitrascu DL . The management of hiatal hernia: an update on diagnosis and treatment. Med Pharm Rep. 2019;92 :321-5.31750430 Omura N Tsuboi K Yano F . Minimally invasive surgery for large hiatal hernia. Ann Gastroenterol Surg. 2019;3 :487-95.31549008 Testini M Girardi A Isernia RM . Emergency surgery due to diaphragmatic hernia: case series and review. World J Emerg Surg. 2017;12 :23.28529538 Petrov RV Su S Bakhos CT . Surgical anatomy of paraesophageal hernias. Thorac Surg Clin. 2019;29 :359-68.31564392 Ceccarelli G Pasculli A Bugiantella W . Minimally invasive laparoscopic and robot-assisted emergency treatment of strangulated giant hiatal hernias: report of five cases and literature review. World J Emerg Surg. 2020;15 :37.32487136 Sakran N Nevo H Dar R . Laparoscopic repair of a large paraesophageal hernia with migration of the stomach into the mediastinum creating an upside-down stomach. Case Rep Surg. 2017;2017 :7428195.28770120 Muller-Stich BP Kenngott HG Gondan M . Use of mesh in laparoscopic paraesophageal hernia repair: a meta-analysis and risk-benefit analysis. PLoS One. 2015;10 :e0139547.26469286 |
Medicine (Baltimore) Medicine (Baltimore) MD Medicine 0025-7974 1536-5964 Lippincott Williams & Wilkins Hagerstown, MD 00067 10.1097/MD.0000000000036591 3 5700 Research Article Clinical Case Report Case report: Successful sequential therapy of crizotinb and entrectinib in ROS1-positive non-small-cell lung cancer with brain metastasis in later-settings Dong Wen MD a* Zhuge Jinke MD [email protected] a Yu Pengli MD [email protected] b Liu Kai MD [email protected] c Yang Mingxing BS [email protected] a Wang Hongkang BS [email protected] a a Department of Respiratory Medicine, Hainan Cancer Hospital, Hainan Province, China b Geneplus Beijing, Beijing, China c Department of Respiratory Medicine, Hainan General Hospital (Affiliated Hainan Hospital of Hainan Medical University), Hainan Province, China. * Correspondence: Wen Dong, Department of Respiratory Medicine, Hainan Cancer Hospital, 570311, Hainan Province, China (e-mail: [email protected]). 22 12 2023 22 12 2023 102 51 e3659121 7 2023 09 10 2023 Copyright (c) 2023 the Author(s). Published by Wolters Kluwer Health, Inc. 2023 This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Rationale: Crizotinib has been approved in many countries for the treatment of patients with advanced ROS1-rearranged non-small cell lung cancers (NSCLC). Entrectinib is a ROS1 inhibitor that has been designed to effectively penetrate and remain in the central nervous system (CNS) and has been recommended as first-line therapy. Few reports have precisely described sequential crizotinb followed by entrectinib in patients with ROS1 fusion in later settings. Patient concerns: A 56-year-old man with a history of occasional smoking visited our hospital with cough, sputum, and shortness of breath. Diagnosis: He was diagnosed with right lung adenocarcinoma (T4N2M1a, stage IV) after image and histological examination, without EGFR or ALK fusion mutation. Interventions: He received three prior lines of therapies, including chemotherapy, nivolumab monotherapy, and paclitaxel plus anlotinib, with progression-free survival (PFS) of 5, 2, and 11.5 months, respectively. Then the patient began to have headaches and dizziness, and brain magnetic resonance imaging showed multiple brain metastases. Next-generation sequencing (NGS) of the biopsy from neck lymph node identified EZR-ROS1 (1.25% abundance). After 2 months of crizotinib (250 mg daily) plus bevacizumab, all pulmonary and brain lesions decreased, but a small liver lesion was discovered. As treatment went on for another 4 months, the liver lesion continued to grow while other lesions kept decreased or stable state. NGS analysis on the peripheral blood found the disappearance of EZR-ROS1 fusion and a new NTRK2 mutation (c.5C>T, p.Ser2Leu, 0.34% abundance) without other targetable molecular alteration. He received entrectinib (600 mg daily) plus bevacizumab and achieved a partial response. After 7 months of therapy, examination revealed progression of brain lesions. Outcomes: The patient had a total PFS of 13 months from sequential crizotinib and entrectinib therapy. Lessons: A ROS1-rearranged NSCLC with CNS metastases responded to sequential tyrosine kinase inhibitors treatment of crizotinb followed by entrectinib. This report has potential implications in guiding decisions for the treatment after crizotinib resistance. crizotinb resistance entrectinib EZR-ROS1 NSCLC OPEN-ACCESSTRUE pmc1. Introduction Chromosomal rearrangements of ROS1, can lead to the formation of constitutively active fusion proteins which act as oncogenic drivers. ROS1 fusions are identified in approximately 1 to 2% of non-small cell lung cancers (NSCLC) and define a distinct molecular subset of NSCLC. CD74-ROS1 is the most common fusion variant detected among patients. Crizotinib has been approved for use in ROS1-positive NSCLC based on the PROFILE 1001 study, which observed a median progression-free survival (PFS) of 19.2 months. Resistance to crizotinib can be mediated by secondary mutations within the ROS1 kinase domain, or by activation of alternative signaling pathways. An updated integrated analysis of 3 clinical trials of another ROS1 tyrosine kinase inhibitor (TKI), entrectinib, demonstrated a high level of clinical benefit and intracranial efficacy in ROS1-rearranged NSCLC. Considering the high risk of CNS metastases in NSCLC, entrectinib is recommended as a first-choice TKI rather than after progression on another TKI. Lorlatinib showed clinical activity in those previously treated with crizotinib and represented an important next-line targeted agent. Through the previous literature and case reports, sequential entrectinib after crizotinib in ROS1-positive NSCLC was rarely reported. Our case has provided valuable clinical evidence for sequential TKI therapy of crizotinb followed by entrectinib in patients with ROS1 fusion. 2. Case report In August 2019, a 56-year-old male patient, with occasional smoking history, was referred to the Hainan Cancer Hospital with symptoms of cough and sputum which had persisted for 2 weeks, and shortness of breath that had persisted for 4 days. The contrast-enhanced computed tomography (CT) scan showed a 8.0 cm x 6.9 cm mass in the lower lobe of right lung, with multiple bilateral pulmonary nodules, hilum of right lung and mediastinal lymph node metastasis, and right sided pleural effusion (Fig. 1A). A right lung biopsy was obtained and established the pathologic diagnosis of invasive lung adenocarcinoma (Fig. 2). EGFR mutation and ALK tests showed negative results. Programmed death ligand 1 (PD-L1) expression was also negative after immunohistochemical (IHC) assay. Finally, his disease was diagnosed as right lung adenocarcinoma (T4N2M1a, stage IV), with an Eastern Cooperative Oncology Group performance status of 1. Figure 1. Timeline summary with dynamic imaging of the different therapeutic lines between August 2019 and May 2022. Baseline chest CT showing (A) a lung mass in the right lower lobe. Best response under chemotherapy with a partial response (B). Chest CT before second-line nivolumab beginning (C) and at disease progression (D). A partial response at 4 months after third-line therapy (E). Baseline chest CT and brain MRI (F) before crizotinib. Assessment showed a partial response of all lung lesions and brain lesions after 2 months of crizotinib (G), but new liver lesions (G, H). Chest CT and brain MRI before entrectinib beginning (I) and follow-up scans with partial response (J) and at brain lesions progression (K). CT, computed tomography, MRI, magnetic resonance imaging. Figure 2. Pathological examination of the patient. Lung tissue biopsy specimen at diagnosis (Hematoxylin-eosin staining, magnification x10). The patient started to received first-line pemetrexed (850mg) plus nidaplatin (140 mg) after diagnosis. After 3 months, CT showed a partial response of the lung (Fig. 1B). He received 6 cycles of platinum-based doublets and 1 cycle of pemetrexed disodium maintenance therapy and experienced disease progression (PD, Fig. 1C), with a progression-free survival (PFS) of 5 months. Second and third-line therapies were prescribed: nivolumab (200 mg, PFS, 2 months, Fig. 1D) and then nanoparticle albumin bound paclitaxel (450mg) plus anlotinib (12mg daily, PFS, 11.5 months, Fig. 1E). In April 2021, he began to have headaches and dizziness. The brain magnetic resonance imaging showed multiple brain metastases (Fig. 1F). At this time, a biopsy from neck lymph node was performed and showed metastasis from lung cancer. Next-generation sequencing (NGS) of the biopsy identified EZR-ROS1(E9: R33) (1.25% abundance). IHC showed positive expression of PD-L1, with tumor cell proportion score equal to 20% (SP263 antibody). On April 23,2021, the patient received crizotinib (250 mg daily). Assessment by CT at 2 months showed a decrease in all pulmonary and brain lesions, but a new liver lesion (Fig. 1G). Additional bevacizumab was added while continuing crizotinib. After 4 months of crizotinib, the liver lesion continued to grow while other lesions kept decreased or stable state. On 8 September, a new CT reassessment showed new and enlarged hepatic and splenic lesions, corresponding to a clear progression (Fig. 1H). Molecular analysis on the peripheral blood by NGS of DNA found the disappearance of EZR-ROS1 and a NTRK2 (c.5C > T, p.Ser2Leu, 0.34% abundance) without other targetable molecular alteration. Hence, after a molecular tumor board discussion, he received entrectinib (600 mg daily) plus bevacizumab on 14 October. Early assessment by CT at 12 days and at subsequent visits showed a partial response, with a decrease of all lesions, including hepatic and splenic lesions (Fig. 1I-K). The patient achieved a PFS about 7 months until progression of brain lesions (Fig. 1K). The patient had a total PFS of 13 months from sequential crizotinib and entrectinib therapy. Liquid biopsy of plasma blood revealed no driver mutations. Then the patient received additional radiation therapy for brain metastases and died of the end of November 2022 with overall survival of 38 months. 3. Discussion ROS1 is among the molecular biomarkers which should be analyzed at diagnosis in non-small cell lung cancer (NSCLC). Testing for these biomarkers is important for identification of potentially efficacious targeted therapies, as well as avoidance of therapies unlikely to provide clinical benefit. Tumor biopsy of the present case at diagnosis was only tested for EGFR, ALK and PD-L1, resulted in negative driver gene mutation. The overall prevalence rate of ROS1 fusion was 2.1% according to a cohort study of Chinese lung cancer patients. Advanced or locally advanced ROS1-rearranged NSCLCs achieved significantly longer median PFS (18.0 months vs 7.0 months, P < .001) from first-line crizotinib compared with first-line therapy chemotherapy. Another study in East Asian patients with ROS1-positive advanced NSCLC showed that crizotinib was beneficial in both later-line settings. The presence of brain metastasis, other concomitant mutations in various genes, and single CD74-ROS1 fusion might impair the crizotinib efficacy. The present case had uncommon single EZR-ROS1 fusion, with no co-occurring driver mutations or tumor suppressor genes detected. ROS1 resistance mutations were identified in 38% cases in the crizotinib-resistant biopsies, over one half of patients had unknown mechanisms of resistance to crizotinib based on gene sequencing alone. Several driver gene mutations were reported after crizotinib resistance in ROS1 positive NSCLC. Our case detected no ROS1 resistance mutation or driver gene mutation on liquid biopsy after progression on crizotinib. The discrepancies were identified between matched tumor and plasma analyses in certain cases, likely owing to multiple factors including tumor heterogeneity. The patient experienced liver progression while other lesions kept response. NGS of new biopsy on liver lesions might help reveal the mechanism of resistance. Entrectinib is a multikinase inhibitor with antitumor activity against ROS1, ALK and pan-tropomyosin receptor kinase. Entrectinib demonstrated a high level of clinical benefit for patients with ROS1 rearrangement NSCLC, including those with CNS metastases. National Comprehensive Cancer Network guidelines recommend ceritinib or crizotinib or entrectinib as preferred first-line tyrosine kinase inhibitors and lorlatinib or entrectinib upon progression. In patients with ROS1 positive, around one third responded to lorlatinib after crizotinib resistance, with median PFS of 8.5 months. However, in patients previously treated with crizotinib, entrectinib is ineffective against the most frequently reported crizotinib-resistance mutation ROS1 G2032R. Mutations other than ROS1 G2032R might be responsible for crizotinib resistance. Few clinical cases described entrectinib treatment after cizotinib resistance. At present, the patient kept responding to entrectinib with a PFS of 7 months after resistance to fourth-line crizotinib therapy, which lasted for about 6 months. These results indicate that entrectinib may be useful after resistance to crizotinib with unknown resistance mechanisms through molecular analysis. Although our result is promising, there are some limitations to this report. First, this report describes only 1 successful case; the underlined mechanisms of crizotinib resistance and entrectinib responsive to liver lesions remain unclear; whether other patients are sensitive to this sequential target regimen is still unknown. Further larger studies may be needed to confirm clinical activity of entrectinib in crizotinib-treated patients. As a conclusion, this case emphasizes the potential benefit of sequential TKI therapy of crizotinb followed by entrectinib despite the absence of resistance mechanism in patient with ZER-ROS1 fusion. However, as this report describes only 1 case, studies on more patients are needed to verify its effectiveness in future. Author contributions Data curation: Jinke Zhuge, Kai Liu, Mingxing Yang, Hongkang Wang. Investigation: Jinke Zhuge, Pengli Yu, Hongkang Wang. Supervision: Wen Dong. Writing - original draft: Wen Dong, Pengli Yu, Mingxing Yang. Writing - review & editing: Wen Dong, Jinke Zhuge. Abbreviations: CNS central nervous system CT computed tomography IHC immunohistochemical NSCLC non-small cell lung cancers PD-L1 programmed death ligand 1 PFS progression-free survival TKI tyrosine kinase inhibitor Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. The authors have no funding and conflicts of interest to disclose. Written informed consent was obtained from the participant for the publication of this case report. How to cite this article: Dong W, Zhuge J, Yu P, Liu K, Yang M, Wang H. Case report: Successful sequential therapy of crizotinb and entrectinib in ROS1-positive non-small-cell lung cancer with brain metastasis in later-settings. Medicine 2023;102:51(e36591). References Drilon A Jenkins C Iyer S . ROS1-dependent cancers - biology, diagnostics and therapeutics. Nat Rev Clin Oncol. 2021;18 :35-55.32760015 Davies KD Doebele RC . Molecular pathways: ROS1 fusion proteins in cancer. Clin Cancer Res. 2013;19 :4040-5.23719267 Bergethon K Shaw AT Ou SH . ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol. 2012;30 :863-70.22215748 Zhang Y Zhang X Zhang R . Clinical and molecular factors that impact the efficacy of first-line crizotinib in ROS1-rearranged non-small-cell lung cancer: a large multicenter retrospective study. BMC Med. 2021;19 :206.34511132 Shaw AT Ou SH Bang YJ . Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med. 2014;371 :1963-71.25264305 Shaw AT Riely GJ Bang YJ . Crizotinib in ROS1-rearranged advanced non-small-cell lung cancer (NSCLC): updated results, including overall survival, from PROFILE 1001. Ann Oncol. 2019;30 :1121-6.30980071 Lin JJ Choudhury NJ Yoda S . Spectrum of mechanisms of resistance to crizotinib and lorlatinib in ROS1 fusion-positive lung cancer. Clin Cancer Res. 2021;27 :2899-909.33685866 Dziadziuszko R Krebs MG De Braud F . Updated integrated analysis of the efficacy and safety of entrectinib in locally advanced or metastatic ROS1 fusion-positive non-small-cell lung cancer. J Clin Oncol. 2021;39 :1253-63.33646820 Shaw AT Solomon BJ Chiari R . Lorlatinib in advanced ROS1-positive non-small-cell lung cancer: a multicentre, open-label, single-arm, phase 1-2 trial. Lancet Oncol. 2019;20 :1691-701.31669155 Wu YL Yang JC Kim DW . Phase II study of crizotinib in East Asian patients with ROS1-positive advanced non-small-cell lung cancer. J Clin Oncol. 2018;36 :1405-11.29596029 Wang P Fabre E Martin A . Successful sequential tyrosine kinase inhibitors to overcome a rare compound of EGFR exon 18-18 and EGFR amplification: a case report. Front Oncol. 2022;12 :918855.35957870 Ardini E Menichincheri M Banfi P . Entrectinib, a Pan-TRK, ROS1, and ALK inhibitor with activity in multiple molecularly defined cancer indications. Mol Cancer Ther. 2016;15 :628-39.26939704 Drilon A Siena S Ou SI . Safety and antitumor activity of the multitargeted Pan-TRK, ROS1, and ALK inhibitor entrectinib: combined results from two phase I trials (ALKA-372-001 and STARTRK-1). Cancer Discov. 2017;7 :400-9.28183697 Drilon A Siena S Dziadziuszko R . trial investigators. Entrectinib in ROS1 fusion-positive non-small-cell lung cancer: integrated analysis of three phase 1-2 trials. Lancet Oncol. 2020;21 :261-70.31838015 National Comprehensive Cancer Network. Non-small cell lung cancer (Version 3. 2022). Gainor JF Tseng D Yoda S . Patterns of metastatic spread and mechanisms of resistance to crizotinib in ROS1-positive non-small-cell lung cancer. JCO Precis Oncol. 2017;2017 :PO.17.00063.29333528 Katayama R Gong B Togashi N . The new-generation selective ROS1/NTRK inhibitor DS-6051b overcomes crizotinib resistant ROS1-G2032R mutation in preclinical models. Nat Commun. 2019;10 :3604.31399568 |
Medicine (Baltimore) Medicine (Baltimore) MD Medicine 0025-7974 1536-5964 Lippincott Williams & Wilkins Hagerstown, MD 00061 10.1097/MD.0000000000036683 3 3300 Research Article Clinical Case Report Acute severe hypoglycemia immediately after induction of anesthesia in an elderly patient with type 2 diabetes mellitus: A case report Tian Qin MM [email protected] a Yi Ming Liang MD [email protected] a Wan Jia Lu MM [email protected] a Yin Hong MD a* a Department of Anesthesiology, Chengdu Fifth People's Hospital (The Second Clinical Medical College, Affiliated Fifth People's Hospital of Chengdu University of Traditional Chinese Medicine), Chengdu, China. * Correspondence: Hong Yin, Department of Anesthesiology, Chengdu Fifth People's Hospital, 33 Mashi Road, Wenjiang District, Chengdu, 611130, China (e-mail: [email protected]). 22 12 2023 22 12 2023 102 51 e3668314 9 2023 22 11 2023 27 11 2023 Copyright (c) 2023 the Author(s). Published by Wolters Kluwer Health, Inc. 2023 This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Rationale: Acute severe hypoglycemia immediately following anesthesia induction is a rare but life-threatening complication that is frequently underdiagnosed due to insufficient awareness. Among the various physiological processes influenced by opioids, alterations in blood glucose levels induced by opioids are a side effect that is commonly overlooked. The significance of this report lies in emphasizing the neglected association between opioids and hypoglycemia and highlighting the importance of close glucose monitoring to prevent hypoglycemic events in the perioperative setting. Patient concerns: An 89-year-old man with type 2 diabetes mellitus experienced acute severe hypoglycemic episode immediately after general anesthesia induction. Baseline blood glucose level before starting anesthesia induction was 4.0 mmol/L. However, it decreased substantially to 0.96 mmol/L immediately after anesthesia induction. Diagnosis: The patient exhibited normal serum insulin, C-peptide, and cortisol levels, alongside unremarkable renal and hepatic function. After excluding other causes of hypoglycemia, we speculate that opioids were the culprits due to the temporal association and the rapid decline in blood glucose levels. Interventions: Forty milliliters of 50% dextrose were administered intravenously followed by an infusion of 5% dextrose. Outcomes: Recovery from anesthesia, extubation, and postoperative recovery were unremarkable. No further hypoglycemic episodes occurred during hospitalization. Lessons: A precipitous and rapid decline in blood glucose following anesthesia induction is extremely uncommon. When a clinical anesthesiologist detects an abnormally low bispectral index during general anesthesia, hypoglycemia should be suspected. Instituting glucose monitoring in these situations can enable a timely diagnosis, forestalling the onset of life-threatening severe hypoglycemia. diabetes mellitus general anesthesia hypoglycemia opioids OPEN-ACCESSTRUE pmc1. Introduction Diabetes mellitus (DM) is a widespread chronic disease that is becoming increasingly prevalent globally, with an estimated 537 million people currently affected. More and more individuals with diabetes will receive anesthesia and surgery. Acute severe hypoglycemia during general anesthesia induction is a rare but serious complication in patients with type 2 diabetes mellitus (T2DM). Hypoglycemia can lead to neurological deficits, cognitive decline, and even neurological damage. It may also result in arrhythmias, myocardial ischemia, and other cardiovascular events. Hypoglycemia induced by analgesics such as tramadol,[4-7] methadone, and morphine has been reported in the literature. However, hypoglycemia in patients during general anesthesia induction with opioids has not been previously reported. The purpose of this case report is to describe an unusual presentation of abrupt fall in blood glucose after opioid general anesthesia induction in an elderly patient with T2DM. Thus, it is very important to increase awareness of the potential for opioid-associated hypoglycemia in elderly T2DM patients undergoing general anesthesia and promote improved anesthesia management strategies to mitigate hypoglycemia-related complications. This report also provides ground for future studies about hypoglycemia as a possible adverse event associated with opioid use. 2. Case presentation An 89-year-old, 49 kg, 167 cm man (body mass index [BMI] of 17.6 kg/m2) was scheduled for transurethral resection of the prostate surgery due to the presence of prostatic hyperplasia. The patient had a 7-year history of T2DM and 5-year history of lumbar disc herniation. He had no prior hypoglycemia events. His medicines included saxagliptin 5 mg oral daily. He had good glycemic control with a fasting blood sugar of approximately 5 to 11 mmol/L, a post-meal blood sugar of about 6 to 15 mmol/L (Table 1), and a glycosylated hemoglobin of 6.9%. During hospitalization, his laboratory evaluations for hepatic function, renal function, and thyroid function were within normal ranges. A computed tomography scan of the abdomen revealed gallstones. No abnormalities were seen on the chest computed tomography or brain magnetic resonance imaging. The patient was instructed to stop saxagliptin the day before surgery and to fast after the dinner until the operation. At 8 am the morning of surgery, his fasting blood sugar was 4.7 mmol/L. Per the urologist's order, the patient was given 500 mL of 5% dextrose solution and 5 units of insulin once, his blood glucose raised to 5.1 mmol/L at 10 am. The baseline blood glucose before starting anesthesia induction was 4.0 mmol/L at 12:53 pm. Preoperative blood pressure was 125/77 mm Hg and heart rate 73 bpm. The patient received intravenous etomidate (14 mg), sufentanil (15 mg), and cisatracurium (10 mg) for general anesthesia induction and was maintained with sevoflurane (1%-1.5%) and remifentanil (0.04-0.05 mg/kg/min). A laryngeal mask airway was placed for mechanical ventilation. Depth of anesthesia was monitored using bispectral index (BIS) monitoring. Twenty minutes after induction of general anesthesia, the BIS value was approximately 20 to 25. The patient's hemodynamics were stable. Arterial blood sampling showed normal electrolytes and acid-base status but severe hypoglycemia with a blood glucose level of 0.98 mmol/L (Table 2). Arterial blood gas analysis at the time showed: pH 7.43, PaCO2 39 mm Hg, PaO2 214 mm Hg, mmol/L, base excess 2 mmol/L, lactate 0.63 mmol/L. Repeat finger stick glucose testing gave a result of 0.96 mmol/L. Further venous blood samples were urgently obtained for a complete blood count, hepatic and renal function tests, coagulation tests, electrolytes, glucose, insulin, C-peptide and cortisol levels, then sent to the hospital laboratory; 40 milliliters of 50% dextrose were administered intravenously followed by an infusion of 5% dextrose. One hour later, the laboratory technologist reported the blood glucose was 0.45 mmol/L. The laboratory test results were as follows: low hemoglobin 8.4 g/L (normal 11-17.2 g/L), mild hypokalemia 3.4 mmol/L (normal 3.5-5.1 mmol/L), and hypoalbuminemia 26.5 g/L (normal 35-55 g/L). The remaining results were unremarkable including normal creatinine 82.1 mmol/L (57-111 mmol/L) and liver enzymes. Concurrent fasting insulin and C-peptide assays showed normal insulin secretion, with insulin at 2.1 mIU/mL (normal range: 2.0-28.0 mIU/mL) and C-peptide at 0.63 ng/mL (normal range: 0.28-2.86 ng/mL). His random cortisol level at 1:20 pm was 8.1 mg/dL (normal range: 6.7-22.6 mg/dL), excluding adrenal insufficiency (refer to Table 2). The patient's hypoalbuminemia was likely due to inadequate oral intake during hospitalization. Ten minutes after treatment, the patient's blood glucose was 5.3 mmol/L and the BIS was about 40. Twenty minutes after treatment, the glucose had risen to 10.7 mmol/L while the BIS ranged from 40 to 50. Recovery from anesthesia, extubation, and postoperative recovery were unremarkable. No further hypoglycemic episodes occurred during hospitalization. The patient had no neurological injury and was discharged home 4 days later. His neurological status remained normal at a 3-month follow-up. Written informed consent was obtained from the patient and his family for the publication of this case report and included data. Table 1 Blood glucose levels during the hospitalization. Fasting blood glucose (mmol/L) Post-meal blood glucose (mmol/L) Day 1 5 8.7 Day 2 9.4 13-12.2-8.6 Day 3 5.4 5.9-10.6-5.7 Day 4 5.2 7.3-10.1-8.9 Day 5 5.5 8.2-7.7-9.5 Day 6 4.7-5.1-4.0-0.96 Day 7 10.8 14.6-14.3 Day 8 7.2 12.2-12.4-12.1 Day 9 7.2 9.5-8.8 Day 1 indicates the day of of admission; Day 6 indicates the day of operation. Table 2 Laboratory results of venous blood samples at hospital admission and during hypoglycemia occurrence. Hospital admission Hypoglycemia occurrence Normal ranges Peripheral blood WBC (10-9/L) 6.63 12.95 3.7-9.6 RBC (10-12/L) 3.41 2.91 3.7-5.7 Hemoglobin (g/L) 9.8 8.4 110-172 Hct (%) 31.2 26.5 34-51 Blood chemistry Glucose (mmol/L) 5 0.45 3.89-6.11 Insulin (mIU/mL) 2.1 2.0-28.0 C-peptide (ng/ml) 0.63 0.28-2.86 TP (g/L) 74.9 52.6 60-85 Alb (g/L) 40 26.5 35-55 Potassium(mmol/L) 4.7 3.41 3.5-5.5 Sodium(mmol/L) 142 142 135-145 AST (U/L) 29 29 8-38 ALT (U/L) 16 12 0-45 Crea (mmol/L) 112 82.1 57-111 BUN (mmol/L) 8.19 4.41 2.7-8.2 Cortisol (mg/dL) 8.1 6.7-22.6 Arterial blood gas analysis pH 7.43 PaCO2 (mm Hg) 39 PaO2 (mm Hg) 214 HCO3- (mmol/L) 26 Base excess (mmol/L) 2 Lactate (mmol/L) 0.63 Glucose (mmol/L) 0.98 Alb = albumin, ALT = alanine aminotransferase, AST = aspartate aminotransferase, BUN = blood urea nitrogen, Crea = creatinine, RBC = red blood cells, TP = total protein, WBC = white blood cells. 3. Discussion There are several potential causes of hypoglycemia in diabetic patients, including improper insulin dosing, concurrent medications, or deteriorating renal and liver function, adrenal insufficiency. The patient in this case was given a 500 mL infusion of 5% dextrose solution along with 5 units of insulin and missed 2 meals before surgery. The relative insulin overdose may have caused hypoglycemia during the operation. However, serum insulin and C-peptide levels checked during the hypoglycemia were within normal ranges. In this case, the hypoglycemia was unlikely due to insulin overdose. Adrenal insufficiency was ruled out based on normal cortisol hormone levels. The patient maintained stable renal and liver function throughout hospitalization, with no evidence of sepsis or starvation ketoacidosis. In the case we speculate that opioids were the culprits due to the temporal association and the rapid decline in blood glucose levels. Baseline blood glucose level before starting anesthesia induction was 4.0 mmol/L. However, it decreased substantially to 0.96 mmol/L immediately after anesthesia induction. And there were no hypoglycemic episodes during the 4-day observation period before discharge. Opioids have been reported to cause hypoglycemia through various mechanisms including increased glucose utilization by liver cells and skeletal muscles, promotion of insulin release, as well as impairment of the counter-regulatory response. Several hypotheses have been proposed for opioid-induced hypoglycemia, but remain controversial. A disproportionality analysis of the WHO global individual safety report database found opioid-induced hypoglycemia was likely a class effect. However, another retrospective analysis revealed a significant association of hypoglycemia with tramadol and methadone but not other opioids in nondiabetic patients. A recent review indicates that while opioid stimulation often elevates blood glucose levels, it can reduce levels in patients with type 2 diabetes. Diabetes appears to be a risk factor. Additionally, a case report described fasting hypoglycemia with acute, transient, opioid-induced secondary hypoadrenalism. We found no prior cases of opioids causing hypoglycemia immediately after anesthesia induction. The exact mechanism remains unknown. Animal studies show intrathecal morphine depletes hepatic glycogen in hypoglycemia. Other animal models demonstrate tramadol directly increases glucose utilization in hepatocytes and muscle through m-opioid receptor activation in diabetic rats. We cautiously suggest opioids likely increased peripheral glucose uptake and impaired gluconeogenesis, causing acute hypoglycemia after induction. Compensatory mechanisms, such as glycogenolysis, are usually activated during hypoglycemia; however, this response may be diminished in patients with diabetes, prolonged fasting, low BMI, poor nutrition, or advanced age. All of these factors were present in our patient, possibly exacerbating the hypoglycemia. Such severe hypoglycemia in our case is explained by depleted hepatic glycogen reserves and gluconeogenesis substrates. We observed abnormally low BIS values during severe hypoglycemia. Two case reports describe intraoperative, abnormally low BIS values with severe hypoglycemia in diabetic patients. BIS may reflect severe hypoglycemia under general anesthesia to some extent. 3.1. Limitations First, the imputation of hypoglycemia to opioids in our case is a conclusion inferred by our team after excluding other possibilities, based on relevant data and a review of previous literature. Second, as a case report, the generalizability of our findings is inherently limited. The particulars of this case and its distinctive circumstances limit the degree to which our results can be generalized to wider patient populations or situations. Therefore, caution should be used when applying these findings more broadly. Given these limitations, additional research with larger sample sizes and more comprehensive designs is necessary to confirm and validate the observed associations between hypoglycemia and opioids. By expanding the scope of inquiry, future studies may produce more robust and generalizable understandings of the relationships between opioids and hypoglycemic events. 4. Conclusions With this report, we would like to highlight that patients exposed to opioids can experience severe hypoglycemia, especially those with diabetes undergoing general anesthesia, long fasting periods, low BMI, poor nutrition status, and advanced age. Blood glucose monitoring tends to be more frequent in the perioperative setting, particularly for diabetic patients under general anesthesia. Acknowledgments We sincerely thank all the anesthesiologists and clinicians in our unit, who were involved in providing care and skilled management to the patient. Author contributions Conceptualization: Qin Tian, Jia Lu Wan. Data curation: Qin Tian, Ming Liang Yi. Formal analysis: Qin Tian, Jia Lu Wan. Investigation: Hong Yin, Ming Liang Yi. Writing - original draft: Qin Tian. Writing - review & editing: Hong Yin. Abbreviations: BIS bispectral index BMI body mass index DM diabetes mellitus T2DM type 2 diabetes mellitus Written informed consent was obtained from the patient and his family for the publication of this case report and included data. All data generated or analyzed during this study are included in this published article [and its supplementary information files]. The authors have no funding and conflicts of interest to disclose. How to cite this article: Tian Q, Yi ML, Wan JL, Yin H. Acute severe hypoglycemia immediately after induction of anesthesia in an elderly patient with type 2 diabetes mellitus: A case report. Medicine 2023;102:51(e36683). References Sun H Saeedi P Karuranga S . IDF Diabetes Atlas: global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045. Diabetes Res Clin Pract. 2022;183 :109119.34879977 Amiel SA . The consequences of hypoglycaemia. Diabetologia. 2021;64 :963-70.33550443 International Hypoglycaemia Study Group. Hypoglycaemia, cardiovascular disease, and mortality in diabetes: epidemiology, pathogenesis, and management. Lancet Diabetes Endocrinol. 2019;7 :385-96.30926258 Puszkiel A Malissin I Cisternino S . Massive tramadol ingestion resulting in fatal brain injury - a pharmacokinetic study with discussion on the involved mechanisms of toxicity. Clin Toxicol (Phila). 2022;60 :1059-62.35506822 Schiemsky T Vundelinckx G Croes K . An unconscious man with profound drug-induced hypoglycaemia. Biochem Med (Zagreb). 2020;30 :010802.31839727 Beis M Lenski M Hennart B . [Severe hypoglycemia with cardiac arrest after massive tramadol ingestion - a case report]. Therapie. 2022;77 :750-3.35624040 Yoshida K Sato H Tanaka T . Autopsy case of fatal hypoglycemia following ingestion of a therapeutic dose of tramadol. Forensic Sci Med Pathol. 2021;17 :465-8.34106422 Malboosbaf R Hatami N Maghsoomi Z . Methadone-induced hypoglycemia: a case report. J Diabetes Investig. 2023;14 :145-6. Masharani U Alba D . Methadone-associated hypoglycemia in chronic renal failure masquerading as an insulinoma. Pain Med. 2018;19 :1876-8.29145621 Lux F Han YH Brase DA . Studies on the mechanism of hypoglycemia induced by intrathecal morphine: dissociation from behavioral effects, effects of tolerance and depletion of liver glycogen. J Pharmacol Exp Ther. 1989;249 :688-93.2732944 Carey M Gospin R Goyal A . Opioid receptor activation impairs hypoglycemic counterregulation in humans. Diabetes. 2017;66 :2764-73.28860128 Chretien B Dolladille C Hamel-Senecal L . Comparative study of hypoglycaemia induced by opioids. Is it a class effect? Expert Opin Drug Saf. 2019;18 :987-92.31317815 Makunts T Andrew U Atayee RS . Retrospective analysis reveals significant association of hypoglycemia with tramadol and methadone in contrast to other opioids. Sci Rep. 2019;9 :12490.31462666 Koekkoek LL van der Gun LL Serlie MJ . The clash of two epidemics: the relationship between opioids and glucose metabolism. Curr Diab Rep. 2022;22 :301-10.35593927 Tabet EJ Clarke AJ Twigg SM . Opioid-induced hypoadrenalism resulting in fasting hypoglycaemia. BMJ Case Rep. 2019;12 :e230551. Cheng JT Liu IM Chi TC . Plasma glucose-lowering effect of tramadol in streptozotocin-induced diabetic rats. Diabetes. 2001;50 :2815-21.11723065 Xi C Pan C Li T . Abnormally low bispectral index and severe hypoglycemia during maintenance of and recovery from general anesthesia in diabetic retinopathy surgery: two case reports. BMC Anesthesiol. 2018;18 :45.29678142 |
ACG Case Rep J ACG Case Rep J ACGCRJ AC9 ACG Case Reports Journal 2326-3253 Wolters Kluwer Maryland, MD ACGCR-23-0641 10.14309/crj.0000000000001239 00029 3 Case Report Endoscopy The Travels of Signet-Ring Cell Carcinoma: From Colon to Stomach and Duodenum Tom Chloe K. MD 1 Placone Nicholas MD [email protected] Yung Evan MD [email protected] Shaker Anisa MD, AGAF [email protected] 1 Division of Gastrointestinal and Liver Diseases, University of Southern California, Los Angeles, CA 2 Department of Pathology, University of Southern California, Los Angeles, CA 3 Division of Gastrointestinal and Liver Diseases and Swallowing and Esophageal Disorders Center, University of Southern California, Los Angeles, CA Correspondence: Chloe K. Tom, MD ([email protected]). 12 2023 21 12 2023 10 12 e0123909 8 2023 16 11 2023 (c) 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology. 2023 This is an open access article distributed under the terms of the Creative Commons Attribution Licence 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. ABSTRACT Colorectal cancer (CRC) metastasizing to the stomach and duodenum is rare. Even rarer is when the CRC subtype is signet-ring cell carcinoma (SRCC). Endoscopic findings of CRC metastasis to the stomach have been described as solitary and submucosal while duodenal metastasis has been observed to be exophytic. In this report, we describe a case of a middle-aged man with colon SRCC presenting with oral intolerance. He was found to have concurrent metastases to the stomach and duodenum and died 8 months after his SRCC diagnosis. KEYWORDS: colorectal cancer signet-ring cell carcinoma metastatic cancer esophagogastroduodenoscopy OPEN-ACCESSTRUE pmcINTRODUCTION Colorectal cancer (CRC) is the fourth most common type of cancer and the second highest cause of cancer deaths in the United States, with over 150,000 expected new CRC diagnoses in 2023.1,2 The mortality from CRC remains high, as over one-third of patients die of the disease, with metastatic disease being the leading cause of CRC-related mortality.2,3 CRC metastasis to the stomach is rare, with an incidence of around 4.7% of cases.4 Even rarer is CRC spreading to the duodenum with only a handful of published case reports.5 Different histologic subtypes of CRC may have different metastatic patterns.6 Whereas adenocarcinoma typically spreads to the liver or lung, the less common mucinous adenocarcinoma and signet-ring cell carcinoma (SRCC) have more atypical metastatic patterns, frequently affecting the peritoneum and distant lymph nodes.7 SRCC is particularly rare, representing approximately 1% of CRC subtypes, and is associated with poor overall survival.8 We present the case of a patient with a SRCC type of CRC histology and atypical gastric and duodenal lesions, which were confirmed to be metastatic SRCC on biopsy. CASE REPORT A 55-year-old man with ulcerative colitis, known T1N0M0 colon SRCC of the sigmoid colon with liver metastases, who was recently treated with partial colectomy and palliative chemotherapy presented to the emergency department with fatigue and weight loss because of early satiety, nausea, and vomiting. Initial blood pressure was 83/51 mm Hg, and heart rate was 111 beats per minute, which improved with fluid resuscitation. On physical examination, he was frail and tachypneic, and his abdomen was distended but nontender. Laboratory tests on admission were remarkable for hemoglobin 7.2 g/dL and acute kidney injury with creatinine 3.3 mg/dL. An abdominal-pelvic computed tomography scan showed diffuse colonic wall thickening, moderate ascites, numerous hepatic lesions consistent with his known metastatic disease, and a fluid and gas-filled stomach. Over 500cc of gastric secretions were removed with a nasogastric tube, and paracentesis was performed with cytology showing adenocarcinoma with signet-ring cell morphology of gastrointestinal origin. He underwent esophagogastroduodenoscopy, which revealed an edematous pylorus in addition to numerous raised coin-shaped lesions with central ulceration in the gastric antrum, along the anterior and posterior walls of the gastric body , and the first and second portions of the duodenum . The pathology of the gastric and duodenal lesions showed poorly differentiated adenocarcinoma with signet-ring cell features suggesting colon cancer metastasis to the duodenum and stomach. Figure 1. Esophagogastroduodenoscopy reveals polypoid lesion with central ulceration in the antrum and anterior and posterior walls of the gastric body. Figure 2. Esophagogastroduodenoscopy reveals multiple raised coin-shaped lesions with central ulceration in the duodenal bulb and second portion of the duodenum. Figure 3. Gastric biopsy showing effacement of gastric architecture by malignancy (H&E, 100x). Figure 4. Higher magnification of the previous figure, showing an oxyntic-type gland (center) surrounded and infiltrated by tumor cells. Many cells contain a large mucin vacuole, imparting a signet-ring morphology (arrowhead) (H&E, 400x). Figure 5. High magnification of the duodenal biopsy. Tumor cells are histologically like those seen in gastric biopsy. Mitotic figures (solid arrowhead) and apoptotic bodies (hollow arrowhead) are readily identified (H&E, 400x). The patient opted for hospice care because of widespread metastatic disease and multiple failed chemotherapy regimens. A palliative pyloric stent was placed, and he died a few weeks after discharge. DISCUSSION Although gastric metastasis from primary CRC is uncommon, based on a series of case reports, endoscopic appearance is typically a solitary lesion resembling a submucosal tumor, fungating lesion, or polypoid masses with erosion, or ulceration.9-12 There is minimal literature describing CRC spreading to the duodenum, although 1 case described an exophytic mass covering 75% of the second portion of the duodenum circumference without obstruction.5 While gastric metastasis of CRC has been described, we identified only 1 case report that described the SRCC subtype extending from the colon to the stomach.13 In this instance, esophagogastroduodenoscopy revealed a 2 cm submucosal lesion in the gastric body and lesser curvature with a smooth surface, central depression, and erosion. We also found 1 report where SRCC of the duodenum spread to the ovaries, peritoneum, and colon, and on endoscopy, there was an exophytic obstructing duodenal bulb mass.14 SRCC is a unique histologic subtype of CRC and is defined as a poorly cohesive carcinoma15 where greater than 50% of tumor cells show abundant cytoplasm mucin and eccentric crescent-shaped nuclei.16 SRCC in the distal gastrointestinal tract comprises 1% of all cases of colon cancer and 15.3% of all SRCC cases.15 It is hypothesized that the loss of cell-cell adhesion and mucin accumulation contribute to its aggressive carcinogenesis and poor prognosis.17 One large epidemiological study found that SRCC was most found in White patients (75% of cases), without gender predilection, and that incidence has declined since 2000 with improvements in CRC screening.18 The most common initial stage of diagnosis was stage IV, usually in the proximal colon and often with multiple metastatic sites.6 The metastatic pattern of SRCC of the colon is unique in its propensity to spread to the peritoneum as opposed to the liver, as is most common in colonic adenocarcinoma.6 In contrast to other colon cancer histologic types, patients younger than 35 years seem to have worse outcomes when diagnosed with SRCC of the colon compared with patients older than 35 years.19 Owing to therapeutic advancements in the treatment of SRCC, including surgical resection, adjuvant chemotherapy, and radiotherapy over the past decade, overall survival for SRCC has slightly improved, but still has an unfavorable prognosis.18 Fortunately, research groups are analyzing the molecular characteristics of SRCC to develop tailored therapy. Using next-generation sequencing, a unique profile of genes and biomarkers, including Kristen Rat Sarcoma Viral oncogene homolog wild-type (wt), PIK3CA wt, TP53, AT-rich interaction domain 1A, and CDH1, have been identified in SRCC compared with those of adenocarcinoma.8,20 Investigations of potential therapeutics include the role of mucin proteins to selectively target SRCC21 and clinical trials targeting a promising biomarker, Claudin18.2 (CLDN18.2).22 Our case is the first to report colon SRCC metastasizing to the stomach and duodenum with raised coin-shaped lesions with central depression and erosion. The aggressive SRCC histopathology and multiple-site metastatic spread portend a poor prognosis. Our patient had tried 6 lines of chemotherapy, yet he died within 8 months of his colon cancer diagnosis. Further research is warranted to characterize macroscopic patterns, prognostication, and treatment plans for patients with SRCC of the colon with multiple sites of metastasis, such as the stomach and small intestine. DISCLOSURES Author contributions: CK Tom: conception and design, acquisition, analysis, interpretation, drafting the work, final approval of the version to be published, agreement to be accountable for all aspects of the work. N. Placone: conception and design, analysis, interpretation, reviewing the work critically, final approval of the version to be published, agreement to be accountable for all aspects of the work. E. Yung: acquisition, reviewing the work critically, final approval of the version to be published, agreement to be accountable for all aspects of the work. A. Shaker: conception and design, reviewing the work critically, final approval of the version to be published, agreement to be accountable for all aspects of the work and is the article guarantor. Financial disclosure: None to report. Previous presentation: This case report has been accepted to the ACG 2023 Annual Scientific Meeting for poster presentation on October 2023; Vancouver, Canada. Informed consent was obtained from the patient's next of kin for this case report. REFERENCES 1. Common Cancer Types. National Cancer Institute (2023). (Accessed March 30 2023). 2. Siegel RL Wagle NS Cercek A Smith RA Jemal A .Colorectal cancer statistics, 2023. CA Cancer J Clin 2023;73 (3 ):233-54.36856579 3. Vatandoust S Price TJ Karapetis CS .Colorectal cancer: Metastases to a single organ. World J Gastroenterol 2015;21 (41 ):11767-76.26557001 4. De Palma GD Masone S Rega M Metastatic tumors to the stomach: Clinical and endoscopic features. World J Gastroenterol 2006;12 (45 ):7326-8.17143949 5. Brahmbhatt P Ross J Saleem A Recurrent adenocarcinoma of colon presenting as duodenal metastasis with partial gastric outlet obstruction: A case report with review of literature. World J Oncol 2013;4 (2 ):102-6.29147339 6. Hugen N van de Velde CJH de Wilt JHW Nagtegaal ID .Metastatic pattern in colorectal cancer is strongly influenced by histological subtype. Ann Oncol 2014;25 (3 ):651-7.24504447 7. An Y Zhou J Lin G Clinicopathological and molecular characteristics of colorectal signet ring cell carcinoma: A Review. Pathol Oncol Res 2021;27 :1609859.34381313 8. Puccini A Poorman K Catalano F Molecular profiling of signet-ring-cell carcinoma (SRCC) from the stomach and colon reveals potential new therapeutic targets. Oncogene 2022;41 (26 ):3455-60.35618879 9. Goel N .Colorectal cancer metastasis to the gastric mucosa. Am Coll Surg Case Rev 2021;1 (3 ):2. 10. Terashima S Watanabe S Kogure M Tanaka M . Long-term survival after resection of a gastric metastasis from transverse colon cancer: A case report. J Med Sci 2019;65 (2 ):37-42. 11. Hsu CC Chen JJ Changchien CS .Endoscopic features of metastatic tumors in the upper gastrointestinal tract. Endoscopy 1996;28 (2 ):249-53.8739742 12. Oda KondoH Kondo H Yamao T Metastatic tumors to the stomach: Analysis of 54 patients diagnosed at endoscopy and 347 autopsy cases. Endoscopy 2001;33 (6 ):507-10.11437044 13. Iwai N Okuda T Harada T Gastric metastasis from colorectal cancer mimicking a submucosal tumor. Case Rep Gastroenterol 2020;14 (2 ):338-45.32884508 14. Henry JN . Signet ring cell carcinoma of the duodenal bulb with metastases to the ovaries and the colon: A case report. J Med Cases 2013;4 (5 ):327-29. 15. Benesch MGK Mathieson A . Epidemiology of signet ring cell adenocarcinomas. Cancers (Basel) 2020;12 (6 ):1544.32545410 16. Bosman FT Carneiro F Hruban RH Theise ND . WHO Classification of Tumours of the Digestive System. World Health Organization: Geneva, Switzerland, 2010. 17. Pernot S Voron T Perkins G Lagorce-Pages C Berger A Taieb J . Signet-ring cell carcinoma of the stomach: Impact on prognosis and specific therapeutic challenge. World J Gastroenterol 2015;21 (40 ):11428-38.26523107 18. Li H Zong Z Zhou T Trends of incidence and survival in patients with gastroenteropancreatic signet ring cell carcinoma: An analysis from the surveillance, epidemiology, and end results program. J Gastrointest Oncol 2019;10 (5 ):979-88.31602336 19. Huang B Ni M Chen C Feng Y Cai S . Younger age is associated with poorer survival in patients with signet-ring cell carcinoma of the colon without distant metastasis. Gastroenterol Res Pract 2016;2016 :2913493.27994618 20. Korphaisarn K Morris V Davis JS Signet ring cell colorectal cancer: Genomic insights into a rare subpopulation of colorectal adenocarcinoma. Br J Cancer 2019;121 (6 ):505-10.31406299 21. Olgun A .Selective targeting of signet ring cell adenocarcinomas. Med Hypotheses 2019;133 :109380.31454636 22. Xu B Liu F Liu Q Highly expressed Claudin18.2 as a potential therapeutic target in advanced gastric signet-ring cell carcinoma (SRCC). J Gastrointest Oncol 2020;11 (6 ):1431-9.33457012 |
Medicine (Baltimore) Medicine (Baltimore) MD Medicine 0025-7974 1536-5964 Lippincott Williams & Wilkins Hagerstown, MD 00019 10.1097/MD.0000000000036740 3 5500 Research Article Clinical Case Report Macrocytic anemia induced by selenium deficiency in the course of anorexia nervosa: A case report Nishi Ryusei MD [email protected] a Sagiyama Kenichiro MD, PhD [email protected] a Hamada Kazumasa MD [email protected] a Fukumoto Takamasa MA [email protected] a Kato Ryuichi MD [email protected] a Yamamoto Takako MD [email protected] a Fuku Yuuki MD [email protected] a Amitani Haruka MD, PhD [email protected] a Asakawa Akihiro MD, PhD a* a Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan. * Correspondence: Akihiro Asakawa, Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan (e-mail: [email protected]). 22 12 2023 22 12 2023 102 51 e3674001 10 2023 30 11 2023 Copyright (c) 2023 the Author(s). Published by Wolters Kluwer Health, Inc. 2023 This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Rationale: Anorexia nervosa is characterized by an extreme fear of weight gain. Clinicians often prescribe meal replacement shakes if patients are unable or unwilling to consume typical foods. However, these shakes sometimes lack essential micronutrients, such as selenium, which may lead to health risks. Moreover, selenium deficiency induces macrocytic anemia. Herein, we present a case of a patient with anorexia nervosa with macrocytic anemia due to selenium deficiency, which was alleviated by selenium supplementation. Patient concerns: An 18-year-old female was admitted to our hospital. The patient was diagnosed with anorexia nervosa. Ultimately, she was unable to walk independently because of fatigue and electrolyte disturbances. Clinical findings: On admission, the height, weight, and body mass index of the patient were 158.5 cm, 27.1 kg, and 10.8, respectively. Our treatment for anorexia nervosa showed relative effectiveness, and the patient's body weight recovered to 29.2 kg by day 60. However, the mean corpuscular volume increased from day 20, suggesting macrocytic anemia. Diagnoses, interventions, and outcomes: Despite our vitamin B12 and folic acid supplementation interventions, the mean corpuscular volume continued to rise. On day 60, the patient was diagnosed with selenium deficiency, and selenium administration of 100 mg/day was initiated. Outcomes: The macrocytic anemia in the patient was alleviated, and treatment for anorexia nervosa was continued in our hospital. Lessons: To the best of our knowledge, this is the first case of macrocytic anemia induced by selenium deficiency with anorexia nervosa comorbidity, underscoring the importance of selenium supplementation in patients with anorexia nervosa, especially in those with macrocytic anemia. anorexia nervosa case report macrocytic anemia selenium OPEN-ACCESSTRUE pmc1. Introduction Anorexia nervosa is an eating disorder characterized by an extreme fear of weight gain. Patients often engage in excessive exercise to reduce weight (restricting subtype) or self-induce vomiting immediately after overeating (binge/purge subtype). Clinicians sometimes prescribe meal replacement shakes if patients are unable or unwilling to consume typical foods. However, these shakes may lack essential micronutrients such as selenium, which can lead to health risks. Moreover, selenium deficiency is known to induce macrocytic anemia. Herein, we report a case of anorexia nervosa in a patient suffering from macrocytic anemia due to selenium deficiency, which was alleviated by selenium supplementation. 2. Patient information and clinical findings An 18-year-old female was admitted to our hospital. Written informed consent was obtained from the patient. Earlier, the patient was diagnosed with anorexia nervosa caused by amenorrhea at another hospital 2 years after dieting and was subsequently referred to our department. Despite the clinician's instructions to gradually increase food intake, the body weight of the patient continued to decrease. Finally, the serum liver enzyme levels of the patient were highly elevated, and she could not walk independently because of fatigue and electrolyte disturbances. The patient was admitted to our department as she desired inpatient care. On admission, the height, weight, and body mass index of the patient were 158.5 cm, 27.1 kg, and 10.8, respectively. The patient did not eat for the first few days, and calorie requirements were met via a peripherally inserted central venous catheter for a week. Thereafter, an intravenous infusion was administered to maintain a total daily calorie (1000 kcal/day) and the dosage was changed according to the oral intake of the patient. Our treatment for anorexia nervosa was relatively effective, and body weight gradually increased to 29.2 kg by day 60. However, the mean corpuscular volume (MCV) increased from day 20, suggesting that anemia could not have been caused by iron deficiency alone, which is frequently observed in patients with anorexia nervosa because of restricted dietary intake. Laboratory results during hospitalization are shown in Table 1. Table 1 Laboratory results during hospitalizaion. Laboratory test Normal range Day 1 Day 20 Day 40 Day 60 Day 66 Day 73 Day 83 Day 90 RBC 3.86-4.92 x 106 mL 3.12 1.75 1.93 2.25 2.46 2.76 2.93 3.42 Hb 11.6-14.8 g/dL 10.3 5.7 6.3 7.6 8.4 9.4 9.9 11.5 MCV 83.6-98.2 fL 95.8 95.4 100.5 105.8 103.3 102.2 99.0 96.2 VB12 233-914 pg/mL - 3670 - - - - - - FA 3.6-12.9 ng/mL - 13.4 - - - - - - Se 10.0-16.0 mg/dL - - - 6.8 - 11.2 - - P 2.7-4.6 mg/dL 2.7 1.9 3.8 4.3 4.7 4.2 3.9 3.4 Ca 8.8-10.1 mg/dL 7.9 7.4 7.5 8.4 8.4 8.7 8.9 9.2 Na 138-145 mmol/L 141 141 144 144 144 142 139 139 K 3.6-4.8 mmol/L 2.9 3.3 3.5 3.5 3.7 3.7 3.9 3.7 Cl 101-108 mmol/L 98 102 109 108 108 106 104 101 TP 6.6-8.1 g/dL - 3.8 3.9 4.7 5.0 5.7 5.9 6.4 Albumin 4.1-5.1 g/dL - 2.2 - 2.7 - - 3.7 - Ca = calcium, Cl = chloride, FA = folic acid, Hb = hemoglobin, K = potassium, MCV = mean corpuscular volume, Na = sodium, P = phosphorus, Se =selenium, TP = total protein, VB12 = vitamin B12. 3. Diagnostic assessment and therapeutic intervention On day 40, vitamin B12 deficiency was suspected to have caused macrocytic anemia. Consequently, we initiated supplementation with folic acid (10 mg/day) and vitamin B12 (500 mg/day). Despite this intervention, MCV continued to increase. We then reduced the folic acid dose to 5 mg/day, suspecting that an inappropriate initial dose might have been administered because of the imbalanced vitamin B12 and folate levels. Nonetheless, the MCV continued to increase and was 105.8 fL on day 60. Despite the oral calorie intake of approximately 700 kcal/day, which would generally not suggest a severe micronutrient deficiency, we considered selenium deficiency to be a possible cause. Finally, the patient was diagnosed with selenium deficiency, and selenium administration of 100 mg/day was initiated on day 60. On day 73, selenium levels increased to normal, MCV started to decrease, and hemoglobin levels increased. 4. Outcomes After 20 days of intravenous selenium administration, the MCV returned to normal levels, and selenium supplementation was stopped. The patient continued receiving treatment for anorexia nervosa in our hospital. 5. Discussion Our case strongly suggests that macrocytic anemia in the patient was induced by selenium deficiency, as confirmed by normalization of the patient's MCV after selenium supplementation. A study on selenium supplementation in anorexia nervosa reported that selenium deficiency is associated with increased severity and suicide risk in anorexia nervosa. To the best of our knowledge, selenium deficiency in patients with anorexia nervosa were diagnosed with white muscle disease, which is an extremely rare condition in humans, has only been reported by Ishihara et al In contrast, Ahmed et al reported the occurrence of macrocytic anemia in adult lambs with white muscle disease. Therefore, the association between macrocytic anemia and anorexia nervosa because of the selenium deficiency appears plausible. However, Ishihara et al did not report macrocytic anemia in their patients. Therefore, this is the first case of macrocytic anemia induced by selenium deficiency with comorbid anorexia nervosa. The mechanism underlying macrocytic anemia induced by selenium deficiency is not fully understood. However, selenium prevents hemolytic anemia by protecting the cell membrane from hemolysis by modulating oxidation-reduction reactions. Therefore, selenium antioxidation may play a key role in preventing macrocytic anemia. Notably, radical-related stress scavenger knockout mice exhibit a macrocytic anemia phenotype. Nonetheless, further research is required to elucidate the role of selenium in macrocytic anemia. Our case highlights the importance of selenium supplementation in patients with anorexia nervosa, especially in those with macrocytic anemia. Author contributions Conceptualization: Ryusei Nishi, Kenichiro Sagiyama, Akihiro Asakawa. Data curation: Ryusei Nishi, Kenichiro Sagiyama. Investigation: Ryusei Nishi, Kazumasa Hamada, Takamasa Fukumoto, Ryuichi Kato, Takako Yamamoto, Yuuki Fuku, Haruka Amitani. Supervision: Haruka Amitani, Akihiro Asakawa. Writing - original draft: Ryusei Nishi. Writing - review & editing: Ryusei Nishi, Kenichiro Sagiyama, Kazumasa Hamada, Takamasa Fukumoto, Ryuichi Kato, Takako Yamamoto, Yuuki Fuku, Haruka Amitani, Akihiro Asakawa. Abbreviation: MCV mean corpuscular volume All data generated or analyzed during this study are included in this published article [and its supplementary information files]. The authors have no funding and conflicts of interest to disclose. How to cite this article: Nishi R, Sagiyama K, Hamada K, Fukumoto T, Kato R, Yamamoto T, Fuku Y, Amitani H, Asakawa A. Macrocytic anemia induced by selenium deficiency in the course of anorexia nervosa: A case report. Medicine 2023;102:51(e36740). References Yagi M Tani T Hashimoto T . Four cases of selenium deficiency in postoperative long-term enteral nutrition. Nutrition. 1996;12 :40-3.8838835 Etani Y Nishimoto Y Kawamoto K . Selenium deficiency in children and adolescents nourished by parenteral nutrition and/or selenium-deficient enteral formula. J Trace Elem Med Biol. 2014;28 :409-13.25294396 Vinton NE Dahlstrom KA Strobel CT . Macrocytosis and pseudoalbinism: manifestations of selenium deficiency. J Pediatr. 1987;111 :711-7.3117996 Strumila R Lengvenyte A Olie E . Selenium deficiency is associated with disease severity, disrupted reward processing, and increased suicide risk in patients with anorexia nervosa. Psychoneuroendocrinology. 2022;140 :105723.35334390 Ishihara H Kanda F Matsushita T . White muscle disease in humans: myopathy caused by selenium deficiency in anorexia nervosa under long term total parenteral nutrition. J Neurol Neurosurg Psychiatry. 1999;67 :829-30.10617385 Ahmed JA Al-Autaish HH Al Saad KM . Acute enzootic muscular dystrophy of adult lambs at Basrah, Iraq. Iraqi J Vet Sci. 2022;36 :471-7. Kristiansson A Bergwik J Alattar AG . Human radical scavenger a1-microglobulin protects against hemolysis in vitro and a1-microglobulin knockout mice exhibit a macrocytic anemia phenotype. Free Radic Biol Med. 2021;162 :149-59.32092412 |
Medicine (Baltimore) Medicine (Baltimore) MD Medicine 0025-7974 1536-5964 Lippincott Williams & Wilkins Hagerstown, MD 00066 10.1097/MD.0000000000036691 3 5300 Research Article Clinical Case Report Sudden bilateral deafness in a patient with vertebrobasilar artery occlusion: A case report Zhang Ying MD [email protected] a Zhao Xin MD a* Zhou Ming MD [email protected] a Chang Pengfei MD [email protected] a Liu Tao MD [email protected] a Li Yang MD [email protected] b a Department of Encephalopathy, Traditional Chinese Medicine Hospital of Weifang, Weifang, China b The Second Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China. * Correspondence: Xin Zhao, Department of Encephalopathy, Traditional Chinese Medicine Hospital of Weifang, Weifang 261000, China (e-mail: [email protected]). 22 12 2023 22 12 2023 102 51 e3669125 9 2023 27 11 2023 Copyright (c) 2023 the Author(s). Published by Wolters Kluwer Health, Inc. 2023 This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Rationale: Sudden bilateral deafness is often associated with serious systematic conditions such as neoplasms, vascular events, autoimmune diseases, infections, and iatrogenic injury, but very rarely to cerebrovascular disease. This is a rare case of sudden bilateral deafness in a patient with the vertebrobasilar artery occlusion. Patient concerns: A 46-year-old man was admitted to a local hospital for sudden bilateral deafness, the patient suffered inarticulate speech and walking unsteadily 6 days later. Diagnoses: Difusion-weighted magnetic resonance imagin demonstrated acute cerebral infarction in the pons and bilateral cerebellum; Magnetic resonance angiography showed vertebrobasilar artery occlusion. Interventions: Aspirin and clopidogrel were given for antiplatelet therapy, revascularization was obtained by endovascular treatment. Outcomes: The symptoms of dysarthria, ataxia and weakness gradually improved and were discharged 14 days after admission revascularization. After 3 months telephone followed-up the patient was self-cared. Lessons: Deafness sometimes can be an early warning sign of impending vertebrobasilar ischemic stroke. Early recognition of deafness with acute ischemic stroke should allow special management, and misdiagnosis may result in significant morbidity, or even mortality. cerebral infarction endovascular treatment sudden bilateral deafness vertebrobasilar artery occlusion OPEN-ACCESSTRUE pmc1. Introduction Sudden bilateral deafness is often associated with serious systematic conditions such as neoplasms, vascular events, autoimmune diseases, infections, and iatrogenic injury, but very rarely to cerebrovascular disease. However, deafness sometimes can be an early warning sign of impending vertebrobasilar ischemic stroke because the blood supply to the auditory originates from vertebrobasilar system. Early recognition of deafness with acute ischemic stroke should allow special management, and misdiagnosis may result in significant morbidity, or even mortality. Sudden deafness has been considered traditionally to be a neglected and underestimated symptom of stroke. Because the anterior-inferior cerebellar artery (AICA) which supply the blood to the auditory system originates from the posterior circulation, sometimes patients with cerebral infarction in the posterior circulation can present with sudden deafness. Case reports and case series data suggest patients with sudden deafness should be considered the possibility of vertebrobasilar occlusion, especially for the patients have risk factors for stroke, even if there was no other neurologic signs.[2-4] Because the early diagnosis and proper management may provide a window to prevent the progression of infarction to larger areas, misdiagnosis may result in significant morbidity and mortality. We report a patient suffered bilateral deafness as initial symptoms 6 days prior to permanent infarction. 2. Case presentation A 46-year-old man with a history of hypertension, smoking and alcohol was admitted to local hospital for sudden bilateral deafness, he was diagnosed as sudden deafness and given alprostadil for intravenous injection. His home medications included 20 mg twice daily of nifedipine. His deafness was completely improved. But the patient suffered inarticulate speech and walking unsteadily 6 days later, he was transferred to our department with head computed tomography returned no signifcant fndings (Fig. 1). On admission his neurological examination revealed dysarthria, nystagmus and ataxia, the National Institute of Health Stroke Scale score was 3. His blood pressure was 160/80 mm Hg, his pulse rate was 70 beats/minute, and his temperature was 36.8degC. His general physical examination was unremarkable. Her laboratory test results showed no obvious abnormalities. Difusion-weighted magnetic resonance imagin demonstrated acute cerebral infarction in the pons and bilateral cerebellum; Magnetic resonance angiography showed vertebrobasilar artery occlusion (Fig. 2). Figure 1. Head computed tomography showed no new lesions in the area of the cerebellar hemispheres and brainstem. Figure 2. Diffusion-weighted brain MRI showing acute multifocal lesions involving the bilateral cerebellar hemispheres, and the vertebrobasilar artery were occluded on MRA. MRA = magnetic resonance angiography, MRI = magnetic resonance imagin. The delivery of recombinant tissue plasminogen activator (rtPA) has been the standard of care in patients with acute ischemic stroke. However, rtPA must be administered within 4.5h of stroke onset, and it has been 10 hours after the neurologic symptom appeared when he arrived in my hospital. Aspirin and clopidogrel and tirofiban were given for antiplatelet therapy, but his condition was gradually dropped and the strength in his right limb dropped to III level 3 days after his admission. Digital subtraction cerebral angiography showed the right vertebral artery was nondominant artery and subtotal occluded in the V4 segment; the left vertebral artery was total occluded in the V2 segment (Fig. 3). Fortunately, revascularization was obtained by endovascular treatment (Fig. 4), though dysarthria, ataxia and weakness were still remained, he was discharged 14 days after his admission with the the National Institute of Health Stroke Scale scored 7. After 3 months telephone followed-up the patient was self-cared, and the modified rankin scale score was 0. Figure 3. Anteroposterior right vertebral angiography revealed the right vertebral artery was nondominant artery and subtotal occluded in the V4 segment; Anteroposterior left vertebral angiography revealed the left vertebral artery was total occluded in the V2 segment. Figure 4. Post-thrombectomy, the last lateralposition left vertebral angiogram demonstrated total recanalization of the BA trunk including the AICA and SCA. AICA = the anterior-inferior cerebellar artery, SCA = superior cerebellar artery. 3. Discussion We report a patient suffered bilateral deafness as initial symptoms 6 days prior to vertebrobasilar system infarction. Fortunately, revascularization was obtained by endovascular treatment and his physical condition was gradually improved. It suggested that deafness sometimes can be an early warning sign of impending vertebrobasilar ischemic stroke. Early recognition of deafness with acute ischemic stroke is very important, because vertebrobasilar ischemia is life threatening and proper management may provide a window to prevent the progression of infarction to larger areas. Sudden-onset deafness is often due to otolaryngologic and very rarely to cerebrovascular disease. However, because AICA which supply the blood to the auditory system originates from the posterior circulation, sometimes patients with cerebral infarction in the posterior circulation can present with sudden deafness. Usually the internal auditory artery (IAA) which originates from the AICA is an end artery with minimal collaterals and especially vulnerable to ischemia.[6-8] Because the labyrinth requires high-energy metabolism and receives its sole supply from the IAA, the labyrinth is especially vulnerable to ischemia. Sometimes, patients with anterior-inferior cerebellar artery infarction have isolated fluctuating hearing loss, or tinnitus as initial symptoms 1 to 10 days prior to permanent infarction.[9-11] At the same time, AICA constantly supplies the peripheral vestibular structures such as the inner ear and vestibulocochlear nerve, in addition to the central vestibular structures. As a result, in contrast to other cerebellar artery territory infarction, complete AICA infarction usually results in combined peripheral and central vestibular damages. Identifying stroke among patients presenting with deafness is one of the most challenging issues in neurology and emergency medicine. Sudden deafness in patients with risk factors of cerebrovascular disease should be prioritized for stroke workup. At the time of admission to his local hospital, the patient in our case presented with only bilateral hearing loss without any other neurological deficits, consequently, initially he was not suspected specifc anomalies including vertebrobasilar impairment. Because the inner ear requires a high-energy metabolism and the IAA is an end artery with little collateral circulation, the inner ear is particularly vulnerable to ischemia.[10-14] Deafness sometimes is an early warning sign of impending vertebrobasilar ischemic stroke. The rtPA has been the standard of care in patients with acute ischemic stroke. However, it has been 10 hours after the neurologic symptom appeared. Though antiplatelet therapy was given, his condition was gradually dropped. Vertebrobasilar ischemia is life threatening and poorly outcome, endovascular treatment was recommended for patients with symptomatic non-acute vertebrobasilar artery occlusion.[17-19] Fortunately, though the patient had dysarthria, ataxia and weakness, the condition was gradually improved after the revascularization by endovascular treatment. Although deafness can present as a sign of AICA infarction, the incidence differs from a low of 30 % to a high of 100 %. There were 2 factors inclued: on the 1 hand neurologists have not included the audiogram as a routine diagnostic tool for the AICA infarction; on the other hand, patients might not be aware of the hearing loss during an attack of vertigo when the unilateral hearing loss is mild or the vertigo is severe. A recent study on the long-term outcome suggest that recovery of hearing loss of a vascular cause is more common than previously thought, approximately 65 % of the patients due to posterior circulation ischemic stroke showed a partial or complete hearing recovery followed for at least 1 year after the onset. 4. Conclusion This is a rare case of sudden bilateral deafness in a patient with the vertebrobasilar artery occlusion. The delayed diagnosis of ischemic stroke in the posterior circulation might be poorly outcome and life threatening. Fortunately, our case had a good outcome after the revascularization by endovascular treatment. The early diagnosis and the proper management may provide a window to prevent the progression of infarction to larger areas. We emphasis that the possibility of vertebrobasilar occlusive disorder should be considered for patients with sudden deafness especially those with risk factors for stroke, even though no neurological signs were found. Author contributions Conceptualization: Ying Zhang, Xin Zhao, Ming Zhou, Tao Liu, Yang Li. Data curation: Ying Zhang, Xin Zhao, Pengfei Chang, Tao Liu, Yang Li. Formal analysis: Ying Zhang, Xin Zhao, Ming Zhou, Tao Liu, Yang Li. Funding acquisition: Ying Zhang, Pengfei Chang. Investigation: Ying Zhang, Ming Zhou. Methodology: Ying Zhang, Tao Liu, Yang Li. Project administration: Ying Zhang, Ming Zhou, Pengfei Chang, Yang Li. Resources: Ying Zhang, Pengfei Chang, Tao Liu, Yang Li. Software: Ying Zhang, Pengfei Chang, Yang Li. Supervision: Yang Li. Validation: Yang Li. Visualization: Yang Li. Writing - original draft: Ying Zhang, Ming Zhou, Pengfei Chang, Yang Li. Writing - review & editing: Ying Zhang, Tao Liu, Yang Li. Abbreviations: AICA the anterior-inferior cerebellar artery IAA internal auditory artery rtPA recombinant tissue plasminogen activator All data generated or analyzed during this study are included in this published article [and its supplementary information files]. We have obtained written consent from the patient. We have obtained the written consent of the Medical Ethics Committee of Weifang Hospital of traditional Chinese Medicine (2022-WFSZYY-014). Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article. This work was funded by the Scientific Research Project of Weifang Health Commission (WFWSJK-2022-25). The authors have no conflicts of interest to disclose. How to cite this article: Zhang Y, Zhao X, Zhou M, Chang P, Liu T, Li Y. Sudden bilateral deafness in a patient with vertebrobasilar artery occlusion: A case report. Medicine 2023;102:51(e36691). References Kim HA Lee H . Recent advances in understanding audiovestibular loss of a vascular cause. J Stroke. 2017;19 :61-6.28030893 Tomoya K1 Keisuke I Shinichi U . Basilar artery occlusion presenting as sudden bilateral deafness: a case report. J Med Case Reports 2021;15 :111. Caroline EP Christina FB Helle KI . Sudden bilateral deafness in a patient with transient ischemic attack: a case report. Case Rep Neurol. 2021;13 :119-22.33790769 Xinlin W Minsun Xiaoping W . Cerebellar artery infarction with sudden hearing loss and vertigo as initial symptoms: a case report. World J Clin Cases. 2021;9 :2519-23.33889616 Ji Soo K Hyung L . Inner ear dysfunction due to vertebrobasilar ischemic stroke. Semin Neurol. 2009;29 :534-40.19834865 Perlman HB Kimura RS Fernandez C . Experiments on temporary obstruction of the internal auditory artery. Laryngoscope. 1959;69 :591-613.13673604 Grad A Baloh RW . Vertigo of vascular origin. Clinical and electronystagmographic features in 84 cases. Arch Neurol. 1989;46 :281-4.2919982 Oas JG Baloh RW . Vertigo and the anterior inferior cerebellar artery syndrome. Neurology. 1992;42 :2274-9.1461378 Yi HA Lee SR Lee H . Sudden deafness as a sign of stroke with normal diffusionweighted brain MRI. Acta Otolaryngol. 2005;125 :1119-21.16298797 Lee H Kim HJ Koo JW . Progression of acute cochleovestibulopathy into anterior inferior cerebellar artery infarction. J Neurol Sci. 2009;278 :119-22.19108852 Kim JS Cho KH Lee H . Isolated labyrinthine infarction as a harbinger of anterior inferior cerebellar artery territory infarction with normal diffusion-weighted brain MRI. J Neurol Sci. 2009;278 :82-4.19135217 Lee H Sohn SI Jung DK . Sudden deafness and anterior inferior cerebellar artery infarction. Stroke. 2002;33 :2807-12.12468774 Amarenco P Hauw JJ . Cerebellar infarction in the territory of the anterior and inferior cerebellar artery. A clinicopathological study of 20 cases. Brain. 1990;113 (Pt 1) (Pt 1 ):139-55.2302529 Amarenco P Rosengart A DeWitt LD . Anterior inferior cerebellar artery territory infarcts. Mechanisms and clinical features. Arch Neurol. 1993;50 :154-61.8431134 Tzu-Pu C Zheyu W Ariel A . Sudden hearing loss with vertigo portends greater stroke risk than sudden hearing loss or vertigo alone. J Stroke Cerebrovasc Dis. 2017;09 :033. Newman-Toker DE . Missed stroke in acute vertigo and dizziness: it is time for action, not debate. Ann Neurol. 2016;79 :27-31.26418192 Berkhemer OA Fransen PS Beumer D . A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med. 2015;372 :11-20.25517348 Saver JL Goyal M Bonafe A . Stent-retriever thrombectomy after intravenous t-PA vs t-PA alone in stroke. N Engl J Med. 2015;372 :2285-95.25882376 Nogueira RG Jadhav AP Haussen DC . Thrombectomy 6 to 24 hours after stroke with a mismatch between defcit and infarct. N Engl J Med. 2018;378 :11-21.29129157 Hyun-Ah K Hyon-Ah Y Hyung L . Recent advances in cerebellar ischemic stroke syndromes causing vertigo and hearing loss. Springer. 2015;17 :11. Cnyrim CD Newman-Toker D Karch C . Bedside differentiation of vestibular neuritis from central Bvestibular pseudoneuritis^. J Neurol Neurosurg Psychiatry. 2008;79 :458-60.18344397 Kim HA Lee BC Hong JH . Longterm prognosis for hearing recovery in stroke patients presenting vertigo and acute hearing loss. J Neurol Sci. 2014;339 :176-82.24581671 Lee H Yi HA Chung IS . Long-term outcome of canal paresis of a vascular cause. J Neurol Neurosurg Psychiatry. 2011;82 :105-9.20587486 |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.49192 Internal Medicine Allergy/Immunology Oncology Exploring the High-Grade and Refractory Neurotoxicity of Teclistamab: An Underreported Entity Muacevic Alexander Adler John R Lutfi Forat 1 Abdallah Al-Ola 1 Nashatizadeh Muhammad 2 Ahmed Nausheen 1 Nelson Maggie 1 Hamideh Janna 3 Mahmoudjafari Zahra 1 Shune Leyla 1 1 Hematologic Malignancies and Cellular Therapeutics, University of Kansas Medical Center, Kansas City, USA 2 Neurology, University of Kansas Medical Center, Kansas City, USA 3 Oncology, University of Florida, Gainesville, USA Forat Lutfi [email protected] 21 11 2023 11 2023 15 11 e4919220 11 2023 Copyright (c) 2023, Lutfi et al. 2023 Lutfi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License CC-BY 4.0., which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from T-cell re-directing bispecific antibodies targeting B-cell maturation antigens have recently entered real-world use in relapsed/refractory multiple myeloma. While no head-to-head comparison has been done, they have generally been observed to have lower-grade toxicities compared with their chimeric antigen receptor T-cell (CAR-T) counterparts. However, in our real-world, single-institution experience, we have encountered two patients receiving teclistamab who experienced high-grade and refractory immune effector cell-associated neurotoxicity syndrome (ICANS) that did not respond to traditional toxicity mitigation strategies of high-dose corticosteroids or other immunosuppressive therapies. As we increase our use of these novel and vital agents, caution must be warranted. immune repose chemotherapy toxicities newest treatment for multiple myeloma bispecific t cell engager immune effector cell-associated neurotoxicity syndrome (icans) pmcIntroduction The multiple myeloma (MM) therapeutic armamentarium has continued to expand rapidly in relapsed/refractory multiple myeloma (RRMM), with particular excitement in the T-cell re-directing bispecific antibody targeting B-cell maturation antigen (BCMA) . The phase I/II MajesTEC-1 study of RRMM patients treated with teclistamab demonstrated a response rate of 63% and a complete response rate of 39.4%, with median progression-free survival and overall survival of 11.3 and 18.3 months, respectively. High-grade (>= grade three) cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS) were reported in 0.6% and 0, respectively. These findings led to FDA approval for treatment in RRMM . We report two unusual cases of RRMM treated with teclistamab with persistent and high-grade neurotoxicity. Our two patients were classified as refractory ICANS since they did not respond to traditional toxicity mitigation strategies employed for bispecific antibodies and chimeric antigen receptor T-cell (CAR-T) therapies. Herein, we provide insight into both cases, the development of ICANS, treatment strategies employed, and finally, discuss the future directions that may be considered. To our knowledge, this is the first report of refractory ICANS secondary to teclistamab in RRMM to date. Case presentation Both patients had high-risk cytogenetics, received at least six lines of previous therapy, and were at least triple class (anti-CD38, proteasome inhibitor, and immunomodulatory drugs) RRMM, with a duration of less than 24 months since diagnosis. These disease characteristics are suggestive of more virulent disease biology when compared with MajesTEC-1 trial patients (see Table 1). Both patients had multiple comorbidities. However, neither had a history of baseline neurologic disease or CNS MM involvement, aside from a remote history of TIA in patient B. Both patients had a baseline Immune Effector Cell-Associated Encephalopathy (ICE) score of 10 out of 10. Table 1 Clinical Characteristics and Outcomes *All values given in MajesTEC-1 study are the median, unless otherwise noted. AutoHSCT= autologous hematopoietic stem cell transplant, RRMM = relapsed refractory multiple myeloma, CRS = cytokine release syndrome, ICANS = immune effector cell associated neurotoxicity syndrome CRS grading was done using Lee criteria and ICANS grading was done using the American Society for Transplantation and Cellular Therapy (ASTCT) grading criteria. MajesTEC-1* (n=165) Patient A Patient B Age, in years 64 64 66 Time since diagnosis, in years 6.0 2 0.7 High-risk cytogenetics 26% Yes Yes Extramedullary plasmacytoma 20% Yes (pleural effusion, muscle) No >=60% plasma cells in bone marrow 11% Yes Yes Previous lines of therapy 5 7 6 Previous autoHSCT 82% No No Triple class RRMM 78% Yes Yes Refractory to last line of therapy 90% Yes Yes CRS Grade III/IV 0.6% No Yes ICANS Grade III/IV 0 Yes No Patient A completed cycle one (0.06-0.3-1.5mg/kg infusions) of teclistamab developing ICANS grade one with an ICE score of 7 out of 10 on day 8 which was initially attributed to overall fatigue and procedures . ICE scores improved spontaneously to 9 out of 10. However, on day 12 he declined further to ICANS grade III with ICE scores of 1 out of 10. Inflammatory markers were elevated with peak concentrations at day 12 with ferritin of 5,486ng/mL (pre-treatment baseline was 1715ng/mL) and c-reactive protein (CRP) of 3.21mg/dL (pre-treatment baseline was <1mg/dL). He was started on dexamethasone 10mg intravenously (IV) every six hours on day 14 and IL-1 antagonist anakinra 100mg IV twice daily on day 15 for severe ICANS. A computed tomography (CT) scan of the head on day 16 (delayed due to instability) did not reveal any mass effect or hemorrhage. There was concern for possible metabolic encephalopathy given uremia, but the patient did not improve following multiple sessions of dialysis. Unfortunately, he had no response to dexamethasone or anakinra and passed on day 18 from refractory ICANS and multiple organ failure. Figure 1 ICANS Timeline and Interventions CRS = cytokine release syndrome, ICANS = immune effector cell associated neurotoxicity syndrome, IV = intravenous, IT = intrathecal Patient B received the first step-up dose (0.06mg/kg) of cycle one and within hours experienced hypotension and tachycardia and cognitive impairment consistent with CRS grade I and ICANS grade I and was started on dexamethasone 10mg IV daily. She continued to decompensate and experienced circulatory shock requiring vasopressors on day 4 consistent with CRS grade III and ongoing ICANS grade I. The circulatory shock resolved within 24 hours on a higher dose of dexamethasone 20mg IV every six hours. However, her ICANS worsened to grade III on day 8. Full neurologic workup was non-revealing with electroencephalogram (EEG) findings of abundant sharply contoured waves of triphasic morphology and generalized delta greater than theta slowing, consistent with moderate non-specific encephalopathy without evidence of epileptiform activity, three magnetic resonance imagings (MRIs) of the brain without any parenchymal signal abnormality or enhancement to suggest neurotoxicity, and two lumbar punctures without any notable findings. Serum ammonia was mildly elevated in the absence of liver disease which led to the initiation of rifaximin without improvement. Given this lack of response and severe ICANS, we administered hydrocortisone 25mg intrathecally on day 12, anakinra 100mg IV twice daily from days 11 to 18, and methylprednisolone 1000mg IV from days 15 to 21. Inflammatory markers were notably elevated with peak ferritin of 1621ng/mL (pre-treatment baseline 709ng/mL) on day 16 and CRP remaining normal throughout. Interestingly, she achieved a brief partial response after a single step-up teclistamab injection. At the last follow-up on day 29, the patient remained with ICANS grade III and passed away due to progressive disease on day 31. Discussion Although no head-to-head comparison has been done, T-cell re-directing bispecific antibodies have typically been observed to have lower grade CRS and ICANS compared with their CAR-T counterparts, making them quite appealing, particularly in outpatient community practices. However, in our recent real-world, single-institution experience of 28 patients with RRMM treated with teclistamab, we encountered two patients (7%) with refractory ICANS which was not reported in the MajesTEC-1 trial. As teclistamab begins to enter greater clinical use, we believe it imperative to report these early findings to initiate a broad discussion and prepare other clinicians and centers for this possibility, however, rare it may be. Certainly, these two patients had notable comorbidities and aggressive disease biology increasing the risk of toxicity, however, importantly, they would not have been excluded based on trial inclusion and exclusion criteria and are reflective of a subset of patients treated with teclistamab in the real-world . There are likely specific factors in these two patients that rendered such severe toxicities after just one cycle in patient A and a single 0.06 mg/kg step-up dose in patient B. It remains to be seen if this includes baseline organ dysfunction (unknown pharmacokinetics in severe renal or hepatic impairment), intrinsic BCMA-directed T-cell re-directing bispecific antibody behavior, native T-cell and other innate/adaptive immunophenotypes, baseline and evolving cytokine milieu, myeloma disease characteristics (disease burden, extramedullary disease), and variations in BCMA expression and in particular on target, off myeloma binding in the CNS . CNS expression of BCMA in neural and support tissue as a source of on-target, off-myeloma neurotoxicity remains debated with conflicting findings. In mouse models, BCMA targeting antibodies had a deleterious impact on axonal elongation, while in a study of healthy adults, BCMA was been found to be negligibly expressed by both immunohistochemistry and RNA-sequencing . However, in a patient developing Parkinsonism in the CARTITUDE-1 trial, BCMA expression was noted on neurons and astrocytes in the patient's basal ganglia . This perhaps suggests heterogeneity in CNS BCMA expression amongst patient populations, which may reflect the patchy incidence of severe ICANS in BCMA-targeted therapies. Importantly, in our two patients, neurologic imaging did not have any abnormalities despite severe ICANS. This contrasts with severe ICANS reported in the literature and our own experience following CD19 and BCMA-directed CAR-T therapy where T2/FLAIR parenchymal hyperintensity, cerebral edema, or midline shift may be seen . Conclusions Unlike the CRS and ICANS, we have seen with CAR-T therapy and even that reported in MajesTEC-1, these two patients did not respond to high-dose steroids, anakinra, or intrathecal steroids as we would expect. This suggests the possibility of a different mechanism of action for these toxicities, although certainly still in the context of a hyper-inflammatory environment with both patients having grossly elevated ferritin. Thus, in the future, novel approaches to toxicity management must be considered and in particular further clinical and translational research is needed to better understand the underlying etiology and pathogenesis of these toxicities. As we increase our use of teclistamab and other bispecifics while caution must be warranted, they remain vital in the RRMM setting, and in time we will learn their appropriate use and management of their toxicities as they arise. Much remains to be learned in the management of these rare but profound toxicities. FL, NA, and JH were responsible for writing and background/literature review for this study. AA and LS provided their expertise in the management and rationale of the report as recognized myeloma experts. MN provided perspective and analysis as a Neuro-Oncologist. MN and ZM provided data on teclistamab and our experience as Clinical Pharmacists. Human Ethics Consent was obtained or waived by all participants in this study The authors have declared that no competing interests exist. References 1 Taking a BiTE out of the CAR T space race Br J Haematol Patel A Oluwole O Savani B Dholaria B 689 697 195 2021 34131894 2 Teclistamab in relapsed or refractory multiple myeloma N Engl J Med Moreau P Garfall AL van de Donk NW 495 505 387 2022 35661166 3 FDA Approves Teclistamab-cqyv for Relapsed or Refractory Multiple Myeloma 6 2023 2022 4 Dose Escalation Study of Teclistamab, a Humanized BCMA*CD3 Bispecific Antibody, in Participants With Relapsed or Refractory Multiple Myeloma (MajesTEC-1) 6 2023 2023 5 A Study of Teclistamab in Participants With Relapsed or Refractory Multiple Myeloma (MajesTEC-1) 6 2023 6 FDA. Tecvayli Highlights of Precribing Information 6 2023 2022 7 Incidence and management of CAR-T neurotoxicity in patients with multiple myeloma treated with ciltacabtagene autoleucel in CARTITUDE studies Blood Cancer J Cohen AD Parekh S Santomasso BD 32 12 2022 35210399 8 Selective regulation of axonal growth from developing hippocampal neurons by tumor necrosis factor superfamily member APRIL Mol Cell Neurosci Osorio C Chacon PJ White M Kisiswa L Wyatt S Rodriguez-Tebar A Davies AM 24 36 59 2014 24444792 9 Comprehensive BCMA expression profiling in adult normal human brain suggests a low risk of on-target neurotoxicity in BCMA-targeting multiple myeloma therapy J Histochem Cytochem Marella M Yao X Carreira V 273 287 70 2022 35193424 10 Neurocognitive and hypokinetic movement disorder with features of parkinsonism after BCMA-targeting CAR-T cell therapy Nat Med Van Oekelen O Aleman A Upadhyaya B 2099 2103 27 2021 34893771 11 Clinical and radiologic correlates of neurotoxicity after axicabtagene ciloleucel in large B-cell lymphoma Blood Adv Strati P Nastoupil LJ Westin J 3943 3951 4 2020 32822484 12 Toxicities of chimeric antigen receptor T cell therapy in multiple myeloma: an overview of experience from clinical trials, pathophysiology, and management strategies Front Immunol Zhou X Rasche L Kortum KM Danhof S Hudecek M Einsele H 620312 11 2020 33424871 |
Arq Bras Cardiol Arq Bras Cardiol abc Arquivos Brasileiros de Cardiologia 0066-782X 1678-4170 Sociedade Brasileira de Cardiologia - SBC 38198359 01001 10.36660/abc.20230162 Imagem Bloqueio de Ramo Alternante a Cada Batimento Temtem Margarida Concepcao e desenho da pesquisa e Obtencao de dados Analise e interpretacao dos dados Redacao do manuscrito Revisao critica do manuscrito quanto ao conteudo intelectual importante 1 Monteiro Joel Ponte Analise e interpretacao dos dados Redacao do manuscrito Revisao critica do manuscrito quanto ao conteudo intelectual importante 1 Serrao Marco Gomes Concepcao e desenho da pesquisa e Obtencao de dados Analise e interpretacao dos dados Revisao critica do manuscrito quanto ao conteudo intelectual importante 1 Freitas Drumond Revisao critica do manuscrito quanto ao conteudo intelectual importante 1 1 Hospital Dr. Nelio Mendonca Funchal Portugal Hospital Dr. Nelio Mendonca, Funchal - Portugal Correspondencia: Margarida Temtem * Hospital Dr. Nelio Mendonca - Avenida Luis de Camoes, 6180. CEP 9000-177, Funchal - Portugal E-mail: [email protected] Potencial conflito de interesse Nao ha conflito com o presente artigo Editor responsavel pela revisao: Mauricio Scanavacca 19 12 2023 12 2023 120 12 e2023016205 3 2023 01 7 2023 04 10 2023 This is an open-access article distributed under the terms of the Creative Commons Attribution License Palavras-chave Arritmias Cardiacas Eletrocardiografia/metodos Bloqueio de Ramo Bloqueio Atrioventricular Hospitalizacao Marca-passo Artificial pmcHomem de 67 anos admitido no servico de urgencia dos cuidados de saude primarios por tonturas. Ao exame fisico foi detectado um ritmo cardiaco irregular e pedido um eletrocardiograma (ECG) de 12 derivacoes. O ECG (Figura 1) mostrou um padrao de bloqueio de ramo alternante, com alternancia a cada batimento de bloqueio de ramo direito e esquerdo (BRD e BRE) e com bloqueio atrioventricular (BAV) de 2o grau tipo Mobitz I. Figura 1 Bloqueio de Ramo Alternante (alternancia a cada batimento de BRD e BRE), com BAV de 2o grau tipo Mobitz I. O paciente foi transferido para o servico de urgencia do hospital onde repetiu dois ECG sequenciais. Um ECG (Figura 2) com BRE persistente com BAV de 1o grau (intervalo PR de 320ms) e outro ECG seguinte (Figura 3) que mostrou um BRD persistente com bloqueio fascicular anterior esquerdo e BAV de 2o grau tipo 2:1 fixo. Figura 2 BRE persistente com BAV de 1o grau (intervalo PR de 320ms). Figura 3 BRD persistente com bloqueio fascicular anterior esquerdo e BAV de 2o grau tipo Os dois ECG sequenciais, realizados poucos minutos depois, complementaram o diagnostico do 1o ECG (Figura 1) que mostrava alternancia a cada batimento entre BRD e BRE com BAV 2o grau tipo Mobitz I. Como demonstrado neste caso clinico, este bloqueio da conducao intraventricular de modo alternante pode ocorrer de forma intermitente ou persistente. O mecanismo exato por detras de um bloqueio alternante nem sempre e totalmente compreendido, podendo estar relacionado com anormalidades do Sistema His-Purkinje; associado a doenca cardiaca estrutural, como fibrose ou cicatriz no sistema de conducao; como tambem a outros mecanismos que podem ser mais ou menos comuns.1 Conforme observado, existe um atraso de conducao variavel em ambos os ramos ventriculares, que podem ser explicados pelos diferentes periodos refratarios.2 Neste caso, quando o PR e mais curto, o estimulo eletrico desce pelo ramo esquerdo (padrao BRD) e, quando o PR e mais longo, o estimulo desce pelo ramo direito (padrao BRE). Adicionalmente, o atraso ou bloqueio do nodulo AV tambem varia, particularmente com a variabilidade da frequencia auricular subjacente, sendo o grau de BAV mais avancado em frequencias auriculares mais elevadas. Assim, nestes tres eletrocardiogramas sao visiveis BAV de diferentes graus: de 2o grau tipo Mobitz I no 1o ECG (Figura 1); BAV 1o grau no 2o ECG (Figura 2) e BAV de 2o grau tipo 2:1 fixo no 3o ECG (Figura 3). O registo eletrocardiografico de bloqueio de ramo alternante e raro na pratica clinica,3 sendo ainda mais invulgar encontrar este padrao no mesmo ECG, com alternancia de conducao a cada batimento ventricular e, adicionalmente, com BAV. Alguns autores afirmam que o bloqueio de ramo alternante constitui cerca de 6% de todos os bloqueios de ramo e o maior receio deste disturbio do ritmo e o risco potencial de BAV completo, sendo uma indicacao classe I para implantacao de marca-passo definitivo.3,4 Neste sentido, o paciente foi internado no servico de Cardiologia tendo sido implantado um marca-passo definitivo de dupla camara. Image Beat-to-Beat Alternating Bundle-Branch Block Temtem Margarida Conception and design of the research and Acquisition of data Analysis and interpretation of the data Writing of the manuscript Critical revision of the manuscript for important intellectual content 1 Monteiro Joel Ponte Analysis and interpretation of the data Writing of the manuscript Critical revision of the manuscript for important intellectual content 1 Serrao Marco Gomes Conception and design of the research and Acquisition of data Analysis and interpretation of the data Critical revision of the manuscript for important intellectual content 1 Freitas Drumond Critical revision of the manuscript for important intellectual content 1 1 Funchal Portugal Hospital Dr. Nelio Mendonca, Funchal - Portugal Mailing Address: Margarida Temtem * Hospital Dr. Nelio Mendonca - Avenida Luis de Camoes, 6180. Postal Code 9000-177, Funchal - Portugal E-mail: [email protected] Keywords Arrhythmias, Cardiac Electrocardiography/methods Atrioventricular Block Hospitalization Permanent Pacemaker A 67-year-old man was admitted to the primary healthcare emergency department due to dizziness. During the physical examination, an irregular heart rhythm was detected, prompting a request for a 12-lead electrocardiogram (ECG). The ECG revealed a beat-to-beat alternating pattern of right and left bundle branch blocks (RBBB and LBBB) with Mobitz I second-degree atrioventricular (AV) block. Figure 1 Alternating Bundle Branch Block (beat-to-beat alternation between RBBB and LBBB), with Mobitz I second-degree AV block. The patient was transferred to the hospital emergency department, where two consecutive ECGs were performed. One ECG showed persistent LBBB with first-degree AV block (PR interval of 320ms), and the subsequent ECG indicated persistent RBBB with left anterior fascicular block and fixed 2:1 second-degree AV block. Figure 2 Persistent LBBB with first-degree AV block (PR interval of 320ms). Figure 3 Persistent RBBB with left anterior fascicular block and fixed 2:1 second-degree AV block. The two sequential ECGs, performed at a few minute intervals, complemented the diagnosis of the first ECG , which showed a beat-to-beat alternation between RBBB and LBBB with Mobitz I second-degree AV block. As demonstrated in this clinical case, this alternating intraventricular conduction block can occur intermittently or persistently. The exact mechanism behind alternating block is not always fully understood; it might be related to abnormalities in the His-Purkinje system, associated with structural heart disease, such as fibrosis or scarring in the conduction system, as well as other mechanisms that may be more or less common.1 As depicted in this case, there is a variable conduction delay in both ventricular branches, which can be explained by different refractory periods.2 In this case, when the PR interval is shorter, the electrical stimulus descends through the left branch (RBBB pattern), and when the PR interval is longer, the stimulus descends through the right branch (LBBB pattern). Additionally, the delay or blockage of the AV node also varies, particularly with underlying atrial frequency variability, with more advanced AV block at higher atrial frequencies. Hence, these three electrocardiograms display varying degrees of AV block: Mobitz I second-degree AV block in the first ECG , first-degree AV block in the second ECG , and fixed 2:1 second-degree AV block in the third ECG . The electrocardiographic recording of alternating bundle branch block is rare in clinical practice,3 and it is even more unusual to find this pattern in the same ECG, with beat-to-beat alternating conduction and, additionally, with AV block. Some authors state that alternating bundle branch block constitutes approximately 6% of all bundle branch blocks, and the primary concern with this rhythm disturbance is the potential risk of complete AV block, which is a Class I indication for permanent pacemaker implantation.3,4 Therefore, the patient was admitted to the Cardiology department and underwent the implantation of a dual-chamber permanent pacemaker. Fontes de financiamento O presente estudo nao teve fontes de financiamento externas. Vinculacao academica Nao ha vinculacao deste estudo a programas de . Aprovacao etica e consentimento informado Este artigo nao contem estudos com humanos ou animais realizados por nenhum dos autores. Potential conflict of interest No potential conflict of interest relevant to this article was reported. Editor responsible for the review: Mauricio Scanavacca Sources of funding There were no external funding sources for this study. Study association This study is not associated with any thesis or dissertation work. Ethics approval and consent to participate This article does not contain any studies with human participants or animals performed by any of the authors. Referencias 1 Carbone V Tedesco MA Bundle branch block on alternate beats: By what mechanism? J Electrocardiol 2002 35 2 147 152 10.1054/jelc.2002.32337 11953915 2 Saini A Padala SK Koneru JN Ellenbogen KA Alternating bundle-branch block Circulation 2018 137 11 1192 1194 10.1161/circulationaha.118.033637 29530894 3 Glikson M Nielsen JC Kronborg MB Michowitz Y Auricchio A Barbash IM 2021 ESC guidelines on cardiac pacing and cardiac resynchronization therapy Eur Heart J 2021 42 35 3427 3520 10.1093/eurheartj/ehab364 34455430 4 Mitrega K Lenarczyk R Pruszkowska P Kalarus Z Sredniawa B. Alternating left and right bundle branch block Kardiol Pol 2014 72 10 987 987 10.5603/KP.2014.0198 25343679 |
eLife Elife eLife eLife 2050-084X eLife Sciences Publications, Ltd 38126357 94410 10.7554/eLife.94410 Insight Developmental Biology Development Investigating the origin of insect metamorphosis Belles Xavier [email protected] 1* 1 Evolution of Insect Metamorphosis Lab, Institute of Evolutionary Biology, CSIC-Pompeu Fabra University Barcelona Spain 21 12 2023 2023 12 e94410(c) 2023, Belles 2023 Belles This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. Experiments exploring the role of juvenile hormone during the life cycle of firebrat insects provide clues about the evolution of metamorphosis. evolution metamorphosis development insects firebrat juvenile hormone Author impact statementExperiments exploring the role of juvenile hormone during the life cycle of firebrat insects provide clues about the evolution of metamorphosis. Template1 pmcRelated research article Truman JW, Riddiford LM, Konopova B, Nouzova M, Noriega F, Herko M. 2023. The embryonic role of juvenile hormone in the firebrat, Thermobia domestica, reveals its function before its involvement in metamorphosis. eLife 12:RP92643. doi: 10.7554/eLife.92643. Given Darwin's longstanding interest in entomology, it is possible he had insects and metamorphosis in mind when he wrote about "endless forms most beautiful" in the final sentence of On the Origin of Species. More than half of the 2.2 million animal species that have been described are insects, and 98% of these undergo some form of metamorphosis during their lives. Insects have three basic types of life cycle: ametaboly (no metamorphosis), hemimetaboly (gradual metamorphosis), and holometaboly (complete metamorphosis). To begin with, all insects were ametabolous, and evolved the ability to mature first via gradual metamorphosis and later via complete metamorphosis (Belles, 2020). Although most insects are holometabolous, this life cycle could not have evolved without hemimetaboly emerging first. However, we do not fully understand how ametabolous insects evolved to become hemimetabolous. Ametabolous insects are wingless and hatch from their eggs as a miniature version of their adult form. The resulting young, known as nymphs, do not undergo any dramatic physical changes, but successively molt their exoskeleton to produce a series of larger, more mature versions known as instars. Hemimetabolous insects, like cockroaches, also hatch as nymphs that resemble the adult but lack fully developed wings and genitalia. This group of insects molt as they grow until they reach a last nymphal instar, at the end of which they shed their exoskeleton for the last time whilst undergoing metamorphic changes that produce their mature genitalia and wings. The addition of metamorphosis to the life cycle likely arose due to the emergence of wings during evolution. While wings were a successful innovation, molting with wings is mechanically complicated - only mayflies, a small order of insects with about 3,000 extant species still do it. Therefore, ceasing to molt after forming adult wings was the next step that completed the invention of hemimetaboly (Belles, 2019). However, it is not known which features of ametabolous insects contributed to the evolution of metamorphosis. Now, in eLife, James Truman from the University of Washington and co-workers report that changing levels of a chemical signal known as juvenile hormone may have had a significant role (Truman et al., 2023). Juvenile hormone is an important player in post-embryonic development, as it represses metamorphosis in both hemimetabolous and holometabolous insects until they reach a critical size to transform into reproductively competent adults. Truman et al. - who are based at institutes in the United States and the Czech Republic - found that juvenile hormone is present in the last quarter of embryogenesis in the ametobolous firebrat insect Thermobia domestica . Treatments suppressing the hormone impaired the differentiation and maturation of embryo structures, as well as hatching. These defects were corrected when juvenile hormone was re-introduced, validating the hormone suppression experiments. Figure 1. Differences in juvenile hormone levels during the life cycle of ametabolous and hemimetabolous insects. During embryogenesis in ametabolous insects (upper panel), the level of juvenile hormone (dark blue line) remains low during morphogenesis, and then increases rapidly after the shape of the embryo has been established, resulting in the onset of differentiation and maturation. Once the nymph hatches from the egg, the hormone level falls and remains low as the nymph successively sheds its exoskeleton to accommodate its growth. After the adult molt, a fully-grown reproductively competent adult emerges, which continues to molt throughout its lifetime. In hemimetabolous insects (middle panel), the level of juvenile hormone follows a similar pattern during embryogenesis. After hatching, however, it remains relatively high as the nymph molts. Juvenile hormone sustains the development of early structures of the wing (known as primordia) and inhibits metamorphosis via the MEKRE93 pathway. In this pathway, juvenile hormone induces the production of Kruppel homolog 1 which, in turn, represses another protein called E93 (bottom panel). When juvenile hormone declines in the last nymphal instar, this leads to a rise in E93 which triggers the insect to undergo metamorphosis as it molts into its final adult form (red line). E93 also promotes the destruction of the gland responsible for producing the molting hormone, preventing the insect from molting again after becoming an adult. The first three quarters of embryogenesis, when there is no juvenile hormone, are characterized by morphogenetic processes that determine the shape of the organism. Differentiation and maturation processes then take over in the last quarter when juvenile hormone is present. Secretion of juvenile hormone therefore appears to mark the end of morphogenesis and the onset of differentiation and maturation of tissues and organs in the firebrat embryo. Artificially applying juvenile hormone during the earlier stages of embryogenesis triggered differentiation processes, providing further evidence for this shift. Truman et al. report that hemimetabolous insects display a similar pattern of juvenile hormone secretion during embryogenesis. However, juvenile hormone levels during the nymphal period are low in the firebrat but high in hemimetabolous insects. This led the team to suggest that the role of juvenile hormone in the embryo - promoting differentiation while repressing morphogenetic changes - may have been extended into post-embryonic development in the ancestral insects from which the first hemimetabolans originated. This event would concur with the activation of the genes responsible for forming the early structures of the wing . Results from previous studies indicate that continuous juvenile hormone secretion has two important roles in the nymphs of hemimetabolous insects. One is to promote wing development by maintaining the production of the protein factor Broad-complex (Erezyilmaz et al., 2006). The other is to prevent metamorphosis by inducing the production of the protein Kruppel homolog 1 (Konopova et al., 2011; Lozano and Belles, 2011). Importantly, Kruppel homolog 1 represses the production of another protein called E93 (Belles and Santos, 2014), which is the trigger of metamorphosis (Urena et al., 2014). This pathway, known as MEKRE93, is the essential axis that regulates metamorphosis in all insects . The protein E93 also causes the gland that secretes the molting hormone to be destroyed after the last nymphal instar, preventing the adult from molting again (Kamsoi and Belles, 2020). The extant firebrat also produces Broad-complex, Kruppel homolog 1, and E93, as did probably ancestral ametabolous insects (Fernandez-Nicolas et al., 2023; Truman et al., 2023). This suggests that these proteins just needed to take on new functions in order for metamorphosis to evolve. In the future, it would be interesting to study the role of these proteins in firebrat insects, and the molecular mechanisms that allowed them to change their function. Although not an easy task, this would provide important insights in to how metamorphosis evolved. Competing interests Xavier Belles is in the Evolution of Insect Metamorphosis Lab, Institute of Evolutionary Biology, CSIC-Pompeu Fabra University, Barcelona, Spain No competing interests declared. References Belles X Santos CG 2014 The MEKRE93 (Methoprene tolerant-Kruppel homolog 1-E93) pathway in the regulation of insect metamorphosis, and the homology of the pupal stage Insect Biochemistry and Molecular Biology 52 60 68 10.1016/j.ibmb.2014.06.009 25008785 Belles X 2019 The innovation of the final moult and the origin of insect metamorphosis Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences 374 20180415 10.1098/rstb.2018.0415 31438822 Belles X 2020 Insect Metamorphosis. From Natural History to Regulation of Development and Evolution Academic Press 10.1016/C2016-0-04530-8 Erezyilmaz DF Riddiford LM Truman JW 2006 The pupal specifier broad directs progressive morphogenesis in a direct-developing insect PNAS 103 6925 6930 10.1073/pnas.0509983103 16641104 Fernandez-Nicolas A Machaj G Ventos-Alfonso A Pagone V Minemura T Ohde T Daimon T Ylla G Belles X 2023 Reduction of embryonic E93 expression as a hypothetical driver of the evolution of insect metamorphosis PNAS 120 e2216640120 10.1073/pnas.2216640120 36745781 Kamsoi O Belles X 2020 E93-depleted adult insects preserve the prothoracic gland and molt again Development 147 dev190066 10.1242/dev.190066 33077428 Konopova B Smykal V Jindra M 2011 Common and distinct roles of juvenile hormone signaling genes in metamorphosis of holometabolous and hemimetabolous insects PLOS ONE 6 e28728 10.1371/journal.pone.0028728 22174880 Lozano J Belles X 2011 Conserved repressive function of Kruppel homolog 1 on insect metamorphosis in hemimetabolous and holometabolous species Scientific Reports 1 163 10.1038/srep00163 22355678 Truman JW Riddiford LM Konopova B Nouzova M Noriega F Herko M 2023 The embryonic role of juvenile hormone in the firebrat, Thermobia domestica, reveals its function before its involvement in metamorphosis eLife 12 RP92643 10.7554/eLife.92643 Urena E Manjon C Franch-Marro X Martin D 2014 Transcription factor E93 specifies adult metamorphosis in hemimetabolous and holometabolous insects PNAS 111 7024 7029 10.1073/pnas.1401478111 24778249 |
eLife Elife eLife eLife 2050-084X eLife Sciences Publications, Ltd 38126364 94720 10.7554/eLife.94720 Insight Biochemistry and Chemical Biology Microbiology and Infectious Disease Protein Kinase A Probing ligand selectivity in pathogens VanSchouwen Bryan 1* Melacini Giuseppe [email protected] 2* 1 Department of Chemistry and Chemical Biology, McMaster University Hamilton Canada 2 Department of Chemistry and Chemical Biology, and the Department of Biochemistry and Biomedical Sciences, McMaster University Hamilton Canada 21 12 2023 2023 12 e94720(c) 2023, VanSchouwen and Melacini 2023 VanSchouwen and Melacini This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. Why does protein kinase A respond to purine nucleosides in certain pathogens, but not to the cyclic nucleotides that activate this kinase in most other organisms? Protein kinase A ligand selectivity trypanosomatid pathogens T. brucei T. cruzi L. donovani Research organism Other Author impact statementWhy does protein kinase A respond to purine nucleosides in certain pathogens, but not to the cyclic nucleotides that activate this kinase in most other organisms? Template1 pmcRelated research article Ober V, Githure GB, Santos YV, Becker S, Moya G, Basquin J, Schwede F, Lorentzen E, Boshart M. 2023. Purine nucleosides replace cAMP in allosteric regulation of PKA in trypanosomatid pathogens. eLife 12:RP91040. doi: 10.7554/eLife.91040. Protein kinase A (PKA) is involved in a wide range of intracellular processes within eukaryotic organisms, and it also has an important role in the life cycles of a number of pathogens that cause various deadly diseases. These include Trypanosoma brucei, which causes sleeping sickness (Bachmaier et al., 2019); Trypanosoma cruzi, which causes Chagas disease (Baker et al., 2021); and the parasites that cause leishmaniosis (Cayla et al., 2022). An ability to target PKA in these pathogens - which are collectively known as trypanosomatid pathogens - could lead to new treatments for these diseases, but only if this can be done without affecting PKA in the body of the person with the disease. Such selective targeting and inhibition may be possible because, in most organisms, PKA is activated by a cyclic nucleotide called cAMP (Rinaldi et al., 2010; Haste et al., 2012; Kurokawa et al., 2011; Taylor et al., 2012; Khamina et al., 2022). However, PKA in T. brucei does not respond to cAMP, and is activated instead by purine nucleosides. These nucleosides are similar in structure to cyclic nucleotides, but lack a phosphate group . Figure 1. Activating PKA in mammals and trypanosomatid pathogens. (A-D) Stick representations of the molecular structures of the cyclic nucleotide cAMP (A), and three purine nucleosides: adenosine (B), guanosine (C) and inosine (D). The main difference between these molecules is that cAMP contains a phosphate group which the purine nucleosides lack. In most organisms, an important kinase called PKA is activated when two cAMP molecules bind to two tandem binding sites in the regulatory subunit of the kinase (Su et al., 1995; Kim et al., 2007; Akimoto et al., 2015). In trypanosomatid pathogens, on the other hand, PKA is activated when purine nucleosides bind to these sites. (E) Ribbon/stick structures showing a purine nucleoside (inosine; yellow sticks) bound to T. brucei PKA at site A (grey ribbons), overlaid with cAMP (cyan sticks) bound to the same site for mammalian (Bos taurus) PKA (purple ribbons). (F) Ribbon/stick structures showing inosine and cAMP bound to PKA at site B. The amino acids that differ between mammalian and trypanosomatid PKA are labelled: Arg209 and Arg333 in mammalian PKA are replaced by Thr318 and Asn442 in trypanosomatid PKA, while Ala202 and Ala326 are replaced by Glu311 and Glu435. For clarity, other parts of the PKA structures have been omitted. The proposed clash between Glu311/Glu435 of trypanosomatid PKA and the phosphate group of cAMP that prevents cAMP from binding is also indicated (dashed ovals). PKA: protein kinase A; the protein structures used for PKA can be found at PDB ID 6FLO (T. brucei) and PDB ID 1RGS (B. taurus). Now, in eLife, Michael Boshart (Ludwig-Maximilians-University Munich) and colleagues - including Veronica Ober, George Githure and Yuri Volpato Santos as joint first authors - report the results of experiments which shed light on the activation of PKA in T. brucei and other trypanosomatid pathogens, opening new opportunities to develop novel treatments for the diseases caused by such pathogens (Ober et al., 2023). To start, Ober et al. assessed structure-activity relationships for kinase activation by various ligands, and found that three purine nucleosides - inosine, guanosine and adenosine - were direct activators of PKA in three trypanosomatid pathogens (T. brucei, T. cruzi and Leishmania donovani), with inosine being the most potent of the ligands. Moreover, no activation by cAMP was observed, in agreement with previous findings for T. brucei (Bachmaier et al., 2019). The results suggest that activation by purine nucleosides, and insensitivity to cAMP, are universal features of these pathogens. Consistent with these results, when Ober et al. measured ligand binding affinities for T. brucei and L. donovani PKA, inosine exhibited the highest affinity, and there was no significant binding of cAMP. For human PKA, on the other hand, cAMP exhibited high-affinity binding, and there was no significant binding of the three nucleosides. Furthermore, analysis of PKA-bound ligands purified from T. brucei cells at various stages of their life cycle confirmed the presence of all three nucleosides - inosine, guanosine and adenosine - in vivo. To explore these interactions in detail, Ober et al. - who are based at institutes across Germany, and also in Denmark - solved three-dimensional crystal structures of inosine bound to the regulatory subunits of PKA from both T. cruzi and T. brucei. From these structures, they identified key amino acid residues in the binding sites of PKA that interact with inosine, including interactions with the ribose moiety of inosine that were conserved in both structures. Comparison of these structures with the structure of cAMP bound to mammalian PKA (Su et al., 1995) highlighted two key differences in each binding site: a conserved arginine residue in mammalian PKA (which interacts with the phosphate group of cAMP) is replaced with a polar amino acid in trypanosomatid PKA; and a conserved alanine residue is replaced with a conserved glutamate residue . Notably, the structure comparison suggested that the conserved glutamate residue in trypanosomatid PKA would clash with the negatively charged phosphate of bound cAMP, which would explain why cAMP does not bind and activate trypanosomatid PKA. Furthermore, when these residues were mutated to the corresponding residues found in mammalian PKA, cAMP was able to activate the trypanosomatid PKA. The work of Ober et al. provides valuable insights into the activation of trypanosomatid PKA at the molecular level. In the future, it would be interesting to explore the complex formed by the regulatory and catalytic subunits of trypanosomatid PKA, and its nucleoside binding affinities, as this complex constitutes the resting state of PKA in other organisms (Kim et al., 2007). Furthermore, there remains the question of how the activation of trypanosomatid PKA by nucleosides is terminated in vivo, as the mechanism responsible is likely different from that found in human PKA (which relies on enzymes called phosphodiesterases). The more we learn about the differences between trypanosomatid PKA and mammalian PKA, the better chances we have of being able to selectively target trypanosomatid PKA in medical treatments for sleeping sickness and other diseases caused by trypanosomatid pathogens. Competing interests Bryan VanSchouwen is in the Department of Chemistry and Chemical Biology, McMaster University, Hamilton, Canada Giuseppe Melacini is in the Department of Chemistry and Chemical Biology, and the Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Canada No competing interests declared. References Akimoto M McNicholl ET Ramkissoon A Moleschi K Taylor SS Melacini G 2015 Mapping the free energy landscape of PKA inhibition and activation: A double-conformational selection model for the tandem cAMP-binding domains of PKA RIa PLOS Biology 13 e1002305 10.1371/journal.pbio.1002305 26618408 Bachmaier S Volpato Santos Y Kramer S Githure GB Klockner T Pepperl J Baums C Schenk R Schwede F Genieser HG Dupuy JW Forne I Imhof A Basquin J Lorentzen E Boshart M 2019 Nucleoside analogue activators of cyclic AMP-independent protein kinase A of Trypanosoma Nature Communications 10 1421 10.1038/s41467-019-09338-z 30926779 Baker N Catta-Preta CMC Neish R Sadlova J Powell B Alves-Ferreira EVC Geoghegan V Carnielli JBT Newling K Hughes C Vojtkova B Anand J Mihut A Walrad PB Wilson LG Pitchford JW Volf P Mottram JC 2021 Systematic functional analysis of Leishmania protein kinases identifies regulators of differentiation or survival Nature Communications 12 1244 10.1038/s41467-021-21360-8 33623024 Cayla M Nievas YR Matthews KR Mottram JC 2022 Distinguishing functions of trypanosomatid protein kinases Trends in Parasitology 38 950 961 10.1016/j.pt.2022.08.009 36075845 Haste NM Talabani H Doo A Merckx A Langsley G Taylor SS 2012 Exploring the Plasmodium falciparum cyclic-adenosine monophosphate (cAMP)-dependent protein kinase (PfPKA) as a therapeutic target Microbes and Infection 14 838 850 10.1016/j.micinf.2012.05.004 22626931 Khamina M Martinez Pomier K Akimoto M VanSchouwen B Melacini G 2022 Non-canonical allostery in cyclic nucleotide dependent kinases Journal of Molecular Biology 434 167584 10.1016/j.jmb.2022.167584 35427632 Kim C Cheng CY Saldanha SA Taylor SS 2007 PKA-I holoenzyme structure reveals a mechanism for cAMP-dependent activation Cell 130 1032 1043 10.1016/j.cell.2007.07.018 17889648 Kurokawa H Kato K Iwanaga T Sugi T Sudo A Kobayashi K Gong H Takemae H Recuenco FC Horimoto T Akashi H 2011 Identification of Toxoplasma gondii cAMP dependent protein kinase and its role in the tachyzoite growth PLOS ONE 6 e22492 10.1371/journal.pone.0022492 21799871 Ober V Githure GB Santos YV Becker S Moya G Basquin J Schwede F Lorentzen E Boshart M 2023 Purine nucleosides replace cAMP in allosteric regulation of PKA in trypanosomatid pathogens eLife 12 RP91040 10.7554/eLife.91040 Rinaldi J Wu J Yang J Ralston CY Sankaran B Moreno S Taylor SS 2010 Structure of yeast regulatory subunit: a glimpse into the evolution of PKA signaling Structure 18 1471 1482 10.1016/j.str.2010.08.013 21070946 Su Y Dostmann WR Herberg FW Durick K Xuong NH Ten Eyck L Taylor SS Varughese KI 1995 Regulatory subunit of protein kinase A: structure of deletion mutant with cAMP binding domains Science 269 807 813 10.1126/science.7638597 7638597 Taylor SS Ilouz R Zhang P Kornev AP 2012 Assembly of allosteric macromolecular switches: lessons from PKA Nature Reviews Molecular Cell Biology 13 646 658 10.1038/nrm3432 22992589 |
, after "Our biochemical, chemical, genetic and electrophysiological results are consistent with the possibility of Cr as a neurotransmitter", we are adding "though not yet reaching the level of proof for the now classic transmitters". In the last sentence of the introduction, we have now added "though the discovery of a receptor for Cr would prove it". I do, however, believe that, however strong the wordings are, criticisms and rebuttals in science are normal and should be conducted even when emotions are involved. One of my major point of differences with at least two of the reviewers is that the criteria for neurotransmitters should be those listed in major textbooks. While everyone can have one's own opinions, the textbooks, especially those accepted by readers of the field for more than 40 years, should be the standards. Kandel has listed the 4 criteria not only 40 years ago but also just 2 years ago in their latest 6th edition. The reviewers have asked for more, while discounting Kandel et al. (2021). So, in essence, the Reviewer is not shy in scientific criticisms when stating "The identification of a role of a neurotransmitter for brain function and animal behavior has reasonably more advanced possibilities in 2023 than a hundred years ago". Reviewer 1 raised another new criterion: brain function and behavior, while this is not in any textbook lists. However, lack of Cr caused behavioral problems, as cited by us in the introduction: both humans and mice were defective in brain function with loss of function mutations in the gene for the specific Cr transporter SLC6A8. If the reviewer meant behavioral abnormalities caused by Cr injection, that was unclear. But that criterion may not be met by other transmitters which is the likely reason that it was not a criterion in any textbook. Reviewer #2 (Public Review): Summary: Bian et al studied creatine (Cr) in the context of central nervous system (CNS) function. They detected Cr in synaptic vesicles purified from mouse brains with anti-Synaptophysin using capillary electrophoresis-mass spectrometry. Cr levels in the synaptic vesicle fraction was reduced in mice lacking the Cr synthetase AGAT, or the Cr transporter SLC6A8. They provide evidence for Cr release within several minutes after treating brain slices with KCl. This KCl-induced Cr release was partially calcium dependent and was attenuated in slices obtained from AGAT and SLC6A8 mutant mice. Cr application also decreased the excitability of cortical pyramidal cells in one third of the cells tested. Finally, they provide evidence for SLC6A8-dependent Cr uptake into synaptosomes, and ATP-dependent Cr loading into synaptic vesicles. Based on these data, the authors propose that Cr may act as neurotransmitter in the CNS. Strengths: 1. A major strength of the paper is the broad spectrum of tools used to investigate Cr. 2. The study provides evidence that Cr is present in/loaded into synaptic vesicles. Weaknesses: 1. There is no significant decrease in Cr content pulled down by anti-Syp in AGAT-/- mice when normalized to IgG controls. Hence, blocking AGAT activity/Cr synthesis does not affect Cr levels in the synaptic vesicle fraction, arguing against a Cr enrichment. Response: Evidence for Cr enrichment in the SVS was obtained robustly with wild type mice. When brain Cr is very low in AGAT-/- mutant mice, because there is little Cr, there is also little Cr in the SVs. One does not require that as a criterion: it does not argue against the normal levels of Cr could be transported into the SVs even if when the much reduced levels of AGAT-/- Cr in mutant mice could be enriched in SVs. 2. There is no difference in KCl-induced Cr release between SLC6A8-/Y and SLC6A8+/Y when normalizing the data to the respective controls. Thus, the data are not consistent with the idea that depolarization-induced Cr release requires SLC6A8. Response: This comment of Reviewer 2 was based on Figure 5D. But if one carefully examines Figure 5G, it was clear that the Ca++ dependent component of KCl -induced Cr release was lower in SLC6A8-/Y than that in SLC6A8+/Y. 3. The rationale of grouping the excitability data into responders and non-responders is not convincing because the threshold of 10% decrease in AP rate is arbitrary. The data do therefore not support the conclusion that Cr reduces neuronal excitability. Response: Comparison of the same neuron, before and after Cr did show effects on neuronal excitability though that would have no statistics if one does not group multiple cells into the same categories. Reviewer #3 (Public Review): SUMMARY: The manuscript by Bian et al. promotes the idea that creatine is a new neurotransmitter. The authors conduct an impressive combination of mass spectrometry (Fig. 1), genetics (Figs. 2, 3, 6), biochemistry (Figs. 2, 3, 8), immunostaining (Fig. 4), electrophysiology (Figs. 5, 6, 7), and EM (Fig. 8) in order to offer support for the hypothesis that creatine is a CNS neurotransmitter. STRENGTHS: There are many strengths to this study. * The combinatorial approach is a strength. There is no shortage of data in this study. * The careful consideration of specific criteria that creatine would need to meet in order to be considered a neurotransmitter is a strength. * The comparison studies that the authors have done in parallel with classical neurotransmitters are helpful. * Demonstration that creatine has inhibitory effects is another strength. * The new genetic mutations for Slc6a8 and AGAT are strengths and potentially incredibly helpful for downstream work. WEAKNESSES: * Some data are indirect. Even though Slc6a8 and AGAT are helpful sentinels for the presence of creatine, they are not creatine themselves. Of note, these molecules themselves are not essential for making the case that creatine is a neurotransmitter. Response: We agree, but those data are not inconsistent with the possibility. * Regarding Slc6a8, it seems to work only as a reuptake transporter - not as a transporter into SVs. Therefore, we do not know what the transporter into the TVs is. Response: SLC6A8 is not the transporter on the SVs, but is an excellent candidate for the transporter on the presynaptic cytoplasmic membrane for uptake of Cr into the presynaptic structure. * Puzzlingly, Slc6a8 and AGAT are in different cells, setting up the complicated model that creatine is created in one cell type and then processed as a neurotransmitter in another. This matter will likely need to be resolved in future studies. Response: We agree. * No candidate receptor for creatine has been identified postsynaptically. This will likely need to be resolved in future studies. Response: We agree. * Because no candidate receptor has been identified, it is important to fully consider other possibilities for roles of creatine that would explain these observations other than it being a neurotransmitter? There is some attention to this in the Discussion. Response: We agree. There are several criteria that define a neurotransmitter. The authors nicely delineated many criteria in their discussion, but it is worth it for readers to do the same with their own understanding of the data. By this reviewer's understanding (and combining some textbook definitions together) a neurotransmitter: 1) must be present within the presynaptic neuron and stored in vesicles; 2) must be released by depolarization of the presynaptic terminal; 3) must require Ca2+ influx upon depolarization prior to release; 4) must bind specific receptors present on the postsynaptic cell; 5) exogenous transmitter can mimic presynaptic release; 6) there exists a mechanism of removal of the neurotransmitter from the synaptic cleft. Response: While any of us can come up with a list according to our own understanding, the paper copies lists from textbooks, especially from Kandel et al. (2021), which lists the same 4 criteria as Kandel et al. (1983), providing consistency and consensus. For a paper to claim that the published work has identified a new neurotransmitter, several of these criteria would be met - and the paper would acknowledge in the discussion which ones have not been met. For this particular paper, this reviewer finds that condition 1 is clearly met. Conditions 2 and 3 seem to be met by electrophysiology, but there are caveats here. High KCl stimulation is a blunt instrument that will depolarize absolutely everything in the prep all at once and could result in any number of non-specific biological reactions as a result of K+ rushing into all neurons in the prep. Moreover, the results in 0 Ca2+ are puzzling. For creatine (and for the other neurotransmitters), why is there such a massive uptick in release, even when the extracellular saline is devoid of calcium? Response: Classic transmitters are released in a Ca++ dependent manner when stimulated by KCl, though they also had a Ca++ independent component as also shown in our Figure 5 E and F. Condition 4 is not discussed in detail at all. In the discussion, the authors elide the criterion of receptors specified by Purves by inferring that the existence of postsynaptic responses implies the existence of receptors. True, but does it specifically imply the existence of creatinergic receptors? This reviewer does not think that is necessarily the case. The authors should be appropriately circumspect and consider other modes of inhibition that are induced by activation or potentiation of other receptors (e.g., GABAergic or glycinergic). Response: Kandel et al. did not list this. Condition 5 may be met, because authors applied exogenous creatine and observed inhibition. However, this is tough to know without understanding the effects of endogenous release of creatine. if they were to test if the absence of creatine caused excess excitation (at putative creatinergic synapses), then that would be supportive of the same. Nicely, Ghirardini et al., 2023 study cited by the reviewers does provide support for this exact notion in pyramidal neurons. Response: For most commonly accepted transmitters, this criterion has never been met. For example, the simplest case would be ACh at the neuromuscular junction. Howver, we have now found that choline is clearly present in SVs. So, how does anyone be sure that only ACh is released only, or how does anyone rule out effects of choline on postsynaptic cells when cholinergic neurons are stimulated? Many synapses are now known to release more than one transmitter, making it difficult to define the effect of one transmitter released endogenously. These are perhaps reasons why some textbooks do not emphasize similarities of endogenously released vs exogenously applied molecules. For condition 6, the authors made a great effort with Slc6a8. This is a very tough criterion to understand or prove for many synapses and neurotransmitters. Response: SLC6A8 is a transporter on the cytoplasmic membrane, thus a good candidate for removal of Cr from the synaptic cleft. In terms of fundamental neuroscience, the story should be impactful. There are certainly more neurotransmitters out there than currently identified and by textbook criteria, creatine seems to be one of them taking all of the data in this study and others into account. Response: We hope that more will join our lonely efforts in trying to discover more transmitters. Reviewer #1 (Recommendations For The Authors): Since the authors largely disregarded questions in the review process, I do not see a point in listing recommendation for the authors again. Reviewer #2 (Recommendations For The Authors): 1. The different sections of the manuscript are not separated by headers. Response: We do have separate subheadings. 2. The beginning of the results section either does not reference the underlying literature or refers to unpublished data. Response: We have a very long introduction which was criticized for being too long and with too much historical citations. We therefore refrained from citation again in the beginning part of the Results section. 3. The text contains many opinions and historical information that are not required (e.g., "It has never been easy to discover a new neurotransmitter, especially one in the central nervous system (CNS). We have been searching for new neurotransmitters for 12 years."; l. 17). Response: We would like to keep these because most readers are young and do not know the history and difficulties of discovering transmitters. 4. Almeida et al. (2008; doi: 10.1002/syn.20280) provided evidence for electrical activity-, and Ca2+-dependent Cr release from rat brain slices. This paper should be introduced in the introduction. Response: Done. 5. Fig. 7: A Y-scale for the stimulation protocol is missing. Response: Done. Reviewer #3 (Recommendations For The Authors): The main suggestion by this reviewer (beyond the details in the public review) was to consider the full spectrum of biology that is consistent with these results. By my reading, creatine could be a neurotransmitter, but other possibilities also exist. The authors have highlighted some of those for their Discussion. No competing interests declared. Data curation, Formal analysis, Funding acquisition, Validation, Investigation, Visualization, Methodology, Writing - original draft, Writing - review and editing, designed the experiments, improved the methods, carried out experiments and supervised technicians to carry out the experiments for this paper. Data curation, Formal analysis, Validation, Investigation, Methodology, Writing - original draft. Data curation, Formal analysis, Validation, Investigation, Visualization, Methodology, Writing - original draft, Writing - review and editing, designed the experiment and reproducibly found Cr in SVs. Data curation, Formal analysis, Validation, Investigation, Visualization, Methodology. Data curation, Formal analysis, Validation, Investigation, Visualization. Data curation, Investigation. Writing - review and editing. Conceptualization, Resources, Formal analysis, Supervision, Funding acquisition, Investigation, Writing - original draft, Project administration, Writing - review and editing, YR conceived the idea of searching for new neurotransmitters and supervised the project. All animal procedures were approved by the Animal Center of Peking University and Animal Care. Experiments were carried out in accordance with the guidelines of Institutional Animal Care and Use Committee (IACUC) of Peking University (LSC-RaoY-9 and LSC-RaoY-10). |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.49193 Infectious Disease Orthopedics Periprosthetic Joint Infection Following Reverse Shoulder Arthroplasty Treated With Continuous Local Antibiotic Perfusion: A Case Report Muacevic Alexander Adler John R Mashiko Ryosuke 1 Hatta Taku 1 Nagashima Chiharu 2 1 Orthopedic Surgery, Joint Surgery, Sports Clinic Ishinomaki, Ishinomaki, JPN 2 Traumatology and Reconstructive Surgery Center, Aizu Chuo Hospital, Aizuwakamatsu, JPN Taku Hatta [email protected] 21 11 2023 11 2023 15 11 e4919321 11 2023 Copyright (c) 2023, Mashiko et al. 2023 Mashiko et al. This is an open access article distributed under the terms of the Creative Commons Attribution License CC-BY 4.0., which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from Prosthetic joint infection (PJI) is a crucial complication of reverse shoulder arthroplasty (RSA). Continuous local antibiotic perfusion (CLAP) with a high-concentration antimicrobial pharmacy administration method has recently received attention owing to its effectiveness in the treatment of bone and soft tissue infections. We herein report a case of PJI following RSA that was successfully treated with CLAP without removal of the entire implant. A 73-year-old woman with comorbidities of diabetes mellitus and hypertension underwent RSA. The wound was found to be swollen eight weeks after RSA, and purulent content that was positive for Propionibacterium granulosum was identified. Blood samples indicated a mildly elevated inflammatory response. With a diagnosis of PJI spread from the intra-articular to subcutaneous regions without implant loosening, the patient underwent surgical treatment nine weeks after RSA. The contaminated tissues were thoroughly debrided, and the prosthetic joint was preserved by replacing the glenosphere and polyethylene liner. Intra-soft tissue antibiotic perfusion (iSAP) tubes and effluent drains were placed intra-articularly and subcutaneously, and gentamicin was infused continuously for 12 days. In addition, ceftriaxone and rifampicin were administered. The patient was subsequently treated with minocycline and sulfamethoxazole/trimethoprim or clindamycin for eight weeks. The inflammatory reaction became negative six weeks postoperatively, and the patient had no recurrence at 15 months postoperatively. Treatment of PJI is considered a long-lasting, challenging process. This case report supports the feasibility of using CLAP in the treatment of PJI. intra-soft tissue antibiotic perfusion surgery reverse shoulder arthroplasty prosthetic joint infection continuous local antibiotic perfusion pmcIntroduction Reverse shoulder arthroplasty (RSA) has been recognized as a reliable surgical procedure that provides satisfactory clinical outcomes, with expanded surgical indications for various shoulder disorders, including cuff tear arthropathy, irreparable rotator cuff tear, bone neoplasm, rheumatoid arthritis, osteoarthritis, and comminuted proximal fracture in elderly patients . Periprosthetic joint infection (PJI) remains a crucial complication following RSA, potentially causing pain, decreased functional recovery, prolonged hospitalization, requirement for additional surgery, and/or increased mortality . PJI has been reported in 0.9%-1.7% of cases following RSA, and complicated and multiple surgeries may be needed for infection control and subsequent functional restoration . Continuous local antibiotic perfusion (CLAP), which continuously circulates antibiotic agents throughout the lesion, has recently received attention as an alternative treatment for severe fracture-related infections with retaining implants . Intra-medullary antibiotic perfusion (iMAP) for intra-medullary infection or intra-soft tissue antibiotic perfusion (iSAP) for soft-tissue infection has the advantage of providing a high local concentration of antibacterial agents in infected regions. Several case reports have demonstrated satisfactory outcomes in patients with fracture-related infection following open fracture and/or surgical intervention . In contrast, there have been few clinical reports on the use of CLAP for PJI. To our knowledge, no reports have described CLAP for cases of PJI in the shoulder joint. We herein report a case of PJI following RSA that was successfully treated via CLAP while preserving the prosthetic joint. Case presentation A 73-year-old woman visited our institution after falling and impacting her left shoulder. The patient had comorbidities of diabetes mellitus and hypertension. Radiologically, the patient was diagnosed with shoulder dislocation with anterior rim fracture of the glenoid. Since an arthroscopic procedure using soft anchors resulted in failed stability with persistent pain and restricted motion, the patient was scheduled to undergo RSA three weeks after the initial trauma . RSA was performed using the AEQUALIS Ascend system (Stryker Ltd., Kalamazoo, MI, USA) via the deltopectoral approach . Figure 1 Plain radiographs The patient underwent reverse shoulder arthroplasty (RSA) for residual fracture-dislocation of the shoulder. Preoperative (a: anteroposterior image, b: lateral image) and postoperative (c: anteroposterior image, d: lateral image) radiographs. Postoperatively, shoulder pain with a swollen wound was detected eight weeks after RSA. Computed tomography (CT) revealed a cystic lesion spreading from the shoulder joint to the subcutaneous tissues . The aspirated purulent fluid contained Gram-positive bacteria, and culture examination for three days identified Propionibacterium granulosum. Before identifying the bacteria, no antibacterial agents were administered. Figure 2 Enhanced computed tomography Yellow arrowheads indicate an infected lesion with rim enhancement spreading subcutaneously to the periprosthetic space. The patient was diagnosed with PJI and underwent surgical treatment nine weeks after RSA. Intraoperatively, contaminated soft tissues were thoroughly debrided using high-power water via the VERSAJET Hydrosurgery System (Smith & Nephew Ltd., London, UK). The prosthetic joint was preserved simply by replacing the glenosphere and polyethylene liner. For the CLAP treatment, two iSAP tubes and an effluent drain were placed in the periprosthetic space. In addition, an iSAP tube and an effluent drain were placed subcutaneously as well . Figure 3 Postoperative radiograph and schematic illustrations Postoperative anteroposterior image (a) demonstrates the placement of intra-soft tissue antibiotic perfusion (iSAP) tubes and effluent drains for continuous local antibiotics perfusion (CLAP). Schematic illustrations represent iSAP tubes (black arrows) and effluent drains (white arrows); two iSAP tubes were placed in the periprosthetic space (b), and one iSAP tube was placed subcutaneously (c). Gentamicin was continuously infused from each iSAP tube at 2.4 mg/h for 12 days. According to the antimicrobial susceptibility testing examined before the surgery, ceftriaxone and rifampicin were administered intravenously and orally respectively for one week, and subsequently, minocycline and sulfamethoxazole/trimethoprim or clindamycin were administered orally for eight weeks . The inflammatory reaction became negative six weeks postoperatively, and the patient had no recurrence at 15 months postoperatively. Figure 4 Timeline to represent continuous local antibiotics perfusion (CLAP) and systemic administration of antibiotics The graph represents the trend in levels of C-reactive protein (CRP, blue line) and the number of white blood cells (WBCs, red line). Discussion We encountered a case of PJI following RSA treated with CLAP. To our knowledge, there have been no clinical reports demonstrating the application of CLAP for PJI of the shoulder joint. The current case of PJI in a shoulder that had undergone RSA was successfully treated with CLAP. Notably, treatment for infection control can be achieved by retaining the prosthetic joint. The current case report indicates that CLAP can be useful for PJI, with the advantages of minimal functional deficiency and medical cost. Regarding the importance of PJI in patients following RSA, several studies have demonstrated risk factors for PJI, such as sex, smoking history, iron-deficiency anemia, pathological weight loss, and obesity . Regarding the treatment of PJI, various surgical procedures, including irrigation and debridement with/without implant retention, implantation of a cement spacer or resection arthroplasty, and two-stage revision . Although the optimal treatment strategies for PJI remain controversial, the relative advantages of one-stage versus two-stage revision have been investigated. In the literature, one-stage revision has been reported to have several advantages, including reduced reinfection rates, reduced medical costs, shorter hospital stays, better functional outcomes, and overall shorter antibiotic protocol administration, leading to less damage to soft tissues and lower rates of surgical comorbidity . However, two-stage revision has shown benefits of its own, including removal of all hardware in which a biofilm may form, soft tissue rest, less surgical time in each intervention, and allowance of careful planning for secondary joint reconstruction . Although the comparative data were insufficient, a recent systematic review including 711 shoulders with PJI demonstrated a lower reinfection rate for one-stage revision (1.14%) than for two-stage revision (8.81%) and a lower complication rate for one-stage revision (6.11%) than for two-stage revision (21.26%) . CLAP has been recently focused on the treatment of persistent soft-tissue infections, especially fracture-related infections . Regarding the administration of antibiotics, it has been recognized that it is difficult to maintain high concentrations to exceed the minimal biofilm eradication concentration (MBEC), rather than to focus on the minimum inhibitory concentration (MIC). The MBEC should be defined as a concentration that is 100-1000 times the MIC . Therefore, surgeons may have to determine the removal of all implants if insufficient concentrations of MBEC with intravenously administered antibiotic agents are considered the sequence of residual, uncontrollable PJI. CLAP has the advantage of allowing the administration of any concentration of antibiotic. Previous clinical reports have successfully controlled fracture-related infections while retaining implants . Although there is insufficient evidence to support CLAP for the treatment of PJI, potential benefits, including effective antibiotic administration at the infected site with retaining prosthesis, decreased medical costs, and a shortened hospital stay, can be mentioned. However, surgical indications should be carefully determined, especially in cases with chronic PJI in which advanced infiltration throughout the implants may be observed. In addition, the generalizability of applying CLAP procedures such as the placement of iSAP tubes should be noted. Conclusions The current case report demonstrated the successful management of PJI using CLAP. We described CLAP as a novel treatment option for PJI with the advantage of maintaining a sufficient concentration of the administered antibiotic agent in the infected region. Notably, the current treatment for infection control can be achieved by retaining the prosthetic joint. We indicate that the application of CLAP with surgical debridement and implant retention may be a feasible option to maintain shoulder function in patients with PJI. Author Contributions Human Ethics Concept and design: Taku Hatta Acquisition, analysis, or interpretation of data: Taku Hatta, Ryosuke Mashiko, Chiharu Nagashima Drafting of the manuscript: Taku Hatta, Ryosuke Mashiko Critical review of the manuscript for important intellectual content: Chiharu Nagashima Consent was obtained or waived by all participants in this study The authors have declared that no competing interests exist. References 1 Surgical trends of shoulder arthroplasty: nationwide epidemiologic study in South Korea Clin Orthop Surg Park JS Lee HJ Jo YH Lee MK Lee BG 290 299 15 2022 37008973 2 The development of multiple periprosthetic joint infections in conjunction with ibrutinib therapy Cureus Muttana S Solowiej Singh C Kim H Smith CJ Michael MB 0 13 2021 3 Comparison of complication types and rates associated with anatomic and reverse total shoulder arthroplasty J Shoulder Elbow Surg Parada SA Flurin PH Wright TW Zuckerman JD Elwell JA Roche CP Friedman RJ 811 818 30 2021 32763380 4 Risk factors for the development of a peri-prosthetic joint infection up to 2 years following primary reverse shoulder arthroplasty J Orthop Walocha D Bogdan P Gordon AM Magruder ML Conway CA Razi AE Choueka J 69 73 35 2023 36411844 5 A novel treatment strategy using continuous local antibiotic perfusion: a case series study of a refractory infection caused by hypervirulent Klebsiella pneumoniae J Orthop Sci Himeno D Matsuura Y Maruo A Ohtori S 272 280 27 2022 33353777 6 Intra-medullary antibiotics perfusion (iMAP) for the control of fracture-related infection early after osteosynthesis J Orthop Surg (Hong Kong) Maruo A Oda T Miya H 23094990211051492 29 2021 34654344 7 Continuous local antibiotics perfusion therapy for acute deep infections after open fractures Case Rep Orthop Takahara S Maruo A Takayama H Harada T 2563939 2022 2022 35087693 8 Potential of continuous local antibiotic perfusion therapy for fracture-related infections Infect Dis Ther Kosugi K Zenke Y Sato N 1741 1755 11 2022 35596921 9 Effect of smoking on complications following primary shoulder arthroplasty J Shoulder Elbow Surg Hatta T Werthel JD Wagner ER Itoi E Steinmann SP Cofield RH Sperling JW 1 6 26 2017 27810265 10 Periprosthetic joint infection of shoulder arthroplasties: diagnostic and treatment options Biomed Res Int Fink B Sevelda F 4582756 2017 2017 29423407 11 Surgical treatment of infected shoulder arthroplasty. A systematic review Int Orthop Marcheggiani Muccioli GM Huri G Grassi A 823 830 41 2017 28124103 12 Success of staged revision reverse total shoulder arthroplasty in eradication of periprosthetic joint infection J Shoulder Elbow Surg Lo EY Ouseph A Badejo M Lund J Bettacchi C Garofalo R Krishnan SG 625 635 32 2023 36243299 13 Periprosthetic shoulder infection management: one-stage should be the way - a systematic review and meta-analysis J Shoulder Elbow Surg Rodrigues-Lopes R Silva F Torres J [Online ahead of press] 2023 14 Measurement of ampicillin, vancomycin, linezolid and gentamicin activity against enterococcal biofilms J Antimicrob Chemother Sandoe JA Wysome J West AP Heritage J Wilcox MH 767 770 57 2006 16464896 |
Eur Heart J Cardiovasc Imaging Eur Heart J Cardiovasc Imaging ehjcimaging European Heart Journal Cardiovascular Imaging 2047-2404 2047-2412 Oxford University Press US 37880858 10.1093/ehjci/jead256 jead256 Editorial AcademicSubjects/MED00200 Time to treat the climate and nature crisis as one indivisible global health emergency+ Abbasi Kamran Editor-in-Chief, BMJ Ali Parveen Editor-in-Chief, International Nursing Review Barbour Virginia Editor-in-Chief, Medical Journal of Australia Benfield Thomas Editor-in-Chief, Danish Medical Journal Bibbins-Domingo Kirsten Editor-in-Chief, JAMA Hancocks Stephen Editor-in-Chief, British Dental Journal Horton Richard Editor-in-Chief, The Lancet Laybourn-Langton Laurie University of Exeter Mash Robert Editor-in-Chief, African Journal of Primary Health Care & Family Medicine Sahni Peush Editor-in-Chief, National Medical Journal of India Sharief Wadeia Mohammad Editor-in-Chief, Dubai Medical Journal Yonga Paul Editor-in-Chief, East African Medical Journal Zielinski Chris University of Winchester The opinions expressed in this article are not necessarily those of the Editors of EHJCI, the European Heart Rhythm Association or the European Society of Cardiology. Corresponding author. E-mail: [email protected] This Comment is being published simultaneously in multiple journals. For the full list of journals see: 1 2024 25 10 2023 25 10 2023 25 1 67 25 10 2023 (c) The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. 2023 This is an Open Access article distributed under the terms of the Creative Commons Attribution License ), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. pmcOver 200 health journals call on the United Nations, political leaders, and health professionals to recognise that climate change and biodiversity loss are one indivisible crisis and must be tackled together to preserve health and avoid catastrophe. This overall environmental crisis is now so severe as to be a global health emergency. The world is currently responding to the climate crisis and the nature crisis as if they were separate challenges. This is a dangerous mistake. The 28th Conference of the Parties (COP) on climate change is about to be held in Dubai while the 16th COP on biodiversity is due to be held in Turkey in 2024. The research communities that provide the evidence for the two COPs are unfortunately largely separate, but they were brought together for a workshop in 2020 when they concluded that: 'Only by considering climate and biodiversity as parts of the same complex problem ... can solutions be developed that avoid maladaptation and maximize the beneficial outcomes.'1 As the health world has recognised with the development of the concept of planetary health, the natural world is made up of one overall interdependent system. Damage to one subsystem can create feedback that damages another for example, drought, wildfires, floods and the other effects of rising global temperatures destroy plant life, and lead to soil erosion and so inhibit carbon storage, which means more global warming.2 Climate change is set to overtake deforestation and other land-use change as the primary driver of nature loss.3 Nature has a remarkable power to restore. For example, deforested land can revert to forest through natural regeneration, and marine phytoplankton, which act as natural carbon stores, turn over one billion tonnes of photosynthesising biomass every eight days.4 Indigenous land and sea management has a particularly important role to play in regeneration and continuing care.5 Restoring one subsystem can help another for example, replenishing soil could help remove greenhouse gases from the atmosphere on a vast scale.6 But actions that may benefit one subsystem can harm another for example, planting forests with one type of tree can remove carbon dioxide from the air but can damage the biodiversity that is fundamental to healthy ecosystems.7 The impacts on health Human health is damaged directly by both the climate crisis, as the journals have described in previous editorials,8,9 and by the nature crisis.10 This indivisible planetary crisis will have major effects on health as a result of the disruption of social and economic systems shortages of land, shelter, food, and water, exacerbating poverty, which in turn will lead to mass migration and conflict. Rising temperatures, extreme weather events, air pollution, and the spread of infectious diseases are some of the major health threats exacerbated by climate change.11 'Without nature, we have nothing,' was UN Secretary-General Antonio Guterres's blunt summary at the biodiversity COP in Montreal last year.12 Even if we could keep global warming below an increase of 1.5degC over pre-industrial levels, we could still cause catastrophic harm to health by destroying nature. Access to clean water is fundamental to human health, and yet pollution has damaged water quality, causing a rise in water-borne diseases.13 Contamination of water on land can also have far-reaching effects on distant ecosystems when that water runs off into the ocean.14 Good nutrition is underpinned by diversity in the variety of foods, but there has been a striking loss of genetic diversity in the food system. Globally, about a fifth of people rely on wild species for food and their livelihoods.15 Declines in wildlife are a major challenge for these populations, particularly in middle-income countries. Fish provide more than half of dietary protein in many African, South Asian and small island nations, but ocean acidification has reduced the quality and quantity of seafood.16 Changes in land use have forced tens of thousands of species into closer contact, increasing the exchange of pathogens and the emergence of new diseases and pandemics.17 People losing contact with the natural environment and the declining loss in biodiversity have both been linked to increases in noncommunicable, autoimmune, and inflammatory diseases and metabolic, allergic and neuropsychiatric disorders.10,18 For Indigenous people, caring for and connecting with nature is especially important for their health.19 Nature has also been an important source of medicines, and thus reduced diversity also constrains the discovery of new medicines. Communities are healthier if they have access to high-quality green spaces that help filter air pollution, reduce air and ground temperatures, and provide opportunities for physical activity.20 Connection with nature reduces stress, loneliness and depression while promoting social interaction.21 These benefits are threatened by the continuing rise in urbanisation.22 Finally, the health impacts of climate change and biodiversity loss will be experienced unequally between and within countries, with the most vulnerable communities often bearing the highest burden.10 Linked to this, inequality is also arguably fuelling these environmental crises. Environmental challenges and social/health inequities are challenges that share drivers and there are potential co-benefits of addressing them.10 A global health emergency In December 2022 the biodiversity COP agreed on the effective conservation and management of at least 30 percent of the world's land, coastal areas, and oceans by 2030.23 Industrialised countries agreed to mobilise $30 billion per year to support developing nations to do so.23 These agreements echo promises made at climate COPs. Yet many commitments made at COPs have not been met. This has allowed ecosystems to be pushed further to the brink, greatly increasing the risk of arriving at 'tipping points', abrupt breakdowns in the functioning of nature.2,24 If these events were to occur, the impacts on health would be globally catastrophic. This risk, combined with the severe impacts on health already occurring, means that the World Health Organization should declare the indivisible climate and nature crisis as a global health emergency. The three pre-conditions for WHO to declare a situation to be a Public Health Emergency of International Concern25 are that it: 1) is serious, sudden, unusual or unexpected; 2) carries implications for public health beyond the affected State's national border; and 3) may require immediate international action. Climate change would appear to fulfil all of those conditions. While the accelerating climate change and loss of biodiversity are not sudden or unexpected, they are certainly serious and unusual. Hence we call for WHO to make this declaration before or at the Seventy-seventh World Health Assembly in May 2024. Tackling this emergency requires the COP processes to be harmonised. As a first step, the respective conventions must push for better integration of national climate plans with biodiversity equivalents.3 As the 2020 workshop that brought climate and nature scientists together concluded, 'Critical leverage points include exploring alternative visions of good quality of life, rethinking consumption and waste, shifting values related to the human-nature relationship, reducing inequalities, and promoting education and learning.'1 All of these would benefit health. Health professionals must be powerful advocates for both restoring biodiversity and tackling climate change for the good of health. Political leaders must recognise both the severe threats to health from the planetary crisis as well as the benefits that can flow to health from tackling the crisis.26 But first, we must recognise this crisis for what it is: a global health emergency. References 1 Otto-Portner H , ScholesB, AgardJ, ArcherE, ArnethA, BaiXet al Scientific outcome of the IPBES-IPCC co-sponsored workshop on biodiversity and climate change. 2021. 2 Ripple WJ , WolfC, LentonTM, GreggJW, NataliSM, DuffyPBet al Many risky feedback loops amplify the need for climate action. One Earth 2023;6 :86-91. 3 European Academies Science Advisory Council . Key Messages from European Science Academies for UNFCCC COP26 and CBD COP15. 2021 August. (1 October 2023, date last accessed). 4 Falkowski P . Ocean science: the power of plankton. Nature 2012;483 :S17-20.22378122 5 Dawson N , CoolsaetB, SterlingE, LoveridgeR, Gross-CampN, WongbusarakumSet al The role of Indigenous peoples and local communities in effective and equitable conservation. Ecol Soc 2021;26 :19. 6 Bossio DA , Cook-PattonSC, EllisPW, FargioneJ, SandermanJ, SmithPet al The role of soil carbon in natural climate solutions. Nat Sustain 2020;3 :391-8. 7 Levia DF , CreedIF, HannahDM, NankoK, BoyerEW, Carlyle-MosesDEet al Homogenization of the terrestrial water cycle. Nat Geosci 2020;13 :656-8. 8 Atwoli L , BaquiAH, BenfieldT, BosurgiR, GodleeF, HancocksSet al Call for emergency action to limit global temperature increases, restore biodiversity, and protect health. BMJ 2021;374 :n1734.34483099 9 Atwoli L , ErhaborGE, GbakimaAA, HaileamlakA, NtumbaJ-MK, KigeraJet al COP27 Climate Change Conference: urgent action needed for Africa and the world. BMJ 2022;379 :o2459.36257789 10 WHO, UNEP, Convention on Biological Diversity . Connecting global priorities: biodiversity and human health: a state of knowledge review. 2015. (1 October 2023, date last accessed). 11 Magnano San Lio R , FavaraG, MaugeriA, BarchittaM, AgodiA. How antimicrobial resistance is linked to climate change: an overview of two intertwined global challenges. Int J Environ Res Public Health 2023;20 :1681.36767043 12 Jelskov U . "Without nature, we have nothing": UN chief sounds alarm at key UN biodiversity event. UN News (Internet). 6 December 2022 (cited 20 June 2023). (1 October 2023, date last accessed). 13 World Health Organization . State of the world's drinking water: an urgent call to Action to accelerate progress on ensuring safe drinking water for all. World Health Organization; 2022 October. (1 October 2023, date last accessed). 14 Comeros-Raynal MT , BrodieJ, BainbridgeZ, ChoatJH, CurtisM, LewisSet al Catchment to sea connection: impacts of terrestrial run-off on benthic ecosystems in American Samoa. Mar Pollut Bull 2021;169 :112530.34087665 15 IPBES . Assessment report on the sustainable use of wild species. 2022 August. 16 Falkenberg LJ , BellerbyRGJ, ConnellSD, FlemingLE, MaycockB, RussellBDet al Ocean acidification and human health. Int J Environ Res Public Health 2020;17 :4563.32599924 17 Dunne D . Climate change "already" raising risk of virus spread between mammals. 28 April 2022 (cited 24 March 2023). (1 October 2023, date last accessed). 18 Altves S , YildizHK, VuralHC. Interaction of the microbiota with the human body in health and diseases. Biosci Microbiota Food Health 2020;39 :23-32.32328397 19 Schultz R , CairneyS. Caring for country and the health of aboriginal and torres strait Islander Australians. Med J Aust 2017;207 :8-10.28659102 20 Macguire F , MulcahyE, RossingtonB. The Lancet Countdown on Health and Climate Change policy brief for the UK. 2022. (1 October 2023, date last accessed). 21 Wong FY , YangL, YuenJWM, ChangKKP, WongFKY. Assessing quality of life using WHOQOL-BREF: a cross-sectional study on the association between quality of life and neighborhood environmental satisfaction, and the mediating effect of health-related behaviors. BMC Public Health 2018;18 :1113.30208869 22 Simkin RD , SetoKC, McDonaldRI, JetzW. Biodiversity impacts and conservation implications of urban land expansion projected to 2050. Proc Natl Acad Sci U S A 2022;119 :e2117297119. 23 Secretariat of the Convention on Biological Diversity . COP15: nations adopt four goals, 23 targets for 2030 in landmark UN biodiversity agreement. Convention on Biological Diversity (Internet). 12 December 2022 (cited 21 April 2023). (1 October 2023, date last accessed). 24 Armstrong McKay DI , StaalA, AbramsJF, WinkelmannR, SakschewskiB, LorianiSet al Exceeding 1.5degC global warming could trigger multiple climate tipping points. Science 2022;377 :eabn7950. 25 WHO guidance for the use of Annex 2 of the International Health Regulations (2005). World Health Organization (Internet). (cited 5 October 2023). (1 October 2023, date last accessed). 26 Australian Government Department of Health and Aged Care . Consultation on Australia's first National Health and Climate Strategy. Australian Government Department of Health and Aged Care (Internet). 26 July 2023 (cited 26 July 2023). (1 October 2023, date last accessed). |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.49200 Internal Medicine Nephrology Effectiveness of Rituximab and Its Biosimilar in Treating Adult Steroid-Dependent Minimal Change Disease and Relapse Muacevic Alexander Adler John R Shan Hui Yi 1 1 Nephrology and Hypertension, Department of Medicine, Keck School of Medicine of University of Southern California, Los Angeles, USA Hui Yi Shan [email protected] 21 11 2023 11 2023 15 11 e4920019 11 2023 Copyright (c) 2023, Shan et al. 2023 Shan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License CC-BY 4.0., which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from Minimal change disease (MCD) is an important cause of nephrotic syndrome in adults. Its course is often complicated by frequent relapses and steroid dependence. Most of the treatment experience of MCD comes from management of pediatric patients rather than adult patients. In this report, the author describes successful experience of using rituximab (RTX) and its biosimilar, RTX-pvvr (ruxience), to treat steroid-dependent MCD and relapses in adult patients. This is the first report of using a RTX biosimilar to treat MCD. This case series demonstrates that RTX and ruxience are well-tolerated, efficacious treatment for managing adult patients with steroid-dependent MCD and relapses. frequent relapses steroid-dependent minimal change disease rituximab biosimilar ruxience rituximab minimal change disease pmcIntroduction Minimal change disease (MCD) is an important cause of nephrotic syndrome in adults, accounting for 10 to 15 percent of cases . While corticosteroid is effective in treating MCD, high relapse rate and steroid dependency have been problematic for patients and challenging for their nephrologists . In addition, long term use of systemic corticosteroids is associated with significant adverse events. Majority of treatment experience for steroid-dependent MCD comes from management of pediatric patients, significantly less is known about the treatment response of MCD in adult patients. In this paper, the author reports successful experience of using rituximab (RTX) and its biosimilar, ruxience, to treat steroid-dependent MCD in adult patients in their 20s and 30s. All patients were able to be tapered off steroid and remained in complete remission for prolonged period. Furthermore, their post-RTX or post-ruxience MCD relapses were treated successfully with small dose and short courses of steroid. This is the first report of using a RTX biosimilar to treat MCD. All patients had three-to-five years of long-term follow up data. With this case series, the author hopes to increase awareness in using RTX and its biosimilar, ruxience, as effective treatments for managing steroid-dependent MCD and relapses in adults. Case presentation Case 1 A 28-year-old female was diagnosed with MCD with renal biopsy in 2015. The patient was treated with prednisone but was unable to taper prednisone to dose below 20 mg daily without experiencing a relapse. She came to clinic for a second opinion in January 2019. After a negative tuberculosis and hepatitis B screening, the patient received RTX 375 mg/m2, four-weekly infusions. Her post-infusion absolute CD 19 positive cell count was 0 x 106/L. Prednisone was subsequently tapered off in six weeks. She stayed in complete remission until October 2019 when she experienced a relapse of MCD, with proteinuria reaching 7.3 g and serum albumin of 3 g/dL, in the setting of a recent upper respiratory tract infection. At that time, her absolute CD 19 positive cell count was 26 x 106/L (normal range is 91-295 x 106/L). A second course of RTX was given (1 g on Day 1 and Day 15). Her proteinuria went from 7.3 g to 1.9 g in two months. The patient was lost to follow up for one year due to travel and returned in May 2021 with urine protein/creatinine 0.2 mg/mg. Her absolute CD 19 positive cell count at that time was 78 x 106/L. No additional immunosuppression regimen was given in the interim . The patient stayed in complete remission until January 2022 when she contracted COVID-19. Her proteinuria increased, as noted by positive protein in urinalysis. Urine protein/creatinine was not performed. She was treated with prednisone 10 mg daily and tapered off in one month. She has since stayed in remission for close to two years. Figure 1 Proteinuria trend with RTX or ruxience treatment RTX: Rituximab Case 2 A 34-year-old male was diagnosed with MCD with renal biopsy in 2008. His MCD was treated with prednisone and went into complete remission. Since 2008, the patient experienced four relapses. Each time, he received a course of prednisone. His last relapse was in 2018. Since then, he has been maintained on 10 mg prednisone chronically and was not able to get off prednisone without experiencing an increase in proteinuria. The patient's bone density test showed osteopenia in the left femoral neck with a T-score of -1.3. He came for a second opinion in August 2021 due to concern of prolonged steroid use and developing a side effect of osteopenia at a young age. This patient was treated with ruxience 1 g IV on Day 1 and Day 15. Prednisone 10 mg daily was subsequently tapered off after two months. He remained in complete remission for 23 months until July 2023, when his urine protein to creatinine ratio increased from 0.06 to 0.9 mg/mg. Because his relapse was detected early and proteinuria was mild, the patient was treated with prednisone 20mg daily; a repeat urine protein to creatinine ratio was below detectable range 20 days later. The patient was then tapered off prednisone over a span of six weeks and remained in complete remission . Case 3 A 31-year-old male was diagnosed with MCD with renal biopsy at age 13. He had a history of multiple relapses and was maintained on steroid and cyclosporine for more than 13 years. The patient self-stopped immunosuppression in 2019 during COVID pandemic. In June 2022, he contracted COVID-19 infection and his MCD relapsed two months later with urine protein to creatinine ratio of 2.3 mg/mg. The patient was treated with 60 mg of prednisone daily and gradual taper of steroid dosage, with improvement of proteinuria. However, he relapsed again in December 2022, urine protein went up to 1.2 g. He was started on prednisone followed by ruxience 1 g IV x two doses on Day 1 and Day 15, which he completed on January 9, 2023. Urine protein to creatinine ratio normalized to 0.1 mg/mg, and prednisone was tapered off over two months. At four months post-infusion, his absolute CD 19 positive cell count was checked and it remained at 0 x 106/L.The patient has stayed in complete remission for more than 10 months until present . Discussion Steroid-dependent MCD and relapses are challenging to treat. Patients with steroid dependence and frequent relapses suffer from well-known side effects of long-term corticosteroids use. Glucocorticoid (GC)-associated toxicity appears to be related to both the average dose and cumulative duration of GC use. These adverse events include osteoporosis and fractures, adrenal suppression, hyperglycemia and diabetes, cushingoid appearance and weight gain, cardiovascular disease, psychiatric disturbances, immunosuppression, and dermatological changes . Rituximab (RTX), a monoclonal antibody against CD20-bearing cells, depletes CD20+ B lymphocytes and showed satisfactory safety and efficacy profile in pediatric nephrotic syndrome patients . The cases described in this report demonstrated the effectiveness of RTX and its biosimilar, ruxience (rituximab-pvvr), in treating MCD relapse and steroid dependency in adult patients. Patients 1 and 2 spent long years of being on maintenance prednisone. They were successfully tapered off prednisone after receiving RTX or ruxience infusion. In addition, both patients were able to maintain sustained complete remission. Patient 1's longest remission period was 27 months, and Patient 2 was in complete remission for 23 months. This supports the efficacy of RTX or ruxience in treating steroid-dependent MCD as monotherapy. Xue et al. published a meta-analysis by pooling data of cohort studies and case series on adult patients with frequent relapsing or steroid-dependent MCD or focal segmental glomerulosclerosis (FSGS). The study found a pooled rate of complete remission after RTX treatment was 84.2% and that of partial remission was 5.8%. The complete remission rates were 100% in Asians and 69.6% in Caucasians. Notably, pooled comparison of the number of relapses per year before and after RTX treatment showed that the relapse rate significantly decreased by 2.15 times/year; the rate of relapse post-RTX treatment was 27.4% adjusted by sample size. Furthermore, RTX also significantly reduced the steroid dose by 17.8mg/day . This paper is the first report of using RTX biosimilar in treating steroid-dependent MCD. Ruxience was approved by the US Food and Drug Administration (FDA) in 2019 for the treatment of non-Hodgkin's lymphoma, chronic lymphocytic leukemia, granulomatosis with polyangiitis and microscopic polyangiitis . There are also other RTX biosimilar available in the market that include truxima and riabni . For Patients 2 and 3, ruxience was used instead of RTX due to insurance coverage. In both patients, ruxience was effectiveness in treating MCD. The average cost of RTX is $99,900/g versus $76,400/g of ruxience . This leads to a difference of $47,000 for each course of treatment, using the 1 g on Day 1 and Day 15 regimen. The RTX biosimilar provides a significantly cost-saving alternative for patients with MCD. Both patients tolerated ruxience infusion well without significant short-term or long-term adverse events. Another important and novel observation was that once patients received RTX or ruxience, a short course of low dose prednisone (20 mg or less per day for four-eight weeks) was able to successfully treat their subsequent relapses. Respiratory tract infection has been reported to be linked to adult-onset and relapse of MCD. In a study published by Han et al., 87 patients with incipient MCD were enrolled, the study found that before disease onset, 20.7% (18/87) of patients with incipient MCD were diagnosed with infection, including 94.5% (17/18) with respiratory tract infection. 14 patients in complete remission post treatment developed an infection before relapse, including 85% (12/14) with respiratory tract infection . Two of the three patients described in this report had relapse of MCD after respiratory tract infections. Specifically, they developed MCD relapse after contracting COVID-19 infections. While kidney injury is one of the known complications following COVID-19 infection and vaccination, only few cases of MCD following COVID-19 infection and vaccination have been reported [11-13]. Our patient cases expand the clinicians' experience in treating MCD relapses following COVID-19 infection. Further studies are needed to determine the incidence and pathophysiology of MCD either post COVID-19 vaccines or following COVID-19 infections. Conclusions This report illustrates that RTX and its biosimilar, ruxience, are well-tolerated, efficacious treatments for managing adult patients with steroid-dependent MCD and relapses. One course of treatment provides long-lasting effect to allow successful steroid withdrawal and sustained complete remission of disease. Importantly, these treatments significantly lessen the need for long-term, high-dose corticosteroid use and, hence, minimize the GC-associated toxicity in these patients. Author Contributions Human Ethics Concept and design: Hui Yi Shan Acquisition, analysis, or interpretation of data: Hui Yi Shan Drafting of the manuscript: Hui Yi Shan Critical review of the manuscript for important intellectual content: Hui Yi Shan Consent was obtained or waived by all participants in this study The authors have declared that no competing interests exist. References 1 Adult minimal-change disease: clinical characteristics, treatment, and outcomes Clin J Am Soc Nephrol Waldman M Crew RJ Valeri A 445 453 2 2007 17699450 2 Minimal-change disease in adolescents and adults: epidemiology and therapeutic response Clin Kidney J Keskar V Jamale TE Kulkarni MJ Kiggal Jagadish P Fernandes G Hase N 469 472 6 2013 26064510 3 A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy Allergy Asthma Clin Immunol Liu D Ahmet A Ward L 30 9 2013 23947590 4 Efficacy and acceptability of immunosuppressive agents for pediatric frequently-relapsing and steroid-dependent nephrotic syndrome: a network meta-analysis of randomized controlled trials Medicine (Baltimore) Tan L Li S Yang H Zou Q Wan J Li Q 0 98 2019 5 Efficacy and safety of rituximab in adult frequent-relapsing or steroid-dependent minimal change disease or focal segmental glomerulosclerosis: a systematic review and meta-analysis Clin Kidney J Xue C Yang B Xu J 1042 1054 14 2021 34094516 6 FDA approves Pfizer's rituximab biosimilar, ruxience AJMC. July 11 2023 Davio K 2019 7 Introduction of biosimilar rituximab: a hospital perspective Hemasphere Cheesman S 0 5 2021 8 Rituxan prices, coupons and patient assistance programs 11 2023 9 Ruxience prices, coupons and patient assistance programs 11 2023 10 Respiratory tract infection: a risk factor for the onset and relapse of adult-onset minimal change disease in Southern China Biomed Res Int Han H Wang S Liang Y 1657208 2018 2018 30228981 11 Minimal change disease secondary to either COVID-19 infection or Pfizer-BioNTech COVID-19 vaccination Am J Clin Pathol Pokharel A Li W Kannan HD Zhang P Blatt NB 30 161 158 2022 12 MO203: minimal change disease secondary to SARS-COV-2 (COVID-19) infection: a report of 2 cases and review of related literatur Nephrology Dialysis Transplantation Pasilian RM Vallanueva AR Manalili SA 0 37 2022 13 Minimal change disease and COVID-19 vaccination: four cases and review of literature Clin Nephrol Case Stud Chandra P Roldao M Drachenberg C 54 63 10 2022 35923765 |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.49202 Pediatrics Pediatric Surgery Emergency Medicine 'Grumbling' Midgut Volvulus in an Older Paediatric Patient With Congenital Solitary Kidney: A Case Report Muacevic Alexander Adler John R Emmerson Matthew K 1 Dawson Moya 1 1 Paediatric Emergency Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, GBR Matthew K. Emmerson [email protected] 21 11 2023 11 2023 15 11 e4920218 11 2023 Copyright (c) 2023, Emmerson et al. 2023 Emmerson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License CC-BY 4.0., which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from Midgut volvulus is a life-threatening condition, with the majority of cases presenting before the first year of life. Congenital gastrointestinal abnormalities can be associated with midgut volvulus; however, similar associations have not been described with congenital renal abnormalities. Congenital solitary kidney (CSK) means that a child is born with only one functional kidney. Here, we describe a case of a five-year-old child with CSK who atypically presents with midgut volvulus. The case highlights how midgut volvulus may present with chronic symptoms in those over the age of one and the importance of upper GI contrast studies for diagnosis of midgut volvulus in this population and suggests CSK along with other causes of solitary kidney as possible risk factors for volvulus. case report paediatric general surgery emergency department congenital solitary kidney midgut volvulus pmcIntroduction Intestinal malrotation is a congenital abnormality resulting from the incomplete rotation of the foetal gut during weeks 4-10 of embryogenesis. Ninety percent of cases present before the first year of life with bilious vomiting and abdominal pain . However, some patients are asymptomatic and are only diagnosed incidentally during surgery or at autopsy . Midgut volvulus is a serious complication of intestinal malrotation which can result in bowel necrosis, obstruction and death . Malrotation and volvulus have a strong association with congenital gastrointestinal abnormalities such as abdominal wall defects (gastroschisis and omphalocele), congenital diaphragmatic hernias and heterotaxic syndromes . However to date, no relationship has been described with congenital abnormalities of the kidneys. Congenital solitary kidney (CSK) is the anatomical or functional absence of one kidney from birth . This can occur due to a failure of embryonic renal tissue formation (renal agenesis), or due to extreme forms of dysplasia (renal aplasia and multicystic dysplastic kidney) . It is a relatively common occurrence with an incidence of 1 in 2000 to 1 in 4300 live births . There have been several case reports of post-nephrectomy patients developing a caecal volvulus [8-10] and one report of a child developing malrotation with a horseshoe kidney . Apart from this one case, no other cases have been reported of children being born with a solitary kidney and developing midgut volvulus after the age of one. Here, we describe a case of intestinal malrotation with midgut volvulus in a five-year-old boy who was born with a solitary right kidney. Case presentation A previously well five-year-old boy presented to A&E with severe abdominal pain around the umbilicus. The pain had started suddenly that morning after he had his usual cup of tea. After the pain started, he began to vomit clear, non-bilious, non-bloody fluid. He was able to drink water but was not eating. He had opened his bowels that morning, passing stool of normal colour and consistency for him. Over the previous two years, he had had several episodes of similar upper abdominal pain. These could occur weekly or monthly and were unpredictable, although appeared to happen towards the end of the week. Usually, there was no vomiting with the pain and it settled within a few hours. He was completely well in-between episodes. His mother had taken him to the GP several times for this, but no investigations had yet taken place. The child's past medical history included being born with a single right kidney, which was discovered at three months of age when he had an episode of urosepsis. He has a regular annual follow-up appointment to check on his renal function. He also had eczema, for which he used emollients and mometasone steroid cream. He was on no other medication. He had no known allergies, his immunisations were up to date and there were no social concerns. On examination, he was pale, afebrile and in a significant amount of pain, unable to stand up straight or lie fully extended. His abdomen was generally soft with no guarding. It was not distended but had a palpable fullness of the epigastrium. Both testes were present and mobile. Post-examination, the child vomited copious amounts of dark green bilious vomitus. Investigations An initial point of care glucose demonstrated a blood glucose level of 10.4 mmol/ml and ketones of 0.4 mmol/L alongside a urine dip showing 2+ glucose. Subsequent laboratory findings showed normal glucose, ketones, amylase and lactate. Ultrasound was unable to identify the superior mesenteric artery and mesenteric vein due to epigastric gas obscuring the view. A water-soluble barium contrast revealed an obstruction in the duodenum at D2 , likely to be intestinal malrotation with midgut volvulus. Figure 1 Water-soluble barium contrast X-ray revealing obstruction in the duodenum at D2 Differential diagnosis Prior to the bilious emesis, the main differential diagnosis was of an atypical presentation of malrotation/volvulus, even though the longevity of the preceding intermittent symptoms caused some diagnostic uncertainty. Other differential diagnoses included pancreatitis, excluded by the normal amylase and early diabetes mellitus, also excluded by a subsequent normal glucose value and normal venous blood gas. Following the bilious emesis and upper GI contrast study results, malrotation with a possible volvulus was our working diagnosis. Treatment and outcome A successful laparotomy and Ladd's procedure were carried out the same evening with no complications. The bowel was found to be dusky with an oedematous mesentery but was not necrotic; reducing the volvulus allowed it to reperfuse successfully. The patient was discharged home four days later and was well at follow-up six months later. Discussion Midgut volvulus is generally seen in infants below the age of one, with over 90% of cases occurring in this population . In those above this age range, volvulus and intestinal malrotation can be mistaken for a range of conditions, such as pancreatitis, abdominal tuberculosis and gastro-oesophageal reflux, or even dismissed as a functional disorder . This risk of misdiagnosis is exacerbated by an increased propensity for more atypical and chronic presentations of volvulus in the older population compared to those below the age of one . Atypical presentations of volvulus most commonly include recurrent colicky abdominal pain and non-bilious vomiting . As such, this case study helps highlight how important it is to consider volvulus as a differential even in patients outside of the classic age range and presentation. When diagnosing volvulus, accurate and reliable imaging is key. The modalities of choice tend to be abdominal Doppler ultrasound, CT scan with contrast and upper GI contrast study. With abdominal ultrasound, malrotation can be identified through the 'whirlpool' sign describing the spiralling of the superior mesenteric vein and small intestine around the superior mesenteric artery . A recent meta-analysis demonstrated a 94% sensitivity and 100% specificity of abdominal ultrasound for diagnosing volvulus . However, not only is this modality highly dependent on radiographer technique and experience , but it is also not as accurate for diagnosing midgut volvulus presenting in patients older than one year due to the presence of bowel gas, as seen in this case study. Instead, upper GI contrast studies, involving anterior-posterior and lateral projections of the abdomen on barium swallow, or CT with contrast are preferred . One study of 35 patients older than one year old showed that upper GI contrast studies diagnosed malrotation in all patients . As such, in older children presenting with midgut volvulus, upper GI contrast studies or contrast abdominal CTs are the preferred imaging modalities. The relationship between paediatric gastrointestinal problems and CSK is not one that has been investigated extensively. One systematic review found that CSK can be associated with other congenital abnormalities, most commonly anomalies of the kidneys and urinary tracts such as vesicoureteral reflex, with a prevalence of 32% in this paediatric population . However, the same review found that 31% of patients had extra-renal abnormalities, 16% of which were gastrointestinal. In another review, anal atresia was found to be the most common gastrointestinal abnormality . Given the correlation between these gastrointestinal anomalies and CSK, it would be interesting to investigate further whether CSK could be a potential risk factor for the development of late-onset midgut volvulus through a systematic review. Only one other case study has described a patient with CSK (in this case, a horseshoe kidney) developing malrotation after the age of one . However, several case studies have described patients who have undergone nephrectomies and then developed caecal volvulus above the age of one. These kidneys have been removed for a variety of reasons including Wilm's tumour treatment , renal carcinoma treatment and palliation . In the majority of cases, the right kidney has been removed. Papers have hypothesised the volvulus may be due to the retroperitoneal approach taken to remove the kidney or that volvulus is simply a potential complication after intra-abdominal surgery . However, given the observations from this case study of a patient who was born without a left kidney developing volvulus later in life, we hypothesise that the lack of renal tissue in the retroperitoneum may predispose patients to a higher risk of volvulus, with lack of a right kidney predisposing to caecal volvulus and lack of a left kidney to midgut volvulus due to their anatomical proximity to surrounding organs. Although extensive further investigations would be required to validate this superficial hypothesis, it does appear to hold for removal of other retroperitoneal organs such as the pancreas which can demonstrate gastric volvulus on removal . Conclusions In patients outside of the classical age range of younger than one year old, midgut volvulus can present abnormally with chronic colicky abdominal pain and non-bilious vomiting. This can be confused with a range of differential diagnoses including pancreatitis, gastro-oesophageal reflux or a functional disorder. In this older patient cohort, a high index of suspicion along with an upper GI contrast study or CT abdomen with contrast is important in diagnosing midgut volvulus. This case and other similar cases suggest that a solitary kidney, due to CSK or post-nephrectomy, may be a risk factor for volvulus development later in life. However, significantly more research is required to elucidate if this correlation is causal. Author Contributions Human Ethics Concept and design: Matthew K. Emmerson, Moya Dawson Acquisition, analysis, or interpretation of data: Matthew K. Emmerson Drafting of the manuscript: Matthew K. Emmerson Critical review of the manuscript for important intellectual content: Matthew K. Emmerson, Moya Dawson Supervision: Moya Dawson Consent was obtained or waived by all participants in this study The authors have declared that no competing interests exist. References 1 Malrotation of the intestine and colon The Surgery of Infancy and Childhood: Its Principles and Techniques Gross RE 192 Philadelphia Saunders 1953 2 Malrotation beyond infancy J Pediatr Surg Nagdeve NG Qureshi AM Bhingare PD Shinde SK 2026 2032 47 2012 23163993 3 Long-term complications following intestinal malrotation and the Ladd's procedure: a 15 year review Pediatr Surg Int Murphy FL Sparnon AL 326 329 22 2006 16518597 4 Surgical concerns in malrotation and midgut volvulus Pediatr Radiol Shew SB 0 71 39 Suppl 2 2009 5 Management of the congenital solitary kidney: consensus recommendations of the Italian Society of Pediatric Nephrology Pediatr Nephrol La Scola C Ammenti A Bertulli C 2185 2207 37 2022 35713730 6 Unilateral renal agenesis: a systematic review on associated anomalies and renal injury Nephrol Dial Transplant Westland R Schreuder MF Ket JC van Wijk JA 1844 1855 28 2013 23449343 7 Unilateral multicystic dysplastic kidney: a meta-analysis of observational studies on the incidence, associated urinary tract malformations and the contralateral kidney Nephrol Dial Transplant Schreuder MF Westland R van Wijk JA 1810 1818 24 2009 19171687 8 Volvulus of cecum following simple nephrectomy Urol Int Ali Khan S Desai PG Siddharth P Smith N 1 2 40 1985 3976085 9 A cruel twist: post-operative cecal volvulus Ulus Travma Acil Cerrahi Derg Scott CD Trotta BM Dubose JJ Ledesma E Friel CM 158 162 14 2008 18523909 10 Intestinal malrotation: varied clinical presentation from infancy through adulthood Surgery Nehra D Goldstein AM 386 393 149 2011 20719352 11 Malrotation of the midgut associated with horseshoe kidney presenting as gastric outlet obstruction in a 15-year-old boy Afr J Paediatr Surg Nwokoro CC Emmanuel EA Olatunji AA Salami BA Amosu LO Ogundele IO 122 126 17 2020 33342849 12 Cecal volvulus following a right nephrectomy for Wilms' tumor: should we need to close the lateral peritoneum? European J Pediatr Surg Rep Gonzalez-Urquijo M Ovalle-Chao C Flores-Villalba E de Jesus Garza-Luna U Velazco-De La Garza JH Garza-Serna U 0 3 6 2018 13 Anomalies of intestinal rotation and fixation: consequences of late diagnosis beyond two years of age Pediatr Surg Int Penco JM Murillo JC Hernandez A De La Calle Pato U Masjoan DF Aceituno FR 723 730 23 2007 17594104 14 Midgut volvulus in a pediatric patient with chronic constipation, congenital intestinal malrotation and internal transmesocolic hernia BMJ Case Rep Brezler E Sico R Seifarth FG 0 16 2023 15 Ultrasound for the diagnosis of malrotation and volvulus in children and adolescents: a systematic review and meta-analysis Arch Dis Child Nguyen HN Kulkarni M Jose J Sisson A Brandt ML Sammer MB Pammi M 1171 1178 106 2021 33879472 16 Intestinal malrotation - Investigations | BMJ Best Practice 8 2023 2023 17 Associated anomalies in children with congenital solitary functioning kidney Pediatr Surg Int Dursun H Bayazit AK Buyukcelik M Soran M Noyan A Anarat A 456 459 21 2005 15883823 18 Caecal volvulus following left-side laparoscopic retroperitoneal nephroureterectomy BMJ Case Rep Abdoolraheem MY Quraishi MK Tonsi A Henderson A 0 12 2019 19 A gastric volvulus after the whipple procedure in a pancreatic cancer: a case report Jundishapur J Oncol Bahreini A Yousefzadeh M Shayestaezadeh B Kazemnia K 63 65 2 2016 20 Gastric volvulus with perforation 1 year after total pancreatectomy: a case report Surg Case Rep Takahashi Y Seki H 74 6 2020 32303917 |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.49198 Dentistry Oncology Complete Response to Cetuximab Plus Paclitaxel Therapy in Nivolumab-Refractory Patients in Distant Metastasis of Squamous Cell Carcinoma of the Tongue: A Report of Two Cases Muacevic Alexander Adler John R Tachinami Hidetake 1 Tomihara Kei 2 Takatsuka Danki 1 Ikeda Atsushi 1 Yamada Shin-ichi 1 Noguchi Makoto 1 1 Oral and Maxillofacial Surgery, Toyama University, Toyama, JPN 2 Oral and Maxillofacial Surgery, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, JPN Hidetake Tachinami [email protected] 21 11 2023 11 2023 15 11 e4919821 11 2023 Copyright (c) 2023, Tachinami et al. 2023 Tachinami et al. This is an open access article distributed under the terms of the Creative Commons Attribution License CC-BY 4.0., which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from Herein, we report two cases of patients diagnosed with nivolumab-refractory distant metastatic squamous cell carcinoma of the tongue who were successfully treated with a combination of paclitaxel and cetuximab. Case 1 had controllable local recurrence and distant metastasis. Case 2 had controllable distant metastatic disease. Thus, demonstrating that some nivolumab-refractory patients with recurrent or distant metastatic oral squamous cell carcinoma may benefit from subsequent salvage chemotherapy. case report cetuximab paclitaxel distant metastatic oral squamous cell carcinoma nivolumab-refractory pmcIntroduction Nivolumab, an immune checkpoint inhibitor (ICI), has revolutionized the treatment of recurrent and metastatic oral cancer . Nivolumab is a human monoclonal IgG4 antibody that targets the negative immunomodulator PD-1 on T-cells. It was approved in Japan in 2017 and has since been used to treat advanced oral cancer. However, the overall response rate (ORR) in patients with advanced oral cancer is less than 20% . Though it has been well-documented in the literature that conventional chemotherapy is highly effective for patients with advanced lung cancer in conjunction with nivolumab administration, only a few reports of its use in head and neck cancer are available . In this study, we report two cases of patients with tongue cancer who presented with progressive disease after nivolumab administration and subsequently responded to salvage chemotherapy. Although there is prolonged overall survival with salvage chemotherapy, a complete response is rare. We report a complete response to cetuximab plus paclitaxel after chemotherapy in two patients with distant metastases to the liver and bone. This article was previously posted to the AUTHOREA preprint server on March 9, 2022. Case presentation Case 1 A 43-year-old male patient (height: 171cm; weight: 79kg; with good nutritional status) presented to our hospital with an ulcer on the left tongue margin. He had no prior relevant medical history, did not consume alcohol or smoke, and had no family history of cancer. He appeared to be well nourished. While there were no significant extraoral findings, intraoral examination revealed a raised, ulcerated lesion measuring 40 x 30 mm that extended from the left lateral margin to the ventral surface of the tongue. The histological diagnosis of the biopsy specimen was squamous cell carcinoma; the patient was diagnosed with squamous cell carcinoma of the tongue (T3N0M0, Stage III). After platinum-based chemotherapy, the patient underwent neck dissection, partial left-sided tongue resection, and anterolateral thigh flap reconstruction. Eight months later, computed tomography (CT) images revealed a swelling in the left submandibular region, pale ring-shaped nodular shadows in both lung fields, and osteolytic changes in the left iliac bone . Fluorodeoxyglucose-positron emission tomography (FDG-PET) revealed an abnormal accumulation in the left submandibular region, both lung fields, and left iliac bone . In view of these findings, nivolumab (3 mg/kg) was administered every two weeks. After completion of 10 cycles, contrast-enhanced CT and FDG-PET revealed enlargement of each target lesion, indicating progressive disease (iliac bone metastasis and left lung lesion) . The patient was started on paclitaxel and cetuximab (PC) therapy (paclitaxel: 80 mg/m2, cetuximab: 400 mg/m2). After 16 courses of PC therapy, all target lesions had decreased in size, indicating a partial response. After 46 courses of PC therapy, all target lesions had almost disappeared, indicating a complete response . There was no recurrence after 36 months. Figure 1 Radiological findings of the tumor in Case 1 before nivolumab administration. Findings before nivolumab administration. Computed tomography (CT; left) revealed a swelling in the left submandibular region (A, B), pale ring-shaped nodular shadows in both the lung fields (C, D), and osteolytic changes in the left iliac bone (E). Fluorodeoxyglucose-positron emission tomography (FDG-PET; right) revealed an abnormal accumulation in the left iliac bone (F). Figure 2 Radiological findings of the tumor in Case 1 after nivolumab administration. Findings after 10 courses of nivolumab administration. Contrast-enhanced CT and FDG-PET revealed enlargement of each target lesion, indicating progressive disease (A-F). Figure 3 Radiological findings of the tumor in Case 1 after salvage chemotherapy. After 16 courses of salvage chemotherapy, all target lesions almost disappeared, indicating a complete response (A-F). As suggested, we have improved. Grade 1 hypothyroidism, which occurred as a secondary immune-related adverse event, was treated with levothyroxine sodium hydrate (Tirazin(r)) at the Endocrinology Department of our hospital. After PC therapy, the patient developed grade 2 interstitial pneumonia; thus, steroid therapy was initiated, which required hospitalization for approximately 1 week. In addition, he developed grade 2 dermatitis. However, no secondary symptoms of grade 3 or higher levels of dermatitis were observed. Case 2 A 67-year-old female patient (height: 148cm; weight: 59kg; with good nutritional status) presented to our hospital with an ulcer on the right tongue margin. The patient's hematological findings at the initial examination revealed a hemoglobin Alc level of 6.0%. She did not consume alcohol or smoke and had no family history of cancer. Extraoral examination revealed no significant findings; however, intraoral examination revealed a raised, ulcerated lesion 30 x 30 mm in size extending from the right lateral margin to the ventral surface of the tongue. The histological diagnosis of the biopsy specimen was squamous cell carcinoma; the patient was diagnosed with squamous cell carcinoma of the tongue (T3N0M0, Stage III). The patient refused surgery and received chemoradiation therapy. Three months later, the primary tumor was under control; however, CT and FDG-PET revealed multiple cavernous nodules in the right lung field . The patient was started on nivolumab (3 mg/kg, administered every two weeks) for multiple lung metastases. After nine courses of nivolumab, contrast-enhanced CT revealed an increase in the size of the target lesion and a new low-density nodule in the left lateral lobe of the liver, which was diagnosed as liver metastasis . The patient was started on PC therapy (paclitaxel: 80 mg/m2, cetuximab: 400 mg/m2). After 19 courses of PC therapy, all target lesions had almost disappeared, which indicated a complete response . No recurrence was observed at the 36-month follow-up. Figure 4 Radiological findings of the tumor in Case 2 before nivolumab administration. Findings before nivolumab administration. Computed tomography (CT; A) and fluorodeoxyglucose positron-emission tomography (FDG-PET; B) revealed multiple cavernous nodules in the right lung field. Figure 5 Radiological findings of the tumor in Case 2 after nivolumab administration. After nine courses of nivolumab, contrast-enhanced CT revealed an increase in the size of the target lesion and a new low-density nodule in the left lateral lobe of the liver. Figure 6 Radiological findings of the tumor in Case 2 after salvage chemotherapy. After 19 courses ofsalvage chemotherapy, all target lesions almost disappeared, which indicated a complete response (A-C). Grade 1 hypothyroidism, which occurred as a secondary immune-related adverse event, was treated with levothyroxine sodium hydrate (Tirazin(r)) at the Endocrinology Department of our hospital. Following PC therapy, the patient developed grade 2 liver function abnormality and grade 2 dermatitis, which were treated with ursodeoxycholic acid (Urso(r)) at the Department of Gastroenterology. However, no severe secondary symptoms of grade 3 or higher levels of dermatitis were observed. Discussion Nivolumab, an ICI that blocks programmed death-1 (PD-1; an immune checkpoint molecule), was approved in 2017 in Japan as a treatment option for recurrent or distant metastatic advanced oral cancer. Nivolumab has brought about a revolution in the treatment of oral cancer by significantly improving patients' prognoses. However, its efficacy is limited. The ORR is low, and additional salvage therapy and subsequent chemotherapy are required for refractory patients. Although there is prolonged overall survival with salvage chemotherapy, a complete response is rare. We report a complete response to cetuximab plus paclitaxel after chemotherapy in two patients with distant metastases in the liver and bone. Following the advent of ICIs in recent years, salvage chemotherapy has been found to be effective for several solid tumors, including those in patients with head and neck cancer [2-5]. Because ICIs targeting PD-1 occupy T cells for over two months, the effects of salvage chemotherapy may overlap those of prior nivolumab therapy. Nivolumab reportedly inhibits the binding of programmed death ligand-1 (PD-L1; expressed on cancer cells) to the PD-1+ CD8+ T cells in the tumor microenvironment, thereby inhibiting PD-1/PD-L1 signaling . However, in the actual tumor microenvironment, immunosuppressive cells, such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), prevent the nivolumab-mediated antitumor immune response . Control of these immunosuppressive cells is expected to improve the antitumor effects of nivolumab. It has long been reported that some chemotherapeutic agents specifically modulate the activities of immunosuppressive cells . For example, cisplatin increases the expression of tumor antigens and activates cytotoxic T cells, while 5-fluorouracil (5-FU) and docetaxel reportedly inhibit the activity of Tregs and MDSCs . Paclitaxel has been shown to upregulate the expression of class I major histocompatibility complex proteins in cancer cells, thereby increasing their antigenicity. It also increases the antigen-presenting ability of dendritic cells . Cetuximab, an epidermal growth factor receptor inhibitor, activates cytotoxic T cells by increasing tumor antigens through antibody-dependent cytotoxicity . Therefore, based on these mechanisms, chemotherapeutic agents administered after ICIs may cause immunosuppression in the tumor-bearing host, thereby enhancing the ICI-driven antitumor immune responses . Compared to other chemotherapeutic regimens, PC therapy has been reported to have a significantly higher response rate for head and neck cancer . There are multiple first-line treatment options for recurrent and distant metastatic advanced oral cancer. However, studies have noted that a course of checkpoint inhibitors and subsequent chemotherapy activates an antitumor immune response . Studies on combination immunotherapy have shown that the administration of an ICI alters the immune environment of the host, which is maintained even after switching to other therapies. Based on the findings of the KEYNOTE-048 study , the combination of pembrolizumab, an ICI, with platinum and 5-FU, a chemotherapeutic, may be an effective treatment strategy for such cancers. Conclusions Our findings from these two cases of tongue cancer demonstrate that some nivolumab-refractory patients with recurrent or distant metastatic oral squamous cell carcinoma may benefit from subsequent salvage chemotherapy. However, further research is warranted on this topic. We would like to express our sincere gratitude to Professor Ryuji Hayashi of the Department of Clinical Oncology, University of Toyama Hospital, and Dr. Narusuke Okazawa of the First Department of Internal Medicine for their cooperation and guidance in completing this article. This work was supported by the Japan Society for the of Science (JSPS) Grants-in-Aid for Scientific Research (KAKENHI) (21K17111 to H.T.). We wish to thank Medical English Service (Editage.jp) for their help with the English proofreading. Author contributions: Data collection was performed by HT. The first draft of the manuscript was written by DT, HT, KT, SY, and MN. All authors read and approved the final manuscript. Human Ethics Consent was obtained or waived by all participants in this study. Institutional Review Board for Human Studies at the University of Toyama Hospital issued approval R2020023 The authors have declared that no competing interests exist. References 1 Nivolumab vs investigator's choice in recurrent or metastatic squamous cell carcinoma of the head and neck: 2-year long-term survival update of CheckMate 141 with analyses by tumor PD-L1 expression Oral Oncol Ferris RL Blumenschein G Jr Fayette J 45 51 81 2018 29884413 2 Response rates to single-agent chemotherapy after exposure to immune checkpoint inhibitors in advanced non-small cell lung cancer Lung Cancer Schvartsman G Peng SA Bis G 90 95 112 2017 29191606 3 Increased response rates to salvage chemotherapy administered after PD-1/PD-L1 inhibitors in patients with non-small cell lung cancer J Thorac Oncol Park SE Lee SH Ahn JS Ahn MJ Park K Sun JM 106 111 13 2018 29101058 4 Progression beyond nivolumab: stop or repeat? Dramatic responses with salvage chemotherapy Oral Oncol Daste A De-Mones E Cochin V Dupin C Digue L Ravaud A Domblides C 116 118 81 2018 29703607 5 Remarkable response of nivolumab-refractory lung cancer to salvage chemotherapy Thorac Cancer Ogawara D Soda H Iwasaki K Suyama T Taniguchi H Fukuda Y Mukae H 175 180 9 2018 29063735 6 Oncology meets immunology: the cancer-immunity cycle Immunity Chen DS Mellman I 1 10 39 2013 23890059 7 Gemcitabine chemotherapy induces phenotypic alterations of tumor cells that facilitate antitumor T cell responses in a mouse model of oral cancer Oral Oncol Tomihara K Fuse H Heshiki W 457 467 50 2014 24582211 8 Response to salvage chemotherapy after progression on immune checkpoint inhibitors in patients with squamous cell carcinoma of the head and neck J Clin Oncol Saleh K Daste A Martin N 6015 36 2018 9 Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (): a randomised, open-label, phase 3 study Lancet Burtness B Harrington KJ Greil R 1915 1928 2019394 31679945 |
J Exp Bot J Exp Bot exbotj Journal of Experimental Botany 0022-0957 1460-2431 Oxford University Press UK 10.1093/jxb/erad431 erad431 eXtra Botany Insights AcademicSubjects/SCI01210 Carnivorous plant evolution: is a killer defense always the best option? Procko Carl Plant Biology Laboratory, Salk Institute for Biological Studies, 10010 N. Torrey Pines Rd, La Jolla, CA 92037, USA Chory Joanne Plant Biology Laboratory, Salk Institute for Biological Studies, 10010 N. Torrey Pines Rd, La Jolla, CA 92037, USA Howard Hughes Medical Institute, Chevy Chase, MD, USA Correspondence: [email protected] 01 1 2024 20 12 2023 20 12 2023 75 1 912 20 12 2023 (c) The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Experimental Biology. 2023 This is an Open Access article distributed under the terms of the Creative Commons Attribution License ), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. This article comments on: Pavlovic A, Koller J, Vrobel O, Chamrad I, Lenobel R, and Tarkowski P. 2024. Is the co-option of jasmonate signalling for botanical carnivory a universal trait for all carnivorous plants? Journal of Experimental Botany 75, 334-349. Carnivorous plants evolution jasmonates prey digestion National Institutes of Health 10.13039/100000002 5R35GM122604 Howard Hughes Medical Institute 10.13039/100000011 pmc We don't often think of plants as hunters. Yet, for a small but diverse group of flesh-eating plants, evolution has crafted them into skilled predators. Indeed, the leaves of plant carnivores have evolved snapping motions, hollow cage-like cavities, sticky secretions, and even suction power all for the purpose of capturing small animals to provide nutrients not otherwise easily obtained from the nutrient-poor soils in which they grow. How these remarkable plants have evolved these killer abilities has long intrigued the scientific community and beyond. In this issue, Pavlovic et al. (2024) suggest that the evolutionary routes to carnivory may actually be broader than first thought. Botanical carnivory has evolved more than once, with at least 11 different origins spread across 20 genera in six plant orders (Fleischmann et al., 2018; Lin et al., 2021). This polyphyletic origin makes the plants ideally suited for studies of convergent evolution: in how many ways can you evolve a killer plant? Traditionally, these studies were limited to descriptions of leaf trap morphologies and their mechanisms of catching prey. However, for a plant to be carnivorous, it not only must catch animal prey typically insects or other small arthropods but must also digest the prey and acquire the nutrients. Recent technological advances in molecular biology have facilitated studies that now probe these other aspects of the carnivorous syndrome and, in particular, prey digestion. Sometimes, digestion in plant carnivores is achieved by other organisms that interact with the plant, such as microbes or mutualistic arthropods (Fleischmann et al., 2018). However, in many genera, digestion is achieved by the plant itself via the secretion of a mix of hydrolytic enzymes from specialized digestive glands (Schulze et al., 2012; Fukushima et al., 2017). These enzymes, which include chitinases, proteases, lipases, and phosphatases, are induced in non-carnivorous plants during defense responses; for example, to defend against fungal pathogens (Schlumbaum et al., 1986; Zhao and Chye, 1999). What then regulates the expression of these pathogenesis-related proteins in plant carnivores, and has this molecular pathway been selected for carnivory independently across diverse plant groups? This is the question addressed by Pavlovic et al. (2024). Molecular phylogenetics has dated the evolution of the oldest known lineage of plant carnivores to ~95 million years ago, within the order Caryophyllales (Fleischmann et al., 2018). This lineage includes the Venus flytrap (Dionaea muscipula), with its bilobed, touch-sensitive snap-trap leaves, as well as sundews of the Drosera and pitcher plants of the Nepenthes genera, with adhesive and pitfall trap leaves, respectively. In these plants, the synthesis and secretion of digestive enzymes is regulated by prey capture (Bemm et al., 2016; Pavlovic and Mithofer, 2019). Extensive studies over the last two decades have shown that the molecular link between prey recognition and enzyme secretion is the jasmonate (JA) signaling pathway (Pavlovic and Mithofer, 2019). JAs are small, lipid-based phytohormones best known for their role in defense against herbivores and pathogens in non-carnivorous plants. Studies using non-carnivorous Arabidopsis thaliana (Arabidopsis) have revealed that electrical and calcium signals following herbivore attack lead to an increase in JA biosynthesis, both at the wounded site and in distal leaves (Mousavi et al., 2013; Toyota et al., 2018). Ultimately, JA signaling alters gene expression, including the induction of chitinases and many other pathogenesis-related genes (Zhao and Chye, 1999). A similar story unfolds in carnivorous Caryophyllales: electrical and calcium signals generated by prey are correlated with increases in JA biosynthesis and JA-dependent gene expression (Escalante-Perez et al., 2011; Nakamura et al., 2013; Procko et al., 2022). Importantly, exogenous application of a JA analog can bypass prey feeding and recapitulate many aspects of the carnivorous syndrome, including digestive enzyme production (Escalante-Perez et al., 2011). This co-option of the JA pathway towards the regulation of prey digestion in Caryophyllales has in part led to the hypothesis that botanical carnivory evolved from an insect and pathogen defense pathway (Pavlovic and Mithofer, 2019). This is perhaps not so surprising; for example, secretory glands including glandular hairs, or trichomes are common in the non-carnivorous sister clade to carnivorous Caryophyllales and are very similar to digestive glands (Heubl et al., 2006; Fleischmann et al., 2018). Such glandular hairs are well known to provide chemical and structural defense to insect predation, synthesizing poisons and secreting sticky exudates to deter and impede small herbivores. Indeed, it has been hypothesized that the ancestral pre-adapted population that gave rise to modern-day Caryophyllales carnivores had these sticky, glandular hairs, which would facilitate both digestion and prey capture via adhesion (Heubl et al., 2006). However, any link between glandular hair stimulation whether mechanical or chemical and JA biosynthesis has not been well explored outside of carnivorous plants. Despite this, in light of these morphological, physiological, and molecular similarities between plant carnivory and defense, we can forgive the 18th century poet-naturalist Erasmus Darwin for erroneously writing in his work The Botanic Garden that the sticky secretions from hairs of the sundew plant were not for attack but rather to protect the leaves from insect herbivores. It was his grandson, Charles Darwin, who supposed that glandular hairs could also be a first rung on the evolutionary ladder towards botanical carnivory (Darwin, 1875). This hypothesis of repurposing the JA defense pathway towards carnivory is certainly an attractive one. However, while likely to be true for carnivorous Caryophyllales, is this a common route through which carnivory has evolved in other plant lineages? Pavlovic et al. now suggest that the answer to this question is an emphatic 'no'. To address this question, the authors looked at two different types of pitcher plants: the purple trumpet pitcher plant Sarracenia purpurea, from the order Ericales, and the independently evolved Australian pitcher plant Cephalotus follicularis (Cephalotus), of the order Oxalidales. Both species use 'pitfall' pitcher-shaped leaves for catching prey and exhibit digestive enzyme activity that bears a close resemblance to that seen in the carnivorous Caryophyllales (Fukushima et al., 2017). Unlike the touch-sensitive Venus flytrap and sundews, Pavlovic and his colleagues found that purple and Cephalotus pitcher plants do not display obvious electrical signaling in response to prey capture. However, as the authors write, this in itself does not exclude the possibility of JA involvement for carnivory; for example, other genera within the Caryophyllales specifically Nepenthes and Drosophyllum also appear to lack robust and/or detectable electrical impulses in response to prey perception but do employ JAs for regulating digestive enzyme production (Yilamujiang et al., 2016; Pavlovic et al., 2024). In these plants, a requirement for electrical impulses may have been lost over time. More strikingly, the purple and Cephalotus pitcher plants fail to produce a detectable increase in JAs following prey capture. In contrast, mechanical wounding caused measureable changes in JA levels, similar to non-carnivorous plants. While this work is understandably not an exhaustive look at all carnivorous plant genera, it is striking that to date the involvement of the JA pathway in regulating digestive enzymes in response to prey has only been observed in the Caryophyllales (Fig. 1). Is, therefore, digestive enzyme secretion in other plant carnivores no longer dependent on prey perception? While Pavlovic et al. suggest that this may be true for Cephalotus, it is likely that prey perception does regulate some enzymatic activity in the purple pitcher plant. Here, the pitcher is open to rainfall that may flush away valuable proteins inside, and which may thus necessitate controlled release of digestive enzymes only as needed. Furthermore, previous work from these same authors, and on which they build their current study (Kocab et al., 2020), showed that the carnivorous genus Pinguicula of the order Lamiales has strongly inducible secretion of pathogenesis-related enzymes which are also independent of JAs. Thus, it seems that these plants probably employ a signal transduction pathway linking prey perception to enzyme biosynthesis and secretion that is not JA based. But if not JAs, then what is this signaling intermediate? To date, the involvement of other phytohormones in carnivorous responses has not been well established, including for other defense-related hormones such as salicylic acid. Why (or how) these other phytohormones would independently regulate genes typically within the domain of JA defense responses is unclear. The answer then to this question remains unresolved. Fig. 1. Co-option of defense-associated genes for prey digestion in carnivorous plants. Powdery mildew fungal infection of a non-carnivorous tomato plant leaf (Solanum lycopersicum; left), the snap-trap leaves of the Venus flytrap (Dionaea muscipula, order Caryophyllales; middle), and pitfall trap leaves of the purple pitcher plant (Sarracenia purpurea, order Ericales; right). Both carnivorous plant species have co-opted one aspect of plant defense during their independent evolution towards carnivory: the expression of pathogenesis-related hydrolytic enzymes. During defense in non-carnivorous plants, these enzymes help protect against fungal pathogens and insect herbivores, and are typically regulated by jasmonate (JA) hormones (left). In botanical carnivory, these enzymes function in digestion of animal prey. The expression of these enzymes is regulated by prey perception in both carnivorous species; however, only the Venus flytrap and other carnivores of the order Caryophyllales regulate enzyme expression by also co-opting the JA signaling pathway. Not only does it seem that JAs are not required for the induction of digestive enzymes outside the Caryophyllales, but Pavlovic et al. also demonstrate that the expression of these genes in non-Caryophyllales pitcher plants is unaffected by exogenous treatment with a JA analog. This is despite the ancestral role of these genes in defense processes. Could there be a benefit to this decoupling of JA signaling and pathogenesis-related hydrolytic enzyme expression in plant carnivores? It is possible to imagine a scenario where carnivory could be in conflict with JA-mediated defenses, which must respond to and protect the plant from environmental stressors independently of whether a trap has caught an animal meal or not. In this scenario, it is beneficial for the plant to use different regulatory pathways: one for defense and the other for prey digestion. Likewise, in Arabidopsis plants, the electrical signals that induce JA biosynthesis in response to herbivory are systemic, initiating defense responses in leaves distal to the site of attack (Mousavi et al., 2013). While systemic electrical and JA signaling probably confers an advantage when protecting oneself from herbivores or pathogens that can easily move between leaves, it does not benefit a plant carnivore, which requires only a local response at the site of prey capture. Indeed, it is noteworthy that electrical signals generated by prey in touch-sensitive Venus flytrap and sundews do not advance beyond the stimulated leaf (Williams and Pickard, 1972). It is conceivable that in these carnivorous Caryophyllales, the JA-regulated hydrolytic enzymes play a dual role, both in defense against pathogens and for prey digestion. However, in non-Caryophyllales, it would seem that the purpose of many is restricted to JA-independent carnivorous functions. Undoubtedly, massively parallel sequencing technologies which have revealed insights into carnivorous plant genomes and in particular trap transcriptomes and their regulation (Bemm et al., 2016; Fukushima et al., 2017) as well as recent advances in carnivorous plant transformation and targeted genetic approaches (Procko et al., 2023) will continue to be instrumental in resolving these open questions. However, for now it seems that the field must rethink how it extrapolates lessons learned about botanical carnivory from the well-studied Caryophyllales to other carnivorous plant groups. Indeed, as Pavlovic et al. well conclude, it seems that co-option of JA defense signaling to carnivory in the Caryophyllales is perhaps the anomaly and not the norm; rather, there are more ways than one to evolve a killer plant. Acknowledgements The authors thank S. Morrison for providing the image of fungal infection of plant leaves. Conflict of interest The authors declare no conflict of interest. Funding This work was supported by National Institutes of Health (NIH) award 5R35GM122604 (to JC) and the Howard Hughes Medical Institute (to JC). References Bemm F , BeckerD, LarischC, et al . 2016. Venus flytrap carnivorous lifestyle builds on herbivore defense strategies. Genome Research 26 , 812-825.27197216 Darwin CR. 1875. Insectivorous plants. London: John Murray. Escalante-Perez M , KrolE, StangeA, GeigerD, Al-RasheidKAS, HauseB, NeherE, HedrichR. 2011. A special pair of phytohormones controls excitability, slow closure, and external stomach formation in the Venus flytrap. Proceedings of the National Academy of Sciences, USA 108 , 15492-15497. Fleischmann A , SchlauerJ, SmithSA, GivnishTJ. 2018. Evolution of carnivory in angiosperms. In: EllisonAM, AdamecL, eds. Carnivorous plants: physiology, ecology, and evolution. Oxford: Oxford University Press, 22-41. Fukushima K , FangX, Alvarez-PonceD, et al . 2017. Genome of the pitcher plant Cephalotus reveals genetic changes associated with carnivory. Nature Ecology & Evolution 1 , 59.28812732 Heubl G , BringmannG, MeimbergH. 2006. Molecular phylogeny and character evolution of carnivorous plant families in Caryophyllales revisited. Plant Biology 8 , 821-830.17066364 Kocab O , JaksovaJ, NovakO, PetrikI, LenobelR, ChamradI, PavlovicA. 2020. Jasmonate-independent regulation of digestive enzyme activity in the carnivorous butterwort Pinguicula x Tina. Journal of Experimental Botany 71 , 3749-3758.32219314 Lin Q , AneC, GivnishTJ, GrahamSW. 2021. A new carnivorous plant lineage (Triantha) with a unique sticky-inflorescence trap. Proceedings of the National Academy of Sciences, USA 118 , e2022724118. Mousavi SAR , ChauvinA, PascaudF, KellenbergerS, FarmerEE. 2013. GLUTAMATE RECEPTOR-LIKE genes mediate leaf-to-leaf wound signalling. Nature 500 , 422-426.23969459 Nakamura Y , ReicheltM, MayerVE, MithoferA. 2013. Jasmonates trigger prey-induced formation of 'outer stomach' in carnivorous sundew plants. Proceedings of the Royal Society B: Biological Sciences 280 , 20130228. Pavlovic A , KollerJ, VrobelO, ChamradI, LenobelR, TarkowskiP. 2024. Is the co-option of jasmonate signalling for botanical carnivory universal trait for all carnivorous plants? Journal of Experimental Botany 75 , 334-349. Pavlovic A , MithoferA. 2019. Jasmonate signalling in carnivorous plants: copycat of plant defence mechanisms. Journal of Experimental Botany 70 , 3379-3389.31120525 Procko C , RadinI, HouC, RichardsonRA, HaswellES, ChoryJ. 2022. Dynamic calcium signals mediate the feeding response of the carnivorous sundew plant. Proceedings of the National Academy of Sciences, USA 119 , e2206433119. Procko C , WongWM, PatelJ, MousaviSAR, DabiT, DuqueM, BairdL, ChalasaniSH, ChoryJ. 2023. Mutational analysis of mechanosensitive ion channels in the carnivorous Venus flytrap plant. Current Biology 33 , 3257-3264.e4.37437572 Schlumbaum A , MauchF, VogeliU, BollerT. 1986. Plant chitinases are potent inhibitors of fungal growth. Nature 324 , 365-367. Schulze WX , SanggaardKW, KreuzerI, et al . 2012. The protein composition of the digestive fluid from the Venus flytrap sheds light on prey digestion mechanisms. Molecular & Cellular Proteomics 11 , 1306-1319.22891002 Toyota M , SpencerD, Sawai-ToyotaS, JiaqiW, ZhangT, KooAJ, HoweGA, GilroyS. 2018. Glutamate triggers long-distance, calcium-based plant defense signaling. Science 361 , 1112-1115.30213912 Williams SE , PickardBG. 1972. Properties of action potentials in Drosera tentacles. Planta 103 , 222-240.24481556 Yilamujiang A , ReicheltM, MithoferA. 2016. Slow food: insect prey and chitin induce phytohormone accumulation and gene expression in carnivorous Nepenthes plants. Annals of Botany 118 , 369-375.27325901 Zhao K-J , ChyeM-L. 1999. Methyl jasmonate induces expression of a novel Brassica juncea chitinase with two chitin-binding domains. Plant Molecular Biology 40 , 1009-1018.10527425 |
J Exp Bot J Exp Bot exbotj Journal of Experimental Botany 0022-0957 1460-2431 Oxford University Press UK 10.1093/jxb/erad408 erad408 eXtra Botany Insights AcademicSubjects/SCI01210 Reciprocal regulation of cellulose and lignin biosynthesis by the transcription factor OsTCP19 Ishida Konan Department of Biochemistry, University of Cambridge, Hopkins Building, The Downing Site, Tennis Court Road, Cambridge CB2 1QW, UK Correspondence: [email protected] 01 1 2024 20 12 2023 20 12 2023 75 1 58 20 12 2023 (c) The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Experimental Biology. 2023 This is an Open Access article distributed under the terms of the Creative Commons Attribution License ), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. This article comments on: Lv S, Lin Z, Shen J, Luo L, Xu Q, Li L, Gui J. 2024. OsTCP19 coordinates inhibition of lignin biosynthesis and promotion of cellulose biosynthesis to modify lodging resistance in rice. Journal of Experimental Botany 75, 123-136. Biomass grain yield growth penalty lodging resistance plant cell wall transcription factor pmc Cultivation of semi-dwarf varieties of cereal plants brought about a dramatic improvement in grain yields due to reduced lodging risk under high fertilization conditions. Lodging resistance is also a useful trait to select promising cultivars. However, semi-dwarf varieties tend to have negative effects on reproductive organ size and limit plant biomass. Hence, new approaches are required to fine-tune the mechanical properties of cereal plants to overcome this trade-off. Lv et al. (2024) revealed that the transcription factor OsTCP19 promotes cellulose biosynthesis and inhibits lignin biosynthesis simultaneously, which contributes to mechanical strength. The fibre cell-specific overexpression of OsTCP19 achieved higher lodging resistance without compromising grain yield per plant, thus overcoming the negative trade-off observed in plants with constitutive OsTCP19 overexpression. These results provide a novel genetic engineering approach towards sustainable food production. The rise of civilizations was accompanied by the domestication of plants with useful traits for human use. In typhoon-prone East Asia, there has been a need for rice plants that are resistant to lodging, which is defined as the permanent displacement of above-ground parts from their upright position as a result of stem buckling and/or root displacement. The ability of plants to withstand lodging is thus governed by the physical strength of their stems, or culms in the case of cereal, which is tightly linked to the cell wall composition. Indeed, many of the genes responsible for 'brittle rice mutants' are cell wall related (Table 1; Fig. 1). Given the negative relationship often observed between lodging resistance and grain yield, there is a need to understand the molecular mechanisms of cell wall biosynthesis genes in order to engineer cell walls with higher flexibility. Fig 1. Electron microscope image of brittle culm6. Most of the brittle culm (bc) mutants listed in Table 1 showed different cell architecture. For instance, the bc6 mutant had round cells that lacked cell corners. WT: Taichung 65 cultivar. Scale bar=5 mm. Image courtesy of Dr Toshihisa Kotake. Table 1. Mechanical traits are often linked to plant cell wall properties Mutant name Responsible gene Reference brittle culm 1 GPI-anchored protein Sato et al. (2010); Liu et al. (2013) brittle culm 3 Dynamin Hirano et al. (2010) brittle culm 6 CESA9 Kotake et al. (2011) brittle culm 7 CESA4 Yan et al. (2007) brittle culm 10 Unclassified glycosyltransferase-related to AGP (DUF266) Zhou et al. (2009) brittle culm 11 CESA4 Zhang et al. (2009) brittle culm 12 Kinesin Zhang et al. (2010) brittle culm 13 CESA9 Song et al. (2013) brittle culm 14 Nucleotide sugar transporter Song et al. (2011) brittle culm 15 Chitinase Yi et al. (2022) brittle culm 16 GPI-lipid O-acetyltransferase Xu et al. (2022) brittle culm 18 Xylan synthase (IRX10) Wang et al. (2022) brittle culm 19 CESA4 Ma et al. (2021) brittle culm 24 UDP-glucose epimerase Zhang et al. (2020) brittle culm 25 UDP-xylose synthase Xu et al. (2023) Mechanically weak rice plants have been isolated by forward genetic screening. Many of the causal genes are related to cell wall biosynthesis. In particular, mutations in CELLULOSE SYNTHASE (CESA) are influential. Others include the cytoskeleton and COBRA-like GPI-anchored proteins known to affect cell morphology in Arabidopsis. AGP, arabinogalactan protein; DUF, domain of unknown function; IRX, irregular xylem. Plant mechanical strength comes from the rigidity of the secondary cell wall, composed primarily of cellulose and lignin. Secondary cell wall synthesis is induced in a hierarchical manner: the VASCULAR-RELATED NAC-DOMAIN transcription factor family is the master regulator, with Tier 2 transcription factors (e.g. MYB46 and MYB83) at an intermediate level. Downstream Tier 3 transcription factors (e.g. MYB4 and MYB58) regulate the expression of multiple sets of cell wall-related genes. Divergent regulatory pathways are thought to enable condition-specific cell wall control (Rao and Dixon, 2018). Cellulose and lignin are both essential elements of the cell wall, but there are several known examples of reciprocal synthesis (e.g. simultaneous suppression of 4-coumarate-CoA ligase and coniferaldehyde 5-hydroxylase decreases lignin content and increases cellulose content) (Li et al., 2003). However, why and how the opposite regulation is caused is still waiting to be elucidated. Lv et al. (2024) found that the transcription factor TEOSINTE BRANCHED1-CYCLOIDEA-PCF 19 in rice (OsTCP19) modulates cellulose and lignin in an opposite manner via two underpinning transcription factors (Fig. 2). First, the authors manipulated the OsTCP19 activity by fusing a repression or activation module on OsTCP19 in rice. While the activation line became physically stronger compared with the wild type, the suppression line became weak against physical force (Table 2). In the field, lodging occurrence decreased by ~35% in the activation line but increased by 40% in the suppression line. The authors then analysed the chemical composition of the transgenic plants. Interestingly, cellulose contents were increased in the activation line, but lignin was less accumulated compared with the wild type. Based on this observation, the authors hypothesized that OsTCP19 induces cellulose biosynthesis genes but suppresses lignin-related genes. To test this hypothesis, they conducted transcriptome analysis using both lines. More than 1500 genes were identified as differentially expressed genes (DEGs). The breakdown of DEGs is dominated by those related to phenylpropanoid synthesis, which overlaps with the lignin metabolism pathway. Furthermore, the OsTCP19 activation line showed higher expression of cellulose biosynthesis genes, and lignin-related gene sets were suppressed. These results indicate that the lodging resistance improvement requires a specific pattern of secondary cell wall synthesis, with an increase in cellulose and a decrease in lignin. Fig 2. Proposed mechanism of OsTCP19 function. OsTCP19 binds to the promoter regions of MYB103L and MYB108. MYB103L induces cellulose biosynthesis genes. MYB108 suppresses lignin biosynthesis genes. This fine-tuned balance leads to higher lodging resistance (based on Lv et al., 2024). Table 2. Phenotypic comparison of OsTCP19 transgenics Activation line Suppression line Fibre-specific activation line Cellulose 12% increased 10% decreased 13% increased Lignin 20% decreased 15% increased 20% decreased Mechanical strength Stronger Weaker Stronger Single plant grain yielda >30% decreased Slightly increased Unchanged Systemic activation of OsTCP19 fell into yield decrease due to the trade-off. However, driving by a fibre-specific promoter enables mechanical strength and normal grain yield. a Observed under greenhouse conditions. To reveal how cellulose and lignin synthesis are regulated in a reciprocal manner, the authors looked for the highly affected Tier 3 transcription factors from RNA-seq data. Together with the literature, MYB103L was identified as the modulator of cellulose biosynthesis, and MYB108 as the candidate for lignin modulation. To obtain direct evidence that OsTCP19 controls their expression, a gel shift mobility assay was performed using recombinant OsTCP19 and the promoter regions of MYB103L or MYB108. OsTCP19 could directly bind to both regions. Together with the results of the transcriptional analysis, the authors deduced that OsTCP19 has dual activity as a positive regulator for cellulose biosynthesis and a negative regulator for lignin biosynthesis. Distinctive sclerenchyma structures in lodging-resistant rice varieties have previously been identified (Zhang et al., 2021). As mentioned, the constant overexpression line of OsTCP19 reduced lodging but also reduced yield. Therefore, Lv et al. (2024) tested tissue-specific OsTCP19 expression using a sclerenchyma fibre cell-specific promoter. Tissue-specific expression lines showed no obvious change in appearance (plant height and tiller number) but increased mechanical resistance (Table 2). Chemical composition in mature stems supports that this promising phenotype came from the increase of cellulose and decrease of lignin the same as the OsTCP19 activation line. Interestingly, the tissue-specific expression line did not show a decrease in individual plant grain yield, overcoming the trade-off between growth and physical strength. It will be important, however, that further outdoor trials are conducted to understand if this relationship remains in nitrogen-rich paddy fields. In a wider context, this study highlights the importance of engineering only those parts of the trade-off that are linked to agriculturally useful traits. In this example, while fibre cells are the key for mechanical strength, they cause a reduction in grain volume in seeds, which could be solved by changing the expression profile. In other words, the key to selective breeding is to identify and eliminate the causes of the unfavourable phenotype. An open question relevant to the current study is why an increase in cellulose and a decrease in lignin change cell wall properties. It is also unknown why fibre cells play a major structural role. Furthermore, the effects of other TCP family members on cell wall synthesis remain to be elucidated. Acknowledgements The image of bc6 in Fig. 1 is courtesy of Dr Toshihisa Kotake at Saitama University, Japan. Conflict of interest The author declares that there is no conflict of interest. Funding The author declares that no financial support was received from any funding body for this manuscript. References Hirano K , KotakeT, KamiharaK, TsunaK, AoharaT, KanekoY, TakatsujiH, TsumurayaY, KawasakiS. 2010. Rice BRITTLE CULM 3 (BC3) encodes a classical dynamin OsDRP2B essential for proper secondary cell wall synthesis. Planta 232 , 95-108.20369251 Kotake T , AoharaT, HiranoK, SatoA, KanekoY, TsumurayaY, TakatsujiH, KawasakiS. 2011. Rice Brittle culm 6 encodes a dominant-negative form of CesA protein that perturbs cellulose synthesis in secondary cell walls. Journal of Experimental Botany 62 , 2053-2062.21209026 Li L , ZhouY, ChengX, SunJ, MaritaJM, RalphJ, ChiangVL. 2003. Combinatorial modification of multiple lignin traits in trees through multigene cotransformation. Proceedings of the National Academy of Sciences, USA 100 , 4939-4944. Liu L , Shang-GuanK, ZhangB, et al . 2013. Brittle Culm1, a COBRA-like protein, functions in cellulose assembly through binding cellulose microfibrils. PLoS Genetics 9 , e1003704.23990797 Lv S , LinZ, ShenJ, LuoL, XuQ, LiL, GuiJ. 2024. OsTCP19 coordinates inhibition of lignin biosynthesis and promotion of cellulose biosynthesis to modify lodging resistance in rice. Journal of Experimental Botany 75 , 123-136. Ma X , LiC, HuangR, et al . 2021. Rice Brittle Culm19 encoding Cellulose Synthase Subunit CESA4 causes dominant brittle phenotype but has no distinct influence on growth and grain yield. Rice 14 , 95.34822039 Rao X , DixonRA. 2018. Current models for transcriptional regulation of secondary cell wall biosynthesis in grasses. Frontiers in Plant Science 9 , 399.29670638 Sato K , SuzukiR, NishikuboN, et al . 2010. Isolation of a novel cell wall architecture mutant of rice with defective Arabidopsis COBL4 ortholog BC1 required for regulated deposition of secondary cell wall components. Planta 232 , 257-270.20424856 Song X , ZhangB, ZhouY. 2011. Golgi-localized UDP-glucose transporter is required for cell wall integrity in rice. Plant Signaling and Behavior 6 , 1097-1100.21822061 Song XQ , LiuLF, JiangYJ, ZhangBC, GaoYP, LiuXL, LinQS, LingHQ, ZhouYH. 2013. Disruption of secondary wall cellulose biosynthesis alters cadmium translocation and tolerance in rice plants. Molecular Plant 6 , 768-780.23376772 Wang H , YangH, WenZ, et al . 2022. Xylan-based nanocompartments orchestrate plant vessel wall patterning. Nature Plants 8 , 295-306.35318447 Xu S , ZhangM, YeJ, et al . 2023. Brittle culm 25, which encodes an UDP-xylose synthase, affects cell wall properties in rice. The Crop Journal 11 , 733-743. Xu Z , GaoY, GaoC, et al . 2022. Glycosylphosphatidylinositol anchor lipid remodeling directs proteins to the plasma membrane and governs cell wall mechanics. The Plant Cell 34 , 4778-4794.35976113 Yan C , YanS, ZengX, ZhangZ, GuM. 2007. Fine mapping and isolation of Bc7(t), allelic to OsCesA4. Journal of Genetics and Genomics 34 , 1019-1027.18037139 Yi S , ZhangX, ZhangJ, MaZ, WangR, WuD, WeiZ, TanZ, ZhangB, WangM. 2022. Brittle Culm 15 mutation alters carbohydrate composition, degradation and methanogenesis of rice straw during in vitro ruminal fermentation. Frontiers in Plant Science 13 , 975456.35991441 Zhang B , DengL, QianQ, XiongG, ZengD, LiR, GuoL, LiJ, ZhouY. 2009. A missense mutation in the transmembrane domain of CESA4 affects protein abundance in the plasma membrane and results in abnormal cell wall biosynthesis in rice. Plant Molecular Biology 71 , 509-524.19697141 Zhang B , GaoY, ZhangL, ZhouY. 2021. The plant cell wall: biosynthesis, construction, and functions. Journal of Integrative Plant Biology 63 , 251-272.33325153 Zhang M , ZhangB, QianQ, YuY, LiR, ZhangJ, LiuX, ZengD, LiJ, ZhouY. 2010. Brittle Culm 12, a dual-targeting kinesin-4 protein, controls cell-cycle progression and wall properties in rice. The Plant Journal 63 , 312-328.20444225 Zhang R , HuH, WangY, et al . 2020. A novel rice fragile culm 24 mutant encodes a UDP-glucose epimerase that affects cell wall properties and photosynthesis. Journal of Experimental Botany 71 , 2956-2969.32064495 Zhou Y , LiS, QianQ, et al . 2009. BC10, a DUF266-containing and Golgi-located type II membrane protein, is required for cell-wall biosynthesis in rice (Oryza sativa L). The Plant Journal 57 , 446-462.18939965 |
Pretilachlor is a herbicide that can cause clinical symptoms in people that are comparable to those of organophosphate poisoning when ingested. Given how closely it mimics the toxicity of organophosphate compounds, it presents a significant challenge to clinicians during management. The following cases were presented to the Emergency Department at Nepalgunj Medical College Teaching Hospital, Kohalpur, Banke, Nepal. pmcINTRODUCTION Ingestion of pretilachlor, a synthetic chloroacetanilide herbicide, is not commonly observed, despite its widespread use in the agricultural regions of the Indian subcontinent . Chloroacetanilide herbicides are a class of anilide herbicides, a subclass of amide herbicides. These include pretilachlor, butachlor, s-metolachlor, acetochlor, and dimethachlor. Pretilachlor is a selective and broad-spectrum herbicide. The compound is known by the name 2-chloro-2',6 diethyl-N-(2-propoxyethanol) acetanilide. In rice and paddy fields, it is used to get rid of practically all kinds of weeds, including annual grasses, sedges, broad-leaved weeds, and floating aquatic species . In comparison to other herbicides, it is less harmful to crops. It has been discovered that it works by preventing the formation of lipids, proteins, fatty acids, alcohol, and isoprenoids, among other things. The prolonged use of these herbicides has likely cancer-causing consequences . Pretilachlor's acute toxicity after ingestion can be mistaken for organophosphate pesticide toxicity, which can lead to improper patient management because these patients frequently exhibit the signs and symptoms of organophosphate toxicity, such as lacrimation, nausea, vomiting, and bladder and bowel incontinence . Tachycardia, hypotension, sweating, and muscular spasms are seen. By treating symptoms, patients frequently make a full recovery without the use of atropine and oximes . Here, we present a report of six cases of attempted suicide poisoning with pretilachlor herbicide and related organophosphorus toxicity symptoms. CASE SERIES A 38 years old female presented to the emergency room with the alleged history of suicidal ingestion of unknown poison 1 h back following an argument with her husband. On presentation, the patient had 2 episodes of vomiting in the ER with excessive salivation, lacrimation, and dizziness. According to her family members, she was found unconscious with an empty container of pretilachlor 50% emulsified concentrate (EC) next to her. They noticed that about 250 ml of the substance had been used from the bottle (2 g/kg). She did not have any chest pain or shortness of breath. There was no previous history of suicidal attempts. On examination, the patient was drowsy with Glasgow Coma Scale (GCS) of 12/15 (E3 V4 M5). She was found to have tachycardia with a radial pulse of 101 beats per minute (BPM) and a blood pressure (BP) of 110/80 mmHg. She was afebrile with an oxygen saturation of 98% in room air and a respiratory rate (RR) of 19 breaths/min. The garlicky odor of organophosphate was not present on her breath. Other systemic examinations were unremarkable. A 25-year-old male was referred by a primary center to our hospital with an alleged history of ingestion of pretilachlor 50% EC around 200 ml (2.2 g/kg) 3 h back. On arrival, the patient presented with complaints of nausea, multiple episodes of vomiting, and abdominal pain. The patient was semiconscious in the state with profuse lacrimation and sweating. He had urinary incontinence; however, bowel function was normal and no shortness of breath was noted. Upon examination, he was found to have a radial pulse of 66/min with blood pressure 100/70 mmHg, respiratory rate of 16 breaths/min, and oxygen saturation at 98% with no raised temperature. The remaining systemic examination was unremarkable. A 21-year-old female presented to the emergency room with a history of ingestion of pretilachlor 50% EC herbicide 2 h back (2.8 g/kg). Her attendant had brought a 250 ml bottle of the same herbicide which she allegedly ingested. She complained of abdominal pain, lacrimation, multiple episodes of vomiting and salivation. Her vitals were; BP: 120/80 mmHg, pulse of 101 BPM, RR of 21/min, afebrile and Spo2 99% in room air. She was ill looking yet oriented to time, place and person with unremarkable systemic examinations. No peculiar garlicky smell was found in her breath. A 59 years old male presented to the emergency room with the alleged history of suicidal ingestion of an unknown poison under the influence of alcohol after a family dispute which was later found to be pretilachlor 50% EC approximately 250 ml in amount (1.9 g/kg). Upon presentation he had mild abdominal cramps, vomiting, frothing from mouth and involuntary passage of urine. He had no known comorbidities. His vitals revealed normal body temperature, blood pressure of 130/90 mmHg, radial pulse 99 beats/min, respiratory rate of 18 breaths/min. His oxygen saturation was at 97%. His systemic examination was found to be unremarkable. No garlicky breath was detected but instead, he smelled of alcohol. A 19 years old female presented to the emergency room with an alleged history of ingestion of 'Hi-fit herbicide' approximately 200 ml, the constituents of which turned out to be pretilachlor 50% EC (2.5 g/kg). Upon presentation she had shortness of breath, vomiting and chest pain. Additionally, there were no frothing or abnormal body movements. Her bowel and bladder habit had no change. Her vitals included a blood pressure of 100/70 mmHg, pulse 102 beats/min, oxygen saturation of 99% at room air and a respiratory rate of 18 breaths/min. In addition to this her systemic examination turned out to be unremarkable. A 24 years old female presented to the emergency room with the alleged history of ingestion of pretilachlor 50% EC approximately 100 ml (1 g/kg). She complained of epigastric burn and nausea following ingestion of the poison. The vitals of the patient upon arrival were a blood pressure of 100/80 mmHg, pulse of 109 beats/min, oxygen saturation of 98% and respiratory rate of 23 breaths/min. The systemic examination was within normal limits. All the above patients confirmed to have ingested pretilachlor 50% emulsified concentrate (EC). Upon presentation they were all subjected to gastric lavage as they all presented within 3 h of time frame. The vital signs were stable and were carefully monitored while being managed with supportive measures such as intravenous fluids, antiemetics and prophylactic antibiotics. The patients were kept nil per oral (NPO). Their vital signs remained steady, and normal urine production was ensured as a result. Later, the early symptoms of nausea, vomiting, salivation, lacrimation, and abdominal cramps disappeared. In all the patients serial blood tests were performed including total blood counts, random blood glucose, liver and renal function tests, the reports of which turned out to be within normal ranges. Serum cholinesterase levels were also examined in a few cases, although they did not exhibit any abrupt changes in levels. The patients were all subjected to close hemodynamic monitoring which turned out to be uneventful. They were kept under observation for a few days and later discharged following a psychological assessment and behavioral therapy. The subsequent visits turned out to be unremarkable. DISCUSSION Pretilachlor, a synthetic chloroacetanilide herbicide, is used to kill practically all weed species in rice and paddy crops, including annual grasses, sedges (grass-like weeds), broad-leaved weeds, and floating aquatic plants. Marketed as a 50% EC, pretilachlor, it is a liquid that has no color or smell. It has alkyl aryl sulfonate of calcium salt as a surfactant and ethoxylated vegetable oil as an emulsifier . We have presented six confirmed cases of pretilachlor ingestion and treated in line with OP poisoning. This is not uncommon in our region, as patients often treated for OP poisoning actually ingest chloroacetanilide products with symptoms similar to those of OP poisoning . While OP poisoning is commonly encountered in the ER and is one of the leading unnatural causes (suicide) of death in Nepal , very few studies have reported pretilachlor poisoning in our part of the world . Despite this, accurate incidence has not been measured. The chloroacetanilide class of herbicides is postulated to cause cytotoxicity by depleting GSH content in a dose-dependent manner in hepatocytes. In addition, it is also found that their mechanism appears to be reactive oxygen species generation, mitochondrial dysfunction and disruption in the cell cycle regulation . In certain investigations, chronic exposure to chloroacetanilide has been linked to genotoxicity, carcinogenicity, and neurotoxicity . Although such situations have only sometimes been documented to date, acute oral exposure may have different effects on people. Despite its modest toxicity, a retrospective investigation of 35 individuals with acute intake of the substance led to the death of one patient and the unconsciousness of three others within 24 h . Another study was carried out by Lo et al in 113 patients who had been exposed orally to chloroacetanilide like butachlor and alachlor, and it found that one-fourth of the patients were asymptomatic, the rest had vomiting and neurological symptoms like drowsiness and central nervous depression, along with three deaths from profound hypotension and coma . Patients with pretilachlor poisoning usually present with clinical symptoms like nausea, vomiting, diarrhea, drowsiness, stupor, seizures, and fever which can closely mimic cholinergic toxicity. However, peculiar characteristics of organophosphate poisoning including miosis, garlicky smell, bradycardia, lacrimation, and salivation are typically not seen . In our instances, patients commonly present with symptoms of nausea, vomiting, abdominal pain, and tachycardia. Signs like fever, bradycardia, miosis, and hypotension were not present in any patients. Below is a table illustrating the common signs and symptoms observed in our patients on initial presentation to the emerg0ency room: Clinical features Number of patients Symptoms Drowsiness 1 Nausea 5 Vomiting 5 Abdominal pain 3 Diarrhea 0 Difficulty breathing 1 Chest pain 1 Increased urination 0 Drowsiness 0 Seizure 0 Signs Bradycardia 0 Tachycardia 4 Hypotension 0 Fever 0 Tachypnea 1 Miosis 0 GCS < 15/15 1 On initial presentation, serum acetylcholinesterase enzyme level was checked in all patients as it was difficult to differentiate pretilachlor poisoning from OP poisoning based on clinical presentation alone. OP poisoning can be detected by measuring acetylcholinesterase (AchE) level which is decreased whereas it is within the normal range in pretilachlor poisoning . In all our patients, the enzyme level came out to be normal, which was a major hint to finally differentiate between the two poisonings. To offset the cholinergic symptoms of OP poisoning, atropine is administered and pralidoxime is given as an antidote which reverses the permanent binding and disintegration of AChE by OP There is no antidote for pretilachlor poisoning unlike OP poisoning where atropine is administered to offset the cholinergic symptoms and pralidoxime is given as an antidote which reverses the permanent binding and disintegration of AChE by OP . The majority of treatment for pretilachlor poisoning is symptomatic care, which includes stabilizing the patient, fluid resuscitation, and vigilant hemodynamic monitoring . Skin decontamination with soap and water as well as GI decontamination is the same in both the poisonings . In all the cases, airway, breathing, and circulation were assessed and simultaneously maintained immediately. Since all the patients presented within 3 h of ingestion and had normal GCS, gastric lavage was done immediately. All of the patients were admitted to the medical ward, where they received IV fluids, and proton pump inhibitors, and were kept nil by mouth (NPO). Urinary output and hemodynamic condition were continuously recorded. Because pretilachlor and its class of herbicides are known to be hepatotoxic and increase liver enzymes , liver function tests (LFTs) were monitored in all patients and were normal. In addition, patients with pretilachlor poisoning are more likely to develop rhabdomyolysis, thus patients' renal function tests (RFT) and serum electrolytes were additionally monitored . The investigations stated above were also within the normal range. Behavioral evaluation and psychiatric consultation were conducted during hospital admission. They were discharged after 3 days of hospital admission as all of them were clinically stable. On follow-up after one week, no clinical signs and symptoms were observed. While all our cases were stable and recovered completely, there are instances of patients requiring critical care and also fatalities. Factors like old age, lower bicarbonate levels, presence of CNS effects , oral ingestion, a higher dose of ingestion, and hypotension have been observed to be associated with poor prognosis. CONCLUSION These instances highlight the fact that, in spite of exhibiting clinical characteristics like those of OP toxicity, pretilachlor poisoning is differentiated from OP poisoning on the basis of absence of typical cholinergic clinical signs and symptoms and presence of normal AChE level. Immediate stabilization, attentive monitoring, and symptomatic treatment are the three crucial elements from the recovery of pretilachlor toxicity. Clinicians must have a thorough understanding of such herbicides in order to manage patients effectively. ACKNOWLEDGEMENTS We appreciate the patients' and their families' participation and assistance in helping us prepare the reports. There were no sources of funding. CONFLICT OF INTEREST STATEMENT The authors declare no conflict of interest. ETHICAL APPROVAL No ethical approval was needed for this case report. CONSENT The authors obtained written informed consent from the patients for this publication. GUARANTOR Agnimshwor Dahal is the guarantor of this article. |
Potato virus X (PVX) vectors expressing the Arabidopsis thaliana FLOWERING LOCUS T (FT) or tomato FT ortholog SINGLE-FLOWER TRUSS (SFT) shortened the generation time in tomato due to accelerated tomato flowering and ripening by 14-21 d, and caused a 2-3-fold increase in the number of flowers and fruits, compared with non-infected or empty vector-infected plants. The Arabidopsis FT was more effective than the tomato orthologue SFT and there was no alteration of the flower or fruit morphology. The virus was not transmitted to the next generation; therefore viral vectors with expression of a heterologous FT will be a useful approach to speed breeding in tomato and other species. Potato virus X-induced overexpression of Arabidopsis FLOWERING LOCUS T (FT ) and tomato SINGLE-FLOWER TRUSS (SFT ) accelerated tomato flowering and ripening, with FT being more effective than the endogenous SFT. Flowering FT potato virus X RNA silencing speed breeding virus vector Biological and Biotechnology Research Council BB/R018529/1 National Natural Science Foundation of China 10.13039/501100001809 31972420 pmcIntroduction Tomato is an a widely cultivated South American crop that is also a model species for basic research because it is informative about aspects of growth and development that cannot be addressed using Arabidopsis the standard model in plant biology. It is useful, for example, for investigation of fleshy-fruit formation (Kimura and Sinha, 2008) and patterns of branching during vegetative development (Xu et al., 2015). A limitation of tomato, however, is the long generation time. It is typically 65-100 d and a system for speed breeding (Wanga et al., 2021) of tomato would, therefore, benefit both basic and applied research. One approach to speed breeding exploits the FLOWERING LOCUS T (FT) regulator of floral transition (Koornneef, 1991; Kardailsky et al., 1999; Kobayashi et al., 1999). The FT protein is transported through the vasculature to the floral meristem where it acts together with its activator CONSTANS (CO; Takada and Goto, 2003; An et al., 2004; Corbesier et al., 2007). The role of FT as a mobile inducer of flowering is conserved in a wide range of plants (Lin et al., 2007; Tamaki et al., 2007; Krieger et al., 2010; Abelenda et al., 2016) and its transgenic expression stimulates early flowering and reduces generation time (Lewis and Kernodle, 2009; Wigge, 2011). An alternative, non-transgenic method of speed breeding uses viruses as expression vectors. For use of such vectors a gene of interest is inserted into the vector at a site that does not interfere with viral genes and it is expressed, often at very high levels, in the infected plant. This virus-mediated overexpression (VOX) allows tracking of virus infection in the plant (Abrahamian et al., 2020) with reporter genes and it is useful for functional analysis of plant genes (Lindbo et al., 2001; Manning et al., 2010; Lee et al., 2012; Zhang et al., 2013; Majer et al., 2017). VOX of FT results in accelerated virus-induced flowering (VIF) in crop breeding programs (McGarry et al., 2017) and research. It has advantages over transgenic FT expression or the use of rapid cycling varieties including microTom (Marti et al., 2006) because it can be deployed on multiple cultivars without the need for multiple transformations or crossing. Potato virus X (PVX) is a well-established virus vector with potential in VIF. This vector is infectious on a broad range of Solanaceous plants and it was initially developed for VOX (Chapman et al., 1992), but has been used widely for virus-induced gene silencing (VIGS; Ruiz et al., 1998; Lu et al., 2003). PVX-based VOX of FT in tobacco was used in a mutation analysis of FT function (Qin et al., 2017) but it has not been tested previously as a system for speed breeding of tomato. In this study, we tested PVX as an alternative to tobacco rattle virus (TRV) or tobacco mosaic virus as a vector of VOX of FT in tomato (Solanum lycopersicum, Sly). We also compared the tomato and Arabidopsis thaliana homologues to accelerate flowering. We hypothesized that, with the tomato insert, there would be VOX of the SINGLE FLOWER TRUSS (SFT) from the viral genome superimposed on VIGS of the endogenous SFT. With the Arabidopsis FT, in contrast, the VIGS of the endogenous sequence would be avoided due to the sequence heterogeneity between the two sequences and the infected plant would express both the viral and endogenous genes. Our findings validate the previously demonstrated use of VIF as an approach to speed breeding. We also illustrate how the overexpression of FT was more effective than SFT, most likely because RNA silencing of the endogenous gene was minimized. Our findings confirm the potential for PVX-mediated expression of FT as a convenient and efficient system for speed breeding in tomato and indicate that heterologous FT genes may be more effective than those from the species being infected. Materials and methods Plant materials and growth conditions Tomato 'M82' (Solanum lycopersicum), Nicotiana benthamiana, and Arabidopsis (Col-0) plants were grown in soil in the plant growth facility under long-day conditions (light/dark: 16 h/8 h, 300 mmol m-2 s-1) at a temperature of 25 degC with 65-70% humidity, before and after inoculation. Recombination with PVX vectors The PVX constitutive expression vector pGR107 has been described previously (Lu et al., 2003). For construction of PVX vectors, we inserted PCR-amplified 325 bp cDNA fragments of the SlyPDS (Phytoene desaturase; Solyc03g123760.3.1, ITAG4.0) and full length insert of SFT (534 bp, Solyc03g063100.2.1, ITAG4.0) and FT (AT1G65480, 528 bp, Araport11) into a SmaI-cut pGR107 vector. Sequences and primers used in these constructions are listed in Supplementary Table S1. Tomato inoculation To prepare the inoculum, we used overnight LB liquid medium cultures of Agrobacterium tumefaciens (strain GV3101) transformed with the above empty or assembled vectors using an electroporation system (BioRad Gene Pulser XcellTM, BioRad, USA). After centrifugation and resuspension of the cells in infiltration medium (10 mM MES, 200 mM acetosyringone) at an OD600 =0.1 we infiltrated tomato cotyledons (14 days after germination, DAG) by using a needleless syringe. There were least four replicate plants for each treatment and we repeated the assays three times or more as indicated in the legend of each figure. RNA extraction and RT-PCR analysis Total RNA was extracted from tomato and Nicotiana benthamiana leaves 21 days after infiltration (DAI) and 28 DAI from Arabidopsis leaves by using Trizol reagent (InvitrogenTM, USA). First-strand cDNA synthesis used 2 mg total RNA with random primers by using RevertAid First Strand cDNA Synthesis Kit (InvitrogenTM, USA) and RT-PCR used the DreamTaq Green DNA Polymerase (Thermo ScientificTM, USA) before fractionation of the product using a 1.2% agarose gel. Primers used in the RT-PCR are listed in Supplementary Table S1. Reverse transcription quantitative PCR (qRT-PCR) analysis qRT-PCR used the Luna(r) Universal qPCR Master Mix (NEB, USA) in a 10 ml total sample volume [5 ml of 2x Luna(r) Universal qPCR Master Mix, 1.0 ml of primers (10 mM), 1.0 ml of cDNA (200 ng ml-1), and 3 ml of distilled, deionized water]. We calculated relative gene expression values using the 2-DDCt method with tomato Tubulin gene (Solyc04g081490.3.1, ITAG4.0) and SKP1 gene (S-phase kinase-related protein 1; Solyc01g111650.3.1, ITAG4.0) as internal reference genes. There were independent samplings of at least two biological replicates and three technical replicates were included for each treatment. Primers used in the qRT-PCR are listed in Supplementary Table S1. Data analysis All the statistical analyses in this study used the Student's t-test method. The histograms and box graphs were generated via GraphPad Prism 9.5.0 (GraphPad Software, San Diego, CA, USA). Results and discussion PVX-mediated gene silencing and expression in tomato To test the PVX system for VIF, we used PVX vectors with the intact ORF of FT from tomato and Arabidopsis. The tomato and Arabidopsis FT homologues have 73.6% and 69.3% identity at the protein and nucleic acid levels, respectively (Supplementary Fig. S1). We also constructed vectors for VIGS with fragments of PDS from tomato and N. benthamiana (Nb) cDNA. The PVX::PDS constructs were introduced to induce VIGS-mediated photobleaching that would report the extent of virus vector movement in the infected plants. All constructs had the inserted sequence placed into the multiple cloning site of the PVX vector pGR107 (Fig. 1A) and they were in Ti plasmid vectors so that Agrobacterium infiltration could be used for virus inoculation. Inoculation of Nb was a positive control that has been well characterized with the PVX vector system. Fig.1. PVX vectors and PVX-induced VIGS and VOX in tomato. (A) Schematic diagram of PVX vector components. (B) PVX-induced PDS silencing phenotypes in N. benthamiana (Nb) leaves, tomato (Sly) leaves and fruit. Scale bar=1 cm. Four N. benthamiana plants and four tomato plants were used in the experiment; the experiment was repeated three times. The control vector used was PVX::Empty (EV, pGR107). (C, D) Relative expression level of PDS in PVX:: PVX::PDS-inoculated (C) tobacco and (D) tomato leaves at 21 DAI (**P<0.01, n=6). The box plot shows minimum to maximum with all points. (E) Tomato plants inoculated and non-inoculated with PVX vectors at 21 DAI. Scale bar=2 cm; eight tomato plants were used for each group and the experiment was repeated three times. (F) Abundance of PVX coat protein (PVX_CP) and 25K RNA (25K movement protein) in tomato plants from (E) determined by RT-PCR, each group has two biological replicates (1 and 2). (G) Relative expression level of FT in PVX::EV and PVX::FT-treated tomato leaves at 21 DAI determined by qRT-PCR; expression values are relative to reference genes (**P<0.01, Student's t-test; n=6). The box plot shows minimum to maximum with all points. (H) Relative expression level of SFT in PVX::EV and PVX::SFT-treated tomato leaves at 21 DAI determined by qRT-PCR (**P<0.01, Student's t-test; n=6). The box plot shows minimum to maximum with all points. At 21 DAI with PVX::PDS, photobleaching was observed due to silencing of PDS in both species (Fig. 1B; Nb and Sly leaves, PVX::PDS panels) but not in the controls (Fig. 1B; Nb and Sly leaves, non-inoculated and PVX::EV panels). PDS transcript levels assayed by qRT-PCR were lower in the photobleached leaves of the PVX::PDS-inoculated plants than in the controls (Fig. 1C, D). Photobleaching of tomato fruits was also observed with PVX:PDS inoculation (Fig. 1B; Sly fruit, PVX::PDS panels), indicating that the PVX vector was persistent in the inoculated plants until fruit ripening. These results confirmed that the PVX vector is functional in tomato. PVX::FT and PVX::SFT were inoculated onto tomato cotyledons at 14 DAG to investigate the potential of this system for VIF. The inoculated plants developed normally with mild PVX-induced systemic symptoms (Fig. 1E), and there was accumulation of PVX RNA (Fig. 1F). Furthermore, qRT-PCR analysis confirmed VOX because FT and SFT RNA were more abundant in plants inoculated with the respective PVX vectors (Fig. 1G, H). There was, however, a lower FT overexpression level with the SFT construct. PVX-induced FT and SFT expression accelerates flowering and fruit production in tomato Both PVX and PVX-expressed FT should be transported towards the shoot apical meristem (Hein et al., 2005; Jaeger and Wigge, 2007) and, consistent with effects on flowering, the inflorescences appeared earlier and the number of floral buds were greater on plants infected with PVX::FT and PVX::SFT than on the controls (Fig. 2A, pink arrowheads). The open flowers appeared consistently at 42-48 DAG rather than 55 DAG (Fig. 2B, yellow arrowheads) and the ripe fruits appeared at 80-90 DAG rather than 100 DAG or longer in the controls (Fig. 2C). Consistent with the VOX of FT (Fig. 1G, H), the acceleration was greater with PVX::FT rather than PVX::SFT (Fig. 2C). Fig. 2. PVX-based VOX of FT-accelerated flowering and fruiting in tomato. (A) Apical shoots of non-inoculated and PVX::EV-, PVX:: PVX::SFT-inoculated tomato plants at 21 DAI. Scale bars=1 cm. (B) PVX:: PVX::FT-inoculated plants at 28 DAI and 42 DAI. Rep1 and Rep2 are two repetitions from two independent plants. Scale bars=2 cm. (C) Timing of first flower and first ripe fruit on non-infected and PVX::EV-infected controls or PVX::::SFT-infected plants. Values are means +-SD and the average days required are shown on the bottom of each bar (P<0.05, Student's t-test). Eight tomato plants were used for each group and the experiment was repeated three times. The number of flowers and fruits also increased in the PVX:: PVX::SFT-infected tomato plants. At 42 DAI, the plants infected with the FT constructs had 100% (PVX::FT) or 87.5% (PVX::SFT) more open flowers than the controls (Fig. 3A-H, Q). By 126 DAI the plants infected with the FT constructs had 100% (PVX::FT) or 62.5% (PVX::SFT) more fruits than the controls (Fig. 3I-P, Q). These findings validate the PVX-induced expression of FT with FT proving more effective than SFT in all of our assays. We cannot rule out a protein-mediated basis for this difference but given the difference in FT RNA levels (Fig. 1G, H) a more likely explanation invokes a VIGS effect in which an SFT but not FT viral insert silences the endogenous SFT RNA. Fig. 3. PVX induced FT expression increased flower numbers and fruit yield in tomato. (A-D) Top view of (A) non-inoculated; (B) PVX:EV; (C) PVX:FT; and (D) PVX:SFT plants at 42 DAI. Scale bars=2 cm. (E-H) A single inflorescence of (E) non-inoculated; (F) PVX:EV; (G) PVX:FT; and (H) PVX:SFT plants at 42 DAI. Scale bars=2 cm. (I-L) Plants that were (I) non-inoculated or inoculated with (J) PVX:EV; (K) PVX:FT; and (L) PVX:SFT at 126 DAI. Scale bars=5 cm. (M-P) Fruits from plants in (I)-(L); scale bars=2 cm. (Q) Number of open flowers and ripe fruits in non-inoculated, PVX:EV, PVX:FT, and PVX:SFT plants at 42 and 126 DAI stages, respectively. Values are means +-SD and the average numbers of flowers or fruits are shown on the bottom of each bar (P<0.05, Student's t-test). Eight tomato plants were used for each group and the experiment was repeated three times. To explore this possibility, we designed RT-PCR primers from the ORF and 3' UTR that would amplify cDNA corresponding to the endogenous rather than viral FT RNA (Fig. 4A). The results showed that SFT endogenous transcript decreased in PVX::SFT-inoculated leaves more than with PVX:EV or PVX:FT (Fig. 4B). It is therefore likely that VIGS of the endogenous FT RNA in PVX::SFT-inoculated leaves resulted in lower levels of FT compared with those inoculated with PVX:FT. Fig. 4. Endogenous SFT gene in the host tomato plant is partially silenced when expressing PVX::SFT. (A) Schematic diagram of SFT cDNA sequence and the primers used for testing expression level of overexpressing SFT from PVX vector (green) and endogenous SFT gene (blue) in the host tomato plant. (B) Relative expression level of SlySFT_3'UTR in PVX::EV-, PVX::SFT-, and PVX::FT-inoculated tomato leaves at 21 DAI determined by qRT-PCR (*P<0.05, Student's t-test; n=6). The box plot shows minimum to maximum with all points. (C) Working model of PVX-induced FT expression. The PVX vector carrying FT was infiltrated in the tomato cotyledons and expressed in the systemic leaves along with the PVX virus. This allows the FT protein to move from leaves to the stem apex to facilitate specific cells to transform into flower primordium. The enlarged box indicates the shoot apical meristem (SAM) region in PVX::FT inoculated tomato. The virus usually cannot pass through into the SAM, however FT proteins encoded from the PVX::FT recombinant vector can. The VOX effect did not persist into the next generation. Seedling progeny of the infected plants (Fig. 5A) did not have viral symptoms or detectable viral RNA (Fig. 5B). We are thus confident that VIF-mediated speed breeding could be used in tomato without the possibility of seed transmission of the PVX vector. Fig. 5. PVX virus was not detected in the progeny of PVX-infected tomato plants. (A) Seeds (top), 14 DAG seedlings (middle), and 35 DAG plants (bottom) of inoculated and non-inoculated tomato plants, with a group of non-inoculated progenies being inoculated with PVX for 21 d (bottom and left). Eight tomato plants were used for each group and the experiment was repeated three times. (B) Abundance of PVX coat protein (PVX_CP) of tomato plants in (A, bottom) determined by RT-PCR; each group included two biological replicates (1 and 2). Our findings advance previous technology in two ways. Firstly, they validate the use of PVX as an alternative to the TRV vector system for use in tomato (Brigneti et al., 2004). PVX has a than bi-partite viral RNA genome and may be simpler to use in many contexts. Secondly, the reduced endogenous RNA silencing resulting from the use of a heterologous gene for overexpression (Fig. 4) is an advantage over previous methods. This strategy to avoid RNA silencing of endogenous genes had a big effect on the overexpression of FT (Figs 2, 3) and may also be generally relevant when using virus vectors for gene overexpression. Supplementary data The following supplementary data available at JXB online. Table S1. Primers used in this study. Fig. S1. Pairwise sequence alignment between Arabidopsis FT and tomato SFT. erad369_suppl_Supplementary_Tables_S1_Figures_S1 Click here for additional data file. Acknowledgements We thank Ms Mel Steer (Department of Plant Science, University of Cambridge, UK) for helping with tomato horticulture. Author contributions DCB and YD designed the experiments; YD and AY conducted the experiments; YD analysed the data and wrote the manuscript draft. DCB and YD revised the manuscript. Conflict of interest The authors declare no conflict of interest. Funding This work is supported by grants from the Biological and Biotechnology Research Council (BB/R018529/1) to DCB, and the National Natural Science Foundation of China (31972420) to YD. Data availability All data supporting the findings of this study are available within the paper and within its supplementary data published online. |
Idiopathic pulmonary hemosiderosis (IPH) is a rare entity with no known underlying etiology. It can be complicated by lung fibrosis. Emphysema is rarely reported as a consequence of IPH. We present a case of a 30-year-old female who presented with recurrent hemoptysis and shortness of breath. Radiographs revealed advanced emphysematous changes of the lower lobes. The diagnosis of IPH was established with an open lung biopsy. She was treated with systemic steroids, underwent bullectomy and was subsequently maintained on inhaled steroids. pmcINTRODUCTION Idiopathic pulmonary hemosiderosis (IPH) is a rare entity of unknown etiology . Although primarily a childhood disease, the diagnosis can be made during adulthood. The clinical hallmark is recurrent episodes of diffuse alveolar hemorrhage (DAH) with no underlying etiology. The recurrence of hemoptysis eventually leads to hemosiderosis and fibrosis. To our knowledge, diffuse pan-acinar emphysema associated with IPH has been rarely reported. We present a case of a 30-year-old female, with remote history of smoking and an unusual combination of pulmonary hemosiderosis and pan-acinar emphysema. CASE REPORT A 30-year-old female, an ex-smoker with a total smoking history of 1 pack year, having quit 2 years ago, presented with a 1-month history of dyspnea on exertion, fatigue and productive cough with intermittent hemoptysis. Amount of blood was approximately one eighth of a teaspoon, mixed with yellow phlegm. She denied any symptoms of gastroesophageal reflux, arthralgia, fever or loss of weight or appetite. There was no known history of marijuana, vaping or illicit drug use. She denied any exposure to asbestos, bird droppings or second-hand smoke. She denies any joint or vascular symptoms. There was no prior history of pneumothorax or any malignancy. There was no family history of emphysema, pneumothorax or Alpha-1-Antitrypsin (A1AT) deficiency. Her physical examination was remarkable for bilateral expiratory wheezing and decreased breath sounds all throughout both lung fields. Skin examination showed a blistering diffuse maculopapular rash. A chest radiograph revealed bi-basilar hyperlucency (Fig. 1). She underwent a chest computed tomography (CT) scan that demonstrated hyperlucency of the lung parenchyma within the lower lung zones, compatible with panacinar emphysematous changes (Fig. 2). Additionally, there was a large bulla located within the right middle lobe. Figure 1 PA chest X-ray. Figure 2 Coronal and axial sections of the chest CT. Spirometry revealed moderate to severe obstructive ventilatory defect (FEV1/% predicted, FEV1-1.35 L [41% predicted]) with post-bronchodilator reversibility (post-bronchodilator FEV1 1.53 [47%] 13% change) with hyperinflation and air trapping (TLC 126% predicted and RV 3.28 L [188% predicted]). The diffusion capacity was reduced at 54% of but normalized for alveolar ventilation. Differential diagnosis included Emphysema due to A1AT deficiency, Parenchymal manifestation of connective tissue disease, and systemic vasculitis. A serum A1AT level was normal with a PI*MM Genotype. Extensive workup, including liver functions, Human Immune Deficiency Virus and hepatitis panels were negative. A vasculitis panel, including anti-nuclear antibody, ESR and rheumatoid factor levels were normal. A panel of autoantibodies including anti-DNA Ab, anti-GBM Ab, anti-Jo-1 Ab, anti-PM-1 Ab, CK, anti-phospholipid antibody, anti-MPO and anti-PR3 was also negative. Complement levels were normal as well. She was found to have elevated IgE levels up to 195 kU/l (normal is <114 kU/L). Echocardiogram of the heart revealed a left ventricular ejection fraction of 65% with normal right ventricular function and trivial tricuspid regurgitation. She underwent a skin biopsy while being off all medications, which did not show any evidence of vasculitis. Her symptoms of hemoptysis failed to respond to a course of antibiotics. Bronchoscopy with trans-bronchial biopsy failed to yield a diagnosis. Thus, a surgical lung biopsy was performed, which showed areas with numerous alveolar hemosiderin-laden macrophages and calcium encrustation of the vascular walls in keeping with prior episodes of alveolar hemorrhage, as well as foci of acute organizing alveolar hemorrhage. Additionally, Focal emphysematous changes were present. No vasculitis or capillaritis were present. Lymphangioleiomyomatosis was excluded by the lack of modified muscle cells (Fig. 3). Figure 3 Emphysematous changes. Numerous alveolar hemosiderin-laden macrophages and calcium encrustation of the vascular walls. Given the lack of identifiable etiology for the pathologic findings, a diagnosis of IPH was established and the patient was started on treatment with intravenous methylprednisolone. The patient was evaluated by Dermatology for the skin rash and they believed it was a delayed reaction to Pulmicort Respules. The patient subsequently developed lip and tongue swelling, and dyspnea, deemed to be secondary to the methylprednisolone. Patient developed similar allergic reaction to Ipratropium bromide, Fluticasone propionate/Salmeterol (Advair), Montelukast and Fluticasone as well. She was treated with Fexofenadine with resolution of her symptoms. Medications were re-introduced to confirm reaction and allergy to Solumedrol was confirmed with a skin test. She was started on Dexamethasone weaning schedule. Patient continued to have episodes of hemoptysis and each episode improved with dexamethasone course for 3 weeks. The patient subsequently developed a post-surgical intercostal herniation of the lung, for which a right thoracotomy was performed for a bullectomy, right lung biopsy and repair of the chest wall hernia using prosthetic material. Pathology showed similar features to the prior sample, consisting of hemosiderosis and panacinar emphysema. Her symptoms were stabilized after the thoracotomy, and she was started on Formoterol Fumarate and Mometasone Furoate, the only inhalers she could tolerate. Since then, she has had poor yet stable lung function (Table 1). Repeat chest CT revealed stable emphysematous changes. We have continued to follow the patient for 15 years after the initial diagnosis, in which she he had no admissions to the hospital. Pulmonary functions (PFT) were mostly stable and a follow up quantitative chest CT (Fig. 4) showed clear lower lobe emphysema. The patient was deemed a poor candidate for a lung transplant secondary to the lack of social support. Table 1 Feb-03 Aug-05 Jun-06 Dec-18 Sep-10 Oct-12 Sep-14 Dec-17 Oct-19 May-20 FVC liters (% predicted) 3.17 (72) 3.05 (79) 3.21 (84) 2.26 (60) 2.66 (68) 2.88 (74) 2.47 (65) 2.22 (59) 1.54 (42) 2.33 (64) FVC in liters Post-Bronchodilator (% Change) 3.2 (16) 3.13 (02) 3.2 (0) FEV1 in liters (% predicted) 1.35 (41) 1.17 (36) 1.07 (33) 0.79 (25) 0.97 (30) 0.97 (31) 0.84 (27) 0.75 (25) 0.56 (19) 0.71 (24.5) FEV1 in liters Post-Bronchodilator (% Change) 1.53 (13) 1.40 (20) 1.10 (2) FEV1/FVC (%) 48.9 (57) 38.4 (41) 33.4 (40) 34.8 (42) 36.4 (44) 33.7 (41) 34.05 (42) 33.83 (42) 36.5 (45) 30 (37.5) TLC in liters (% predicted) 7.36 (138) 7.3 (140.7) RV in liters (% predicted) 4.24 (257) 4.55 (253.9) DLCO ml/mmHg/min (% predicted) 24.66 (60) 24.4 (63) 10.64 (45.6) Figure 4 Quantitative chest CT scan parametric response mapping. DISCUSSION IPH is a rare disease of unknown etiology and prevalence . Estimated incidence of 0.24 per million children per year was recorded from 1950 to 1979 in a Swedish study as compared to 1.23 per million per year in a Japanese study . Over 80% of cases occur among children, mostly in their first decade of life with balanced sex distribution . Remaining cases constitute adult-onset and/or undiagnosed childhood-onset IPH, mostly being diagnosed before the age of 30 years with inclination toward male predominance . To date, the etiology remains unknown, yet a few hypotheses have been proposed. The presence of plasma circulating immune complexes and response to immune-suppressants therapy suggests an underlying auto-immune pathophysiology . Additionally, celiac disease, [9-11] cow's milk allergy , exposure to insecticides and fungi (especially Stachybotrys atra) , defects in iron metabolism , genetic pre-disposition and a role of neutrophilic accumulation in alveoli , have also been linked to IPH. Patients can present acutely with dyspnea, cough and hemoptysis. However, many have a more subtle presentation with worsening dyspnea, fatigue and anemia. Adults usually present with respiratory symptoms , while children tend to present with failure to thrive and anemia. Physical examination depends on the acuity of presentation. In an acute phase of intra-alveolar bleeding episode, there will be signs of respiratory failure. On the other end, the chronic phase of presentation, there will be pallor, failure to thrive and hepato-splenomegaly . Rarely, no signs of disease are present on examination, as in our patient. The complete blood count may reveal anemia, with an otherwise unremarkable workup like platelets count, coagulation profile, liver and kidney functions. Sputum examination can show erythrocytes and hemosiderin-laden macrophages pointing toward intra-alveolar bleeding. Broncho-alveolar lavage (BAL) has higher diagnostic yield than the sputum examination exhibiting hemosiderin-laden macrophages, intact erythrocytes and occasional neutrophils . PFTs in general show restrictive pattern with reduced diffusion capacity (DLCO) in chronic cases and within normal limits when presenting acutely . However, our patient PFTs demonstrated an obstructive pattern. There is no pathognomonic imaging finding for IPH. During the acute phase, the chest radiographs show diffuse infiltrates, predominantly in the lower lung fields, with corresponding ground-glass attenuation on the CT scan . Subsequently, these shadows are absorbed with treatment with limited interstitial damage. However, during the chronic phase, lung structure gets modified and variable degree of fibrosis is seen . In our patient, CT scan revealed panacinar emphysematous changes with clear predilection to the lower lobes. We believe that the lack of fibrotic changes on CT maybe attributable to presenting in the acute phase. The diagnosis of IPH relies on the clinical presentation with excluding other etiologies for DAH. A clinical picture of hemoptysis, iron deficiency anemia, sputum/BAL analysis, imaging studies and PFTs including basic spirometry and DL,CO measurements help suspect the diagnosis. The laboratory investigation for ANA, anti-double stranded DNA, ANCA (both perinuclear and cytoplasmic variants), anti-GBM antibodies, anti-phospholipid antibodies and RF allow to rule out other caused of DAH . Lung biopsy may be required to establish the diagnosis, which reveals hemosiderin-laden macrophages (siderophages) and an absence of focal or diffuse smooth muscle cell proliferations, vascular malformations, malignancy, pulmonary infarcts, capillaritis/vasculitis, granulomatous inflammation or infectious agents . The differential diagnosis of emphysema is wide in such a case. A1AT Deficiency must be ruled out in young patients presenting with Emphysema. Ehlers Danlos can present with parenchymal changes and pneumothorax , our patient did not have a personal or family history of pneumothorax or joint disease. Complication of IPH and emphysematous change is very rarely reported. Ikeda et al. suspected that repeated alveolar hemorrhage and hemosiderin deposition might lead to destruction of the lung structure i.e. alveolar elastic fibers . Stainer et al. reported peri-bronchovascular emphysema in three patients who were initially diagnosed with IPH, however years later became ANCA positive. They noted known association between ANCA associated vasculitis and emphysema with pathogenesis related to inflammatory mechanisms with the ANCA antibodies, or with noxious insults like proteolytic enzymes and free oxygen radicals. . Gocho et al. described peribronchial hemosiderosis induced strictures potentially causing air trapping and damage to peripheral bronchioles and alveoli eventually leading to centrilobular emphysema . Our case is different from above mentioned cases in the severity of distribution of emphysema i.e. panacinar emphysema and even leading to formation of bullae. Noxious insults associated with recurrent alveolar hemorrhage and hemosiderin deposition leading to destruction of lung interstitium is a plausible explanation. Since it is a rare disease, there are no controlled treatment trials. Management is based upon personal experiences and anecdotal evidence. One approach has been use of systemic glucocorticoids, mostly in the acute phase of IPH, with favorable response . Some authors recommend a starting dose of <=1 mg/kg/day for a couple of months followed by a tapered dose. There is favorable response to chronic oral corticosteroids, with fewer IPH exacerbations . Immunosuppressant agents, including azathioprine, hydroxychloroquine, cyclophosphamide and methotrexate, have been tried as well with variable results [2, 30-33]. Lung transplantation have been performed with a risk of recurrence in the transplanted lungs. Our patient's symptoms stabilized after bullectomy. This approach has been previously reported to improve the dyspnea in patients with emphysema but not reported in patients with IPH. Our patient developed a post-surgical thoracic wall herniation, which was reported in to occur spontaneously in a patient with IPH . The lack of prospective data on patients with IPH makes prognostication difficult. The most frequent cause of death is massive DAH resulting in acute respiratory failure . Our case exhibited unusual features different from descriptions in prior studies of in terms of imaging and pathologic findings. CONFLICT OF INTEREST STATEMENT No conflicts of interest. FUNDING No sources of funding. CONSENT Verbal and written consent was obtained from the patient. GUARANTOR Atul C. Mehta, MD, FACP, FCCP. |
J Exp Bot J Exp Bot exbotj Journal of Experimental Botany 0022-0957 1460-2431 Oxford University Press UK 10.1093/jxb/erad407 erad407 eXtra Botany Insights AcademicSubjects/SCI01210 Advances in virus-induced flowering in tomato Bellinazzo Francesca Laboratory of Molecular Biology, Wageningen University and Research, 6708 PB, Wageningen, The Netherlands Bioscience, Wageningen Plant Research, Wageningen University and Research, 6708 PB, Wageningen, The Netherlands Correspondence: [email protected] 01 1 2024 20 12 2023 20 12 2023 75 1 14 20 12 2023 (c) The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Experimental Biology. 2023 This is an Open Access article distributed under the terms of the Creative Commons Attribution License ), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. This article comments on: Deng Y, Yarur-Thys A, Baulcombe DC. 2024. Virus-induced overexpression of heterologous FLOWERING LOCUS T for efficient speed breeding in tomato. Journal of Experimental Botany 75, 36-44. Florigen Flowering Locus T lifecycle shortening potato virus X Solanum lycopersicum speed breeding tomato virus-induced flowering pmc Many plants use information on day length, which is sensed in the leaves, to time their flowering response at the shoot apical meristem (SAM). What makes this mechanism possible is a transmissible molecule called florigen, a small protein encoded by the gene FLOWERING LOCUS T (FT). Based on this knowledge, virus-induced flowering (VIF) can be applied to promote the change to the reproductive phase and to facilitate the breeding of plants with long juvenility or unsynchronized flowering time. In their study, Deng et al. (2024) describe a potato virus X (PVX)-based method to transiently deliver the florigen in tomato plants and thereby control their flowering time. Viral vectors have been widely used for transient genetic manipulation to study gene function in plants. This approach is especially useful as an alternative to the generation of stable mutant lines in recalcitrant species. The most common virus-based technology is the so-called virus-induced gene silencing (VIGS), which turns the immune response of the plant host against its own transcripts (Lu et al., 2003). In essence, a viral vector is engineered with a fragment of the target gene. Upon infection, the virus produces the engineered transcript in double-stranded form. The presence of double-stranded RNAs triggers the plant's post-transcriptional gene-silencing machinery, which is sequence specific. Consequently, targeted RNA degradation occurs, resulting in down-regulation of the endogenous target gene together with the engineered fragment produced by the virus (Rossner et al., 2022). The use of viral vectors not only allows gene down-regulation; its opposite, overexpression, can also be obtained. In fact, by inserting the full-length coding region of the gene of interest into a viral vector, transient ectopic expression can be obtained. This technology is called virus-induced overexpression (VOX) (Rossner et al., 2022). Building upon these research methods, a new breeding tool has been developed to induce flowering on demand and to facilitate crossing. A tailored version of the VOX technology, VIF (McGarry et al., 2017), uses FT to harness its florigenic power (Fig. 1). The key aspect behind the success of this method can be found in the mobile nature of FT. In fact, a common bottleneck of virus-based systems is the inability of a viral infection to reach the correct plant tissue. This problem is especially relevant for meristematic areas including the SAM, from which most viruses are effectively excluded (Bradamante et al., 2021). Although the meristematic barrier against viruses is crucial for blocking vertical transmission of the infection to the next generation (and therefore allowing transient manipulation to remain as such), it can, in principle, prevent the manipulation of meristematic genes. By using a systemically transmissible inducer of flowering, the VIF technique can exert its effect in virus-free meristematic cells. Fig. 1. Illustration showing the mode of action of florigen. (A) Florigen, the gene FT, is expressed and translated in leaf vasculature, specifically in phloem companion cells. In many plant species, FT expression occurs in response to photoperiod. (B) The FT protein is transported systemically through the plant phloem (indicated by the red arrows). (C) On reaching the shoot apical meristem (SAM), FT binds to the bZIP transcription factor FD in a higher-order complex, allowing the expression of flower meristem identity genes (exemplified by AP1 in the figure), which mediate the change to the reproductive phase (Turck et al., 2008; Taoka et al., 2011; Collani et al., 2019). VIF has been applied to multiple crops, including melon (Cucurbita moschata), cotton (Gossypium hirsutum), soybean (Glycine max), and grapevine (Vitis vinifera), demonstrating that FT can be delivered and flowering can be successfully induced in these species (McGarry et al., 2017; Maeda et al., 2020). Notably, VIF is effective even during the juvenile stage, as it has been demonstrated in apple (Malus domestica) (Yamagishi et al., 2011) and in orange (Citrus sinesis) (McGarry et al., 2017). Nevertheless, there is no single solution for performing VIF in all plant species: in fact, whereas FT is highly conserved in angiosperms (Bennett and Dixon, 2021; Liu et al., 2023), most plant viruses have a relatively narrow host range (McLeish et al., 2019). For this reason, VIF requires customization, which can be challenging. In their study, Deng et al. (2024) successfully optimized the VIF method for tomato (Solanum lycopersicum). Tomato is a major vegetable crop, accounting for 16% of the total global vegetable production in 2020 (FAOSTAT, 2022). The viral vector used in their study is based on PVX, a monopartite virus, which is advantageous because only one viral molecule needs to be transformed into each plant cell for the system to function. To prove that the PVX vector can effectively be delivered in tomato plants, a VIGS system was first designed to silence the gene PHYTOENE DESATURASE (PDS) in tomato. PDS is commonly used as a visual marker because its silencing causes photobleaching, and therefore the sites of viral infection and spread can be easily identified by the whitening of the infected tissues (Romero et al., 2011; Killiny, 2022). In parallel, the presence of the PVX coat protein and of the 25K protein, which is essential for movement of the virus inside the plant (Leshchiner et al., 2008), was verified at the RNA level by quantitative PCR. Subsequently, two versions of PVX-based VIF vectors were engineered, one carrying the Arabidopsis FT coding region and the other with the coding sequence of the main tomato florigen SINGLE FLOWER TRUSS (SFT). Treated tomato plants flowered 28-34 days after inoculation, approximately 10 days earlier than untreated controls. Moreover, VIF-treated plants produced >85% more flowers per truss and, ultimately, more ripe fruits (>62% increase). These results are in line with what is observed in sft mutants, where a late-flowering phenotype is paired with single-flower trusses. In striking contrast with the Arabidopsis ft mutants (Perilleux et al., 2019), the single-flowered sft phenotype is due to the fact that SFT not only promotes flower induction but is also necessary to maintain the reproductive identity of meristems, which otherwise would reverse to the vegetative state (Molinero-Rosales et al., 2004). Interestingly, enhanced VIF-related effects were observed when using Arabidopsis FT instead of the native SFT. Although this might seem surprising, the authors explain the milder phenotypes by showing that the presence of native SFT transcripts partially triggers silencing as well as overexpression. The use of heterologous genes to avoid silencing of the corresponding endogenous gene might be more generally useful when VOX is used as a research tool. Finally, PVX-infected plants produced healthy seeds that germinated into virus-free plants. This excludes the possibility of vertical transmission of the viral vector, indicating that this system is, in principle, safe to use for breeding. In conclusion, a reliable method has been established to transiently induce flowering in tomato. This advancement has been made possible thanks to the discovery of florigen (Chailakhyan, 1936), obtained through fundamental research conducted around 100 years ago, sometimes in difficult circumstances (Romanov, 2012). This shows that the effects of a past great discovery keep reverberating in a cascade of new conceptualization and technology, ultimately sustaining the production of new plant varieties that have potential to withstand the climatic crisis today and in the future. Acknowledgements Marian Bemer and Bas Heidemann were consulted for their expertise in tomato flowering and virus-mediated techniques, respectively. Moreover, my mentor Rainer Melzer supervised this work. Thank you all for your contribution. References Bennett T , DixonLE. 2021. Asymmetric expansions of FT and TFL1 lineages characterize differential evolution of the EuPEBP family in the major angiosperm lineages. BMC Biology 19 , 181.34465318 Bradamante G , ScheidOM, IncarboneM. 2021. Under siege: virus control in plant meristems and progeny. The Plant Cell 33 , 2523-2537.34015140 Chailakhyan MK. 1936. New facts in support of the hormonal theory of plant development. Proceedings of the USSR Academy of Sciences 13 , 79-83. Collani S , NeumannM, YantL, SchmidM. 2019. FT modulates genome-wide DNA-binding of the bZIP transcription factor FD. Plant Physiology 180 , 367-380.30770462 Deng Y , Yarur-ThysA, BaulcombeDC. 2024. Virus-induced overexpression of heterologous FLOWERING LOCUS T for efficient speed breeding in tomato. Journal of Experimental Botany 75 , 36-44. FAOSTAT. 2022. Agricultural Production Statistics 2000-2020. Analytical Brief 41. Killiny N. 2022. Silencing phytoene desaturase causes alteration in monoterpene volatiles belonging to the methylerythritol phosphate pathway. Plants 11 , 276.35161256 Leshchiner AD , MininaEA, RakitinaDV, VishnichenkoVK, SolovyevAG, MorozovSY, KalininaNO. 2008. Oligomerization of the potato virus X 25-kD movement protein. Biochemistry (Moscow) 73 , 50-55.18294129 Liu H , LiuX, ChangX, ChenF, LinZ, ZhangL. 2023. Large-scale analyses of angiosperm Flowering Locus T genes reveal duplication and functional divergence in monocots. Frontiers in Plant Science 13 , 1039500.36684773 Lu R , Martin-HernandezAM, PeartJR, MalcuitI, BaulcombeDC. 2003. Virus-induced gene silencing in plants. Methods 30 , 296-303.12828943 Maeda K , KikuchiT, KasajimaI, LiC, YamagishiN, YamashitaH, YoshikawaN. 2020. Virus-induced flowering by apple latent spherical virus vector: effective use to accelerate breeding of grapevine. Viruses 12 , 70.31936111 McGarry RC , KlockoAL, PangM, StraussSH, AyreBG. 2017. Virus-induced flowering: an application of reproductive biology to benefit plant research and breeding. Plant Physiology 173 , 47-55.27856915 McLeish MJ , FraileA, Garcia-ArenalF. 2019. Evolution of plant-virus interactions: host range and virus emergence. Current Opinion in Virology 34 , 50-55.30654270 Molinero-Rosales N , LatorreA, JamilenaM, LozanoR. 2004. SINGLE FLOWER TRUSS regulates the transition and maintenance of flowering in tomato. Planta 218 , 427-434.14504922 Perilleux C , BoucheF, RandouxM, Orman-LigezaB. 2019. Turning meristems into fortresses. Trends in Plant Science 24 , 431-442.30853243 Romanov GA. 2012. Mikhail Khristoforovich Chailakhyan: the fate of the scientist under the sign of florigen. Russian Journal of Plant Physiology 59 , 443-450. Romero I , TikunovY, BovyA. 2011. Virus-induced gene silencing in detached tomatoes and biochemical effects of phytoene desaturase gene silencing. Journal of Plant Physiology 168 , 1129-1135.21377758 Rossner C , LotzD, BeckerA. 2022. VIGS goes viral: how VIGS transforms our understanding of plant science. Annual Review of Plant Biology 73 , 703-728. Taoka KI , OhkiI, TsujiH, et al . 2011. 14-3-3 proteins act as intracellular receptors for rice Hd3a florigen. Nature 476 , 332-335.21804566 Turck F , FornaraF, CouplandG. 2008. Regulation and identity of florigen: FLOWERING LOCUS T moves center stage. Annual Review of Plant Biology 59 , 573-594. Yamagishi N , SasakiS, YamagataK, KomoriS, NagaseM, WadaM, YamamotoT, YoshikawaN. 2011. Promotion of flowering and reduction of a generation time in apple seedlings by ectopical expression of the Arabidopsis thaliana FT gene using the Apple latent spherical virus vector. Plant Molecular Biology 75 , 193-204.21132560 |
Background snake envenomation is a serious healthcare issue. Daboia palaestinae is an endemic species to the Middle East that is responsible for the majority of envenomation cases with serious health issue consequences. Case Presentation we report a case of a 20-year-old Palestinian man who presented to emergency room following a snake bite. He developed atrial fibrillation which is a rare but serious complication of D. palaestinae snakebite. We reviewed the proper approach and management to such cases. Conclusion cardiac arrhythmias are a rare but serious, often fatal, complication of snake envenomation. Early detection and proper management is key to avoid morbidity and mortality. snake envenomation arrhythmia cardiotoxicity Palestine viper pmcINTRODUCTION Daboia palaestinae (Dp) is an endemic, venomous species of snakes endemic to Palestine and the surrounding region . Without immediate care, its bite can be life-threatening and result in substantial mortality and morbidity . The severity and the venomous activity is the result of various proteins and enzymes, usually leading to increased capillary permeability, endothelial damage, and disruption of the coagulation system leading to hemorrhagic activity and edema. Myotoxicity, myonecrosis, and cardiotoxicity were also reported as less likely effect of envenomation . Here we present a case of a 20-year-old Palestinian male presenting with atrial fibrillation following a snake bite by Dp. CASE PRESENTATION A 20-year-old male patient with a free past medical and surgical history, presented to emergency room (ER) complaining of right sided hand swelling after sustaining a snake bite. The bite was associated with severe pain and numbness at the back of his hand, in addition to nausea, vomiting and diffuse sweating. He had a blood pressure of 100/60 mmHg, a heart rate of 120 beats per minute (bpm), a temperature of 36.6 degrees, and an O2 saturation of 90% on room air. He was sweaty and anxious, his right hand, shown in fig. 1, was edematous, nearly doubling in size compared to the left side with two obvious puncture wounds as seen in fig. 2. These findings were associated with ecchymosis and tenderness to palpation extending from the dorsum of the hand to above the elbow joint. Range of motion was limited at the wrist joint, while the elbow joint had a full range of motion. Sensation was intact and both the radial and brachial pulses were full and palpable. Otherwise, his examination was unremarkable. Electrocardiogram (ECG) showed sinus tachycardia, mostly related to stress (shown in fig. 4). Complete blood count (CBC) showed a hemoglobin level of 15.8 mg/dl, white blood cell count was 13 300, platelet count was 430 000. Prothrombin time (PT) was 14.3, activated partial thromboplastin time (aPTT) was 25, international normalized ratio (INR) was 1.1. Figure 1 Right upper limb showing the bite site, marked. Swelling and tenderness extending from the site of the bite at the ulnar aspect of the dorsum of the hand to the elbow joint. Figure 2 Puncture wounds resulting from snake bite. The snake was killed and brought to the ER, it was identified as the Palestine viper, known by its scientific name D. palaestinae. The snake is shown in fig. 3. Figure 3 The snake responsible for the bite, identified as Daboia palaestinae. Figure 4 Electrocardiogram at presentation. The rhythm here shows sinus tachycardia, mostly related to stress. The patient received eight vials of polyvalent anti-venom while in the emergency room, after which he reported significant improvement in terms of pain. He was admitted to intensive care unit (ICU) for close monitoring. On the second day of admission, the patient developed sudden onset palpitation associated with shortness of breath without chest pain. His heart rate was 155 bpm, blood pressure 130/65 mmHg, O2 saturation 95%, temperature 36.6. CBC, obtained during morning routine labs prior to the episode, showed the following findings: hemoglobin: 14.4 mg/dl, white blood cell count: 17 500, platelet count 355 000. Other labs, including a comprehensive metabolic panel, lactate dehydrogenase (LDH): 243. PT: 14.7, INR: 1.3, aPTT: 28, fibrinogen 271 mg/dl. His troponin I peaked at 0.04 ng/ml (Reference range < 0.029), creatine kinase-muscle/brain was 0.3% (reference range 0-25). Electrocardiogram (ECG), shown in fig. 5, showed irregularly irregular pulse with absent P-wave, these changes were absent on the ECG done on admission, as it showed a sinus, regular heart rate (shown in fig. 4). The picture was suggestive of new-onset atrial fibrillation. Transthoracic echocardiography noted normal biventricular function with no focal wall motion abnormality, and no valvular heart diseases with normal ejection fraction. Figure 5 Electrocardiogram showed an irregularly irregular rhythm with absent P-waves, suggestive of atrial fibrillation. As the patient had a free past medical history, review of medications did not disclose any medication that could incite such an event, no previous episodes within the patient known relatives was reported by the patient. The new onset cardiovascular findings were considered part of the disease process, and a manifestation of ongoing venom toxicity. Based on that interpretation, six more vials of polyvalent anti-venom were administered. Cardiology team was consulted and the patient was started on bisoprolol 5 mg per os (PO) once daily (OD), which failed to control his rate. He was given amiodarone 300 mg STAT then kept on continuous infusion of 900 mg over 24 h. The patient was monitored for any new onset hematologic or cardiac events via serial CBC, INR, fibrinogen and troponin I every 6 h. The patient's cardiac enzymes improved the next day, CBC parameters and coagulation profile remained within normal. After 24 h of monitoring, in which the patient had no new concerning events, the patient was transferred to the medical ward. ECG next day showed normal sinus rhythm with ventricular rate of 76 bpm (shown in fig. 6). Left upper limb swelling improved over the following three days, and the patient was discharged home on oral amoxicillin-clavulanate for 7 days. Figure 6 Electrocardiogram following resolution of the event, it shows a sinus rhythm with a heart rate of 76 bpm. He was seen in the outpatient clinic 5 weeks later, the swelling of his upper limb had completely resolved, he reported no new episodes of palpitation of chest discomfort. CBC, basic metabolic panel, and coagulation profile were within normal limits. New echocardiography showed no abnormalities. The patient was maintained on bisoprolol, 5 mg PO OD. As no new episodes were reported, no further investigations were requested as the entire episode was deemed secondary to snake envenomation, which had completely resolved by the time of follow up. DISCUSSION Snake envenomation is considered a major public health issue worldwide. 4.5-5.4 million people fall victims to snakebites every year . Dp, a ubiquitous, venomous viper species endemic to the Eastern Mediterranean region, accounts for the majority of snakebites in the region. Due to its arsenal of enzymatic polypeptides, which exert pernicious vascular, neurotoxic and hemostatic effects, the clinical outcome following envenomation can be quite variable, depending on the anatomic location and amount of venom delivered. Localized signs are often limited to pain, hemorrhage, edema and sometimes regional lymphadenopathy. In more severe cases, bleeding, cardiac arrhythmias, and even shock can ensue . Hemorrhage is the main cause of death following Dp envenomation , however, cardiac toxicity has been also documented in Dp victims, this was more observed in individuals with underlying co-morbidities (diabetes, ischemic heart disease, hypertension, dyslipidemia and advanced age). Patients might be asymptomatic, or they may develop chest pain, palpitation, and hypotension. Myocardial infarction was reported in adult males from tropical regions with free past medical history. ECG dysfunction due to Dp can be due to direct or indirect effects of the venom. While direct effects result from alteration of the action potential of cardiac cell membranes, or changes in intracellular ion activity, indirect effects develop in response to hypotension . Sinus tachycardia is the most commonly seen change, it is observed in the setting of hypovolemia due to extravasation of fluid in the affected limb, or due to hypotension predisposed by anaphylaxis . Atrial fibrillation, on the other hand, has been rarely reported in the setting of Dp envenomation. Wang A et al reported a case of myocarditis following Dp snake bite without specifying if any ECG changes were observed . Sogut O et al reported a case of atrial fibrillation following a snake bite of unknown species, however, the effect was attributed to epinephrine administered subcutaneously due to anaphylaxis developing secondary to antivenom administration rather than the venom itself . Thillainathan S et al reported a case of Hypnale hypnale bite resulting in ECG changes suggestive of atrial fibrillation and inferior wall myocardial infarction. The episode was attributed to coronary artery spasm at it resolved spontaneously . Although not well understood, myotoxicity is attributed to two major classes of snake venom toxins. The first class is phospholipases, which exhibit numerous pharmacological effects, including myotoxicity, neurotoxicity and cytotoxicity, with the other class being L-amino acid oxidases (LAAO), which are flavoproteins that function by catalyzing the stereospecific oxidative deamination of L-amino acid to a-keto acids. This class exerts direct cytotoxic activity, leading to edema, hemorrhage, myotoxicity and apoptosis . The cause of specific arrhythmias and ECG changes is poorly understood. Several mechanisms have been hypothesized to address the issue: (1) direct cytotoxic effect (2) toxin-induced arrhythmia (3) acute coronary syndrome secondary to coagulopathy (4) toxin-mediated coronary spasm (5) hyperkalemia secondary to acute renal failure and (6) inflammatory processes secondary to venom-induced hypersensitivity . Treatment of viper envenomation consists of supportive care and immobilization of the affected extremity. Tourniquets, compression dressing, and attempts to remove the venom by cutting or suction should be discouraged. Coagulopathy and hemorrhage are common complications of Dp envenomation. All patients should be evaluated with hemoglobin, platelet count and fibrinogen. Polyvalent antivenom remains the treatment of choice for viper envenomation . Patients should be monitored due to significant risk of allergic reaction (20% of cases). Tetanus toxoid and antibiotics can be administered if there is high-risk of infection . Patients who develop ECG dysfunction often require more aggressive measures, including respiratory support via mechanical ventilation for those who develop respiratory failure. More specific measures include administering additional doses of antivenom to neutralize snake venom and reduce cardiac dysfunction. Lidocaine, amiodarone, and beta blockers can be used against cardiac arrhythmias . A proposed algorithm is shown in fig. 7. Figure 7 Proposed approach for snake envenomation associated with cardiovascular abnormalities . CONCLUSION Cardiac arrhythmia is a serious, often fatal, complication of snake envenomation. Screening for arrhythmia, conduction disorders and other cardiac-related issues, particularly in the setting of severe envenomation, can prevent further complication and death. CONFLICT OF INTEREST STATEMENT None declared. FUNDING None declared. ETHICAL APPROVAL Not applicable. CONSENT Written informed consent was obtained from the patient to publish this report following the journal's patient consent policy. DATA AVAILABILITY The data used in this case report is available upon reques from the corresponding author. GUARANTOR Hasan Arafat. |
J Exp Bot J Exp Bot exbotj Journal of Experimental Botany 0022-0957 1460-2431 Oxford University Press UK 37846132 10.1093/jxb/erad394 erad394 eXtra Botany Viewpoint AcademicSubjects/SCI01210 How do brassinosteroids fit in bud outgrowth models? Kelly Jack H Waite Research Institute, School of Agriculture Food & Wine, The University of Adelaide, Adelaide, SA 5064, Australia Brewer Philip B Waite Research Institute, School of Agriculture Food & Wine, The University of Adelaide, Adelaide, SA 5064, Australia Australian Research Council Training Centre for Future Crops Development, The University of Adelaide, Adelaide, SA 5064, Australia Australian Research Council Centre of Excellence for Plant Success in Nature and Agriculture, The University of Queensland, Brisbane, QLD 4072, Australia Byrne Mary University of Sydney, Australia Editor Correspondence: [email protected] 01 1 2024 17 10 2023 17 10 2023 75 1 1316 07 6 2023 05 10 2023 10 10 2023 31 10 2023 (c) The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Experimental Biology. 2023 This is an Open Access article distributed under the terms of the Creative Commons Attribution License ), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. A network of plant hormonal signals coordinates plant branching. Brassinosteroids are important in this network, acting as repressors of the strigolactone pathway and TEOSINTE BRANCHED1 . Auxin brassinosteroid bud outgrowth crop architecture cytokinin gibberellin strigolactone TB1 Australian Research Council 10.13039/501100000923 FT180100081 CE200100015 IC210100047 CE230100015 pmc Short stature crops were developed during the green revolution mainly due to their resistance to falling over (lodging), improved crop harvestability and management, and a greater proportion of biomass in the grains, leading to superior yield. These crops were disrupted in the gibberellin (GA) pathway, which caused the reduced height ( Gao and Chu, 2020 ). GA disruption can introduce unwanted effects in other important traits such as fertility, leaf expansion, seed quality, and stress response ( Gao and Chu, 2020 ). Hence, there are currently efforts to uncouple negative side effects of GA-related short stature or utilize alternative dwarfing pathways, such as brassinosteroids (BRs). A negative side effect of GA-related short stature in grain crops can be increased tillering, leading to unproductive tillers and small grains (Kertesz et al., 1991). This is probably because the GA pathway affects a range of traits that help the plant to adapt to its environment, which can have positive or negative impacts on plant growth and yield. Short stature with unchanged tillering would be preferable. To achieve optimal height and tiller number, it will be essential to have a full understanding of how hormonal, resource, and environmental signals act on stature and bud outgrowth. Although models for bud outgrowth regulation have been proposed (Beveridge et al., 2023), they still lack some important information, such as why increased tillering occurs in GA-deficient plants. BRs have emerged as a plant hormone that also influences stature and bud outgrowth (Xia et al., 2021), and they have become a key piece of the bud outgrowth puzzle. For instance, the rice BR mutant dwarf and low tillering (dlt) exhibits reduced stature coupled with reduced tillering (Tong et al., 2009). Understanding how BRs integrate within the branching signalling network may be important for decoupling tillering from height and achieving optimal crop shoot architecture. TB1 integrates multiple signals to regulate bud outgrowth The decision in determining whether a bud is released or held in a state of dormancy is regulated by a complex network of hormonal signals (Kelly et al., 2023). Many of these signals act via interactions with TEOSINTE BRANCHED1 (TB1), a transcription factor gene that inhibits bud outgrowth in monocotyledons [known as BRANCHED1 (BRC1) in dicotyledons]. An overview of the key interactors is shown in Box 1, but more details can be found in recent reviews (Beveridge et al., 2023; Dun et al., 2023; Kelly et al., 2023). Strigolactones (SLs) are a key inhibitor of branching, whereby promoting the expression of TB1 then can repress axillary bud outgrowth (Dun et al., 2012). Cytokinins (CKs) are also important, acting antagonistically to SLs by repressing SL biosynthesis and TB1 expression in buds to promote branching (Dun et al., 2012). While GA has been selected for modifying plant height, findings in Rosa sp. show that GA biosynthesis in buds becomes up-regulated during bud burst, suggesting that GA also plays a positive role in branching (Choubane et al., 2012). This aligns with findings that highlight a direct repressive effect of GA on TB1 (Ni et al., 2015). However, GA also represses SL biosynthesis, which might be expected to promote TB1 and subsequently reduce branching (Ito et al., 2017). However, findings in tomato show a repressive effect of GA on CK response (Fleishon et al., 2011). Hence, it may be that targeting dampened GA for reduced height can result in increased CK levels, which may contribute to increased tillering in GA-related semi-dwarf crops. Moreover, soluble sugars may over-ride the effect of low GA on SL biosynthesis, as sucrose also promotes branching through the DWARF53 (D53) suppressor of SL signalling (Dun et al., 2023). In Arabidopsis, abscisic acid (ABA) gene expression is up-regulated in wild-type plants treated with far-red light, while brc1 mutants exhibit no response (Gonzalez-Grandio et al., 2013). This suggests that ABA acts downstream of TB1, where it is promoted to repress bud outgrowth and maintain bud dormancy (Box 1). Box 1. BRs integrate TB1 to regulate bud outgrowth BR perception via receptor BRASSINOSTEROID INSENSITIVE 1 (BRI1) and co-receptor BRI1-ASSOCIATED RECEPTOR KINASE 1 (BAK1) promotes increased BES1/BZR1 levels. BZR1 interacts with D53 to repress TB1, which promotes bud outgrowth. MAX2-mediated BES1 degradation is promoted by SLs, which de-repress TB1 and inhibit bud outgrowth. D53 also represses SQUAMOSA PROMOTER BINDING PROTEIN LIKE 14 (SPL14), a positive regulator of TB1. BR, CK, SUC, and GA promote branching, while SL represses branching by promoting TB1. ABA is promoted by TB1, acting downstream to negatively regulate branching. Created with BioRender.com. By promoting SL biosynthesis and repressing CK biosynthesis, auxin can modulate TB1 levels to regulate branching responses (Beveridge et al., 2023). This is part of the mechanism of apical dominance, whereby auxin synthesized in a growing apex (shoot tip) maintains dormancy in nearby buds and allows buds to grow out if the shoot tip is removed (Beveridge et al., 2023). Auxin also promotes the expression of PIN-FORMED (PIN) auxin transporters and their localization at the plasma membrane towards cells in the stem where auxin is depleted (Beveridge et al., 2023). This allows auxin to flow from actively growing leaves (sources) to established channels of auxin flow in the stem vasculature (sinks). This flow triggers new vasculature formation needed to support a growing shoot. Auxin flowing within the stem can also prevent auxin canalization from an axillary bud, potentially inhibiting ongoing outgrowth independently of TB1 (Waldie and Leyser, 2018). Elevated PIN1 levels in SL biosynthesis mutants also suggest that SLs act to inhibit auxin transport (Waldie and Leyser, 2018). This decreases the sink strength of auxin flow in the main stem, thus inhibiting new auxin canalization from lateral sources, such as buds (Waldie and Leyser, 2018; Zhang et al., 2020). Moreover, CK can modulate PIN levels, suggesting that it may also act on auxin canalization from buds (Waldie and Leyser, 2018). These findings highlight TB1 as a hub for shoot branching together with TB1-independent pathways. Understanding the details of the model may provide ideas for changing plant architecture, such as optimizing tillering in reduced-stature crops. However, it is essential to also include other important factors, as these may be needed to solve conflicts in the model. How do brassinosteroids function in this network? When observing BR mutant phenotypes, it is clear that BRs play an important role in regulating branching and stem elongation. The question is: how do they carry out this effect? It has been previously reported in Arabidopsis that the BR signalling component BRI-EMS SUPPRESSOR-1 (BES1) interacts with the key SL signalling component MORE AXILLARY GROWTH 2 (MAX2), which results in the degradation of BES1 (Wang et al., 2013). It has also been observed that SL-mediated tiller responses in rice are dependent on levels of the BES1 homologue BRASSINAZOLE-RESISTANT 1 (BZR1) (Fang et al., 2020). SL and BR double mutants produce fewer tillers than the dwarf14 (d14) SL-insensitive single mutant, suggesting that upstream BR signalling or downstream BZR1 function is required for D14-regulated tillering response (Fang et al., 2020). BZR1 also interacts with D53 to coordinate both BR-mediated tiller responses in rice, where BZR1 recruits D53 to the promoter of the TB1 rice homolog FINE CULM1 (FC1) to regulate its expression (Fang et al., 2020). Xia et al. (2021) further explored the relationship between BRs and TB1/BRC1, observing that decapitation in tomato resulted in increased levels of BL and BZR1; however, BRC1 was not as significantly repressed in dwf and bzr1 mutants. This suggests that BRs are required for BRC1 repression to release bud outgrowth. Additionally, mutation of brc1 or overexpression (OE) of DWF in tomato both enhanced bud outgrowth; however, brc1 in DWF-OE plants did not further increase bud outgrowth, suggesting that BRC1 acts downstream to regulate BR-mediated branching responses (Xia et al., 2021). Xia et al. also conducted multiple assays in tomato to examine if BZR1 directly regulates BRC1 expression, where they observed multiple potential binding sites for BZR1 in the PBRC1-bait vector, and that PBRC1 was inhibited by BZR1 binding (Xia et al., 2021). This suggests that BR signalling positively regulates bud outgrowth by down-regulating BRC1 expression via BZR1 (Box 1). Thus, BRs and SLs appear to act antagonistically on TB1/BRC1 expression by, respectively, promoting or inhibiting BES1/BZR1. Importantly, these key findings cement BRs firmly into the branching network. It has also been recently observed that light-mediated effects on bud outgrowth are partly BR dependent. Dong et al. (2023) observed lower transcript levels of DET2 and DWF and reduced levels of BL and BZR1 in lateral buds in response to red/far-red (R/FR) light, causing up-regulation of BRC1 and repression of bud outgrowth in tomato. This response is regulated by LONG HYPOCOTYL 5 (HY5), which can bind the promoters of BRC1, DET2, and DWF to dampen BRC1 levels and up-regulate BR biosynthesis to enhance shoot branching (Dong et al., 2023). Outlook While we highlight results showing significant direct effects of BRs on the SL and TB1 pathway, what remains less understood are the effects of BRs on the other branching hormones. This will perhaps help solve some discrepancies in the model and increase our ability to refine or uncouple genetic outputs for crop architecture improvement. Modifications to crop shoot architecture have played a significant role in boosting productivity, which has largely been facilitated by targeting hormone pathways such as GA. As hormones regulate many aspects of plant function and development, stronger mutations of hormonal function can introduce unwanted effects, such as elevated tillering associated with dampened GA. Hence it is important to continue expanding our understanding of the fundamental mechanisms that regulate height and tillering, as this may elucidate new alternative targets for modifying shoot architecture. BRs promote stem elongation and tillering, in part by dampening TB1. Therefore, biosynthesis or signalling components may serve as ideal targets for genetic manipulation. This can be possible using a quantitative trait engineering approach, where candidate genes can be targeted to uncover intermediate (hypomorphic) alleles that promote beneficial crop architecture. These findings highlight that the BRs are another core component of the complex network that regulates tillering. Acknowledgements We apologize to authors whose important work we did not cite due to space limitations. Conflict of interest The authors declare no conflicts of interest. Funding This research was supported by the Australian Research Council grants FT180100081, CE200100015, IC210100047, an Australian Government Research Training Program (RTP) Scholarship, and a Thyne Reid Foundation/Playford Trust Scholarship. References Beveridge CA , RameauC, Wijerathna-YapaA. 2023. Lessons from a century of apical dominance research. Journal of Experimental Botany 74 , 3903-3922.37076257 Choubane D , RabotA, MortreauE, et al . 2012. Photocontrol of bud burst involves gibberellin biosynthesis in Rosa sp. Journal of Plant Physiology 169 , 1271-1280.22749285 Dong H , WangJ, SongX, et al . 2023. HY5 functions as a systemic signal by integrating BRC1-dependent hormone signaling in tomato bud outgrowth. Proceedings of the National Academy of Sciences, USA 120 , e2301879120. Dun EA , BrewerPB, GillamEMJ, BeveridgeCA. 2023. Strigolactones and shoot branching: what is the real hormone and how does it work? Plant and Cell Physiology 64 , 967-983.37526426 Dun EA , de Saint GermainA, RameauC, BeveridgeCA. 2012. Antagonistic action of strigolactone and cytokinin in bud outgrowth control. Plant Physiology 158 , 487-498.22042819 Fang Z , JiY, HuJ, GuoR, SunS, WangX. 2020. Strigolactones and brassinosteroids antagonistically regulate the stability of the D53-OsBZR1 complex to determine FC1 expression in rice tillering. Molecular Plant 13 , 586-597.31837469 Fleishon S , ShaniE, OriN, WeissD. 2011. Negative reciprocal interactions between gibberellin and cytokinin in tomato. New Phytologist 190 , 609-617.21244434 Gao S , ChuC. 2020. Gibberellin metabolism and signaling: targets for improving agronomic performance of crops. Plant and Cell Physiology 61 , 1902-1911.32761079 Gonzalez-Grandio E , Poza-CarrionC, SorzanoCO, CubasP. 2013. BRANCHED1 promotes axillary bud dormancy in response to shade in Arabidopsis. The Plant Cell 25 , 834-850.23524661 Ito S , YamagamiD, UmeharaM, et al . 2017. Regulation of strigolactone biosynthesis by gibberellin signaling. Plant Physiology 174 , 1250-1259.28404726 Kelly JH , TuckerMR, BrewerPB. 2023. The strigolactone pathway is a target for modifying crop shoot architecture and yield. Biology 12 , 95.36671787 Kertesz Z , FlinthamJE, GaleMD. 1991. Effects of Rht dwarfing genes on wheat grain yield and its components under Eastern European conditions. Cereal Research Communications 19 , 297-304. Ni J , GaoC, ChenMS, PanBZ, YeK, XuZF. 2015. Gibberellin promotes shoot branching in the perennial woody plant Jatropha curcas. Plant and Cell Physiology 56 , 1655-1666.26076970 Tong H , JinY, LiuW, LiF, FangJ, YinY, QianQ, ZhuL, ChuC. 2009. DWARF AND LOW-TILLERING, a new member of the GRAS family, plays positive roles in brassinosteroid signaling in rice. The Plant Journal 58 , 803-816.19220793 Waldie T , LeyserO. 2018. Cytokinin targets auxin transport to promote shoot branching. Plant Physiology 177 , 803-818.29717021 Wang Y , SunS, ZhuW, JiaK, YangH, WangX. 2013. Strigolactone/MAX2-induced degradation of brassinosteroid transcriptional effector BES1 regulates shoot branching. Developmental Cell 27 , 681-688.24369836 Xia X , DongH, YinY, et al . 2021. Brassinosteroid signaling integrates multiple pathways to release apical dominance in tomato. Proceedings of the National Academy of Sciences, USA 118 , e2004384118. Zhang J , MazurE, BallaJ, et al . 2020. Strigolactones inhibit auxin feedback on PIN-dependent auxin transport canalization. Nature Communications 11 , 3508. |
Case Rep Orthop Case Rep Orthop CRIOR Case Reports in Orthopedics 2090-6749 2090-6757 Hindawi 10.1155/2023/8626419 Case Report Surgical Management of Latissimus Dorsi and Teres Major Tears in a Water-Skiing Injury: A Case Report and Literature Review Constantinou Demitri [email protected] 1 Kastanos Konstantinos 2 1Department of Exercise Science and Sports Medicine, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa 2Linksfield Orthopaedic, Sport and Rehabilitation Centre, Netcare Linksfield Hospital, Johannesburg, South Africa Academic Editor: John Nyland 2023 8 12 2023 2023 862641916 5 2023 5 10 2023 21 11 2023 Copyright (c) 2023 Demitri Constantinou and Konstantinos Kastanos. 2023 This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Tears of the latissimus dorsi and/or teres major tendons are uncommon, with no definitive management. Surgical repair has been reported in high-level athletes, mostly in baseball players. Simultaneous tears of both latissimus dorsi and teres major tendons are rare, with little known of surgical intervention outcomes. We report on the first published case of surgical repair of both latissimus dorsi and teres major tendon tears from a water-skiing injury in a 45-year-old male with favorable outcomes. SANLiC Gold pmc1. Introduction The latissimus dorsi (LD) muscle is the largest muscle in the upper body and functions to internally rotate and move the arm inferiorly and posteriorly and extend the shoulder medially, whilst drawing the shoulder downward and backward . The teres major (TM) muscle functions in opposition to the muscles comprising the rotator cuff by extending the arm when it is in the flexed position and rotating it medially . Simultaneous injuries to both the LD and TM tendons are rare. Those that have been reported are primarily in high-level athletes and mostly in professional baseball pitchers [2-4]. There are reports of favorable outcomes in recreational athletes of nonsurgical management, including nonsurgical management in a novice golfer who made good recovery following avulsion of LD and TM tendons. In elite athletes, some authors have suggested primary tendon repair to improve function and retrain to sport sooner . There is a sparsity of data on surgery for injuries of both tendons. This case report is the first, as far as the authors are aware, of a water-skiing injury with tears of both the latissimus dorsi and teres major tendons and in which surgical repair was performed. 2. Case Report A right-hand dominant 46-year-old male with no significant medical history sustained an injury whilst being pulled out of the water when water-skiing. He felt acute pain in his left shoulder, accompanied by an audible snap. He reported an immediate loss of function in his shoulder. Over the next week, he had an audible click and pain with movement, and although he showed slight improvement in pain, he sought medical attention due to continued dysfunction. Clinical examination revealed a good range of motion of both passive and active flexion (140deg), extension (50deg), abduction, internal rotation (thumb to T6), and external rotation (50deg) with no neurological deficit. There was pain with active shoulder adduction and with internal rotation against resistance and pain inhibition of these affected movements (strength 2/5). An MRI scan with postgadolinium arthrogram was performed. This suggested a type II SLAP lesion and complete tear of the latissimus dorsi tendon insertion onto the humerus . There was no associated bone avulsion visible. The teres major tendon injury was not obvious on the scan as a separate injury, even with retrospective review, perhaps due to the tendon injury being at the junction of the larger LD tendon. Due to the rarity of the injury, there is no established superlative treatment approach; the treatment options were discussed with the patient. Both surgical management and nonsurgical management were considered including rehabilitation, levels of activity, risks and benefits, and possible outcomes. In relation to surgical repair, neurological harm and other potential surgical complications were detailed to the patient. Based on this, the patient made the informed choice to have surgical intervention with primary repair of the torn tendon. At surgery , in the right decubitus position, a posterior axillary fold chevron incision was made. The LD was identified, and lack of tension in the tendon was noted. The tendon was followed proximally. Bruising and oedema were noted. To allow retraction of the triceps and teres minor tendons, the shoulder was abducted and internally rotated. A contained haematoma was encountered, which was evacuated. Complete rupture of both the LD and TM tendons were recognised. The tendon margins were debrided. The bare insertion at the humerus was readily palpable and visible and was debrided. Repair of the combined tendon mass was performed with ORTHOCORDTM (DePuy Mitek, Massachusetts, United States) Mason-Allen sutures and ArthrexTM Pec Buttons (Munich, Germany). Three of these constructs were inserted. The repair was readily achievable. The surgical site was thoroughly irrigated out and haemostasis confirmed. Layered closure was performed using absorbable sutures. A padded dressing was applied and shoulder immobilisation achieved with a sling. Postoperative transcapular radiological views revealed the in situ anchor devices and mild posterior subluxation of the humerus head . At 4-week postoperative follow-up consultation, the patient did not report any problems. He confirmed compliance with using the sling. The skin wound was clean, and there were no neurological injury signs. He was advised to continue with light activities of daily living and referred for physiotherapy, targeting scapula movement and range of motion. This included warm-up, active range of motion (ROM) of upper limb, passive ROM in forward flexion, elevation in scapula plane, and external rotation. Rehabilitation progressed from week 6 with passive ROM in forward elevation to 90deg and external rotation to 30deg. At 5 months after initial physiotherapy, the patient had undergone final phase rehabilitation with strengthening of deltoid, periscapular muscles, internal and external rotation, biceps, and triceps all in supine and lying position and progressed to standing/seated positions. He was satisfied with his functional progress. The latissimus dorsi and teres major mass was palpably active. Active shoulder elevation reached 140deg, external rotation to 50deg, and internal rotation thumb to T8. There was no clinical weakness. He was referred progressive return to sport rehabilitation with progression to return to swimming. At 32 months, he reported being pleased with the outcome of the procedure. Activities of daily living had normalised. The patient had returned to exercising in the gym without any difficulty, except for pull-ups, which he self-restricted. He had successfully returned to open water swimming (1-mile event). Examination revealed symmetrical posterior axillary fold contour and bulk. Left scapula stability was paradoxically better than the right, probably due to asymmetrical rehabilitation. 3. Discussion Water-skiing injuries are primarily reported as being traumatic and include falls, propeller-related incidents, and injuries of the lower limb . Most reported tendon injuries are of the hamstring muscle . Erickson et al. reported on 11 baseball players that underwent surgical repair of latissimus dorsi and/or teres major. They did not, however, report how many of those had injuries of both the latissimus dorsi and teres major tendons. They did report that all 11 returned to their athletic activities postsurgery. Donohue et al. , in a review, reported 55 injuries of LT and/or TM tendons with 32 in baseball. Only 3 were of both tendons (2 in baseball and 1 in golf). They described that 5 cases were injuries from water-skiing, of which 3 were of the latissimus dorsi tendon and 2 of the teres major tendon. None was both latissimus dorsi and teres major tendon tears. In that report, two of the latissimus dorsi water-skiing injuries were surgically repaired. They further reported in their review that "all patients eventually return to play with full range of motion and full subjective strength." In light of our case, in those patients of isolated LT or TM tears that were treated nonsurgically, one needs to consider injuries to both tendons that have been missed clinically and on MRI scans. Surgical management and nonsurgical management have been reported , with nonsurgical management sufficing for latissimus dorsi injuries, particularly for recreational athletes . The only reported cases of isolated teres major tears in professional ice hockey players were treated nonsurgically with rapid return to activity. There are no randomized studies to compare outcomes of surgical versus nonsurgical management. Other reports of surgical repair are with chronic latissimus dorsi tear-related degenerative pathology and not traumatic. The latissimus dorsi and teres major musculotendinous complex contributes to complex shoulder functions; particularly, they together extend the arm and rotate it internally. Although rare, injuries to either of these structures have been reported, more so of the latissimus dorsi. These occur mostly in baseball players with few occurrences of both tendon ruptures occurring simultaneously. Injuries reported include a partial tear of latissimus dorsi in water-skiing and two cases (servicemen) with latissimus dorsi tendon avulsion, which were managed nonoperatively. Surgical repair in a water-skier for acute latissimus dorsi avulsion has been reported . Surgical repair for a complete LD tendon tear in a semiprofessional rock climber was reported with good outcomes and return to rock climbing at 9 months with continued improvement at 16 months . A 38-year-old male competitive slalom water-skier had a LD tendon tear repaired with suture anchors, with postsurgery isokinetic testing showing total work performance not only restored but better in comparison to the nonoperated shoulder. Our patient likewise exhibited clinical stability better than the uninjured side at 32-month follow-up. This is likely due to the compliance and concerted effort of rehabilitation of the injury. The first water-skiing injury with the uncommon isolated tear of TM was reported by Maldjian et al. . There have been reports of nonoperative management of isolated TM tendon tear in water-skiers. The mechanism of these injuries was all related to the arms being pulled forward as the boat accelerated. This was in keeping with the reported mechanism of injury in our patient. However, to date, no combined traumatic LD and TM tendon tears have been reported in water-skiing and undergoing surgical repair. In our case, an injury whilst water-skiing presented clinically with dysfunction and signs suggestive of LD rupture. The injury occurred when being extracted from the water, a process known to exert substantial forces (equivalent to one and a half times the body weight) on the upper extremities . Takeoff forces transmitted to the upper extremity during water-skiing (Orthopedics, 26 (7), 707-710). Maldjian et al. postulated the anatomic and kinematic factors of shoulder extensor (teres major and latissimus dorsi) injuries in water-skiing. To resist the force of the held rope tightening as the boat accelerates, these extensors oppose flexion of the upper limb. The teres major is at greater risk, due to its insertion further away from the axis of rotation and inferior to the rotator cuff, where a greater force acts on it, and in a stretched position, when the arm is flexed. The rotator cuff exhibits less constraint in that position. They further postulated that although the insertion of latissimus dorsi is anatomically close to that of teres major, it is less at risk due to its larger size. This suggests that in our patient, significant forces were at play to result in tears of both tendons. The suspected latissimus dorsi tear was confirmed by MRI, but at surgery grade 3, tears of both latissimus dorsi and teres major tendons were evident. Of 5 cases in the literature of similar injuries, caused by activities other than water-skiing, 2 were treated surgically. It is known that some tendon injuries require surgery to restore function and include quadriceps tendon (common in over 40 year olds), patellar tendon, peroneal tendon, Achilles tendon, and hip abductors. Surgical outcomes are positive with repairs of rotator cuff, pectoralis major tendons, and subscapularis. Outcomes for tendon repairs vary depending on whether they are traumatic or degenerative, and there may be age-dependent variables. It has been shown that shoulder tendon repairs in under 40 year olds performed arthroscopically recover adequate function. Our patient was over 40 years old at the time of injury and, after discussion of options, opted for surgery. The surgical procedure was technically without complication; the patient was compliant and underwent graded return to activities whilst undergoing rehabilitation. The intermediate-term postoperative course was uneventful. As improvement may be expected beyond 16 months , our patient was followed up to 32 months. The limitations of this case include that it is just one case study, and outcomes of other interventions or management are unknown. 4. Conclusion Surgical repair of combined latissimus dorsi and teres major tears in a 45-year-old with a water-skiing accident was technically feasible, with good medium-term clinical and functional outcomes. Future possible studies are required including need of further comparison of surgical vs. nonsurgical outcomes of these injuries in elite athletes as well as in the general population. Acknowledgments The authors are grateful to the patient for granting permission to use his case and intraoperative photographs. Open Access funding was enabled and organized by the SANLiC Gold. Data Availability The data used to support the findings of this study are restricted by the Wits Human Research Ethics Committee (Medical) in order to protect patient privacy. Data are available from Demitri Constantinou ([email protected]) for researchers who meet the criteria for access to confidential data. Conflicts of Interest The authors have no conflicts of interest relevant to this article. Figure 1 Magnetic resonance imaging coronal view demonstrating disruption and fluid accumulation at insertion of right latissimus dorsi tendon. Figure 2 Magnetic resonance imaging axial view demonstrating disruption of right latissimus dorsi tendon. Figure 3 Surgical exposure revealing tears in latissimus dorsi and teres major tendons. The top of the picture is proximal, the bottom left is distal arm (covered by stockinette), and the right-hand side is medial. Figure 4 At surgery, tears of both latissimus dorsi and teres major were identified. The top of the picture is the proximal arm, the bottom is distal, and the right-hand side is medial. Figure 5 Postoperative radiography demonstrating anchor placements. 1 Jeno S. H. Varacallo M. Anatomy, back, latissimus dorsi StatPearls 2023 Treasure Island (FL) StatPearls Publishing 2 Donohue B. F. Lubitz M. G. Kremchek T. E. Sports injuries to the latissimus dorsi and teres major American Journal of Sports Medicine 2017 45 10 2428 2435 10.1177/0363546516676062 2-s2.0-85026802144 28125914 3 Erickson B. J. Chalmers P. N. Waterman B. R. Griffin J. W. Romeo A. A. Performance and return to sport in elite baseball players and recreational athletes following repair of the latissimus dorsi and teres major Journal of Shoulder and Elbow Surgery 2017 26 11 1948 1954 10.1016/j.jse.2017.05.015 2-s2.0-85021789337 28689823 4 Schickendantz M. S. Kaar S. G. Meister K. Lund P. Beverley L. Latissimus dorsi and teres major tears in professional baseball pitchers: a case series American Journal of Sports Medicine 2009 37 10 2016 2020 10.1177/0363546509335198 2-s2.0-70649090044 19541846 5 Hummel G. Gainor B. J. Waterskiing-related injuries American Journal of Sports Medicine 1982 10 4 215 218 10.1177/036354658201000405 7125042 6 Sallay P. I. Friedman R. L. Coogan P. G. Garrett W. E. Hamstring muscle injuries among water skiers: functional outcome and prevention American Journal of Sports Medicine 1996 24 2 130 136 10.1177/036354659602400202 2-s2.0-0029925665 8775108 7 Henry J. C. Scerpella T. A. Acute traumatic tear of the latissimus dorsi tendon from its insertion: a case report American Journal of Sports Medicine 2000 28 4 577 579 10.1177/03635465000280042301 2-s2.0-0033854638 10921654 8 Livesey J. P. Brownson P. Wallace W. A. Traumatic latissimus dorsi tendon rupture Journal of Shoulder and Elbow Surgery 2002 11 6 642 644 10.1067/mse.2002.126212 2-s2.0-0041846883 12469095 9 Maldjian C. Adam R. Oxberry B. Chew F. Kelly J. Isolated tear of the teres major: a waterskiing injury Journal of Computer Assisted Tomography 2000 24 4 594 595 10.1097/00004728-200007000-00014 2-s2.0-0034466481 10966192 10 Keverline J. P. Englund R. Cooney T. E. Takeoff forces transmitted to the upper extremity during water-skiing Orthopedics 2003 26 7 707 710 10.3928/0147-7447-20030701-15 12875566 |
Case Rep Hematol Case Rep Hematol CRIHEM Case Reports in Hematology 2090-6560 2090-6579 Hindawi 10.1155/2023/1691996 Case Report Spontaneous Hyphema during Ibrutinib Treatment in a CLL Patient Aldecoa Kim Abbegail Tan [email protected] 1 2 Macaraeg Chef Stan L. 3 Dadlani Akash 1 4 Yadlapalli Sri 5 1Department of Internal Medicine, Trinity Health Oakland, Pontiac, MI, USA 2Wayne State University, Detroit, MI, USA 3University of Connecticut, Farmington, CT, USA 4Ross University School of Medicine, Bridgetown, Barbados 5Department of Hematology and Oncology, Trinity Health Oakland, Pontiac, MI, USA Academic Editor: Pier Paolo Piccaluga 2023 14 12 2023 2023 169199613 10 2023 28 11 2023 29 11 2023 Copyright (c) 2023 Kim Abbegail Tan Aldecoa et al. 2023 This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Ibrutinib is an oral, first-line, targeted therapy for chronic lymphocytic leukemia (CLL). Commonly reported adverse events are diarrhea, fatigue, and musculoskeletal pain, but rarely it has been associated with visual disturbances. Here, we present a rare case of spontaneous hyphema in a 60-year-old patient with a known diagnosis of CLL on ibrutinib treatment. pmc1. Introduction Targeted therapy for cancer treatment is becoming popular because of less toxic side effects than conventional chemotherapy. Ibrutinib is a medication that blocks the activity of a protein called Bruton's tyrosine kinase (BTK) and is primarily used as a first-line agent for treating chronic lymphocytic leukemia (CLL). It is also used for other disorders, including Waldenstrom's macroglobulinemia, and previously treated chronic graft versus host disease . By binding irreversibly to BTK, which is essential for replication and spread in B cell cancers, ibrutinib prevents the downstream effects of BTK. In the product information for ibrutinib, adverse events were analyzed across clinical trials, revealing that among treated CLL patients, common side effects occurred in >=30% of the cases. These include thrombocytopenia, diarrhea, fatigue, musculoskeletal pain, neutropenia, rash, anemia, bruising, and nausea . Bleeding events, encompassing bruising and petechiae, were also prevalent, occurring in 39% of the cases, although the underlying mechanism remains unclear . Visual disturbances have infrequently been reported, with limited case reports and case series available in the literature . The study aims to present a rare ocular side effect associated with ibrutinib. 2. Case Presentation The patient is a 60-year-old Caucasian woman with CLL, on ibrutinib treatment 420 mg daily for four months. Her past medical history included hypothyroidism on levothyroxine and chronic complex regional pain syndrome on medical marijuana. She has no family history of blood disorders. She presented to the emergency department (ED) with a 1-day history of visual disturbance described as a "smudge on her glasses." She denied any pain or trauma to the eye. Physical examination was significant for left eye hyphema at the 6 o'clock position ). There were no other obvious signs of bruises or bleeding noted. Complete blood count (platelet count 189,000/mL), prothrombin time, and activated partial thromboplastin time were unremarkable. Computed tomography of the head showed intact globes without conspicuous intraocular hemorrhage or foreign body. Ophthalmology was consulted. Her visual acuity was 20/20 on the right eye and 20/25 on the left eye. Tonometry in the ED showed intraocular pressure of 4-6 mmHg in the left eye and 5-7 mmHg in the right eye. A Seidel test with a fluorescein dye was also carried out, which did not reveal any corneal or scleral defect. Oncology was consulted, and ibrutinib was discontinued. She was discharged on prednisolone 1% four times daily, timolol 0.25% twice daily, and cyclopentolate hydrochloride 1% eye drops twice daily. On a two-day follow-up with the ophthalmologist, the patient is still complaining of intermittent blurring of vision, but it has improved. A slit lamp exam revealed a 1 x 1 mm blood clot at the 6 o'clock position of the anterior chamber of the left eye. Fundus examination, tonometry (12 mmHg right eye and 13 mmHg left eye), pupillary exam, and visual fields were unremarkable. She was advised to continue using prednisolone 1% eye drops for the next two weeks. Timolol was discontinued. Symptoms resolved completely at a two-week follow-up ). Although there was no life-threatening reaction, after careful consideration and discussion with the patient, a decision was made to switch to different chemotherapeutic agents (bendamustine and rituximab) due to concerns about the potential recurrence of hyphema. Fortunately, there were no further occurrences of hyphema following the change in medication. 3. Discussion Hyphema is a condition where there is blood collection in the eye's anterior chamber from disruption of the vessels of the iris or ciliary body. The most common cause is blunt trauma, but it can occur spontaneously or after minor trauma in patients with bleeding tendencies . Risk factors for spontaneous hyphema include neovascularization from uncontrolled diabetes mellitus, clotting disorders, medications that act as anticoagulants, or those that inhibit platelet function . None of these are present in our patient. Ibrutinib generally has a safe ophthalmologic profile, although there have been increasing isolated ocular toxicities reported recently. This includes red or dry eyes, blurred vision, subconjunctival hemorrhage, uveitis, branch retinal artery occlusion, and cystoid macular edema, and the development of cataracts has been identified [2, 5-9]. Table 1 summarizes the ocular side effects reported in a few case studies. The reason for ocular disturbances associated with ibrutinib is still unclear, but several mechanisms have been suggested. One case report showed a patient experiencing a spontaneous hyphema, which Bohn and colleagues attributed to ibrutinib's deficiency in platelet adhesion . Levade et al. found in vitro evidence that ibrutinib reduces platelet adhesion to von Willebrand factor and platelet aggregation induced by collagen , supporting this hypothesis. Compared to other BTK inhibitors, ibrutinib was reported to carry a higher risk of bleeding due to its angiogenesis inhibition and stronger cytotoxic effect on endothelial cells . It is worth noting that our patient's platelet counts and bleeding parameters were normal. In addition, uveitis is a more common visual disturbance reported with ibrutinib, as shown in Table 1. This could be due to ibrutinib's off-target effect on mitogen-activated protein kinase kinase (MEK) protein, which is responsible for protecting the eyelids, conjunctiva, and cornea. The inhibition of MEK protein may lead to inflammation and uveitis by dysregulation of tight junctions of the endothelial cells of the ciliary body, which may contribute to inflammation leading to uveitis . Furthermore, the inhibition of these protein kinases has been shown to trigger a Th1 proinflammatory response and autoimmune phenomenon . Other kinase inhibitors have also been reported to cause nonspecific visual toxicities, such as anaplastic lymphoma kinase (ALK) inhibitors, epidermal growth factor receptor (EGFR) inhibitors, MEK inhibitors, FMS-like tyrosine kinase 3 (FLT3) inhibitors, and other tyrosine kinase inhibitors, including ibrutinib and acalabrutinib . Since the mechanism is still unclear for visual disturbances associated with ibrutinib, treatment has been limited to case reports and case series. Most patients have complete resolution of symptoms upon discontinuation of ibrutinib and topical steroid eye drops (as shown in Table 1), similar to our patient. Some case studies have reported changing to different chemotherapeutic agents after discontinuation of ibrutinib , while others have restarted ibrutinib after their symptoms have resolved . 4. Learning Points/Conclusion The resolution of the patient's hyphema upon discontinuation of ibrutinib treatment suggests a causative link. Our research highlights the occurrence of spontaneous hyphema as another potential ocular toxicity of ibrutinib. As targeted immunotherapies become more common in the treatment of hematologic malignancies, it is important to remain vigilant for such ocular toxicities as they may become more common in the future. A more comprehensive understanding of the cellular and biochemical processes associated with these treatments is still necessary as the mechanism is still unclear. Lastly, it is essential to be aware of possible ocular toxicities associated with this first-line immunotherapy and to discontinue the drug early, if necessary, to prevent catastrophic consequences. Acknowledgments We would like to express our gratitude to Dr Shawn Gappy, the ophthalmologist for providing the pictures in this study. Abbreviations BTK: Bruton's tyrosine kinase CLL: Chronic lymphocytic leukemia ED: Emergency department MEK: Mitogen-activated protein kinase kinase ALK: Anaplastic lymphoma kinase FLT3: FMS-like tyrosine kinase 3. Data Availability Additional information for this study is available upon reasonable request. Consent Written informed consent was obtained from the patient including the images used in this study. Conflicts of Interest The authors declare that they have no conflicts of interest. Authors' Contributions Kim Abbegail Aldecoa, Akash Dadlani, and Sri Yadlapalli were directly involved in patient's care. Kim Abbegail Aldecoa, Chef Stan L. Macaraeg, and Akash Dadlani wrote, reviewed, and edited the original draft of the manuscript. Sri Yadlapalli supervised the manuscript. Figure 1 Left eye showing (a) 1 x 1 mm blood clot on presentation (red arrow) and (b) resolution on a two-week follow-up. Table 1 Summary of ocular findings observed with ibrutinib. Reference Age (years) Duration of ibrutinib treatment Initial symptoms Ophthalmologic findings Treatment Outcome Bohn et al. 65 1 day Bilateral blurring of vision Uveitis Ibrutinib discontinued; significant improvement after local and oral steroids Clinical improvement Bohn et al. 64 9 months 1-week blurring of vision and photophobia, with 3-day hyphema Uveitis Responded poorly with local steroids while continuing ibrutinib and with significant improvement when ibrutinib was discontinued Clinical improvement Chiu et al. 60 1 year Bilateral increase in floaters Uveitis Ibrutinib continued; resolved with topical steroids Clinical improvement Chiu et al. 63 2 years Left eye floaters Uveitis and cystoid macular edema Ibrutinib continued; responded well with topical and oral steroids initially, but with relapses of uveitis with cystoid macular edema Clinical improvement, but with relapses Chiu et al. 69 1 year and 6 months Right eye loss of vision and floaters Uveitis Ibrutinib was discontinued temporarily but restarted after a trial of topical and IV steroids Clinical improvement Chiu et al. 66 3 years 3-week history of bilateral floaters Uveitis Ibrutinib continued; responded well with topical steroids Clinical improvement Saenz-de-Viteri and Cudrnak 67 4 weeks 4-week history of bilateral blurry vision Cystoid macular edema Ibrutinib continued at a normal dose; responded well with topical steroids and NSAIDS Clinical improvement Ben-Avi et al. 73 Over 3 years Left eye decreased in vision Cystoid macular edema Ibrutinib was discontinued; responded well with topical steroids and NSAIDS Clinical improvement Kolomeyer et al. 75 6 months Blurring of vision after cataract surgery Anterior chamber fibrinoid syndrome after cataract extraction Unknown if ibrutinib was continued; responded well with topical steroids after 2 weeks Clinical improvement 1 Pharmacyclics Imbruvica [package Insert] 2014 Sunnyvale, CA, USA Pharmacyclics, Inc 2 Chiu Z. K. Goh J. K. Ling C. Lin M. L. Hall A. J. Ibrutinib-related uveitis: a case series American Journal of Ophthalmology Case Reports 2022 25 101300 10.1016/j.ajoc.2022.101300 3 Davis M. E. Ocular toxicity of tyrosine kinase inhibitors Oncology Nursing Forum 2016 43 2 235 243 10.1188/16.onf.235-243 2-s2.0-84962179632 26906134 4 Gragg J. Blair K. Baker M. B. Hyphema [Internet] 2022 St. Petersburg, FL, USA StatPearls Publishing 5 Byrd J. C. Brown J. R. O'Brien S. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia New England Journal of Medicine 2014 371 3 213 223 10.1056/nejmoa1400376 2-s2.0-84904252369 24881631 6 Kunkler A. L. Binkley E. M. Mantopoulos D. Known and novel ocular toxicities of biologics, targeted agents, and traditional chemotherapeutics Graefes Archive for Clinical and Experimental Ophthalmology 2019 257 8 1771 1781 10.1007/s00417-019-04337-8 2-s2.0-85066031432 7 Bohn M. Bravo-Ljubetic L. Lee R. W. J. Petrushkin H. Ibrutinib-related uveitis: a report of two severe cases European Journal of Ophthalmology 2022 32 4 Np94 NP97 10.1177/11206721211001268 8 Saenz-de-Viteri M. Cudrnak T. Bilateral cystoid macular edema in a patient with chronic lymphocytic leukemia treated with ibrutinib Leukemia and Lymphoma 2019 60 3 842 844 10.1080/10428194.2018.1508673 2-s2.0-85053336331 30188238 9 Ben-Avi R. Dori D. Chowers I. Cystoid macular edema secondary to ibrutinib American Journal of Ophthalmology Case Reports 2022 26 101436 10.1016/j.ajoc.2022.101436 10 Kolomeyer A. M. Hwang C. K. Kim B. J. Anterior chamber fibrinoid syndrome after cataract extraction in a patient on ibrutinib for B-cell chronic lymphocytic leukemia: a case report and review of the literature Journal of Medical Case Reports 2018 12 1 p. 349 10.1186/s13256-018-1822-9 2-s2.0-85056655380 11 Levade M. David E. Garcia C. Ibrutinib treatment affects collagen and von Willebrand factor-dependent platelet functions Blood 2014 124 26 3991 3995 10.1182/blood-2014-06-583294 2-s2.0-84919494922 25305202 12 Liu J. Liu Z. Zhang J. Ibrutinib inhibits angiogenesis and tumorigenesis in a BTK-independent manner Pharmaceutics 2022 14 9 p. 1876 10.3390/pharmaceutics14091876 13 Duncan K. E. Chang L. Y. Patronas M. MEK inhibitors: a new class of chemotherapeutic agents with ocular toxicity Eye 2015 29 8 1003 1012 10.1038/eye.2015.82 2-s2.0-84939131477 26043707 14 Niro A. Strippoli S. Alessio G. Sborgia L. Recchimurzo N. Guida M. Ocular toxicity in metastatic melanoma patients treated with mitogen-activated protein kinase kinase inhibitors: a case series American Journal of Ophthalmology 2015 160 5 959 967.e1 10.1016/j.ajo.2015.07.035 2-s2.0-84948719596 26231307 |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.49203 Internal Medicine Cardiology Radiology One Patient: Two Variants of Takotsubo Cardiomyopathy Muacevic Alexander Adler John R Almajed Mohamed Ramzi 1 Babwi Ahmed 1 Mohammed Mustafa 2 Gorgis Sarah 2 Azzo Zain 2 Parikh Sachin 2 1 Internal Medicine, Henry Ford Hospital, Detroit, USA 2 Cardiology, Henry Ford Hospital, Detroit, USA Mohamed Ramzi Almajed [email protected] 21 11 2023 11 2023 15 11 e4920319 11 2023 Copyright (c) 2023, Almajed et al. 2023 Almajed et al. This is an open access article distributed under the terms of the Creative Commons Attribution License CC-BY 4.0., which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from Takotsubo cardiomyopathy (TCM) is a form of non-ischemic cardiomyopathy that can present with signs of heart failure and volume overload; it often mimics acute coronary syndrome. It is characterized by stress-induced transient left ventricular (LV) dysfunction. Echocardiography classically demonstrates LV apical ballooning and akinesis in typical TCM, although other less common variants exist. Patients typically present with one variant. A 32-year-old woman with a past medical history of alcohol use disorder, anxiety, and hypertension presented to the hospital with chest pain, shortness of breath, nausea, vomiting, and diarrhea. She was diagnosed with cardiogenic shock in the setting of a newly identified LV ejection fraction (EF) of 24% on echocardiogram with findings consistent with typical apical TCM. Ischemic workup was unremarkable, and she was medically managed with clinical improvement and subsequent recovery of cardiac function. Four months later, the patient presented with similar symptoms at which time she was found to have a recurrence of heart failure with reduced LV EF; echocardiography showed reverse TCM. Patients with TCM who develop a recurrence typically maintain the same variant. The recurrence of TCM in a single patient with different anatomical variants is rare and poorly understood. We presented a case of a patient with alcohol use disorder who developed a recurrence of TCM with two anatomical variants. Further studies are necessary to investigate the predictors of recurrence and better understand the underlying mechanisms behind the different variants. stress-induced cardiomyopathy takotsubo cardiomyopathy stress-related cardiomyopathy double takotsubo reverse takotsubo atypical takotsubo typical takotsubo pmcIntroduction Takotsubo cardiomyopathy (TCM), or stress-induced cardiomyopathy, is a syndrome of cardiac dysfunction that was first described in 1990 by Sato et al. . It is characterized by transient regional left ventricular (LV) dysfunction with a severe reduction of ejection fraction (EF) in the absence of significant coronary artery disease. Clinical presentation is variable and most commonly involves chest pain or dyspnea [2-3]. Investigations often show electrocardiograms with features concerning myocardial ischemia and elevated cardiac biomarkers. Echocardiography shows a reduced LV EF with abnormal wall movement . Women are disproportionately affected as 90% of identified cases occur in post-menopausal women between the ages of 58 and 75 . The pathophysiology of TCM involves a stress-induced catecholamine surge, which causes myocardial dysfunction; physical and emotional stress are, therefore, inciting factors. Alternative causes of myocardial dysfunction including ischemia and myocarditis are ruled out to attribute the presentation to non-ischemic cardiomyopathy . TCM anatomical variants have been extensively described based on the LV site involved in echocardiography. Four distinct morphologies are reported by the International Takotsubo Registry, which includes apical or typical, midventricular, basal or reverse, and focal . The pattern of myocardial dysfunction involves a concentrated anatomic area that is not consistent with a single coronary artery territory. Recurrence of TCM is rare but remains higher than the incidence of TCM in the general population, which is estimated to be less than 1% . The incidence of recurrence has been reported in multiple studies and is variable; the largest multi-center study reports a 4% lifetime recurrence [9-12]. The time between the index episode and subsequent recurrence is variable. Risk factors for recurrence have not been clearly identified, although patients who experienced recurrence tended to be younger . Patients with TCM who develop recurrence of the condition typically maintain the same variant . The recurrence of TCM in a single patient with different anatomical variants is rare and poorly understood [11-12]. We present a case of a young woman with alcohol use disorder who experienced recurrent TCM with two distinct anatomical variants. Case presentation A 32-year-old woman presented with three days of chest pain, shortness of breath, nausea, vomiting, and diarrhea. She had a past medical history of primary hypertension, anxiety, and moderate alcohol use disorder. Physical exam was notable for bilateral lower limb swelling and tremors concerning alcohol withdrawal. Initial vital signs revealed tachycardia but were otherwise within normal limits. Laboratory investigations were significant for a lactate of 5.5 mmol/L (reference: <2.1 mmol/L) and an anion gap of 19, consistent with alcoholic ketoacidosis (Table 1). She had a high-sensitivity troponin I elevation with a peak of 10,995 ng/L (reference: <19 ng/L) and brain natriuretic peptide (BNP) of 970 pg/mL (reference: <50 pg/mL). An electrocardiogram showed sinus tachycardia with non-specific T-wave changes . Chest x-ray showed pulmonary vascular congestion with diffuse bilateral opacities concerning pulmonary edema . Limited bedside transthoracic echocardiogram noted a newly identified LV EF of 15%. Table 1 Laboratory investigations BNP, brain natriuretic peptide Laboratory Test (units) Patient's Result Reference Range Lactate (mmol/L) 5.5 <2.1 Anion Gap (N/A) 19 3-13 High-sensitivity Troponin I (ng/L) 10,995 <19 BNP (pg/mL) 970 <50 Figure 1 Electrocardiogram showing sinus tachycardia with non-specific T-wave changes Figure 2 Chest x-ray showing bilateral pleural effusions and pulmonary vascular congestion suggestive of pulmonary edema Chest radiograph annotated demonstrating bilateral pleural effusions (red arrows), cardiomegaly (blue arrow), and pulmonary vascular congestion (yellow arrow) The patient was initially admitted to the general medical unit where she was managed for presumed acute coronary syndrome, heart failure with reduced EF, and alcohol withdrawal. Her course was complicated by hemodynamic instability and acute hypoxia requiring intubation after which she was transferred to the cardiovascular intensive care unit. A complete transthoracic echocardiogram was notable for an LV EF of 24% with severe global hypokinesis of the majority of the LV wall with relatively preserved function of the basal wall segments . Right and left heart catheterizations demonstrated non-obstructive coronary artery disease and a cardiac index of 1.22 L/min/m2 . She was treated for cardiogenic shock due to non-ischemic cardiomyopathy with milrinone and norepinephrine and was placed on mechanical circulatory support with an intra-aortic balloon. Figure 3 Transthoracic echocardiogram in apical four-chamber view demonstrating the patient's first episode of TCM with apical variant morphology Apical TCM visualized in systole (1A) and diastole (1B) TCM, Takotsubo cardiomyopathy Figure 4 Coronary angiography showing the absence of obstructive coronary artery disease Absence of obstructive coronary artery disease visualized on coronary angiography in the RAO caudal view (2A) and LAO cranial view (2B) LAO, left anterior oblique; RAO, right anterior oblique Our patient had marked clinical recovery over the next three days, and she was weaned off hemodynamic support and extubated. A repeat echocardiogram three days later was notable for marked recovery in LV EF to 50% with mild hypokinesis of the LV basal inferior, anterior, mid-distal anteroseptal, and anterolateral walls. The diagnosis of apical variant TCM was made in the setting of these findings, and she was discharged on medical therapy for heart failure with a beta-blocker and angiotensin II receptor blocker (ARB). Repeat echocardiogram seven days and three months later showed normalization of cardiac function and a complete absence of LV wall motion abnormalities. Four months after the patient's initial presentation, she presented to the hospital with central chest pain that radiated to her left arm, diaphoresis, nausea, and tremulousness. She had stopped consuming alcohol for the past three days after having consumed six drinks of hard liquor daily the month prior. She had also been non-adherent to her medications. Vital signs revealed tachycardia and tachypnea but were otherwise within normal limits. Laboratory investigations were significant for a lactate of 4.5 mmol/L and an anion gap of 21. High-sensitivity troponin I and BNP were elevated at 8,894 ng/L and 111 pg/mL, respectively. The electrocardiogram showed non-specific T-wave changes. Transthoracic echocardiogram showed an LV EF of 38% with severe LV wall hypokinesis at the basal-to-mid LV wall segments in a noncoronary distribution; the apical wall segment was functioning normally . Heart catheterization was not performed given the low clinical suspicion of coronary obstruction and the unremarkable recent left heart catheterization. Figure 5 Transthoracic echocardiogram in apical four chamber view demonstrating the patient's second episode of TCM with reverse variant morphology Reverse TCM visualized in systole (3A) and diastole (3B) with basal hypokinesis (red arrow) and apical normal contraction (blue arrow) TCM, Takotsubo cardiomyopathy The clinical picture was consistent with a recurrence of TCM with this episode manifesting with a different variant, reverse TCM. Our patient was medically managed for TCM and alcohol withdrawal after which she had clinical improvement and was subsequently discharged. Discussion TCM is an uncommon diagnosis in patients thought to have acute coronary syndrome; it shares similar symptoms, electrocardiogram abnormalities including ST-segment changes, and cardiac biomarker elevation . The prevalence of TCM is estimated at 5.2 cases per 100,000 women and 0.6 cases per 100,000 men in the United States . Recurrence of TCM has been reported but remains rare given the prevalence rate; therefore, its risk factors and predictors remain unknown. The pathogenesis of TCM has been hypothesized in many studies but the exact mechanism remains unclear. Patients who develop TCM are likely to have a genetic predisposition to an exaggerated myocardial response to stress. Stress-induced activation of biochemical and hormonal pathways is thought to be at the center of this syndrome. Inflammatory and catecholamine-driven myocardial damage occurs due to resultant catecholamine toxicity, microcirculatory dysfunction, transient ischemia from plaque rupture, and epicardial spasm [2-3,15]. In our patient, her two episodes of TCM occurred in the setting of alcohol withdrawal during which she was likely experiencing a profound catecholamine-mediated stress response. TCM has been reported in the setting of alcohol withdrawal across several cases in the literature [16-18]. The stress-induced cardiomyopathy in our patient was likely triggered by alcohol withdrawal on two separate occasions. It is important to note that alcohol use can induce cardiomyopathy, and patients often present with decompensated heart failure; however, if alcohol-associated cardiomyopathy is the sole reason for the cardiomyopathy, the clinical presentation and workup will be discordant to that of TCM. Chronic alcohol ingestion leads to an imbalance of neurotransmitters GABA-A and glutamate, with longer use resulting in decreased sensitivity of the receptors. The immediate cessation of alcohol use results in a hyperadrenergic state with a high level of plasma catecholamines in the first few days of detoxification and an increase in beta-adrenergic receptor sensitivity . This physiologic stress and adrenergic surge can lead to myocardial stunning and transient cardiomyopathy. Our patient interestingly experienced two episodes of TCM in the setting of alcohol withdrawal during which she had two different variants of the syndrome. There have only been a few reported cases of multiple TCM variants in one patient [9-11]. Most previously reported cases occurred in women aged 50 years and older. Previous studies have hypothesized that a relative decline in estrogen levels is linked to TCM recurrence in postmenopausal women . Our patient was 32 years old at the time of her presentation, which suggests that other mechanisms could be contributing. Neurological and psychiatric disorders are consistent findings among these cases including our patient. Age trends among patients with TCM consistently demonstrate a low prevalence among young patients, which further increases the rarity of our case in which a young patient presented twice with two variants of this condition. An analysis of the InterTAK Registry revealed that among all reported cases of TCM, only 10% involved patients aged 50 years and younger . Among these younger patients, uncommon variants of TCM were disproportionately more common. Patients also had more severe presentations with a larger portion of them presenting with cardiogenic shock requiring advanced therapies for management including mechanical circulatory support. Moreover, this population had a higher prevalence of neurologic and psychiatric disorders, which supports prior observations and is consistent with our patient's clinical vignette. Based on the German Italian Spanish Takotsubo (GEIST) Registry, patients with recurrence had greater cardiovascular risk factors, but there was no significant difference in exposure to stressful events . The earliest time for recurrence was within eight days of the index episode, and the latest recurrence was 2555 days afterward. Most cases of recurrent TCM were in the form of apical TCM, with a minority having a midventricular form; there were no cases of recurrent basal or focal variants. Among recurrent cases, 20% had a variant that was discordant with the initial presenting variant. No predictive factors for recurrence were found, and the mechanism for this remains unclear. It remains unknown why some patients are predisposed to a recurrence of TCM with different morphologies and the mechanism for this change. Medical management of TCM has been associated with better outcomes and a decreased recurrence of TCM. The GEIST Registry noted a lower rate of recurrence in patients treated with a combination of a beta-blocker and an angiotensin-converting enzyme inhibitor (ACE-I) or ARB . Another systematic review and meta-analysis of recurrent TCM found that ACE-I and ARB therapy was associated with a decreased recurrence of TCM, although beta-blocker therapy was not . Moreover, patients with more severe initial presentations of TCM were more likely to develop recurrence. This finding is consistent with our case as our patient's index presentation was that of a cardiogenic shock. The clinical outcome of patients who develop TCM is favorable, as most patients experience a recovery in cardiac function, improvement in LV EF, and resolution of cardiac wall motion abnormalities . Despite her severe presentation and recurrent episodes of TCM, our patient had a complete resolution in symptoms and recovery in cardiac function on subsequent follow-up. Best practice regarding monitoring and medical management following an episode of TCM is unclear and requires further research and expert consensus. Conclusions Patients with TCM who develop a recurrence typically maintain the same variant. The recurrence of TCM in a single patient with different anatomical variants is rare and poorly understood. We presented a case of a patient with alcohol use disorder who developed a recurrence of TCM with two anatomical variants. This case highlights the need for further studies to investigate the predictors of recurrence and better understand the underlying mechanisms behind the different variants. Author Contributions Human Ethics Concept and design: Mohamed Ramzi Almajed, Mustafa Mohammed, Sarah Gorgis, Zain Azzo, Sachin Parikh Acquisition, analysis, or interpretation of data: Mohamed Ramzi Almajed, Ahmed Babwi, Mustafa Mohammed Drafting of the manuscript: Mohamed Ramzi Almajed, Ahmed Babwi, Mustafa Mohammed Critical review of the manuscript for important intellectual content: Mohamed Ramzi Almajed, Mustafa Mohammed, Sarah Gorgis, Zain Azzo, Sachin Parikh Supervision: Mustafa Mohammed, Sarah Gorgis, Zain Azzo, Sachin Parikh Consent was obtained or waived by all participants in this study The authors have declared that no competing interests exist. References 1 Tako-tsubo-like left ventricular dysfunction due to multivessel coronary spasm Clinical Aspect of Myocardial Injury: From Ischemia to Heart Failure Sato HT 56 64 1990 2 International expert consensus document on Takotsubo syndrome (part I): clinical characteristics, diagnostic criteria, and pathophysiology Eur Heart J Ghadri JR Wittstein IS Prasad A 2032 2046 39 2018 29850871 3 International expert consensus document on Takotsubo syndrome (part II): diagnostic workup, outcome, and management Eur Heart J Ghadri JR Wittstein IS Prasad A 2047 2062 39 2018 29850820 4 Clinical features and outcomes of Takotsubo (Stress) cardiomyopathy N Engl J Med Templin C Ghadri JR Diekmann J 929 938 373 2015 26332547 5 Apical ballooning syndrome (Tako-tsubo or stress cardiomyopathy): a mimic of acute myocardial infarction Am Heart J Prasad A Lerman A Rihal CS 408 417 155 2008 18294473 6 Natural history and expansive clinical profile of stress (Tako-tsubo) cardiomyopathy J Am Coll Cardiol Sharkey SW Windenburg DC Lesser JR 333 341 55 2010 20117439 7 Takotsubo cardiomyopathy: a unique cardiomyopathy with variable ventricular morphology JACC Cardiovasc Imaging Hurst RT Prasad A Askew JW III Sengupta PP Tajik AJ 641 649 3 2010 20541719 8 Apical and midventricular transient left ventricular dysfunction syndrome (Tako-tsubo cardiomyopathy): frequency, mechanisms, and prognosis Chest Kurowski V Kaiser A von Hof K 809 816 132 2007 17573507 9 Incidence and clinical impact of recurrent Takotsubo syndrome: results from the GEIST registry J Am Heart Assoc El-Battrawy I Santoro F Stiermaier T 0 8 2019 10 Clinical and echocardiographic analysis of patients suffering from recurrent Takotsubo cardiomyopathy J Geriatr Cardiol El-Battrawy I Ansari U Behnes M 888 13 2016 28133464 11 Four-year recurrence rate and prognosis of the apical ballooning syndrome J Am Coll Cardiol Elesber AA Prasad A Lennon RJ Wright RS Lerman A Rihal CS 448 452 50 2007 17662398 12 Natural history of Tako-tsubo cardiomyopathy Chest Parodi G Bellandi B Del Pace S 887 892 139 2011 20884730 13 Proposed Mayo Clinic criteria for the diagnosis of Tako-tsubo cardiomyopathy and long-term prognosis Herz Madhavan M Prasad A 240 243 35 2010 20582391 14 Prevalence of Takotsubo cardiomyopathy in the United States Am Heart J Deshmukh A Kumar G Pant S Rihal C Murugiah K Mehta JL 66 71 164 2012 22795284 15 Characterization of the myocardial inflammatory response in acute stress-induced (Takotsubo) cardiomyopathy J Am Coll Cardiol Basic Transl Sci Wilson HM Cheyne L Brown PA 766 778 3 2018 16 Takotsubo cardiomyopathy: a case report J Am Soc Echocardiogr Mitchell SA Crone RA 1190 1110 19 2006 17 An atypical case of "Takotsubo cardiomyopathy" during alcohol withdrawal: abnormality in the transient left ventricular wall motion and a remarkable elevation in the ST segment Intern Med Suzuki K Osada N Akasi YJ 300 305 43 2004 15168772 18 Takotsubo cardiomyopathy in the setting of acute alcohol withdrawal Hawaii J Med Public Health Stout BJ Hoshide R Vincent DS 193 194 71 2012 22787571 19 Alcohol withdrawal and noradrenergic function Ann Intern Med Linnoila M Mefford I Nutt D Adinoff B 875 889 107 1987 2825572 20 [Atypical acute myocardial ischemia syndrome with reversible left ventricular (LV) wall motion abnormalities ("apical ballooning") without significant coronary artery disease] Z Kardiol Glockner D Dissmann M Behrens S 156 161 93 2004 14963682 21 Age-related variations in Takotsubo syndrome J Am Coll Cardiol Cammann VL Szawan KA Stahli BE 1869 1877 75 2020 32327096 22 Systematic review and meta-analysis of incidence and correlates of recurrence of Takotsubo cardiomyopathy Int J Cardiol Singh K Carson K Usmani Z Sawhney G Shah R Horowitz J 696 701 174 2014 24809923 |
Arch Plast Surg Arch Plast Surg 10.1055/s-00051611 Archives of Plastic Surgery 2234-6163 2234-6171 Thieme Medical Publishers, Inc. 333 Seventh Avenue, 18th Floor, New York, NY 10001, USA 10.1055/s-0043-1771272 APS-22-Sep-0180-IDEA Research/Experimental Idea and Innovation High-Fidelity Perforator Visualization for Cadaver Dissection in Surgical Training Wong Allen Wei Jiat MBBS, MRCS 12 Kok Yee Onn MBBS, MRCS 12 Chew Khong Yik MBBS, MRCS 2 Tan Bien Keem MBBS, FRCS 2 1 Plastic Reconstructive and Aesthetic Surgery Service, Sengkang General Hospital, Singapore, Singapore 2 Department of Plastic Reconstructive and Aesthetic Surgery, Singapore General Hospital, Singapore, Singapore Address for correspondence Allen Wei-Jiat Wong, MBBS, MRCS Plastic Reconstructive and Aesthetic Surgery Service, Sengkang General Hospital110 Sengkang E Way, Singapore [email protected] 31 8 2023 11 2023 1 8 2023 50 6 621626 30 9 2022 15 6 2023 The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( ) 2023 The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In the first half of the third century B.C., Herophilus and Erasistratus performed the first systematic dissection of the human body. For subsequent centuries, these cadaveric dissections were key to the advancement of anatomical knowledge and surgical techniques. To this day, despite various instructional methods, cadaver dissection remained the best way for surgical training. To improve the quality of education and research through cadaveric dissection, our institution has developed a unique method of perforator-preserving cadaver injection, allowing us to achieve high-fidelity perforator visualization for dissection studies, at low cost and high efficacy. Ten full body cadavers were sectioned through the base of neck, bilateral shoulder, and hip joints. The key was to dissect multiple perfusing arteries and draining veins for each section, to increase "capture" of vascular territories. The vessels were carefully flushed, insufflated, and then filled with latex dye. Our injection dye comprised of liquid latex, formalin, and acrylic paint in the ratio of 1:2:1. Different endpoints were used to assess adequacy of injection, such as reconstitution of eyeball volume, skin turgor, visible dye in subcutaneous veins, and seepage of dye through stab incisions in digital pulps. Dissections demonstrated the effectiveness of the dye, outlining even the small osseous perforators of the medial femoral condyle flap and subconjunctival plexuses. Our technique emphasized atraumatic preparation, recreation of luminal space through insufflation, and finally careful injection of latex dye with adequate curing. This has allowed high-fidelity perforator visualization for dissection studies. Keywords cadaver high fidelity dissection perforator pmcIntroduction In the first half of the third century B.C., Herophilus and Erasistratus performed the first systematic dissection of the human body. 1 For subsequent centuries, these cadaveric dissections were key to the advancement of anatomical knowledge and surgical techniques. Meticulous lead oxide injection into cadavers enabled Ian Taylor to identify the now-classic angiosomes. 2 3 To this day, despite various instructional methods, cadaver dissection remained the best way for surgical training. 4 5 6 7 The quality of the injected cadavers would have a direct impact on the quality of dissection. Anatomical information could be obscured by leaked dyes, or simply lost to decomposition due to inadequate preservation. To improve the quality of education and research through cadaveric dissection, our institution has developed a unique method of perforator-preserving cadaver injection, allowing us to achieve high-fidelity perforator visualization for dissection studies, at low cost and high efficacy. This technique has allowed us to perform detailed research on anatomy as well as advanced training for our plastic surgery residents and fellows. Ideas Ten fresh full body cadavers were obtained from Science Care (Phoenix, USA) for the purpose of education and research. These bodies were thawed out to room temperature, so that the intraluminal spaces would not be obstructed by ice formation. Preparation of Cadavers via Subunits For better results, we sectioned the cadaver bodies into subunits, at the neck, shoulder, and hip joint. The resulting subunits of the head, trunk, and upper and lower limbs were prepared and injected separately, so that each subunit could be processed separately, to preserve in greater detail traits that were unique to each part. Identification and Cannulation of Main Pedicle The main perfusing arteries and draining veins for each section were dissected and identified. For the head and neck region, the main vessels were the carotid arteries, internal jugular veins, external jugular veins, vertebral arteries, and vertebral veins. For the upper limbs, the main vessels were brachial artery, radial artery, venae comitantes, axillary vein, and distal cephalic vein. For the torso, the main vessels were the subclavian artery, subclavian veins, external iliac artery, and external iliac vein. For the lower limbs, the main vessels were the superficial femoral artery, superficial femoral vein, great saphenous vein, posterior tibial artery, and its venae comitantes. If greater details were needed, we would need to separately process the superficial and deep venous system of each subunit. After identification and exposure of the pedicles, they would be cannulated with 18G intravenous cannulas in the anterograde and retrograde fashion. This would facilitate the next step of intraluminal preparation. Intraluminal Preparation After demise, the intraluminal contents of the cadaver would coagulate and form a physical barrier to injection. At the same time, the biological debris would act as a sponge sump, which would adsorb the dye and prevent a homogenous spread of dye. Therefore, it is critical to evacuate the intraluminal space for the best dye results. Saline infusion bags would be connected to the arteries and veins via the 18G intravenous cannula and elevated at 150 cm above the specimen ( Fig. 1 ). This would create a flushing pressure of 150 cm H 2 O, which would be equivalent to 110 mm Hg. This amount of pressure was chosen as it is physiological and would minimize trauma to the vessels, especially that of small perforators. Depending on the size of the body subunits, around 200 to 400 mL of saline would be used each. If performed correctly, an outflow of debris would be seen at the arteries and veins. If there were resistance or obstruction within the vessel, the saline flush would be performed for the arteries and veins in a retrograde fashion, to dislodge any remaining thrombus by flushing at it from the opposite direction. Fig. 1 Our laboratory setup for cadaver injection, with drip stands for infusion of the specimen. Next, using 20-mL Luer-lock syringes connected to the cannula, the arteries and veins were gently insufflated with air to recreate the intraluminal space for the dye. The relatively small size of the syringe would prevent overzealous injection that can cause high pressure. This insufflation of air served to splint vessels open so that there would be less resistance for the next step which would be the injection of latex dye. If done appropriately, one would see bubbling at the opposite end of the vessels. For example, after insufflating through the superficial femoral artery, one will see bubbling from the cannula inserted into the anterior tibia artery. Latex Dye Injection The injection dye formula comprised of a mixture of liquid latex (Castin' Craft Mold Builder Fields Landing, CA), 10% formalin, and acrylic paint (Daler-Rowney, United Kingdom), in the ratio of 1:2:1, respectively. These latex dyes were injected by hand through 20-mL syringes through the intravenous cannula of each vessel. We would use red dye for arteries and blue dye for veins. One could also inject different shades of colors between the superficial and deep venous system to demonstrate the unique territory that each perfused. For veins, injection was done in the anterograde fashion via the intravenous cannula, so that valves would not obstruct the flow of the viscous dye. For example, the dye would be injected vial the great saphenous vein or anterior tibial venae comitantes, from the distal end of the lower limb. Generally, the valves in the cadavers would still be impede retrograde flow, hence retrograde injection may result in excessive pressures that can damage the veins. The volume of latex dye required for each subunit would be approximately 100 to 150 mL of latex dye per arterial or venous vessel. Specific endpoints were observed to determine adequacy of preparation, such as the reconstitution of eyeball volume, restoration of skin turgor, and seepage of dye through skin pricks in the digital pulps ( Fig. 2 ). In thin cadavers, the dye could even be seen to perfuse through superficial veins under the skin. Fig. 2 Preparation of the right lower limb cadaveric specimen, showing the various injection cannulas placed into both the posterior tibial artery and veins. The picture on the right showed the endpoint of injection, where the dye could be seen from stab incisions in the toe pulps. Dye Fixation Deep freezing would be required for the latex dye to solidify and set, allowing easier handling of the tissue during dissection. If the latex dye was not fixed, it would tend to seep around the tissue during the dissection, obscuring fine anatomical details. To fix the latex dye, the cadavers were frozen at below 20 to 40degC for approximately 2 to 5 days. At this temperature range, musculoskeletal tissue could also be preserved for up to 6 months with minimal degradation. 8 Prior to leaving it in the freezer, tourniquets were tied at the open-ending stumps of the cadaveric subunit, to prevent seepage of the dye out of the cadaver. The intravenous cannula would be left in situ and capped to prevent leakage of the dye. It would not be advisable to remove the cannula as it would leave behind a puncture mark within the vessel. This puncture mark would not seal in a cadaver because it would not behave like living tissue, hence causing the dye to leak out from the vessels during fixation. By sealing the stumps and vessels, it would force the dye to stay within the lumen of the vessels, allowing maximal fill of the vessel for visualization with high fidelity. To utilize the cadavers after dye fixation, they would need to be removed from deep freeze (below 20degC), then thawed at 4degC for 48 hours, followed by another 12 hours at room temperature. Results A total of 10 full body cadavers were prepared and partitioned into subunits for preparation. The bodies were thawed at room temperature for 12 hours prior to injection. An average of 60 minutes was required for full preparation for one upper limb, and an average of 90 minutes was required for full preparation of one lower limb. After adequate period of dye fixation, the cadavers were dissected to evaluate the technique. The vascular trunk was well filled with latex dyes, from large named vessels to intramuscular branches and skin perforators. Even the small periosteal vessels of the medial femoral condyle periosteal flap could be seen ( Fig. 3 ). The latex also did not seep out or become too runny, maintaining the cleanliness of the dissection field ( Fig. 4 ). Fig. 3 Demonstration of the medial femoral condyle periosteal flap, showing good fill of the periosteal vessels that supply this flap. Fig. 4 Demonstration of the anterolateral thigh flap, with good fill of small perforators and low leak rate, keeping the dissection field clean and neat. Discussion Cadaver dissection remained as one of the best methods for surgical training. 5 Cadaver dissection would provide the most anatomically correct experience, including accurate tactile feedback to the learner. Such lessons could not be imparted by silicon or artificial models. Also, anatomical variances were random and unpredictable events. Only cadavers could recreate such anatomical variants that would be useful for training and research. Thus, short of vivisecting live patients, cadaver dissection would continue to be the best method for surgical training and research. Therefore, we required an easily reproducible method of dye injection that would best preserve the vessel quality, and visibility, down to the perforator level, allowing a high-fidelity visualization of anatomy. We would elaborate on key principles behind our cadaver injection technique below. Atraumatic Preparation of Cadavers First, the atraumatic preparation of the cadavers was key to the preservation of anatomical details. The first step was to partition the body into smaller manageable units. This avoided injection of the entire body at one go, which would have resulted in injection of large volumes at higher pressure. This would result in inadvertent damage to anatomical structures, especially that of finer caliber perforators. After death, organic debris would accumulate within the vessel lumens, preventing the latex dye from filing up the same space. A low-pressure saline flush would be required to clear these debris without damaging the vessels. If the vessels were damaged, the eventual latex dye would seep out and contaminate the surrounding tissue, making dissection a messy affair. Using saline bags elevated to 150 cm above the cadaver would produce a physiological pressure of approximately 110 mm Hg, reducing potential damage to the vessels. This simple application of physics would also obviate the need for injection pumps that are costly or avoid the use of special magnetic devices to push fluid along. 9 10 In the case of veins, the valvular patency has to be considered. Retrograde preparation and infusion of the vein may not be possible and could even rupture the vein due to the presence of valves. Hence, we advise anterograde preparation for veins, in the direction of distal limb toward proximal limb. Recreating Luminal Space with Insufflation After flushing the debris from the vessels, the lumen would tend to collapse due to low internal pressure. This would create high resistance in the vessel, which would require higher injection force to push the latex dye through. Doomernik et al even had to use an injection pressure that was equivalent to 2,000 cm H 2 O to inject their cadavers. 10 Such high pressure would certainly damage some vessels inadvertently. To minimize this damage, the air would need to be gently and smoothly injected via a 20-mL syringe, making sure to stop whenever there was excessive resistance. In vessels with excessive resistance, one would need to repeat the saline flushes to clear the intraluminal obstructions. The novel concept of air insufflation was not described before, but was key to allowing smooth, even latex dye injection. Latex Dye and Fixation Many different types of injection fluid had been attempted for cadaver preparation, including acrylic paint, latex, gelatin, silicon, Araldite F, and Batson's no. 17. 9 10 Acrylic paint, by itself, did not cure well, and tended to leak into surrounding tissue very easily. Gelatin was water-soluble but lost its color intensity fast. Liquid silicone was expensive but did not have good color intensity. Araldite F was too viscous in its liquid form, making injection difficult. Adding hardener to Araldite F also caused an exothermic reaction that even melted a plastic stirrer and three-way valve. 10 Batson's no. 17 was toxic and required a fumigation hood. Watanabe et al described a method of using magnetic dye 9 to help improve uptake of dye into the cadaver, but we found that such methods were expensive, and would be difficult to obtain. Latex was a cheap, water-soluble, flexible, and elastic product; hence, it was our preferred choice. To preserve the quality of the cadaver, we mixed latex with formaldehyde. To add color to the latex, we added acrylic paint. Our injection dye formula comprised of a mixture of liquid latex, formalin, and acrylic paint in the ratio of 1:2:1. We find this injection dye to be cheap, effective, and relatively nontoxic. To fix the latex dye, the cadavers are frozen at below 20 to 40degC for approximately 2 to 5 days. This temperature was chosen because it was also the temperature range recommended for storage of musculoskeletal allografts by the American Association of Tissue Banks, and it allowed for preservation without degradation for 6 months. 8 This would then serve the dual purpose of setting the latex dye and preserving the cadavers for high-fidelity visualization. The advantages of our injection technique lie in high-fidelity visualization of perforators, low cost, and easy replication in other institutions. Authors' Contributions Ethical Approval Patient Consent Conflict of Interest None declared. Cadavers were purchased from Science care, the United States. B.K.T. is an editorial board member of the journal but was not involved in the peer reviewer selection, evaluation, or decision process of this article. No other potential conflicts of interest relevant to this article were reported. A.W.J.W.: surgeon, design of study, data collection and analysis, interpretation of data, drafting the manuscript, approval of manuscript. Y.O.K.: surgeon, design of study, data collection, interpretation of data, drafting and revising the manuscript, approval of manuscript. K.Y.C.: data collection, interpretation of data, drafting and revising the manuscript, approval of manuscript. B.K.T.: interpretation of data, drafting and revising the manuscript, approval of manuscript. This was not required for the study. Since bodies were deceased and unidentified, consent was not necessary and not applicable. References 1 von Staden H The discovery of the body: human dissection and its cultural contexts in ancient Greece Yale J Biol Med 1992 65 03 223 241 1285450 2 Taylor G I Palmer J H The vascular territories (angiosomes) of the body: experimental study and clinical applications Br J Plast Surg 1987 40 02 113 141 3567445 3 Saint-Cyr M Wong C Schaverien M Mojallal A Rohrich R J The perforasome theory: vascular anatomy and clinical implications Plast Reconstr Surg 2009 124 05 1529 1544 20009839 4 Estai M Bunt S Best teaching practices in anatomy education: a critical review Ann Anat 2016 208 151 157 26996541 5 Singh M Sharma M Nair A G Cadaver dissection for oculoplastic procedures: a beginner's guide Indian J Ophthalmol 2022 70 09 3239 3244 36018092 6 Are C Stoddard H A Thompson J S Todd G L The influence of surgical demonstrations during an anatomy course on the perceptions of first-year medical students toward surgeons and a surgical career J Surg Educ 2010 67 05 320 324 21035773 7 Song Y K Jo D H Current and potential use of fresh frozen cadaver in surgical training and anatomical education Anat Sci Educ 2022 15 05 957 969 34538016 8 American Association of Tissue Banks AATB Standards for Tissue Banking. 14th edition McLean, VA American Assocation of Tissue Banks 2016 9 Watanabe K Tabira Y Saga T Novel cadaver injection method using latex and magnetic fluid Kurume Med J 2018 64 (1.2):39 43 29057759 10 Doomernik D E Kruse R R Reijnen M M Kozicz T L Kooloos J G A comparative study of vascular injection fluids in fresh-frozen and embalmed human cadaver forearms J Anat 2016 229 04 582 590 27329696 |
Arch Plast Surg Arch Plast Surg 10.1055/s-00051611 Archives of Plastic Surgery 2234-6163 2234-6171 Thieme Medical Publishers, Inc. 333 Seventh Avenue, 18th Floor, New York, NY 10001, USA 10.1055/s-0043-1771271 APS-23-Mar-0289-IDEA Pediatric/Craniomaxillofacial/Head & Neck Idea and Innovation A Fully Digital Auricular Splint Workflow for Post-Keloid Excision Maria Rahmat BDS, MDS, MRD, RCSEd 1 Kok Yee Onn MBBS, MRCS, MMed, MCI, FAMS (Plastic Surgery) 2 Teoh Khim Hean BDS, MDS, FRACDS, FAMS 3 1 Department of Restorative Dentistry, National Dental Centre of Singapore, Singapore, Republic of Singapore 2 Department of Plastic, Reconstructive and Aesthetic Surgery, Singapore General Hospital, Singapore, Republic of Singapore 3 Department of Restorative Dentistry, National Dental Centre of Singapore, Singapore, Republic of Singapore Address for correspondence Rahmat Maria, BDS, MDS, MRD, RCSEd National Dental Centre Singapore, 5 Second Hospital AveSingapore 168938Republic of [email protected] 31 8 2023 11 2023 1 8 2023 50 6 563567 23 3 2023 15 6 2023 The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( ) 2023 The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Ear keloids are challenging lesions to treat due to high recurrence rates postexcision. Conservative compression techniques as adjunct treatment have been reported to be effective. An innovative technique of using computer-aided design/computed-aided manufacturing to print a customized auricular splint improves efficiency and comfort level for patients compared with conventional methods. The ear is scanned using an intraoral scanning 2 weeks postsurgery. A two-piece auricular splint is designed on the digital model, incorporating perforated projections for three nylon screws for retention of the splint. The splint is printed with clear acrylic material, postprocessed, and finished. The patient is taught to assemble the components of the splint and instructed to wear for at least 8 hours daily. The surgery site reviewed for any ulceration, pain, or recurrence of keloid for 6 months. During the 6-month review, the excision scar remained flat and pink. The patient also reports unrestricted daily activities. The digital workflow increases comfort for the patient and reduces the number of hours required to produce a customized auricular splint compared with conventional methods. A fully digital workflow for a printed auricular splint should be considered for adjunctive treatment to excision of ear keloids. Keywords printed auricular splint digital workflow ear keloid pmcIntroduction Computer-aided design/computer-aided manufacturing is increasingly utilized in dentistry and a digital workflow can be extended to replace conventional methods of fabricating extraoral appliances. Keloids are challenging lesions to treat as they have a high recurrence after excision, regardless of technique. 1 2 After surgical excision, alternative adjunct procedures may include corticosteroid injections, cryotherapy, and radiation which are relatively invasive treatment options, especially for young patients. Compression auricular splints are efficacious in preventing keloid recurrence. It has been reported that 80 to 83% of patients had no recurrence after an 18-month follow-up. 3 Various methods of fabricating ear replicas and splints have been described in the literature, many being variations of the conventional oyster-splint design and workflow by Mercer and Studd. 4 A fully digital workflow involves scanning of the ear, digitally designing, and printing of the splint. This case report describes the workflow to fabricate an auricular splint to patient post-keloid excision ( Fig. 1 ). Fig. 1 Conventional and digital workflow. A summary of the fully digital workflow described, which entails fewer steps compared with the conventional workflow. The design and wax-up of splint requires detailed planning as there are two pieces to the splint and needs to be packed in two parts. Careful removal of the splint postpacking is required as the pieces are thin and are of nonuniform shapes. Idea A 21-year-old male presented with a keloid of unknown cause on his right ear. The keloid was excised and treated with intralesional steroid injections, silicone gel application, and an auricular splint ( Fig. 2 ). Fig. 2 Photos of the patient's ear. Photos of the patient's right ear ( A ) during consultation, ( B ) during surgery, and ( C ) 2 weeks postexcision of keloid. The photos show the size of the keloid and the outcome postsurgery. The patient was referred 2 weeks after excision of the keloid to the dental center. The steps for fabricating the splint were as follows: His right ear was scanned using a portable 3Shape Trios 3 Move+ intraoral scanner (3Shape, Copenhagen, Denmark). The scanning starts with the antitragus and moves superiorly via a horizontal motion along the helix, capturing from the antihelix to the posterior of the helix. From the superior of the external ear, the scanning continues medially to the inferior crus to the concha and then the antitragus to the anterior of lobule and finally, the posterior of the lobule. The intraoral scanner provides immediate feedback on captured images and missing areas can be recaptured easily. This technique can be utilized for majority of cases except when the scanner head is too large to capture the posterior of the external ear without moving the ear. This produced a digital model for subsequent steps. The three-dimensional (3D) model was transferred to the 3Shape Appliance Designer 2021 (3Shape) software where extensions were indicated on the digital model and a 2-mm-thick "shell" fabricated ( Fig. 3A ). This "shell" is the main body of the customized auricular splint which would later on be split into two and semicircular interlocking designs incorporated for intuitive fitting of pieces. At least three nylon screws are required to clamp the final two-piece auricular splint together. This is done by importing the "shell" body into Proplan CMF 3.0 software (Materialise NV, Leuven, Belgium) where "box and cylinder" designs were positioned at the predicted mating surfaces of the splint. This design provides perforated projections for the nylon screws to fit and be tightened with nuts ( Fig. 3B ). The enhancement of the design, such as smoothening and subtracting of the surfaces to complete the design, was done in Geomagic Freeform Touch software 2016.2.62 (Geomagic, 3D Systems, NC). The "shell" was split by using an osteotomy cut ( Fig. 3B ) for the final product ( Fig. 3C ). Finally, the two pieces were separately printed with clear acrylic (NextDent Ortho Clear, Nextdent B.V., Vertex Global Holding, Soesterberg, The Netherlands). The printed parts were cleaned with ethanol for no more than 5 minutes and set to rest for at least 10 minutes after. Postcuring was done in the NextDent LC-3DPrint Box (Nextdent B.V., Vertex Global Holding). The support structures were removed and polished. Fig. 3 Digital design of splint. The three main steps for designing the splint: ( A ) a 2-mm-thick shell fabricated with planned extensions; ( B ) addition of three "box and cylinder" designs with an osteotomy cut to fabricate the two pieces; and ( C ) the final product of the two-piece auricular splint. The design of the splint was a modification of the oyster splint described by Mercer and Studd. The splint extended at least 2/3 of the external helix. It included the scar with a margin of 3 mm to ensure adequate coverage and relieved the external auditory meatus. No relief spacer was incorporated and each piece required their own path of insertion. Two nylon screws, each close to the inferior and superior borders, and one additional nylon screw in the middle, were planned in the design. This ensured adequate clamping and that the pieces would not open up when tightened. The splint was printed with a clear acrylic as it enables visualization of the wound site for complications and amount of pressure applied. The splint had cleansable surfaces for hygiene purposes. During the issue of the splint, the fit was checked, with rough or sharp areas adjusted accordingly. Retention and pressure of the splint was tested to ensure comfort. The patient was able to fit the splint and attach screws independently and wore it for at least 8 hours for the first 2 weeks and subsequently, throughout the day. Weekly reviews were done for the first month to detect any pressure-induced erythema early. Subsequently, 6-month reviews of the appliance and surgical site were done. The patient has since worn the splint for 6 months ( Fig. 4 ) and the scar remains flat and pink. In a questionnaire provided, he reported ease with handling the splint, unimpaired appearance, and unrestricted daily activities. Fig. 4 Photos of the splint in situ. The patient at 6-month review, ( A ) with the auricular splint and ( B ) without the auricular splint. Instructions provided to the patient are as follow: Start daily application of the silicone sheet 2 weeks after surgery if well healed. Clean the surgical wound gently with a damp cloth after removing the silicone sheet. During the issue of ear splint, adjustments would be made to ensure comfort and to practice fitting the splint on. The splint should be worn over the silicone sheet for at least 6 hours, or as long as there is no discomfort. It is possible to sleep with the splint as long as it is not too uncomfortable. Cleaning of the splint should be done every 1 to 2 days by using a damp cotton bud, with soap if necessary. Both the outer and inner surfaces should be cleaned. Discussion The treatment for keloids is challenging and a combination of treatment modalities produces the best results, especially for larger keloids. For larger keloids on the ear, in addition to surgical removal, adjunct treatment such as corticosteroid injections, cryotherapy, radiation, and compression therapy have been described. Cryotherapy is effective for smaller keloids but often causes hyperpigmentation. 5 Keloid irradiation is successful, however, there have been isolated reports of skin tumor development. 6 7 8 As such, adjunct treatment modalities have potential complications, and a conservative approach of compression splint therapy is increasingly recommended to patients. Hassel et al found that 80% of patients felt the auricular splint treatment absolutely painless, with the remaining 20% finding it minimally painful. 3 The key challenge in producing a customized splint is obtaining a replica of an ear to fabricate the splint on, owing to the unique shape an ear. In the conventional workflow, a physical model is made with either an alginate or an additional polymerized silicone impression material which can be messy, but more importantly, uncomfortable for the patient. Hair gets tugged and incorporated into the impression despite a recommended layer of Vaseline coat over pulled-back hair around the ear. In addition, tugging of the ear and the recent surgical site is unavoidable when removing the impression from the ear due to the multiple undercuts of the ear anatomy. A fully digital workflow eliminates the physical process of impression-making. The comfort level improves as the scanner head moves around the patient's ear without contact. Another large advantage with utilizing a digital impression is the immediate feedback that digital scanning provides. During the scanning process, the software captures and stitches images in real time and the clinician can check the 3D digital model on the monitor immediately. The scanning process can be paused, 3D digital model checked, and additional details of deficient areas can be scanned and captured immediately. In contrast, a conventional model with inadequate pertinent features captured would require a remake of the whole impression. The conventional method of fabricating a splint requires a high level of mastery and is time-consuming. The impression has to be carefully prepared, poured, and then removed from the model to preserve the integrity and prevent breaking of the model. There is detailed planning involved in packing the various layers of the acrylic splint in the flask to ensure that deflasking the cured acrylic would be straightforward and the thin acrylic parts would not break. The total amount of hours required from model pouring stage to postprocessing in the conventional workflow would easily exceed 10 hours while the digital workflow potentially at least halve it. In addition, the painstakingly made model would be destroyed during the process of extracting the splint and cannot be reused. In the case where a patient misplaces or requests an addition splint, the splint can be easily reprinted if a digital workflow is utilized, compared with starting from scratch with the conventional workflow. In the center, the cost of printing an ear splint is comparable to conventionally fabricating one. In the literature, various designs of compression therapy and appliances have been described. 3 4 9 10 11 12 13 The above design adapted from the oyster splint has various advantages incorporated. The components of the main splint are sleek and follow closely to the contours of the ear, with minimal projections, which are only for the nylon screws. This provides a more aesthetic and compact appliance which would be increased acceptability with patients, in turn increased compliance. The nylon screws provide adjustable pressure onto the tissues and reduce the chance of ulcerations and pressure sores compared with the use of magnets and clips. A minimum of three screws are required to produce an even pressure onto the tissue surface within the splint and prevents the splint from opening up as the splint is tightened. The design also incorporates a relief of the external auditory meatus to ensure that patient's hearing and daily activities are minimally impeded. Compared with the digital workflow described by Nejat et al, the scanning protocol that has been described here does not require any indicators or markings on the ear, improving the patient's experience. Our design starts with a shell that covers the entire relevant areas that is subsequently split into two. This allows very accurate piecing of parts and allows incorporation of interlocking designs to make fitting the pieces more intuitive. This treatment modality is not without limitations. The workflow requires a clinician familiar and trained with using intraoral scanners and 3D digital designing, with a laboratory which is familiar with 3D digital designing, printing, and postprocessing of the splint. While keeping the design compact and simple, the assembly of the splint requires the patient to have a certain level of dexterity, especially since direct vision during assembly is not possible. The patient should have a family member or a friend present during the issue visit to understand the sequence of assembling the splint in the event the patient requires assistance outside the clinic setting. A detailed discussion on the rationale of treatment is necessary for the patient to understand that compliance is key for the treatment to be effective. Studies have described utility hours of up to 23 hours a day; however, there could be discomfort when patients are sleeping. A daily 6 to 12 hours recommended wear was advised. This reduces the need of wearing and removing the splint too many times a day, potentially improving compliance. A fully digital workflow for a printed auricular splint should be considered for adjunctive treatment to excision of ear keloids. Authors' Contributions Ethical Approval Patient Consent Conflict of Interest None declared. Conceptualization: Y.O.K., K.H.T., and R.M. Data curation: R.M. and Y.O.K. Methodology: K.H.T., and R.M. Writing - original draft, review and editing: R.M. The study was performed in accordance with the principles of the Declaration of Helsinki. The patient provided written informed consent for the publication and the use of his images and medical data. References 1 Cosman B Wolff M Correlation of keloid recurrence with completeness of local excision. A negative report Plast Reconstr Surg 1972 50 02 163 166 5045380 2 Berman B Bieley H C Adjunct therapies to surgical management of keloids Dermatol Surg 1996 22 02 126 130 8608373 3 Hassel J C Loser C Koenen W Kreuter A Hassel A J Promising results from a pilot study on compression treatment of ear keloids J Cutan Med Surg 2011 15 03 130 136 21561580 4 Mercer D M Studd D M "Oyster splints": a new compression device for the treatment of keloid scars of the ear Br J Plast Surg 1983 36 01 75 78 6821732 5 Olabanji J K Onayemi O Olasode O A Keloids: an old problem still searching for a solution Surg Pract 2005 9 2 7 6 Botwood N Lewanski C Lowdell C The risks of treating keloids with radiotherapy Br J Radiol 1999 72 864 1222 1224 10703484 7 Epstein R Hanham I Dale R Radiotherapy-induced second cancers: are we doing enough to protect young patients? Eur J Cancer 1997 33 04 526 530 9274430 8 Ragoowansi R Cornes P G Glees J P Powell B W Moss A L Ear-lobe keloids: treatment by a protocol of surgical excision and immediate postoperative adjuvant radiotherapy Br J Plast Surg 2001 54 06 504 508 11513512 9 Kadouch D J van der Veer W M Mahdavian Delavary B Kerkdijk D Niessen F B Therapeutic hotline: an alternative adjuvant treatment after ear keloid excision using a custom-made methyl methacrylate stent Dermatol Ther 2010 23 06 686 692 21054713 10 Park T H Rah D K Successful eradication of helical rim keloids with surgical excision followed by pressure therapy using a combination of magnets and silicone gel sheeting Int Wound J 2017 14 02 302 306 26593457 11 Tanaydin V Beugels J Piatkowski A Efficacy of custom-made pressure clips for ear keloid treatment after surgical excision J Plast Reconstr Aesthet Surg 2016 69 01 115 121 26507863 12 Li H Song T 3d printed custom made pressure clips for ear keloid treatment after surgical excision Am J Otolaryngol 2020 41 04 102516 32381347 13 Nejat A H Hamdan S Abrego I Lindsey J T Vitter R Fully digital workflow for fabrication of a 3D printed ear stent for auricular keloids: a technique article J Prosthodont 2022 31 03 266 270 34811842 |
Arch Plast Surg Arch Plast Surg 10.1055/s-00051611 Archives of Plastic Surgery 2234-6163 2234-6171 Thieme Medical Publishers, Inc. 333 Seventh Avenue, 18th Floor, New York, NY 10001, USA 10.1055/s-0043-1771520 aps-22-sep-0166-cr Hand/Peripheral Nerve Case Report Surgical Management of Pachyonychia Congenita in a 3-Year-Old Sudduth Jack D. MD, MS 1 Clinker Christopher BS 1 Holdaway Matthew BS 1 Marquez Jessica L. BA 1 Veith Jacob MD 1 Wright Thomas MD 1 Rockwell W. Bradford MD 1 1 Division of Plastic Surgery, Department of Surgery, The University of Utah Hospital, Salt Lake City, Utah Address for correspondence Jack D. Sudduth, MD, MS 30 North 1900 East, 3B205, Salt Lake City, UT [email protected] 21 12 2023 11 2023 1 12 2023 50 6 573577 03 11 2022 15 6 2023 The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( ) 2023 The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Pachyonychia congenita is a rare genetic disorder characterized by hypertrophic nail plates, hyperkeratotic nail beds, and thickened hyponychium of the fingers and toes, impairing manual dexterity and resulting in poor aesthetics. The current body of literature describes various treatment modalities, but no singular approach has been defined as the gold standard. In this case, the authors employed different surgical techniques for treating pachyonychia congenita to evaluate the most effective approach. A 3-year-old boy presented with hypertrophic nail growth involving all digits of both hands and feet. Three surgical procedures were performed on the patient's fingers and toes using germinal matrix excision (GME) alone, GME plus partial sterile matrix excision (pSME), or GME plus complete sterile matrix excision (cSME). The digits treated with GME + cSME exhibited no recurrence of nail growth. Those treated with GME alone exhibited recurrence of hypertrophic nail growth, although their growth slowed. Excision of GME + cSME prevented recurrence of hypertrophic nails, while GME alone or with pSME led to slower-growing hypertrophic nails. Complete excision of the germinal and sterile matrices with skin graft closure may be a definitive treatment for pachyonychia congenita, but further studies are needed to validate these findings. Keywords pachyonychia congenita germinal matrix excision nail bed excision surgical dermatology congenital Funding None. pmcIntroduction Pachyonychia congenita (PC) is an autosomal dominant genetic disorder characterized by hypertrophic nail plates, hyperkeratotic nail beds, and thickened hyponychium of the fingers and toes. 1 The distal two-thirds of the nail plates become thickened, elevated, and transversely arched due to hyperkeratosis of the nail bed. The thickened portion often becomes discolored, resulting in yellow or brown nails. Additional symptoms associated with PC include leukoplakia, palmar and plantar hyperkeratosis, and epidermal cysts but vary depending on the genetic variant. Management is often determined by both type and severity of the keratin genetic mutation. 1 Because of this, the importance of genetic testing prior to treatment cannot be understated. Because of the effect PC has on the nail beds, it also impairs manual dexterity and often leads to surgical referral. Despite increased awareness and ongoing research into PC, literature regarding the surgical management of the disorder remains limited. 2 3 Many treatments for PC focus on pain management with Botox injection and sirolimus, which has shown some efficacy in managing symptoms. 1 4 We present our experience and results of treating a pediatric patient with a combination of germinal matrix excision (GME) alone, GME with partial sterile matrix excision (pSME), and GME with complete sterile matrix excision (cSME). Case A 3-year-old boy presented with hypertrophic nail growth involving all digits of both hands and feet ( Fig. 1 ). The nails caused persistent pain and discomfort and required frequent trimming. This patient's parents opted for definitive surgical treatment. No previous genetic testing was done on the patient. Fig. 1 Right hand preoperatively. The nail plates show significant thickening on all five digits. With no established surgical technique for definitive treatment of the nails, three varying surgical procedures were performed on the patient's fingers and toes to identify which would be most effective in preventing painful regrowth. These techniques included GME alone, GME plus pSME, or GME plus cSME ( Table 1 , Fig. 2 ). All nail beds were closed with local skin grafts when unable to be closed primarily. Table 1 A summary of involved digits, procedures, and outcomes Digits Procedure Outcome Right fingers 1, 2, 3, 4, and 5 Right finger 2 Germinal matrix excision Subsequent thinning 2/3 thickness of sterile matrix Mild, slower hypertrophic nail growth in 1, 2, and 3. Hyperkeratinization approximating normal nail thickness in 4 and 5. Thinner but still hypertrophic nail Right toe 1 Germinal matrix excision Subsequent sterile matrix excision; primary skin closure Recurrent hypertrophic nail growth Primary skin healing, no nail growth Right toes 2, 3, and 4 Germinal matrix excision Hyperkeratinization approximating normal nail thickness Right toe 5 Germinal and sterile matrix excision; primary skin closure Primary skin healing, no nail growth Left finger 1 Germinal matrix excision Recurrent hypertrophic growth, slight improvement Left finger 2, 3, 4, and 5 Germinal matrix excision Mild, slower hypertrophic growth Left toes 1, 2, and 3 Germinal matrix excision Mild, slower hypertrophic growth Left toes 4 and 5 Germinal and sterile matrix excision; primary skin closure Primary skin healing, no nail growth Fig. 2 Illustration showing a longitudinal cross section of the nail tip and demonstrating the procedure. The three toes treated with GME + cSME with proximal nail fold closure exhibited primary skin healing with no nail growth. This method of treatment was the most successful ( Table 1 ). The right hallux, treated with GME alone, exhibited slow but recurrent growth of the hypertrophic nail. Subsequent cSME and local skin closure resulted in no nail growth. The remaining toes, treated with GME alone, developed hyperkeratinization at a slower growth rate than before the operation ( Fig. 3 ). Fig. 3 The right foot 8 months after germinal matrix resection on toes 1, 2, 3, and 4 and germinal matrix and sterile matrix resection on toe 5. Recurrence of the thickened nail on the great toe is noted. Subsequent resection of the sterile matrix of the great toe was curative. Toes 2, 3, and 4 show hyperkeratinization. Toe 5 has no nail regrowth. The thumbs exhibited bilateral thickened nail plate growth, though to a lesser degree than preoperatively. Additionally, the rate of growth was slower. The remaining two to five fingers exhibited nail plate hypertrophy but less than that of the thumbs ( Fig. 4 ). Nail growth was significantly slowed. Before surgery, nail trimming was necessary every month, but following GME, nail trimming was necessary every 3 to 6 months. Fig. 4 The right hand 8 months after germinal matrix resection of all five digits. The thumb, index, and middle show recurrence while the ring and little have hyperkeratinization approximating the thickness of a normal nail. Due to recurrent hypertrophy, the thickness of the right index sterile matrix was thinned by two-thirds, resulting in a significantly thinner nail plate. Improvement was noted with this method, but the result was not ideal compared with GME + cSME. These results have persisted for 19 months following surgery. Discussion Medical therapy to reduce hyperkeratosis is limited; however, several surgical techniques have been described to improve the function and appearance of digits with hypertrophic nail plates. The various methods address the germinal matrix and nail bed separately. Grinding and milling the nail plates to reduce nail plate thickness (under general anesthesia) followed by regular maintenance grinding of the nail plates (without anesthesia) effectively controls nail plate thickness. 5 The ongoing maintenance required for this control must be compared with the benefits of more permanent interventions. Daroach et al found that nail plate avulsion in combination with oral sirolimus significantly improved pain, but did not prevent the regrowth of abnormal nail plates and, consequently, was only of temporary benefit. 4 6 7 8 Control of the hypertrophic nail plates by amputation of the distal phalanx, while effective, is unacceptably extreme. 9 Cosman et al reported nail plate, GME, and pSME followed by full-thickness skin graft coverage with the remaining nail bed developing hyperkeratinization. 10 A more aggressive approach was reported by White and Noone in which the nail plate was excised with GME and then covered with a split-thickness skin graft. 11 No nail plate growth recurred. Thomsen et al treated different fingers with different surgical procedures. 6 They concluded that GME or destruction was sufficiently effective in treating the nail plate abnormalities and that cSME was unnecessary. The remaining nail bed developed hyperkeratinization, which they felt was acceptable. Vigorous curettage and fulguration of the germinal and sterile matrices produced smooth nail beds without nail plate growth on four of the six digits treated. Minimal hyperkeratosis developed on one nail bed, and a small spicule of recurrent nail plate grew on another. Preservation of the germinal matrix deep to the eponychium with excision of the distal germinal matrix and nail bed resulted in thickened nail plate regrowth. Excision was chosen in place of chemical germinal matrix ablation, seeing that ablation has reduced success in cases of recurrent nail growth. 12 13 A 2020 retrospective study by DeKlotz et al looked at 18 patients who had their nails removed and found that of the 18 individuals, 13 would recommend nail removal to others with PC. Most of the patients who had no regrowth of at least one nail would recommend that treatment. 14 This suggests that if nail removal is to be attempted, finding the process that would allow minimal regrowth would be of much benefit. In this patient, the results implicate the involvement of both germinal and sterile matrix contributing to nail hypertrophy. In the toes treated with GME + cSME, no nail growth occurred. As Thomsen et al's study also suggests, the thickness of the sterile matrix remaining may correlate with the amount of hyperkeratinization. The presented results support this theory. 6 Initial postoperative hyperkeratinization of the right index finger was improved with thinning two-thirds of sterile matrix thickness. GME with cSME and closure of the defect secondarily or with a skin graft is a safe and effective option for treating nail hypertrophy in PC. This option showed to be the most definitive and successful treatment. An alternative that avoids skin grafting is full-thickness GME and pSME with thinning two-thirds thickness of the sterile matrix. Patients and their families should be counseled that some hyperkeratinization may result in preserving one-third thickness of the sterile matrix. The hyperkeratinization is significantly decreased compared with preserving the entire thickness of the sterile matrix. This option also does produce the appearance of a nail plate. PC is a rare disease, and large cohorts are challenging to find. Although successful, the surgical management of this rare disorder is described in a single case, potentially limiting its applicability to all patients afflicted with PC. Therefore, inferences cannot be made on the most appropriate treatment for all PC patients. This patient was lost to follow-up prior to completing genetic testing. Therefore, the appropriateness of this procedure for specific genotypes of PC patients cannot be commented on. Further studies are needed to assess which exact mutations are appropriate for GME + cSME. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008 (5). Informed consent was obtained from all patients for being included in the study. Additional informed consent was obtained from all patients for which identifying information is included in this article. Authors' Contributions Ethical Approval Patient Consent Conflict of Interest None declared. All authors contributed equally to the concept, writing, and submission process of this manuscript. This project was deemed exempt from IRB approval per local institution guidelines. Written patient consent was obtained for this study. References 1 Wu A G Lipner S R Distinctions in the management, patient impact, and clinical profiles of pachyonychia congenita subtypes Skin Appendage Disord 2021 7 03 194 202 34055907 2 Milstone L M Fleckman P Leachman S A Treatment of pachyonychia congenita J Investig Dermatol Symp Proc 2005 10 01 18 20 3 Goldberg I Fruchter D Meilick A Schwartz M E Sprecher E Best treatment practices for pachyonychia congenita J Eur Acad Dermatol Venereol 2014 28 03 279 285 23363249 4 Daroach M Dogra S Bhattacharjee R Tp A Smith F Mahajan R Pachyonychia congenita responding favorably to a combination of surgical and medical therapies Dermatol Ther 2019 32 05 e13045 31364784 5 Rohold A E Brandrup F Pachyonychia congenita: therapeutic and immunologic aspects Pediatr Dermatol 1990 7 04 307 309 2080126 6 Thomsen R J Zuehlke R L Beckman B I Pachyonychia congenita: surgical management of the nail changes J Dermatol Surg Oncol 1982 8 01 24 28 7056926 7 Soderquist N A Reed W B Pachyonychia congenita with epidermal cysts and other congenital dyskeratoses Arch Dermatol 1968 97 01 31 33 5694033 8 Jackson A D Lawler S D Pachyonychia congenita; a report of six cases in one family, with a note on linkage data Ann Eugen 1951 16 01 142 146 14885876 9 Wright C S Guequirre J P Pachyonychia congenita; report of two cases, with studies on therapy Arch Derm Syphilol 1947 55 06 819 827 20247744 10 Cosman B Symonds F C Jr Crikelair G F Plastic surgery in pachyonychia congenita and other dyskeratoses. Case report and review of the literature Plast Reconstr Surg 1964 33 226 236 14131617 11 White R R IV Noone R B Pachyonychia congenita (Jadassohn-Lewandowski syndrome: case report Plast Reconstr Surg 1977 59 06 855 858 577013 12 Anderson J H Greig J D Ireland A J Anderson J R Randomized, prospective study of nail bed ablation for recurrent ingrowing toenails J R Coll Surg Edinb 1990 35 04 240 242 2102672 13 Grieg J D Anderson J H Ireland A J Anderson J R The surgical treatment of ingrowing toenails J Bone Joint Surg Br 1991 73 01 131 133 1991748 14 DeKlotz C MC Schwartz M E Milstone L M Nail removal in pachyonychia congenita: patient-reported survey outcomes J Am Acad Dermatol 2017 76 05 990 992 28411774 |
Arch Plast Surg Arch Plast Surg 10.1055/s-00051611 Archives of Plastic Surgery 2234-6163 2234-6171 Thieme Medical Publishers, Inc. 333 Seventh Avenue, 18th Floor, New York, NY 10001, USA 10.1055/a-2077-5745 APS-22-Sep-0173-CR Extremity/Lymphedema Case Report Meek Micrografting Technique for Reconstruction of Extensive Necrotizing Fasciitis of the Anterior Abdomen and Bilateral Femoral Region: A Case Report Ng Jyi Cheng 1 Ahmad Zaidi Ahmad Ibrahim 2 Lee Jun De 1 Jabar Mohd Faisal 1 1 Department of Surgery, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Malaysia 2 Department of Surgery, Universiti Putra Malaysia Teaching Hospital, Serdang, Malaysia Address for correspondence Ahmad I.A. Zaidi Department of Surgery, Universiti Putra Malaysia Teaching HospitalPersiaran , Serdang, Selangor [email protected] 24 8 2023 11 2023 1 8 2023 50 6 610614 19 10 2022 28 3 2023 The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( ) 2023 The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Necrotizing fasciitis is an uncommon yet fatal soft tissue infection. Current recommended treatment includes antibiotics with repeat surgical exploration and wound debridement followed by reconstruction. In burn patients, the Meek micrograft has demonstrated a higher true expansion ratio, faster reepithelialization rate, more resilient toward infection, and reduced risk of graft failure as compared with meshed graft. To our best knowledge, the use of Meek micrografting technique in reconstruction of postdebridement wounds of necrotizing fasciitis has not been reported. Hereby, we present a case of a 57-year-old gentleman who was referred to us for wound reconstruction after surgical debridement of Fournier's gangrene and extensive necrotizing fasciitis involving the anterior abdomen and bilateral femoral region. Meek micrografting technique was used to reconstruct the anterior abdomen as the wound bed was large. Although the graft was complicated with a small area of localized infection, it did not spread across the entire graft and was successfully treated with topical antibiotics and regular wound dressing. In our case, wound reconstruction using Meek micrografting technique in a patient with extensive necrotizing fasciitis was successful and showed positive outcome. Therefore, we suggest further studies to be conducted to investigate the applications and outcomes of the Meek micrografting technique, especially in patients with extensive wound bed and limited donor site availability. Keywords necrotizing fasciitis reconstructive surgery skin transplantation skin graft Funding None. pmcIntroduction Fournier's gangrene is defined as an infective necrotizing fasciitis of the perineal, genital, or perianal region. 1 The infection usually extends following the course of the superficial perineal fascia that is in continuity with Colles fascia and Scarpa's fascia, into the abdominal wall as well as the legs. Necrotizing fasciitis carries a high morbidity and mortality rate, especially when intervention is delayed as the infection spreads rapidly. 2 Urgent and radical debridement of devitalized tissue is crucial in ceasing the progression of the infection. Meshed split-thickness skin graft (SSG) is usually used thereafter for reconstruction, but it has a limited expansion ratio leading to increased donor site morbidity when grafted on extensive wounds. 3 First introduced by Cicero Parker Meek in 1958 for the use in burn patients, 4 Meek micrograft technique was quickly overshadowed by the mesh technique due to cheaper and faster production of meshed grafts. 5 In the 1990s, this technique was revived by physicians in Beverwijk and later modified by Kreis and Raff to take advantage of its higher expansion ratio over mesh grafts. 5 The use of the Meek micrograft technique in burn patients has been widely discussed. It has shown to be a viable alternative for SSG in burns patients, due to a higher expansion ratio, faster reepithelialization rate, can be used in wounds with poor vascularity, and is also superior in terms of long-term scar and functional outcome. 3 6 7 8 It is especially favorable in burn patients with limited autograft donor sites. 6 Here, we describe a case of successful reconstruction using the Meek micrografting technique in a patient with a large anterior abdomen wound bed postdebridement for extensive necrotizing fasciitis. The patient provided written informed consent for the publication and use of his images. Case A 57-year-old gentleman with underlying hypertension and meatal stenosis was referred to us for wound reconstruction postsurgical debridement for Fournier's gangrene and extensive necrotizing fasciitis involving the anterior abdomen and bilateral femoral region. In addition, he also developed obstructive uropathy and bladder stone. He has completed surgical exploration and wound debridement over the penis, scrotum, lower abdomen, and bilateral anterior femoral region thrice: on day 1, 5, and 10, respectively ( Fig. 1A and B ). The debridement was comanaged by the surgical, orthopaedics, and urological team. Intraoperative findings revealed necrotic tissue involving the anterior abdomen, suprapubic, paraumbilical, and bilateral flank region, extending down to the bilateral femoral region, with Fournier's gangrene. After multiple wound debridements, the patient was not in good condition with prolonged hospitalization, in which he developed septic shock, bacteremia with deep wound infection, evidenced by methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa cultured on deep tissue culture and sensitivity, despite meticulous efforts to reduce the risk of infection, such as granulation tissue debridement and thorough irrigation with hydrogen peroxide, povidone-iodine, and copious saline prior to tissue sampling for culture and sensitivity. Fig. 1 ( A ) Granulation tissue seen over the anterior abdomen and bilateral femoral region extending to the proximal thigh after three surgical exploration and wound debridement (anterior view). ( B ) Granulation tissue seen over the anterior abdomen and bilateral femoral region extending to the proximal thigh after three surgical explorations and wound debridement (lateral view). Unfortunately, wound reconstruction could not be done earlier due to complications of the infection and there were no plastic surgeons in the primary care team hospital. In addition, our patient was facing financial difficulties and the primary team could not refer him to other institutions. Therefore, our team was invited to the hospital to perform the case, and wound reconstruction was done on day 65 since the first debridement. The testes were placed in the lower abdomen by the primary team following previous surgical debridements ( Fig. 1A and B ). The testes were plastered to the wound bed, and there is a high risk of testicular artery bleeding if we attempt to separate the testes from the abdomen. After discussing the risk with our patient, abdominal implantation of the testicles was done instead of scrotal reconstruction. SSG was harvested from the left anterior thigh ( Fig. 2 ). Part of the SSG was meshed with an expansion ratio of 1:3 and grafted over the testes. The reconstruction of the circumferential penile shaft was done by meshing the SSG without expanding it. As the involvement of the anterior abdomen was extensive ( Fig. 1A and B ), with an estimated total body surface area of 10%, we decided to use the Meek micrografting technique ( Fig. 3 ) with an expansion ratio of 1:6. It was done by cutting the SSG to be fitted in a 42 mm x 42 mm damp cork base with the dermal side downward. The autografts along with cork squares were placed into the Meek Mesher (Humeca) where the autografts were cut into 14 x 14 small squares, with a total of 196 small "postage stamp" squares measuring 3 mm x 3 mm each. Next, an adhesive dressing spray was sprayed on the epidermal side of the grafts, and it was pressed onto a prefolded polyamide gauze with aluminum backing with an expansion ratio of 1:6. The cork was then removed, and the pleated sheath was extended at all sides until it became entirely unfolded. The aluminum backing was removed, leaving the polyamide gauze with the expanded autografts ready for grafting. The margins were trimmed and the gauze was applied to the wound bed and secured with surgical staples. The donor site and graft sites were properly managed with appropriate dressings. Preemptive scar massage and pressure garment were applied over the grafted and donor site to prevent contracture. Fortunately, our patient survived after 3 months of intensive inpatient care with resolved candidemia and resolved multiresistant Klebsiella pneumoniae bacteremia. He was discharged upon request 3 weeks after the reconstructive surgery. During follow-up, we noticed a small area of infection over the graft on the anterior abdomen ( Fig. 4 ). The infection was localized and did not spread across the entire graft. He was treated as an outpatient with topical hydrocortisone and neomycin with regular wound dressing. The infection was well-controlled and healed without complications ( Fig. 5 ). Fig. 2 The donor site is on the left anterior thigh, where split-thickness skin graft was harvested. The donor site is relatively small in comparison to the graft site. The picture was taken 6 weeks after the operation. Fig. 3 Meek micrograft technique. ( A ) Split-thickness skin graft (SSG) was harvested from the left anterior thigh. ( B ) SSG was fitted in a 42 mm x 42 mm damp cork base with the dermal side inward. ( C ) SSG was placed into the Meek Mesher (Humeca) along with cork squares to be cut into 14 x 14 small squares (total of 196 small "postage stamp" squares, 3 mm x 3 mm each). ( D ) An adhesive dressing spray was sprayed on the epidermal side of the grafts, and it was pressed onto a prefolded polyamide gauze with aluminum backing with an expansion ratio of 1:6. ( E ) The cork was then removed, leaving the graft on the prefolded polyamide gauze. ( F ) The pleated sheath was extended at all sides until it became entirely unfolded. ( G ) The aluminum backing was removed, leaving the polyamide gauze with the expanded autografts ready for grafting. ( H ) The margins were trimmed, and the gauze was applied to the wound bed and secured with surgical staples. Fig. 4 Graft complicated with infection, localized to a small area over the right flank, right iliac fossa, and right inguinal region, sparing the central and left parts of the graft. The picture was taken 2 months after the operation. Fig. 5 The wound bed and donor site healed well with minimal contracture. The picture was taken 1 year after the operation. Discussion About one in five patients with necrotizing fasciitis died, 9 10 11 and the mortality rate is even higher when intervention is delayed. 10 11 Necrotizing fasciitis is a fatal, aggressive, and rapidly progressive disease. It is a clinical diagnosis, and the cornerstone of management of this lethal condition is to reduce systemic toxicity, halt the progression of the infection, and eliminate the causative microorganisms, achieved via urgent hemodynamic resuscitation, broad-spectrum antibiotics and repeat surgical exploration, and wound debridement, 12 13 followed by skin grafting and complex genital reconstructive surgery. 13 Early and extensive debridement of necrotic and nonviable tissues together with a slim window of healthy adjacent tissue is crucial in ceasing the progression of the devastating infection and reducing mortality. 10 11 12 The procedure may be repeated to achieve adequate infection control. A previous study has suggested a mean of 3.5 debridement operations per patient, 14 which is in keeping with our patient who completed surgical debridement thrice. After multiple wound debridement, our patient was not in good condition with prolonged hospitalization as he was unable to sit up or ambulate. He also developed bacteremia with deep wound infection, despite meticulous efforts to reduce the risk of infection, such as granulation tissue debridement and thorough washing with hydrogen peroxide, povidone-iodine, and copious saline prior to tissue sampling for culture and sensitivity. In view of the patient's condition, we decided to opt for Meek micrograft because it has a better graft resilience toward infection, and a higher true expansion ratio to cover the extensive wound bed, along with minimal donor site morbidity and reduced risk of graft failure. 3 6 7 8 This is as opposed to meshed SSG where there will be a higher graft load, increased risk of graft infection and failure, as well as prolonged hospitalization. 3 7 8 Meshed SSG has a limited true expansion ratio of 1:1.5, which exhibits a significant discrepancy from the theoretical expansion ratio. 3 Even though an expansion ratio of up to 1:6 has been reported with skin meshers, the majority did not reach the claimed expansion when the ratio becomes greater than 1:3 mesher. 15 When it is further expanded to a larger ratio, it leaves significant gaps in between, exposing a larger area of wound bed that may potentially impede reepithelialization or even graft failure, in addition to the higher risk of infection. 8 In contrast, Meek micrograft has a higher true expansion ratio of 1:3 or up to 1:9, 3 without compromising the reepithelialization rate and risk of extensive infection. 8 16 The high expansion ratio is particularly important in our patient as we were able to reconstruct an extensive area without increasing donor site morbidity. Infection is a significant complication following skin allograft transplantation, as it often results in graft loss. 17 18 Meek grafts have been reported to be more resilient toward infection when compared with meshed SSG. 8 19 This is an unexpected observation seen in our patient, who developed an infection over the graft at the right anterior abdomen. Surprisingly, the infection was contained and did not spread across the entire graft. There was no graft failure necessitating regrafting. A proposed explanation is that the skin autograft islands in Meek technique lack continuity between each other, limiting the progression of infection across the wound bed. This is unlike meshed SSG, which often results in the loss of the whole graft, as infection could creep under the entire graft causing loss of contact. 8 Our patient was treated successfully with topical antibiotics and regular wound dressing without regrafting. This is consistent with a study by Medina et al, where the Meek skin grafts survived and resumed the reepithelialization process in patients with graft infection treated with topical management and systemic antibiotic therapies. 19 As for penile reconstruction, we decided to use the mesh graft instead of the unfenestrated sheet graft to allow better drainage of hematomas or seromas. 20 A randomized trial has shown a lower percentage of graft loss due to hematoma formation in meshed grafts as compared with sheet grafts. 20 Even though the graft was meshed, we did not expand the graft to reduce contracture. There was minimal contracture seen in our patient postreconstruction, as we prevented it early with meticulous technique, in which preemptive scar massage and pressure garment were applied over the grafted and donor site. Although tedious and laborious, Meek micrografting technique is a feasible option for the reconstruction of postdebridement wounds in patients with extensive necrotizing fasciitis. There is a paucity of data reporting the outcome of Meek micrograft technique other than in burn patients. Therefore, we suggest further studies to be conducted to investigate the applications and outcomes of the Meek Micrografting technique, especially in patients with extensive wound beds and limited donor site availability. Acknowledgments The authors gratefully acknowledge technical support from the Department of Surgery of Serdang Hospital and Universiti Putra Malaysia Teaching Hospital. Authors' Contributions Ethical Approval Patient Consent Note Conflict of Interest None declared. Substantial contribution to the conception and design of the work: J.C.N. and J.D.L. under the guidance of A.I.A.Z. and M.F.J. Drafting the work and critical revision: J.C.N. and J.D.L. under the guidance of A.I.A.Z. and M.F.J. All the authors read and approved the final version of the manuscript. This study was performed in accordance with the principles of the Declaration of Helsinki. Written consent was obtained from the patient for the publication of images or data related to the patient. This work was presented at the 48th Annual Scientific Congress of the College of Surgeons Malaysia, August 27, 2022. References 1 Smith G L Bunker C B Dinneen M D Fournier's gangrene Br J Urol 1998 81 03 347 355 9523650 2 Radcliffe R S Khan M A Mortality associated with Fournier's gangrene remains unchanged over 25 years BJU Int 2020 125 04 610 616 31975540 3 Quintero E C Machado J FE Robles R AD Meek micrografting history, indications, technique, physiology and experience: a review article J Wound Care 2018 27 (Sup2):S12 S18 4 Meek C P Successful microdermagrafting using the Meek-Wall microdermatome Am J Surg 1958 96 04 557 558 13571547 5 Ottomann C Hartmann B Branski L Krohn C A tribute to Cicero Parker Meek Burns 2015 41 08 1660 1663 26233898 6 Houschyar K S Tapking C Nietzschmann I Five years experience with Meek grafting in the management of extensive burns in an adult burn center Plast Surg (Oakv) 2019 27 01 44 48 30854361 7 Lee S Z Halim A S Superior long term functional and scar outcome of Meek micrografting compared to conventional split thickness skin grafting in the management of burns Burns 2019 45 06 1386 1400 31054957 8 Noureldin M A Said T A Makeen K Kadry H M Comparative study between skin micrografting (Meek technique) and meshed skin grafts in paediatric burns Burns 2022 48 07 1632 1644 35248428 9 Dhanasekara C S Marschke B Morris E Kahathuduwa C N Dissanaike S Regional variations in microbiology and outcomes of necrotizing soft tissue infections: a systematic review and meta-analysis Surg Infect (Larchmt) 2022 23 07 634 644 35904966 10 Gelbard R B Ferrada P Yeh D D Optimal timing of initial debridement for necrotizing soft tissue infection: a practice management guideline from the Eastern Association for the Surgery of Trauma J Trauma Acute Care Surg 2018 85 01 208 214 29485428 11 Nawijn F Smeeing D PJ Houwert R M Leenen L PH Hietbrink F Time is of the essence when treating necrotizing soft tissue infections: a systematic review and meta-analysis World J Emerg Surg 2020 15 4 31921330 12 Singh A Ahmed K Aydin A Khan M S Dasgupta P Fournier's gangrene. A clinical review Arch Ital Urol Androl 2016 88 03 157 164 27711086 13 Tarasconi A Perrone G Davies J Anorectal emergencies: WSES-AAST guidelines World J Emerg Surg 2021 16 01 48 34530908 14 Chawla S N Gallop C Mydlo J H Fournier's gangrene: an analysis of repeated surgical debridement Eur Urol 2003 43 05 572 575 12706005 15 Kamolz L P Schintler M Parvizi D Selig H Lumenta D B The real expansion rate of meshers and micrografts: things we should keep in mind Ann Burns Fire Disasters 2013 26 01 26 29 23966895 16 Dahmardehei M Vaghardoost R Saboury M Comparison of modified Meek technique with standard mesh method in patients with third degree burns World J Plast Surg 2020 9 03 267 273 33330002 17 Unal S Ersoz G Demirkan F Arslan E Tutuncu N Sari A Analysis of skin-graft loss due to infection: infection-related graft loss Ann Plast Surg 2005 55 01 102 106 15985801 18 Rode H Martinez R Potgieter D Adams S Rogers A D Experience and outcomes of micrografting for major paediatric burns Burns 2017 43 05 1103 1110 28318749 19 Medina A Riegel T Nystad D Tredget E E Modified Meek micrografting technique for wound coverage in extensive burn injuries J Burn Care Res 2016 37 05 305 313 27355651 20 Nikkhah D Booth S Tay S Gilbert P Dheansa B Comparing outcomes of sheet grafting with 1:1 mesh grafting in patients with thermal burns: a randomized trial Burns 2015 41 02 257 264 25175303 |
Arch Plast Surg Arch Plast Surg 10.1055/s-00051611 Archives of Plastic Surgery 2234-6163 2234-6171 Thieme Medical Publishers, Inc. 333 Seventh Avenue, 18th Floor, New York, NY 10001, USA 10.1055/a-2122-6029 aps-22-oct-0195-cr Hand/Peripheral Nerve Case Report Venous Free Flap with Interposition Bypass Graft for Arteriovenous Fistula Preservation: A Case Report Awaida Cyril MD 1 Aribert Marion MD 1 Weger Natalie DO 2 Keck Kendall MD 2 Odobescu Andrei MD, PhD 3 1 Division of Plastic and Reconstructive Surgery, University of Montreal Hospital Center, Montreal, Quebec, Canada 2 Department of Surgery, University of Iowa Hospitals and Clinics, Iowa City, Iowa 3 Department of Plastic Surgery, University of Texas-Southwestern, Dallas, Texas Address for correspondence Andrei Odobescu, MD, PhD Department of Plastic Surgery, University of Texas-Southwestern1801 Inwood Road, Dallas, TX [email protected] 12 10 2023 11 2023 1 10 2023 50 6 568572 29 12 2022 27 6 2023 The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( ) 2023 The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Cutaneous squamous cell carcinoma (CSCC) overlying an arteriovenous fistula (AVF) is rare and presents unique challenges. This case report describes a method of fistula preservation after CSCC excision using a flow-through venous free flap. The saphenous vein of the venous flap was used as flow-through segment for AVF preservation. The flap was inserted along the dorsal aspect of the forearm wound and microvascular anastomosis of the arterial inflow was completed using a vein just proximal to the radiocephalic fistula anastomosis. Venous outflow was established by creating an end-to-end vascular anastomosis between the cephalic vein and the greater saphenous vein. A separate subcutaneous vein was used to provide a low-pressure outflow for the flap to avoid congestion. This case demonstrates an option for AVF preservation that has not been previously described. It also highlights the importance of a multidisciplinary approach for the safe treatment of CSCCs overlying AVFs. Keywords arteriovenous fistula saphenous vein squamous cell carcinoma venous free flap Funding None. pmcIntroduction In recent years there has been significant improvement in patient survival, overall health, and quality of life after solid organ transplant. However, chronic immunosuppression places patients at risk for several complications including malignancy. 1 In fact, cutaneous squamous cell carcinoma (CSCC) remains the most common cutaneous cancer in transplant patients and one of the leading causes of morbidity and mortality. 2 CSCC overlying an arteriovenous fistula (AVF) is a rare occurrence and presents an additional clinical challenge. 3 These patients require expeditious recognition and treatment as invasion of the underlying AVF by the tumor may leave them at risk of life-threatening bleeding and loss of functional access. 4 Treatment goals for these cases include complete surgical resection of the CSCC and AVF preservation. However, patients are often left with sizable soft tissue defects after adequate resection with concern for exposed underlying vital structures. This is especially evident in patients with CSCC of upper extremities where primary closure of the wound is seldom possible. 4 5 6 This poses a reconstructive challenge often requiring microsurgical expertise and free tissue transfer. 6 7 8 Only a few cases of skin malignancy overlying AVF have been reported. 4 We report a case of a renal transplant patient with a CSCC overlying a radiocephalic AVF treated by surgical excision of the lesion with preservation of the fistula using arterialized venous free flap based on the saphenous vein. Case The patient is a 77-year-old man with a history of congenital atrophic kidney disease that required hemodialysis via right distal wrist AVF. Six months after initiating hemodialysis he received a living related renal transplant and had adequate renal graft function to this day. His AVF was functional but not in use at the time of presentation when he was found to have an enlarging cutaneous lesion overlying his AVF measuring 2.5 cm in diameter. Initially, excision of the cutaneous lesion without AVF ligation was performed. The pathology demonstrated well-differentiated invasive CSCC with an invasion depth of 0.4 cm. The deep resection margin was insufficient (less than 0.1 mm). Reexcision with AVF reconstruction using a flow-through venous flap was planned. A 5 cm x 3 cm x 2 cm skin and soft tissue area including the anterior wall of the AVF was resected, and negative margins were confirmed. Given patient's comorbidities, desire to limit donor site morbidity and need for AVF wall reconstruction, a venous free flap based on the saphenous vein was chosen as the preferred reconstructive option. The flap was harvested from the patient's left medial calf to cover the forearm defect. The saphenous vein was used as an interposition bypass graft for AVF preservation. Microvascular anastomosis of the arterial inflow was completed using the venous stump of the radiocephalic fistula for inflow. Fistula outflow was established by creating an end-to-end vascular anastomosis between the cephalic vein and the distal end of the greater saphenous vein. To prevent venous congestion, an additional venous anastomosis was performed ( Fig. 1 ). The venous flap was inset after confirming adequate perfusion. At outpatient follow-up, the patient was noted to have developed necrotic edges on his flap that were debrided and treated with appropriate dressings. The patient's flap healed and the fistula remained functional ( Fig. 2 ). Informed consent was obtained from the patient for this case report. Fig. 1 Schematic diagram of flap design. Arterial inflow to the flap is completed using the venous stump of the radiocephalic fistula. The saphenous vein of the venous free flap is used as an interposition bypass graft for arteriovenous fistula preservation and a second subcutaneous vein serves as additional venous outflow. Fistula outflow is established by creating an end-to-end vascular anastomosis between the cephalic vein and the distal end of the greater saphenous vein. Fig. 2 (Above, left) Preoperative photo of the cutaneous squamous cell carcinoma overlying the arteriovenous fistula (AVF) prior to excision. Note the distance to the radial head and location of the tumor in composing much of the distal one-third of the forearm. (Above, right) Preoperative photo of the forearm and AVF after initial excision and prior to further excision of margins and venous free flap. (Center, left) Intraoperative photo during resection of the tumor margins. (Center, right) Isolation of the AVF. The red vessel loop identifies the venous stump of the radiocephalic fistula, whereas the blue vessel loop identifies the cephalic vein. (Below, left) Day of surgery postoperative photo. (Below, right) Postoperative photo during clinic follow-up. Discussion Very little literature exists on the management of cutaneous malignancies overlying AVFs. A case series written by Lucero et al describes two cases with resection of the overlying cutaneous cancer and linear approximation of the wound without disruption of the fistula. 4 Another report by Nath et al described treatment of small CSCC overlying AVF with radiotherapy only. 9 While this is an option in select cases, radiation therapy efficacy is dependent on the size of the lesion, its histopathologic profile, and its location. It is also known to cause serious complications such as fibrosis and skin necrosis that would potentially lead to AVF exposure and subsequent rupture. 10 Thus, this was not a viable treatment approach in our patient as the CSCC was invasive and required wide local excision per standard of care. 2 However, resection of a cutaneous cancer overlying a superficial AVF presents unique challenges as the risk of potential complications including laceration, hemorrhage, and the need for ligation are high. 4 9 Damage to these fistulas rendering them unusable has consequences in patients who may need them for lifeline dialysis access. While there is ongoing debate in medical community regarding optimal management of AVF in patients after successful renal transplant, most agree with AVF preservation unless there is concern for high output fistula leading to cardiac strain. 11 12 13 14 AVF preservation in our case was important as the patient had a history of multiple hospital readmissions with possible impending renal transplant failure. Defect reconstruction using free flaps allow for appropriate coverage with preservation of function but often lead to significant donor site morbidity and require ligation of one of the major arterial branches. 15 Given these constraints venous free flaps were developed to treat burn scars and other wounds in the upper and lower extremities. 16 Venous flaps are readily available, don't require sacrifice of major arterial branch, are pliable, and can be harvested as composite grafts. 17 A new method described in this paper achieved simultaneous goals of adequate cancer resection and large soft tissue defect coverage with AVF preservation using a flow-through free venous flap. This technique showed promising results in our patient who had a functional fistula, healed free flap, and donor sites. His 5-month postoperative duplex ultrasound showed a functional AVF ( Fig. 3 ). The flap showed some marginal loss and delayed healing to the tissues of the forearm. Given the high flow nature of the reconstructed fistula, steal syndrome could have accounted for the poor marginal perfusion within the flap. 6 18 19 20 Fig. 3 Duplex of the arteriovenous fistula 5 months after reconstruction with the venous flap. In conclusion, this case report describes a new method of fistula preservation and soft tissue coverage after resection of an upper limb CSCC using a flow-through venous free flap. It demonstrates an option for AVF preservation that has not been previously described. It also highlights the importance of a multidisciplinary approach for the safe treatment of cutaneous cancers overlying AVFs for best patient outcomes. Authors' Contributions Ethical Approval Patient Consent Conflict of Interest None declared. The authors confirm contribution to the paper as follows: study conceptualization: A.O. and N.W.; data curation: M.A., K.K.; writing review and editing: C.A. All authors reviewed and approved the final version of the manuscript. This case report was exempted form institutional review board (IRB) approval form the IRB Board of University of Iowa. Informed consent was obtained for all patient images and information included in this case report. References 1 Genders R E Osinga J AJ Tromp E E O'Rourke P Bouwes Bavinck J N Plasmeijer E I Metastasis risk of cutaneous squamous cell carcinoma in organ transplant recipients and immunocompetent patients Acta Derm Venereol 2018 98 06 551 555 29405246 2 Lanz J Bouwes Bavinck J N Westhuis M Aggressive squamous cell carcinoma in organ transplant recipients JAMA Dermatol 2019 155 01 66 71 30516812 3 Abreo K Sachdeva B Abreo A P To ligate or not to ligate hemodialysis arteriovenous fistulas in kidney transplant patients J Vasc Access 2021 22 06 942 946 33176556 4 Lucero O M Echaiz C F Jafarian F Keratinocyte carcinomas arising near arteriovenous fistulas: case series and safety considerations for dermatologic surgery: a report of the International Transplant Skin Cancer Collaborative JAAD Case Rep 2018 5 01 7 11 30547074 5 Giesen T Forster N Kunzi W Giovanoli P Calcagni M Retrograde arterialized free venous flaps for the reconstruction of the hand: review of 14 cases J Hand Surg Am 2014 39 03 511 523 24559628 6 Agarwal P Kumar A Sharma D Feasibility of type III venous flap in coverage of hand defects following trauma and burns J Clin Orthop Trauma 2016 7 02 150 153 28053377 7 Efanov J I ElHawary H Chollet A Mottard S Borsuk D E The pediatric arterialized venous flow-through flap Plast Reconstr Surg Glob Open 2021 9 03 e3488 33777601 8 Yu G Lei H Y Guo S Huang J H Yu H Dorsalis pedis arterialized venous flap for hand and foot reconstruction Chin J Traumatol 2012 15 01 32 35 22300917 9 Nath N S Gilmore B F McCann R K Mosca P J Management of a cutaneous squamous cell carcinoma overlying an AV fistula BMJ Case Rep 2017 2017 bcr-2016-218932 10 Locke J Karimpour S Young G Lockett M A Perez C A Radiotherapy for epithelial skin cancer Int J Radiat Oncol Biol Phys 2001 51 03 748 755 11697321 11 Letachowicz K Banasik M Krolicka A Vascular access perspectives in patients after kidney transplantation Front Surg 2021 8 640986 33996883 12 Yaffe H C Greenstein S M Should functioning AV fistulas be ligated after renal transplantation? J Vasc Access 2012 13 04 405 408 22865530 13 Wilmink T Hollingworth L Dasgupta I Access ligation in transplant patients J Vasc Access 2016 17 (1, suppl 1):S64 S68 26951908 14 Allon M Vascular access for hemodialysis patients: new data should guide decision making Clin J Am Soc Nephrol 2019 14 06 954 961 30975657 15 Benanti E De Santis G Leti Acciaro A Colzani G Baccarani A Starnoni M Soft tissue coverage of the upper limb: a flap reconstruction overview Ann Med Surg (Lond) 2020 60 338 343 33224487 16 Odobescu A 478 complex burn reconstruction with venous flaps J Burn Care Res 2019 40 01 213 213 17 Roberts J M Carr L W Haley C T Hauck R M Michelotti B F Venous flaps for revascularization and soft-tissue coverage in traumatic hand injuries: a systematic review of the literature J Reconstr Microsurg 2020 36 02 104 109 31454834 18 Yan H Brooks D Ladner R Jackson W D Gao W Angel M F Arterialized venous flaps: a review of the literature Microsurgery 2010 30 06 472 478 20238385 19 Goldschlager R Rozen W M Ting J WC Leong J The nomenclature of venous flow-through flaps: updated classification and review of the literature Microsurgery 2012 32 06 497 501 22434451 20 Rozen W M Ting J WC Gilmour R F Leong J The arterialized saphenous venous flow-through flap with dual venous drainage Microsurgery 2012 32 04 281 288 22377842 |
PLoS BiolPLoS BiolpbioplosbiolPLoS Biology1544-91731545-7885Public Library of Science San Francisco, USA 10.1371/journal.pbio.0030152ObituaryEcologyEvolutionNoneOn the Importance of Being Ernst Mayr "Darwin's apostle" died at the age of 100ObituaryMeyer Axel 5 2005 5 4 2005 5 4 2005 3 5 e152Copyright: (c) 2005 Axel Meyer.2005This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.Ernst Mayr lived for a century and accomplished more than several lifetimes worth of science in different biological disciplines, most notably evolutionary biology. Axel Meyer reflects on this remarkable man Born on July 5, 1904, in Kempten in southern Germany, Ernst Mayr passed away peacefully at the Methuselah-like age of 100 on February 3, 2005, in Bedford near Cambridge, Massachusetts. Mayr was, by the accounts of his Harvard colleagues the late Stephen Jay Gould and Edward O. Wilson, not only the greatest evolutionary biologist of the 20th century, but even its greatest biologist overall. Thomas Henry Huxley was dubbed "Darwin's bulldog" for fighting for the acceptance of Darwinian ideas soon after their inception in the last decades of the 19th century. Similarly, Ernst Mayr has been called "Darwin's apostle" or the "Darwin of the 20th century" for promoting and dispersing Darwin's hypotheses throughout the past century. Mayr lived for a century and accomplished more than several lifetime's worth of science in different biological disciplines. Brought up by parents who loved nature and who took the young Ernst on long hikes, he was exposed to natural history early on, but although birds were his passion all his life, he was, like Darwin, first compelled to study medicine. He began his studies at Greifswald a prime birding spot and through the chance observation of a rare species of duck that had not been seen in Germany for many years, he came in contact with the Berlin ornithologist Erwin Stresemann, who proposed that he switch to biology. Mayr abandoned medicine for biology and published his first scientific paper (of a total of almost 700) at the age of 19 in 1923, receiving his Ph.D. from Humboldt University in Berlin after only 16 months of graduate work and dissertation research; he was just 22. Ernst Mayr's last book (of a total of 25) was published in August 2004, a month after he turned 100 . In 1931, thinking that he would not be offered a permanent post in Germany, he moved from Berlin to the American Museum of Natural History in Manhattan. In New York he called himself an ornithologist, and believed then, like many of his contemporaries, in Lamarkian inheritance. Sent by his advisor Erwin Stresemann from Berlin and financed by Lord Rothschild, he had just returned from over two years of perilous fieldwork in New Guinea and the Solomon Islands. The parallels to the lives of Darwin and Wallace may not be coincidental. During these expeditions, forlorn, at times given up for dead, exposed to tropical diseases and the danger of headhunters, he collected the skins of thousands of specimens, eating the flesh of many. Mayr was not only the ornithologist who probably tasted the largest number of different species of birds, but he also named 26 new species and over 400 new subspecies, more than any other taxonomist. In over 300 publications throughout his life, he discussed and described the geographic variation and distribution of birds and he also edited the last eight volumes of the Checklist of the Birds of the World. His main occupation during his 20 years at the American Museum was to curate and research the 280 000 specimens of the Rothschild collection. Ernst Mayr in 1994, after receiving an honorary degree at the University of Konstanz (Photo: University of Konstanz) In the 1930s, Mayr's friendship and interactions with the Russian-born Columbia University population geneticist Theodosius Dobzhansky, author of the landmark text Genetics and the Origin of Species published in 1937 , started to influence his thinking. Mayr's interests subsequently began to diversify beyond taxonomy into evolutionary biology, and this expansion of his interests culminated in his first, and possibly still most important book, Systematics and the Origin of Species, published in 1942 . This was his main contribution to the so-called Modern Synthesis of the 1930s and 1940s, a scientific sea change that came about largely through the contributions of Mayr and Dobzhansky and other scientists such as Ronald A. Fisher and George G. Simpson. Mayr's first book combined insights and methods from paleontology, population genetics, systematics, and natural history, thus providing a unified modern evolutionary theory. Patterns and processes in natural populations would now be seen as consistent with Darwinian natural selection and Mendelian mechanisms of inheritance, and the behavior of genes in populations came to be understood through laboratory population genetic experiments and theoretical mathematical predictions. Mayr was the last survivor, and historical eyewitness, among the architects of the Modern Synthesis. Ernst Mayr had many fundamental insights into evolutionary biology, and almost every topic of importance in evolution was advanced by his ideas. Perhaps his most widely known contribution is to the current notion of what constitutes a species. Darwin did not think that species were real in the philosophical sense, but rather that they were the result of the human predilection to perceive discontinuity among continuously varying individuals. Most biologists nowadays disagree with Darwin's view of species, largely because of Mayr's "biological species concept". Together with Dobzhansky, Mayr developed this definition of species "as groups of interbreeding populations in nature, unable to exchange genes with other such groups living in the same area" . Barriers to gene flow between species termed reproductive isolating mechanisms keep biological species distinct through processes such as species-specific mate choice and hybrid sterility. Although there are theoretical and operational problems with the biological species concept (e.g., it does not apply to asexually reproducing organisms such as bacteria), it is still, by far, the most widely used species concept among the 20 or so competing definitions that have been proposed in the past several decades. Students of biology all over the world have memorized Mayr's definition of species for more than half a century. The biological species concept made it possible to study how species arise, since the criterion of reproductive isolation provided a scientifically rigorous litmus test. The origin of species is a topic to which Darwin himself, in spite of the promising title of his famous book, did not say all that much. Mayr's understanding of the biogeographic distributions of bird species, overlaid with extensive knowledge about variation in morphology, led him to develop concepts about the geographic mechanisms of speciation cornerstones for those studying speciation today. The geographic separation of populations, such as by rivers or valleys, he argued, prohibits homogenizing gene flow between them. If such isolated (termed allopatric) populations accumulate mutations over time, this might lead to the divergence of such populations from each other, and reproductive isolation might arise as a simple byproduct of these separate evolutionary histories. Mayr staunchly defended this idea during sometimes heated debates and further developed it and other hypotheses regarding geographic mechanisms of speciation over many decades (outlined in depth in the 797 pages of Animal Species and Evolution ). One mechanism of speciation in particular is still contested (see and ). Mayr called it "peripatric speciation" or "founder-effect speciation." And it is an idea that Ernst Mayr was particularly fond of. He believed it to be his most important contribution to evolutionary biology. This model was again inspired by Mayr's own natural history observations. He noted that on some New Guinea islands, populations of birds differed markedly from individuals of the mainland population. He reasoned that this differentiation and speciation could result from a small number of individuals founding the island population. By bringing only a subset of all the genes of the main population (causing a genetic bottleneck), genetic drift (random fixation) and natural selection (due to a different set of selection pressures on these islands) would not only promote the formation of new species but would do so rapidly. This mechanism might also account for the paleontological pattern called "punctuated equilibrium," which was proposed by Nils Eldredge and Gould in 1972 . They noted that long periods of morphological stasis were sometimes interrupted (punctuated) by short periods of drastic phenotypic change in the fossil record. Somewhat ironically, Mayr, who considered himself a "gradualist" all his life, seems to have also provided a mechanism for variability in rates of evolution along evolutionary lineages. After establishing the Society for the Study of Evolution and serving as the first editor of its journal, Evolution, Mayr moved to Harvard University in 1953 as the Alexander Agassiz Professor of Zoology and curator of birds at the Museum of Comparative Zoology. By this time, one surely would have labeled him primarily an evolutionary biologist rather than an ornithologist. His interests expanded even further into the theory of systematics another field to which he made many contributions (see Principles of Systematic Zoology ). A lifelong and, it seems fair to say, futile fight with the then emerging idea of cladistics in systematic biology began. Ernst Mayr also served as director of the Museum of Comparative Zoology before his retirement in 1975 and oversaw the building of a new addition to the museum, whose library was renamed after him ten years ago. What of his retirement? Mayr published 14 of his 25 books in the 30 years that followed after his official retirement. During the last two decades of his life, Mayr began to think and write more about the history and philosophy of biology. His most important work of this period was The Growth of Biological Thought , a monumental 974 pages. Here, and in later books and publications (he also founded the Journal of the History of Biology), he laid out why he thought that the philosophy of biology is an autonomous science that differs fundamentally from the philosophy of science, which, Mayr implied, was largely derived from physics. He argued that biology is a science that is based on historical contingency as well as on many unpredictable and coincidental factors that make it impossible to discover laws. Rules, not laws, are all that one will be able to find in biology. Clearly, Ernst Mayr felt very strongly that he had something of importance to say to the world. And the world, not only in its scientific realms, seemed to think likewise. He received almost 20 honorary degrees from major universities, was a member of more academies than any other scientist before him, and received most of the prizes that could possibly be awarded to a biologist, including the Japan Prize, the Balzan Prize, and the Crafoord Prize, the "Nobel Prize for ecologists and evolutionary biologists." How could one person possibly fit so much into one lifetime, even such an astonishingly long one? For a start, he was a man of stringent self-discipline, who would get up with (or before) the birds, like a good ornithologist should. Writing (longhand or dictation) was done mostly in the mornings, and long walks were part of every day, as were extended periods of reading and corresponding with his colleagues. Just like Darwin, Mayr wrote thousands of letters minding the business of others, telling his fellow scientists what he thought of their work, praising them but also advising them on missed literature and new directions for further study. He did not like to be bothered with those other menial things that also belong to living on this planet, and, luckily for him, Gretel, his wife of 55 years, mostly took care of that part. So after her death ten years ago, when he was in his early 90s, he had to learn how to cook a hamburger for himself. Ernst was gifted with an astonishing clarity of thought. Something that always impressed and humbled me was that the transcripts of his dictated manuscripts required very little further editing. Even Mayr's native-English-speaking competitors praised him, obviously a nonnative, for his lucid and clear writing style. Ernst also had the ability to store an astonishing amount of information drawn from many different sources his memory was spectacular. His ability to synthesize ideas, combined with an amazing recall of natural history, an exact visual memory, and an overall wide scientific horizon, was awe-inspiring and, more than in anyone else I've ever met, produced a plethora of novel ideas. His vitality was also legendary. He would still climb trees in his mid-80s to inspect birds' nests, and he bought his last new car after having passed the age of 90, much to the astonishment of the car salesman, as he once told me. Pulitzer Prize winner Natalie Angier from the New York Times once described Ernst Mayr in an interview as "opinionated and elitist, courtly and generous." Ernst Mayr was all that. He was strong-willed, had little patience for people who had not done their homework or talked without having their natural history straight or their line of reasoning well thought out, and he could be damning in his judgment of the ideas of others. Yet he generously shared not only his thoughts, but also charitably donated a good portion of his salary and most of his significant prize money to causes such as the Nature Conservancy and to endow prizes for young evolutionary biologists. Although Ernst Mayr lived only about a tenth of the 969 years that Methuselah is purported to have lived, he still accomplished much more than one might expect to get done, even in a 100 years. More important than his scientific output is the overarching influence he has had on the thinking of three or four generations of biologists that he was a contemporary of and interacted with. The scientific world lost a giant and an inspirational thinker. His doctoral advisor Stresemann once called Mayr a rising star. Nobody since Darwin shed the light of insight as bright over the firmament of evolutionary biology as Ernst Mayr did. His star has not stopped shining, and his ideas will continue to live on for generations of young evolutionary biologists to come. On the occasion of his 100th birthday Mayr published an article in Science looking back over eight decades of research in evolution that he closed with the following words: "The new research has one most encouraging message for the active evolutionist: it is that evolutionary biology is an endless frontier and there is still plenty to be discovered. I only regret that I won't be present to enjoy these future developments." Citation: Meyer A (2005) On the importance of being Ernst Mayr. PLoS Biol 3(5): e152. Axel Meyer is Professor of Zoology and Evolutionary Biology at the University of Konstanz in Germany. E-mail: [email protected] References Mayr E What makes biology unique? 2004 Cambridge Cambridge University Press 246 Dobzhansky T Genetics and the origin of species 1937 New York Columbia University Press 364 Mayr E Systematics and the origin of species 1942 New York Columbia University Press 334 Mayr E Animal species and evolution 1963 Cambridge (Massachusetts) Belknap Press 797 Coyne JA Orr HA Speciation 2004 Sunderland (Massachusetts) Sinauer Associates 545 Gavrilets S Fitness landscapes and the origin of species 2004 Princeton (New Jersey) Princeton University Press 476 Eldredge N Gould SJ Schopf TJM Punctuated equilibria: An alternative to phyletic gradualism Models in paleobiology 1972 San Francisco Freeman, Cooper and Co 82 115 Mayr E Principles of systematic zoology 1969 New York McGraw-Hill 428 Mayr E The growth of biological thought 1982 Cambridge (Massachusetts) Belknap Press 974 Mayr E Happy birthday: 80 years of watching the evolutionary scenery Science 2004 305 46 47 15232092 |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.