title: Genome-wide pleiotropy analysis identifies novel blood pressure variants and improves its polygenic risk scores

abstract: Systolic and diastolic blood pressure (S/DBP) are highly correlated modifiable risk factors for cardiovascular disease (CVD). We report here a bidirectional Mendelian Randomization (MR) and pleiotropy analysis of systolic and diastolic blood pressure (BP) summary statistics from the UKB-ICBP BP genome-wide association study (GWAS) and construct a composite genetic risk score (GRS) by including pleiotropic variants. The composite GRS captures greater (1.11-3.26 fold) heritability for BP traits and increases (1.09- and 2.01-fold) Nagelkerkes R2 for hypertension (HTN) and cardiovascular disease (CVD). We replicated 118 novel BP pleiotropic variants including 18 novel BP loci using summary statistics from the Million Veteran Program (MVP) study. An additional 219 novel BP signals and 40 novel loci were identified after meta-analysis of the UKB-ICBP and MVP summary statistics but without further independent replication. Our study provides further insight into BP regulation and provides a novel way to construct a GRS by including pleiotropic variants for other complex diseases.


title: Two Data-Driven Approaches to Identifying the Spectrum of Problematic Opioid Use: A Pilot Study within a Chronic Pain Cohort

abstract:
ASTRACTO_ST_ABSBackgroundC_ST_ABSAlthough electronic health records (EHR) have significant potential for the study of opioid use disorders (OUD), detecting OUD in clinical data is challenging. Models using EHR data to predict OUD often rely on case/control classifications focused on extreme opioid use. There is a need to expand this work to characterize the spectrum of problematic opioid use.

MethodsUsing a large academic medical center database, we developed 2 datadriven methods of OUD detection: (1) a Comorbidity Score developed from a Phenome-Wide Association Study of phenotypes associated with OUD and (2) a Textbased Score using natural language processing to identify OUD-related concepts in clinical notes. We evaluated the performance of both scores against a manual review with correlation coefficients, Wilcoxon rank sum tests, and area-under the receiver operating characteristic curves. Records with the highest Comorbidity and Text-based scores were re-evaluated by manual review to explore discrepancies.

ResultsBoth the Comorbidity and Text-based OUD risk scores were significantly elevated in the patients judged as High Evidence for OUD in the manual review compared to those with No Evidence (p = 1.3E-5 and 1.3E-6, respectively). The risk scores were positively correlated with each other (rho = 0.52, p < 0.001). AUCs for the Comorbidity and Text-based scores were high (0.79 and 0.76, respectively). Follow-up manual review of discrepant findings revealed strengths of data-driven methods over manual review, and opportunities for improvement in risk assessment.

ConclusionRisk scores comprising comorbidities and text offer differing but synergistic insights into characterizing problematic opioid use. This pilot project establishes a foundation for more robust work in the future.

category: health informatics


title: Race and Ethnic Group Dependent Space Radiation Cancer Risk Predictions

abstract: Future space missions by national space agencies and private industry, including space tourism, will include a diverse makeup of crewmembers with extensive variability in age, sex, and race or ethnic groups. The relative risk (RR) model is used to transfer epidemiology data between populations to estimate radiation risks. In the RR model cancer risk is assumed to be proportional to background cancer rates and limited by other causes of death, which are dependent on genetic, environmental and dietary factors that are population dependent. Here we apply the NSCR-2020 model to make the first predictions of age dependent space radiation cancer risks for several U.S. populations, which includes Asian-Pacific Islanders (API), Black, Hispanic (white and black), and White (non-Hispanic) populations. Results suggest that male API and Hispanic populations have the overall lowest cancer risks, while White females have the highest risk. Blacks have similar total cancer rates as Whites, however their reduced life expectancy leads to modestly lower lifetime radiation risks compared to Whites. There are diverse tissue specific cancer risk ranking across sex and race, which include sex specific organ risks, females having larger lung, stomach, and urinary-bladder radiation risks, and males having larger colon and brain risks.

category: health policy


title: Advancing convergent mixed methods design using the Diamond Approach for clinical multiple case studies: an example using data on time to treatment in aneurysmal subarachnoid haemorrhage

abstract: Using a new approach to the analysis and synthesis of a clinically focused mixed-methods multiple case study of aneurysmal subarachnoid haemorrhage (aSAH), we explored barriers and facilitators to timely treatment. In this paper we provide guidance for the multiple steps of analysis and synthesis of qualitative and quantitative data from across and within 27 case studies. Results showed that median (IQR) time to treatment was 15.1 (9.0, 24.1) hours. Only 37% of cases had treatment within 12-hours of onset. Early recognition of aSAH, good coordination, and availability of resources for treatment were main facilitators for treatment within 12 hours from onset. Lack of recognition of aSAH at onset and lack of resources for immediate in-hospital treatment were major barriers.

category: health systems and quality improvement


title: Experienced hearing aid users perspectives of assessment and communication within audiology: A qualitative study using digital methods

abstract:
ObjectiveTo explore experienced hearing aid users perspectives of audiological assessments and the patient-audiologist communication dynamic during clinical interactions.

DesignA qualitative study was implemented incorporating both an online focus group and online semi-structured interviews. Sessions were audio-recorded and transcribed verbatim. Iterative-inductive thematic analysis was carried out to identify themes related to assessment and communication within audiology practice.

Study samplesSeven experienced hearing aid users took part in an online focus group and 14 adults participated in semi-structured interviews (age range: 22 - 86 years; 9 males, 11 females).

ResultsThemes related to assessment included the unaided and aided testing procedure and relating tests to real world hearing difficulties. Themes related to communication included the importance of communication strategies, explanation of test results and patient centred care in audiology.

ConclusionTo ensure that hearing aid services meet the needs of the service users, we should explore user perspectives and proactively adapt service delivery. This approach should be ongoing, in response to advances in hearing aid technology. Within audiology, experienced hearing aid users value 1) comprehensive, relatable hearing assessment, 2) clear, concise, deaf aware patient-audiologist communication, 3) accessible services and 4) a personalised approach to recommend suitable technology and address patient specific aspects of hearing loss.


title: TerraFlow, A New High Parameter Data Analysis Tool, Reveals Systemic T-cell Exhaustion and Dysfunctional Cytokine Production in Classical Hodgkin Lymphoma

abstract: The incredible variety of immune-related proteins presents enormous challenges in immuno-monitoring. Combinatorial expression of these proteins defines cell types that may influence disease. Using high-parameter flow cytometry, and a new data analysis algorithm (TerraFlow), immunophenotypes can be comprehensively surveyed for disease associations. In classical Hodgkin lymphoma, where systemic T-cell immunity has not been investigated in detail, we reveal immune perturbations in newly-diagnosed patients (compared to healthy controls): 1) reduced levels of early (CD127+ CCR7+) memory T-cells, 2) elevated levels of activated (CD278+) memory T-cells primed for apoptosis (CD95+) and expressing inhibitory/exhaustion receptors (CD272+, PD1+, CD152+, CD366+), 3) increased suppressive (GITR+) cells, and 4) a shift away from TH1 and TH2 cells (IFNg+, IL4+) toward IL17-producing cells. Many of these perturbations remain after treatment. Our results provide mechanistic support for past reports of immune deficiency in Hodgkin lymphoma, detail new immunotherapy and biomarker research targets, and suggest strategies for combination therapies.

category: allergy and immunology


title: Coronavirus disease (COVID-19) associated Mucormycosis: An Anaesthesiologist's Perspective

abstract: In India, the second wave of coronavirus disease (COVID -19) was associated with a distinct surge in cases of invasive fungal infection with mucormycosis. This disease was seen typically in the sinonasal form in COVID-19 patients. Uncontrolled diabetes, steroid use in COVID-19 treatment, etc. were some of the postulated risk factors for the association of COVID 19 and Mucormycosis. The management plan of these cases included surgical debridement, systemic antifungal therapy, sugar control, and management of antifungal related systemic adverse effects. In this retrospective case record review, we aimed to evaluate the airway management plan, demographics, and overall outcomes in patients undergoing surgical resection for COVID-19 associated mucormycosis. Forty-one (71.9 %) patients had a diagnosis of sino-nasal mucormycosis, fourteen (24.6%) had a diagnosis of rhino-orbital mucormycosis, and 2 patients (3.5%) were diagnosed with palatal mucormycosis. Total 44 (77.19 %) patients had co-morbidities. The most common co-morbidity was Diabetes Mellitus 42 (73.6%), followed by hypertension 21 (36.84%) and Acute kidney injury 14 (28.07%). We used the intubation difficulty scale score to assess intubating conditions. Intubation was easy to slightly difficult in 53 out of 57 patients. In our study, mortality occurred in 7 (12.28 %) patients. The median mortality time was 60 (range, 27-74) days. The median time to hospital discharge was 53.5 (range,10-85) days. Managing COVID-19 on its own is challenging and additional mucormycosis can lead to increased morbidity and mortality. Despite challenges and risks, timely and meticulous interventions can reduce complications.

category: anesthesia


title: Airway management, procedural data, and mortality records of patients undergoing surgery for mucormycosis associated with coronavirus disease (COVID-19)


title: Expanding The Use Of Friedewald Equation In Lipid Profile Testing Among HIV Positive And Negative Elderly Persons

abstract: Hypercholesterolemia and hypocholesterolemia are associated with mortality which warrants routine lipid profile testing. This financially burdens the already overwhelmed health sector especially in developing countries. Additionally, lipid profile test reagent stock-out or failure to afford all tests affects result interpretation. In 1972, James Friedewald published a statistical model to calculate low density lipo-protein. The study aim was to determine the percentage error of the James Friedewald equation in calculating all lipid profile test parameters. A retrospective study from 2018 was performed at Mildmay Uganda involving lipid profile results of 103 persons (48 HIV-positive and 55 HIV-negative) 50 years and older enrolled in a previous cross-sectional study. The Friedewald equation was used to calculate total cholesterol, high density lipoprotein, triglycerides and low density lipo-protein. The percentage error of calculated values in reference to measured values was ascertained. Pearson correlation between measured and calculated results was determined among all persons and classified by HIV status. The total error of calculated analytes was 7% (low density lipo-protein), 17% (high density lipo-protein), 39% (triglycerides) and 4% (total cholesterol). Pearson correlations were 0.98 (all persons), 0.98 (HIV-negative) and 0.98 (HIV-positive) for low density lipo-protein, 0.89 (all persons), 0.90 (HIV-positive) and 0.88 (HIV-negative) for high density lipo-protein, 0.75 (all persons), 0.76 (HIV-negative) and 0.77 (HIV-positive) for triglycerides, 0.99 (all persons), 0.98 (HIV-negative) and 0.99 (HIV-positive) for total cholesterol. In conclusion, Friedewald equation reliably calculated low density lipo-protein, total cholesterol (most accurate) and high density lipo-protein while triglycerides calculation was erroneous among persons aged [≥] 50 years.

category: cardiovascular medicine


title: Young onset diabetes in Asian Indians is associated with lower measured and genetically determined beta-cell function: an INSPIRED study

abstract:
BackgroundSouth Asians have higher risk of type 2 diabetes compared to white Europeans and a younger age of onset. Reasons for the younger age of onset in relation to beta-cell function and insulin sensitivity are under-explored.

MethodsTwo cohorts of Asian Indians, ICMR-INDIAB (Indian Council of Medical Research-INdia DIABetes Study) and DMDSC (Dr. Mohans Diabetes Specialties Centre) and one of white Europeans, ESDC (East Scotland Diabetes Cohort) were used. We examined the comparative prevalence of healthy, overweight, and obese BMI in young onset diabetes. We explored the role of clinically measured beta-cell function in diabetes onset in Asian Indians. Finally, the comparative distribution of a partitioned polygenic score (pPS) for risk of diabetes due to poor beta cell function was examined.

ResultsPrevalence of young onset with normal BMI was 9.3% amongst white Europeans and 24%-39% amongst Asian Indians. In young diagnosed Asian Indians, after adjustment for family history of T2DM, sex, insulin sensitivity and HDL-c, stimulated C-peptide was 492pmol/mL (IQR: 353,616,P<0.0001) lower in lean compared to obese individuals. Asian Indians have lower genetically determined beta-cell function than white Europeans(P <0.0001). The pPS was associated with age of diagnosis in Asian Indians but not in white Europeans. The pPS explained 2% of variation in clinically measured beta cell function and 1.2%, 0.97%, and 0.36% of variance in age of diabetes amongst Asian Indians with normal, overweight, and obese BMI respectively.

ConclusionsAsian Indians have over two times the prevalence of lean BMI in young onset diabetes compared to white Europeans. This phenotype of lean, young onset diabetes appears driven in part by lower beta cell function. We demonstrate that Asian Indians with diabetes also have lower genetically determined beta cell function.

category: endocrinology


title: Analysis of the prediction of the 2021 time-evolution of the COVID-19 Pandemic in Italy using a Planck's distribution

abstract: In a previous paper we studied the time evolution of the Covid-19 pandemic in Italy during the first wave of 2020 using a number of distribution laws. We concluded that the best distribution law to predict the evolution of the pandemic, if basic conditions of the pandemic (such as distancing measures, use of masks, start of schools, intensive use of public transportation, beginning and end of holidays, vaccination campaign and no significant onset of new Covid variants) do not appreciably change, is a distribution of the type of Plancks law with three parameters. In our 2020 study we did not use the number of daily positive cases in Italy but the ratio of daily positive cases per number of daily tests, ratio today sometimes referred to as: "positivity rate". We showed that, if basic conditions do not change, the Plancks distribution with three parameters provides very good predictions of the positivity rate about one month in advance. In particular, in a second paper, using the Plancks distribution with three parameters, we predicted, about one month in advance, the spread of the pandemic in Italy during the Christmas 2020 holidays with an error of a few percent only. We then study the present (September 2021) evolution of the pandemic in Italy and we show that the Plancks distribution, based on the data of July and August, predicts well the evolution of the pandemic. In particular, we show that the peak of the positivity rate was predicted to occur approximately around the middle of August and that the agreement of this Plancks function (obtained fitting the data up to 10 July 2021) and the positivity rate observed after 5 weeks, on 12 September 2021 is very good. However, the end of the Italian holidays and the start of all the activities including schools, intensive use of public transportation and further changes in distancing measures may cause a discrepancy of the predicted trend of the positivity rate of the pandemic with respect to the real observed values.

category: epidemiology


title: A standardized system and App for continuous patient symptom logging in gastroduodenal disorders: design, implementation, and validation

abstract:
BackgroundFunctional gastroduodenal disorders include functional dyspepsia, chronic nausea and vomiting syndromes, and gastroparesis. These disorders are common, but their overlapping symptomatology poses challenges to diagnosis, research, and therapy. This study aimed to introduce and validate a standardized patient symptom-logging system and App to aid in the accurate reporting of gastroduodenal symptoms for clinical and research applications.

MethodsThe system was implemented in an iOS App including pictographic symptom illustrations, and two validation studies were conducted. To assess convergent and concurrent validity, a diverse cohort with chronic gastroduodenal symptoms undertook App-based symptom logging for 4-hours after a test meal. Individual and total post-prandial symptom scores were averaged and correlated against two previously validated instruments: PAGI-SYM (for convergent validity) and PAGI-QOL (for concurrent validity). To assess face and content validity, semi-structured qualitative interviews were conducted with patients.

Key ResultsApp-based symptom reporting demonstrated robust convergent validity with PAGI-SYM measures of nausea (rS=0.68), early satiation (rS=0.55), bloating (rS=0.48), heartburn (rS=0.47), upper gut pain (rS=0.40) and excessive fullness (rS=0.40); all p<0.001 (n=79). The total App-reported Gastric Symptom Burden Score correlated positively with PAGI-SYM (rS=0.56; convergent validity; p<0.001), and negatively with PAGI-QOL (rS=-0.34; concurrent validity; p=0.002). Interviews demonstrated that the pictograms had adequate face and content validity.

Conclusions and InferencesThe continuous patient symptom-logging App demonstrated robust convergent, concurrent, face, and content validity when used within a 4-hour post-prandial test protocol. The App will enable standardized symptom reporting and is anticipated to provide utility in both research and clinical practice.

category: gastroenterology


title: Prevalence and Incidence of Stress, Depression and Anxiety Symptoms among Brazilians in Quarantine across the early phases of the COVID-19 Crisis

abstract:
ObjectiveThe present study aimed to measure the prevalence and incidence of stress, depression, and anxiety symptoms in Brazilians during the COVID-19 pandemic.

MethodWe assessed 103 (54 women, 49 men) participants online in three periods of the pandemic: March 2020 (T1), April 2020 (T2), and June 2020 (T3). Prevalence and incidence were identified when mental health scores were two standard deviations above the mean compared to normative data. Mental health indicators were measured using the Perceived Stress Scale, the Filgueiras Depression Index, and the State-Trait Anxiety Inventory - State Subscale.

ResultsAt T1, 89% of individuals were below cut-off scores for stress, anxiety, and depression, which dropped to 35% by T3. Stress prevalence was 1.9% at T1, 7.8% at T2, and 28.2% at T3. Depression prevalence was 0% at T1, 23.3% at T2, and 25.2% at T3. State anxiety prevalence was 10.7% at T1, 11.7% at T2, and 45.6% at T3. Stress incidence increased by 7.8% from T1 to T2, and 23.3% from T2 to T3. Depression incidence increased by 23.3% from T1 to T2, and 15.5% from T2 to T3. Anxiety incidence increased by 9.7% from T1 to T2, and 39.8% from T2 to T3. Stress severity scores significantly increased from 16.1{+/-}8.7 at T1 to 23.5{+/-}8.4 at T2, and 30.3{+/-}6.0 at T3. Depression severity scores significantly increased from 48.5{+/-}20.5 at T1 to 64.7{+/-}30.2 at T2, and 75.9{+/-}26.1 at T3. Anxiety increased from 49.0{+/-}13.4 at T1 to 53.5{+/-}12.5 at T2 and 62.3{+/-}13.4 at T3. Females had significantly higher anxiety scores than males by T3 (66.7{+/-}11.8 vs. 57.4{+/-}13.5).

ConclusionPrevalence and incidence of stress, depression, and anxiety significantly increased throughout the pandemic. The largest increase in stress and anxiety occurred between T2 and T3, and between T1 and T2 for depression. Severity of stress, depression, and anxiety increased throughout the study.

category: psychiatry and clinical psychology


title: Prevalence and incidence of stress, depression, and anxiety symptoms among Brazilians in quarantine across the early phases of the COVID-19 crisis


title: Psychosis in Alzheimer's Disease is Associated with Excitatory Neuron Vulnerability and Post-Transcriptional Mechanisms Altering Synaptic Protein Levels

abstract: Alzheimers disease with psychosis (AD+P) is a phenotypic variant of the disease which is associated with a much more rapid deterioration compared to Alzheimers disease without psychosis (AD-P). The neurobiological basis of AD+P is poorly understood. AD is thought to be a disease of the synapse, and our previous studies suggest that those with AD+P have a differentially affected synaptic proteome relative to those with AD-P. We previously demonstrated that multiple neuropathologies only account for approximately 18% of the variance in the occurrence of psychosis in AD. In this study, we utilized RNA-sequencing of dorsolateral prefrontal cortex (DLPFC) in a cohort of 80 AD cases to evaluate novel transcriptomic signatures that may confer risk of psychosis in AD. We found that AD+P was associated with a 9% reduction in excitatory neuron proportion compared to AD-P [Mean (SD) AD+P 0.295 (0.061); AD-P 0.324 (0.052), p = 0.026]. Network analysis identified altered expression of gene modules from protein ubiquitination, unfolded protein response, eukaryotic initiation factor 2 (EIF2) signaling and endoplasmic reticulum stress pathways in AD+P. Including cell type proportions and differentially expressed modules with neuropathology measures explained 67.5% of the variance in psychosis occurrence in our AD cohort.


title: Change in Measles Vaccine Coverage and Estimated Impact on Measles Mortality in Low and Middle Income Countries, 2020: An Investigation into Secondary Public Health Effects of the COVID-19 Pandemic Using the Lives Saved Tool

abstract:
With the global COVID-19 pandemic, many public health services were severely disrupted. Estimating the overall health effects of this is difficult as most disease surveillance systems have also been substantially affected during the pandemic. For some diseases, this effect is mitigated by the methods enacted to fight the pandemic, such as use of facial coverings, social distancing and quarantine, but measles is infectious to the degree that this mitigation is likely to be limited. Thus, outbreaks and an increase in global measles mortality are expected. However, the severity of this impact is not yet known.

In early 2020, a study by Roberton and colleagues predicted an additional 12,360 to 37,920 deaths in children under-five worldwide from measles over the coming year based on three potential levels of vaccine coverage reductions ranging from 18.5 to 51.9%. Our study investigates the magnitude of the increase in measles mortality due to decreased vaccine coverage because of COVID-19, based on official estimates of 2020 measles vaccine coverage from WHO/UNICEF released in July 2021. Using the Lives Saved Tool (LiST), an interventions modeling program, we estimated measles mortality for low/middle income countries (LMICs) based on the 2020 WHO/UNICEF estimates of national immunization coverage (WUENIC). Because these calculations use actual reported vaccine coverage, they provide a more accurate picture of measles mortality related to COVID-19 disruptions in 2020.

Using the WUENIC data, LiST predicted fewer additional deaths in 2020 due to decreases in measles vaccine coverage than estimations made by LiST based on Roberton, 2020 due to remarkable recovery efforts by national immunization programmes in the second half of 2020.

category: public and global health


title: Serial evaluation of anti-SARS-CoV-2 IgG antibody and breakthrough infections in BNT162b2 Vaccinated migrant workers from Bangladesh

abstract:
BackgroundWhile Bangladesh has started its mass COVID-19 vaccination drive, it is struggling to cover its huge population similar to other low- and middle-income countries due to the lack of vaccine availability. One of the major remittance sources for Bangladesh is its migrant workers who are required to receive mRNA vaccines to return to their jobs. Despite reports of higher efficacy of mRNA vaccine against COVID-19, breakthrough infection cases are arising especially with the emergence of Delta variant. It is highly important to understand the post-vaccination immune response and breakthrough infections in different populations so that the necessity of booster dosage can be assessed properly.

MethodsWe observed post BNT162b2 full vaccination immune response in a small older group (mean age= 59.5{+/-}5.44 years) of migrant workers (n=10) for six months at the Sheikh Hasina National Institute of Burn and Plastic Surgery, Dhaka, Bangladesh. The plasma samples from the participants were collected after 14 days, 2 months, 3 months, 4 months, 5 months, and 6 months of receiving the 2nd dose of the BNT162b2 vaccine. Anti S1 RBD IgG responses were measured as optical density ratios using a commercially available ELISA kit.

ResultsAll 10 of the participants were male migrant workers and none of them had a history of previous COVID-19 infection. The median antibody response [IQ1:IQ3] was 9.05 [7.53; 10.0] on day 14 then it increases to 13.6 [12.0; 14.0] at the second month which gradually decreased to a median of 8.63 [8.34; 9.37] on the 6th-month post-vaccination. There were two breakthrough infection cases after receiving the second dose and the antibody responses were highly increased in the following months. Two of the breakthrough cases were diagnosed with mild COVID-19 as the symptom duration was less than 3 days with no respiratory complications and no hospital admission were required.

ConclusionsThe BNT162b2 mRNA vaccine produces a strong immune response that sustains at least 6 months after getting fully vaccinated. But even after getting fully vaccinated people are susceptible to breakthrough infections that are not severe and boost the immune response greatly offering a hybrid immunity from both vaccine and natural infection. Hence, it is still important to fully vaccinate a greater number of people rather than thinking of offering booster dosage to a privileged population out of the fear of breakthrough cases. If the LMICs can quickly cover at least 80% of their population with usual priority targets (healthcare workers, migrant workers, older people, etc.) then a global risk reduction and pandemic control would be possible that will allow additional variant-specific boosters for targeted populations if evidence support.


title: Anticarcinogenic effects from plasma elderly trained: the role of mitochondrial function

abstract: This study aimed to evaluate the effects of a multimodal exercise training on systemic cytokine levels of the elderly, and the impact of post-exercise training plasma on prostate cancer cell viability and proliferation in vitro. Fasting blood samples were collected from eight institutionalized elderly before and after eight weeks of multimodal exercise training (twice a week). The levels of interleukin(IL)-1ra, IL-1{beta}, IL-2, IL-6, IL-10, IL-17, interferon (IFN)-, tumor necrosis factor (TNF)-, fibroblast growth factor (FGF)-1, platelet-derived growth factor (PDGF) and transforming growth factor (TGF)- were evaluated in the peripheral blood. PC3 prostate cancer cell lines were incubated with 10% plasma acquired before and after exercise training from each participant. Multimodal exercise training increased the plasma levels of IL-2, IL-10, IFN-, and FGF-1, and decreased TNF- concentrations. PC3 cells presented decreased cell viability evaluated by MTT and lactate dehydrogenase activity as well as lower rates of cell proliferation after the incubation with post-training plasma samples. Furthermore, the incubation of PC-3 cells with post-training plasma decreased the mitochondrial membrane polarization and increased mitochondrial reactive oxygen species (ROS) production without changes in cytosolic ROS. Post-training plasma did not change apoptosis or necrosis rates in the PC-3 cell line. In conclusion, we showed that systemic adaptations in plasma mediators of institutionalized elderly might alter cell viability and proliferation by targeting mitochondrial ROS in a prostate cancer cell line.

category: sports medicine


title: Causal Associations of Self-Reported Walking Pace with Telomere Length in 405,981 middle-aged adults: a UK Biobank study

abstract:
ObjectivesWalking pace is a strong marker of functional and health status. We investigated whether walking pace is also associated with leucocyte telomere length (LTL), which is causally associated with several diseases and has been proposed as a marker of biological age.

MethodsWe used baseline data from UK Biobank participants recruited from March-2006 to July-2010. Walking pace was self-reported as slow, steady/average, or brisk. Accelerometer-assessed measures of total physical activity and intensity were included to support interpretation of walking pace data. LTL was measured by qPCR assay. Bi-directional Mendelian randomization (MR) analyses were undertaken to inform likely causal directions.

ResultsThe analysed cohort comprised 405,981 adults (54% women) with mean age of 56.5 years (SD, 8.1) and body mass index 27.2 kg/m2 (SD, 4.7). Steady/average and brisk walkers had significantly longer LTL compared with slow walkers, with a Z-standardised LTL difference of 0.066 (0.053-0.078) and 0.101 (0.088-0.113), respectively. Associations remained but were attenuated following full covariate adjustment: 0.038 (0.025-0.051) and 0.058 (0.045-0.072), respectively. Accelerometer data (n=86,002) demonstrated a non-linear association between LTL and habitual movement intensity, but not total activity. MR analysis supported a causal association of walking pace on LTL, with an increase in Z-standardised LTL of 0.192 (0.077, 0.306) for each difference in walking pace category. No evidence of a causal association was observed for LTL on walking pace.

ConclusionFaster walking pace may be causally associated with longer LTL, which could explain some of the beneficial effects of brisk walking on health status.


title: University of Texas at Arlington (UTA) in-house COVID-19 testing program

abstract: The pandemic caused by the spread of the virus SARS-CoV-2 threatened to severely disrupt the activities of student-athletes. (REF) In order to provide a safe environment for athletic competition, the National Collegiate Athletic Association (NCAA) mandated testing of student-athletes. The goal was to rapidly identify student-athletes and the athletic staff member who either tested positive for SARS-CoV-2 or were in contact with individuals who tested positive. Rapid identification of infected individuals and their contacts allowed the University to implement quarantine standards and quarantine facilities quickly as needed. The University of Texas at Arlington (UTA) developed an in-house testing program and was quickly able to meet the NCAA requirements, allowing UTA to continue its athletic participation with minimal forfeiture of scheduled games. The purpose of this paper is to report the implementation UTAs COVID prevention program for the universitys athletic program. This program will provide valuable information to other universities planning for the management of COVID prevention in their athletic programs. Challenges and solutions are identified.


title: The phenomenology of tics and tic-like behavior in TikTok

abstract:
Background and ObjectivePediatricians and pediatric subspecialists worldwide have reported a marked increase in functional (conversion) disorders with tic-like behaviors during the COVID-19 pandemic. These patients often report frequent viewing of Tourette Syndrome (TS) TikTok videos, suggesting disease modeling. We aimed to evaluate tic phenomenology in videos posted on TikTok.

MethodsThe 100 most-viewed videos under #tourettes in TikTok were randomly assigned to two primary reviewers (n=3; <2 years independent practice), all pediatric neurologists specializing in movement disorders, for extraction and classification of tic phenomenology. Initial disagreements were solved by consensus. If not resolved, a senior reviewer (n=5; >2 years independent pediatric movement-disorder practice) served as tiebreaker. In addition, two primary and one senior reviewer rated each video on a Likert scale from 1= "All the tics are typical of TS" to 5= "None of the tics are typical of TS". Mean scores and Spearman correlation between primary and senior reviewers were calculated.

ResultsSix videos without tic-like behaviors were excluded. Most videos depicted coprophenomena (coprolalia: 53.2%; copropraxia: 20.2%), often with unusual characteristics. Frequently, videos demonstrated atypical phenomenology such as very strong influence by the environment (motor: 54.3%; phonic: 54.3%), aggression (19.1%), throwing objects (22.3%), self-injurious behaviors (27.7%), and long phrases (>3 words; 45.7%). Most videos portrayed atypical, non-tic behaviors (Median [IQR] Likert ratings: Primary 4.5 [4-5]; Senior 5 [3-5]). Primary vs. senior rater scores demonstrated moderate agreement (r = 0.46; p<0.001).

ConclusionsTS symptoms portrayals on highly-viewed TikTok videos are predominantly not representative or typical of TS.

HighlightsO_LIMany teenagers with functional tic-like disorder have been reported during the COVID-19 pandemic.
C_LIO_LIThese patients report increased viewing of Tourette Syndrome TikTok videos, a popular social media platform, and present with similar tic-like behaviors.
C_LIO_LICurrent TikTok videos are poorly representative of Tourette syndrome and more consistent with functional tic-like behavior.
C_LIO_LIWe provide a detailed description of the phenomenology tics and tic-like behavior portrayed in TikTok.
C_LI

category: neurology


title: Electrophysiological correlates of thalamocortical function in acute severe traumatic brain injury

abstract:
Few reliable biomarkers of consciousness exist for patients with acute severe brain injury. Tools assaying the neural networks that modulate consciousness may allow for tracking of recovery. The mesocircuit model, and its instantiation as the ABCD framework, classifies resting-state EEG power spectral densities into categories reflecting widely separated levels of thalamocortical network function and correlates with outcome in post-cardiac arrest coma.

We applied the ABCD framework to acute severe traumatic brain injury and tested four hypotheses: 1) EEG channel-level ABCD classifications are spatially heterogeneous and temporally variable; 2) ABCD classifications improve longitudinally, commensurate with the degree of behavioural recovery; 3) ABCD classifications correlate with behavioural level of consciousness; and 4) the Coma Recovery Scale-Revised arousal facilitation protocol improves EEG dynamics along the ABCD scale. In this longitudinal cohort study, we enrolled 20 patients with acute severe traumatic brain injury requiring intensive care and 16 healthy controls. Through visual inspection, channel-level spectra from resting-state EEG were classified based on spectral peaks within frequency bands defined by the ABCD framework:  A = no peaks above delta (<4 Hz) range (complete thalamocortical disruption);  B = theta (4-8 Hz) peak (severe thalamocortical disruption);  C = theta and beta (13-24 Hz) peaks (moderate thalamocortical disruption); or  D = alpha (8-13 Hz) and beta peaks (normal thalamocortical function). We assessed behavioural level of consciousness with the Coma Recovery Scale-Revised or neurological examination and, in 12 patients, performed repeat EEG and behavioural assessments at [≥]6-months post-injury.

Acutely, 95% of patients demonstrated  D signals in at least one channel but exhibited heterogeneity in the proportion of different channel-level ABCD classifications (mean percent  D signals: 37%, range: 0-90%). By contrast, healthy participants and patients at follow-up predominantly demonstrated signals corresponding to intact thalamocortical network function (mean percent  D signals: 94%). In patients studied acutely, ABCD classifications improved after the Coma Recovery Scale-Revised arousal facilitation protocol (P<0.05), providing electrophysiological evidence for the effectiveness of this commonly performed technique. ABCD classification did not correspond with behavioural level of consciousness acutely, where patients demonstrated substantial within-session temporal variability in ABCD classifications. However, ABCD classification distinguished patients with and without command-following in the subacute-to-chronic phase of recovery (P<0.01). Patients also demonstrated significant longitudinal improvement in EEG dynamics along the ABCD scale (median change in  D signals: 37%, P<0.05).

These findings support the use of the ABCD framework to characterize channel-level EEG dynamics and track fluctuations in functional thalamocortical network integrity in spatial detail.


title: Low linoleic acid foods with added DHA given to Malawian children with severe acute malnutrition improves cognition: a randomized, triple blinded, controlled clinical trial

abstract:
BackgroundThere is concern that the PUFA composition of ready-to-use therapeutic food (RUTF) for treatment of severe acute malnutrition (SAM) is suboptimal for neurocognitive recovery.

ObjectiveWe tested the hypothesis that RUTF made with reduced amounts of linoleic acid, achieved using high oleic (HO) peanuts, with or without added DHA, improves cognition when compared to standard RUTF (S-RUTF).

MethodsA triple-blind, randomized, controlled clinical feeding trial was conducted among children with uncomplicated SAM in Malawi with 3 types of RUTF; DHA-HO-RUTF, HO-RUTF and S-RUTF. The primary outcomes, measured in a subset of subjects, were the Malawi Developmental Assessment Tool (MDAT) global and 4 domain (gross motor, fine motor, language and social) z-scores and a modified Willatts problem solving assessment (PSA) intention score for 3 standardized problems, measured 6 months and immediately after completing RUTF therapy, respectively. Plasma fatty acid content, anthropometry and eye tracking were secondary outcomes. Comparisons were made between the novel PUFA RUTFs and S-RUTF.

ResultsAmong the 2565 SAM children enrolled, global MDAT z-score was -0.69 {+/-} 1.19 and - 0.88 {+/-} 1.27 for children receiving DHA-HO-RUTF and S-RUTF, respectively (difference 0.19, 95% CI 0.01 to 0.38). The gross motor and social domains had higher z-scores among children receiving either DHA-HO-RUTF than S-RUTF. The PSA problem 3 scores did not differ by dietary group (Odds ratio 0.92, 95% CI 0.67 to 1.26 for DHA-HO-RUTF). After 4 weeks of treatment, plasma phospholipid EPA and -linolenic acid were greater in children consuming DHA-HO-RUTF or HO-RUTF when compared to S-RUTF (for all 4 comparisons P values < 0.001), but only plasma DHA was greater in DHA-HO-RUTF than S-RUTF (P <0.001).

ConclusionsTreatment of uncomplicated SAM with DHA-HO-RUTF resulted in an improved MDAT score, conferring a cognitive benefit six months after completing diet therapy. This treatment should be explored in operational settings.

category: nutrition


title: COVID-19 Outcomes in Patients with Cancer: Findings from the University of California Health System Database

abstract:
BackgroundPatients with cancer are at risk for poor COVID-19 outcomes. We aimed to identify cancer-related risk factors for poor COVID-19 outcomes.

Patients and MethodsWe conducted a retrospective cohort study using the University of California Health COVID Research Data Set. This database includes prospectively-collected, electronic health data of patients who underwent testing for SARS-CoV-2 at seventeen California medical centers. We identified adult patients tested for SARS-CoV-2 between February 1, 2020 and December 31, 2020, and selected a cohort of patients with cancer using diagnostic codes. We obtained demographic, comorbidity, laboratory, cancer type, and antineoplastic therapy data. The primary outcome was hospitalization within 30 days after first positive SARS-CoV-2 test. Secondary outcomes were SARS-CoV-2 positivity and composite endpoint for severe COVID-19 (intensive care, mechanical ventilation, or death within 30 days after first positive test). We used multivariable logistic regression to identify cancer-related factors associated with outcomes.

ResultsWe identified 409,462 patients undergoing SARS-CoV-2 testing. Of 49,918 patients with cancer, 1,781 (3.6%) tested positive. Patients with cancer were less likely to test positive (OR 0.69, 95%CI 0.66-0.73, P<0.001). BCR-ABL-negative myeloproliferative neoplasms (polycythemia vera, essential thrombocythemia, and primary myelofibrosis) (OR 2.51, 95%CI 1.29-4.89, P=0.007); venetoclax (OR 3.63, 95%CI 1.02-12.92, P=0.046); methotrexate (OR 3.65, 95%CI 1.17-11.37, P=0.026); Asian race (OR 1.92, 95%CI 1.23-2.98, P=0.004); and Hispanic/Latino ethnicity (OR 1.96, 95%CI 1.41-2.73, P<0.001) were associated with increased hospitalization risk. Among 388 hospitalized patients with cancer and COVID-19, cancer type and therapy type were not associated with severe COVID-19.

ConclusionsIn this large, diverse cohort of Californians, cancer was not a risk factor for SARS-CoV-2 positivity. Patients with BCR/ABL-negative myeloproliferative neoplasm and patients receiving methotrexate or venetoclax may be at an increased risk of hospitalization following SARS-CoV-2 infection. Further mechanistic and comparative studies are needed to explain and confirm our findings.

category: oncology


title: Microbiome Dynamics During Chemoradiotherapy for Anal Cancer

abstract:
IMPORTANCEPatients with localized squamous cell carcinoma of the anus (SCCA) who experience treatment toxicity or recurrences have few therapeutic options.

Investigation into the microbiomes influence on treatment toxicity or its potential use as a predictive biomarker in this rare disease could improve these patients outcomes.

OBJECTIVETo longitudinally characterize the SCCA tumor microbiome and assess its association with treatment-related toxicities.

DESIGNProspective cohort study.

SETTINGSingle tertiary cancer center.

PARTICIPANTSTwenty-two patients with biopsy-confirmed non-metastatic SCCA receiving standard-of-care chemoradiotherapy as part of an Institutional Review Board-approved study from April 2017 to July 2019.

MAIN OUTCOMES AND MEASURESDiversity and taxonomic characterization of the SCCA microbiome throughout chemoradiotherapy using swab-based anorectal microbial specimen collection and 16S rRNA gene sequencing.

RESULTSTwenty-two SCCA patients were included in this study with a median (range) age of 58.5 (39-77), and 18 (82%) were women. Alpha diversity remained relatively stable throughout chemoradiotherapy, except for decreases in the Chao1 (P=0.03) and Observed Features (P=0.03) indices at week 5 relative to baseline. Tumor microbial compositions measured using weighted UniFrac changed significantly by the end of treatment (P=0.03). Linear discriminant analysis effect sizes revealed differential enrichment of bacteria at specific time points, including the enrichment of Clostridia at both baseline and follow-up and the enrichment of Corynebacterium at week 5. Patients experiencing high toxicity at week 5 had higher relative abundances of Clostridia, Actinobacteria, and Clostridiales at baseline (P=0.03 for all).

CONCLUSIONS AND RELEVANCEOur study presents the first longitudinal characterization of the SCCA microbiome throughout chemoradiation. The tumor microbiome undergoes significant changes during and after chemoradiotherapy, and patient-reported toxicity levels are associated with patients microbial profiles. Further studies into these microbial characterizations and associations are needed to elucidate the tumor microbiomes role in predicting treatment-related outcomes for SCCA patients.

Key PointsO_ST_ABSQUESTIONC_ST_ABSHow does the squamous cell anal tumor microbiome change during chemoradiotherapy, and how do these changes influence treatment-related toxicity?

FINDINGSProspective longitudinal characterization of anal cancer patients revealed significant modulation of the local tumor microbiome in response to chemoradiotherapy including shifts in overall composition and differential enrichment of key taxa.

Additionally, enrichment of specific taxa at baseline was associated with increased levels of treatment-related toxicities by the end of treatment.

MEANINGThe anal tumor microbiome is significantly altered by chemoradiotherapy and could potentially serve as a biomarker for treatment-related toxicities.


title: Anthropometric measures and their relationship to corneal refractive power in the United States population

abstract:
PurposeTo determine the relationship between anthropometric measures and corneal refractive power (CRP).

MethodsParticipants from the 1999-2008 United States National Health and Nutrition Examination Survey (NHANES) visual exam with demographic, ocular, and anthropometric data (20,165 subjects) were included. Cases with steep cornea were defined by corneal power [≥] 48.0 diopters (n = 171) while controls had dioptric power < 48.0 D (n = 19,994). Multivariable analyses were performed for pooled and sex-stratified populations. Separate models assessed body mass index, height, and weight in relation to steep cornea.

ResultsA relationship between BMI and steep cornea in the pooled population was not detected (P for trend = 0.78). There was a strong inverse relationship between height and steep cornea in the pooled population (P for trend <0.0001) and women (P for trend <0.0001). For every 1-inch increase in height, there was a 16% reduced odds of steep cornea in the pooled population (OR, 0.84; 95% CI: 0.78-0.91). There was also a significant inverse relationship between weight and steep cornea in the pooled population (P for trend = 0.01) and in men (P for trend = 0.02). For each 10-pound increase in weight there was a 7% reduced odds of steep cornea (OR, 0.927; 95% CI: 0.882-0.975) in the pooled analysis.

ConclusionsGreater height and greater weight were associated with a lower risk of steep cornea. These findings can contribute to an improved understanding of the pathogenesis of corneal ectasias.

category: ophthalmology


title: Dense Optic Nerve Head Deformation Estimated using CNN as a Structural Biomarker of Glaucoma Progression

abstract:
PurposeTo present a new structural biomarker for detecting glaucoma progression based on structural transformation of the optic nerve head (ONH) region.

MethodsA dense ONH deformation was estimated using deep learning methods namely DDCNet-Multires, FlowNet2, and FlowNet-Correlation, and legacy computational methods namely the topographic change analysis (TCA) and proper orthogonal decomposition (POD) methods using longitudinal confocal scans of the ONH for each study eye. A candidate structural biomarker of glaucoma progression in a study eye was estimated as average magnitude of flow velocities within the ONH region. The biomarker was evaluated using longitudinal confocal scans of 12 laser-treated and 12 contralateral normal eyes of 12 primates from the LSU Experimental Glaucoma Study (LEGS); and 36 progressing eyes and 21 longitudinal normal eyes from the UCSD Diagnostic Innovations in Glaucoma Study (DIGS). Area under the ROC curves (AUC) was used to assess the diagnostic accuracy of the candidate biomarker.

ResultsAUROC (95% CI) for LEGS were: 0.83 (0.79, 0.88) for DDCNet-Multires; 0.83 (0.78, 0.88) for FlowNet2; 0.83 (0.78, 0.88) for FlowNet-Correlation; 0.94 (0.91, 0.97) for POD; and 0.86 (0.82, 0.91) for TCA methods. For DIGS: 0.89 (0.80, 0.97) for DDCNet-Multires; 0.82 (0.71, 0.93) for FlowNet2; 0.93 (0.86, 0.99) for FlowNet-Correlation; 0.86 (0.76, 0.96) for POD; and 0.86 (0.77, 0.95) for TCA methods. Lower diagnostic accuracy of the learning-based methods for LEG study eyes were due to image alignment errors in confocal sequences.

ConclusionDeep learning methods trained to estimate generic deformation were able to detect ONH deformation from confocal images and provided a higher diagnostic accuracy when compared to the classical optical flow and legacy biomarkers of glaucoma progression. Because it is difficult to validate the estimates of dense ONH deformation in clinical population, our validation using ONH sequences under controlled experimental conditions confirms the diagnostic accuracy of the biomarkers observed in the clinical population. Performance of these deep learning methods can be further improved by fine-tuning these networks using longitudinal ONH sequences instead of training the network to be a general-purpose deformation estimator.


title: Trans-ancestry genome-wide analysis of atrial fibrillation provides new insights into disease biology and enables polygenic prediction of cardioembolic risk

abstract: To understand the genetic underpinnings of atrial fibrillation (AF) in the Japanese population, we performed a large-scale genome-wide association study comprising 9,826 cases of AF among 150,272 individuals and identified five new susceptibility loci, including East Asian-specific rare variants. A trans-ancestry meta-analysis of >1 million individuals, including 77,690 cases, identified 35 novel loci. Leveraging gene expression and epigenomic datasets to prioritize putative causal genes and their transcription factors revealed the involvement of IL6R gene and transcription factor ERG besides the known ones. Further, we constructed a polygenic risk score (PRS) for AF, using the trans-ancestry meta-analysis. PRS was associated with an increased risk of long-term cardiovascular and stroke mortality, and segregated individuals with cardioembolic stroke in undiagnosed AF patients. Our results provide novel biological and clinical insights into AF genetics and suggest their potential for clinical applications.

category: genetic and genomic medicine


title: Out-of-Pocket expenditures associated with Congenital Zika Syndrome in Brazil: an analysis of household health spending

abstract:
IntroductionThe study aims to estimate out-of-pocket household expenditures associated with the diagnosis and follow-up treatment of Congenital Zika Syndrome (CZS) in children affected during the 2015-2016 epidemic in Brazil.

MethodsNinety-six interviews were held in the cities of Fortaleza and Rio de Janeiro in a convenience sample, using a questionnaire on sociodemographic characteristics and private household expenditures associated with the syndrome, which also allowed estimating catastrophic expenditures resulting from care for CZS.

ResultsMost of the mothers interviewed in the study were brown, under 34 years of age, unemployed, and reported a monthly family income of two minimum wages or less. Spending on medicines accounted for 77.6% of the out-of-pocket medical expenditures, while transportation and food were the main components of nonmedical expenditures, accounting for 79% of this total. The mean annual out-of-pocket expenditures by households was equivalent to almost a quarter of the annual minimum wage.

ConclusionsThe affected households were largely low-income and suffered catastrophic expenditures due to the disease. Public policies should consider the financial and healthcare needs of these families to ensure adequate support for individuals affected by CZS.

category: health economics


title: Impact of direct-acting antiviral treatment of hepatitis C on the quality of life of adults in Ukraine

abstract:
BackgroundDirect-acting antivirals (DAAs) are highly effective in achieving sustained virologic response among those with chronic hepatitis C virus (HCV) infection. Quality of life (QOL) benefits for an HCV-infected population with high numbers of people who inject drugs and people living with HIV (PLHIV) in Eastern Europe have not been explored. We estimated such benefits for Ukraine.

MethodsUsing data from a demonstration study of 12-week DAA conducted in Kyiv, we compared self-reported QOL as captured with the MOS-SF20 at study entry and 12 weeks after treatment completion (week 24). We calculated domain scores for health perception, physical, role and social functioning, mental health and pain to at entry and week 24, stratified by HIV status.

ResultsAmong the 857 patients included for the final analysis, health perception was the domain that showed the largest change, with an improvement of 85.7% between entry and week 24. The improvement was larger among those who were HIV negative (104.4%) compared to those living with HIV (69.9%). Other domains that showed significant and meaningful improvements were physical functioning, which improved from 80.5 (95% CI: 78.9-82.1) at study entry to 89.4 (88.1-90.7) at 24 weeks, role functioning (64.5 [62.3-66.8] to 86.5 [84.9-88.2], social functioning (74.2 [72.1-76.2] to 84.8 [83.2-86.5] and bodily pain (70.1 [68.2-72.0] to 89.8 [88.5-91.1]). Across all domains, QOL improvements among PLHIV were more modest than among HIV-negative participants.

ConclusionQOL improved substantially across all domains between study entry and week 24. Changes over the study period were smaller among PLHIV.

category: infectious diseases


title: Low dose prime and delayed boost can improve COVID-19 vaccine efficacies by increasing B cell selection stringency in germinal centres

abstract: The efficacy of COVID-19 vaccines appears to depend in complex ways on the vaccine dosage and the interval between the prime and boost doses. Unexpectedly, lower dose prime and longer prime-boost intervals have yielded higher efficacies in clinical trials. To elucidate the origins of these effects, we developed a stochastic simulation model of the germinal centre (GC) reaction and predicted the antibody responses elicited by different vaccination protocols. The simulations predicted that a lower dose prime could increase the selection stringency in GCs due to reduced antigen availability, resulting in the selection of GC B cells with higher affinities for the target antigen. The boost could relax this selection stringency and allow the expansion of the higher affinity GC B cells selected, improving the overall response. With a longer dosing interval, the decay in the antigen with time following the prime could further increase the selection stringency, amplifying this effect. The effect remained in our simulations even when new GCs following the boost had to be seeded by memory B cells formed following the prime. These predictions offer a plausible explanation of the observed paradoxical effects of dosage and dosing interval on vaccine efficacy. Tuning the selection stringency in the GCs using prime-boost dosages and dosing intervals as handles may help improve vaccine efficacies.


title: Elevated plasma levels of CXCL16 in severe COVID-19 patients

abstract: Genome-wide association studies have recently identified 3p21.31, with lead variant pointing to the CXCR6 gene, as the strongest thus far reported susceptibility risk locus for severe manifestation of COVID-19. In order the determine its role, we measured plasma levels of Chemokine (C{square}X{square}C motif) ligand 16 (CXCL16) in the plasma of COVID-19 hospitalized patients. CXCL16 interacts with CXCR6 promoting chemotaxis or cell adhesion. The CXCR6/CXCL16 axis mediates homing of T cells to the lungs in disease and hyper-expression is associated with localised cellular injury. To characterize the CXCR6/CXCL16 axis in the pathogenesis of severe COVID-19, plasma concentrations of CXCL16 collected at baseline from 115 hospitalized COVID-19 patients participating in ODYSSEY COVID-19 clinical trial were assessed together with a set of controls. We report elevated levels of CXCL16 in a cohort of COVID-19 hospitalized patients. Specifically, we report significant elevation of CXCL16 plasma levels in association with severity of COVID-19 (as defined by WHO scale) (P-value<0.02). Our current study is the largest thus far study reporting CXCL16 levels in COVID-19 hospitalized patients (with whole-genome sequencing data available). The results further support the significant role of the CXCR6/CXCL16 axis in the immunopathogenesis of severe COVID-19 and warrants further studies to understand which patients would benefit most from targeted treatments.


title: Local patterns of spread of influenza A(H3N2) virus in coastal Kenya over a one-year period revealed through virus sequence data

abstract:
BackgroundThe patterns of spread of influenza A viruses in local populations in tropical and sub-tropical regions are unclear due to sparsity of representative spatiotemporal sequence data.

MethodsWe sequenced and analyzed 58 influenza A(H3N2) virus genomes sampled between December 2015 and December 2016 from nine health facilities within the Kilifi Health and Demographic Surveillance System (KHDSS), a predominantly rural region, covering approximately 891 km2 along the Kenyan coastline. The genomes were compared with 1,571 contemporaneous global sequences from 75 countries.

ResultsWe observed at least five independent introductions of A(H3N2) viruses into the region during the one-year period, with the importations originating from Africa, Europe, and North America. We also inferred 23 virus location transition events between the nine facilities included in the study. International virus imports into the study area were captured at the facilities of Chasimba, Matsangoni, Mtondia, and Mavueni, while all four exports from the region were captured from the Chasimba facility, all occurring to Africa destinations. A strong spatial clustering of virus strains at all locations was observed associated with local evolution.

ConclusionOur study shows that influenza A(H3N2) virus epidemics in local populations appear to be characterized by limited introductions followed by significant local spread and evolution.


title: Comprehensive Evaluation of COVID-19 Patient Short- and Long-term Outcomes: Disparities in Healthcare Utilization and Post-Hospitalization Outcomes

abstract:
BackgroundUnderstanding risk factors for short- and long-term COVID-19 outcomes have implications for current guidelines and practice. We study whether early identified risk factors for COVID-19 persist one year later and through varying disease progression trajectories.

MethodsThis was a retrospective study of 6,731 COVID-19 patients presenting to Michigan Medicine between March 10, 2020 and March 10, 2021. We describe disease progression trajectories from diagnosis to potential hospital admission, discharge, readmission, or death. Outcomes pertained to all patients: rate of medical encounters, hospitalization-free survival, and overall survival, and hospitalized patients: discharge versus in-hospital death and readmission. Risk factors included patient age, sex, race, body mass index, and 29 comorbidity conditions.

ResultsYounger, non-Black patients utilized healthcare resources at higher rates, while older, male, and Black patients had higher rates of hospitalization and mortality. Diabetes with complications, coagulopathy, fluid and electrolyte disorders, and blood loss anemia were risk factors for these outcomes. Diabetes with complications, coagulopathy, fluid and electrolyte disorders, and blood loss were associated with lower discharge and higher inpatient mortality rates.

ConclusionsThis study found differences in healthcare utilization and adverse COVID-19 outcomes, as well as differing risk factors for short- and long-term outcomes throughout disease progression. These findings may inform providers in emergency departments or critical care settings of treatment priorities, empower healthcare stakeholders with effective disease management strategies, and aid health policy makers in optimizing allocations of medical resources.


title: Effectiveness of the Single-Dose Ad26.COV2.S COVID Vaccine

abstract:
ImportanceVaccination against the SARS-CoV-2 virus is critical to control the pandemic. Randomized trials demonstrated efficacy of the single-dose Ad26.COV2.S COVID vaccine but data on longer-term protection in clinical practice and effectiveness against variants are needed.

ObjectiveTo assess the effectiveness of Ad26.COV2.S in preventing COVID infections and COVID-related hospitalizations in clinical practice, the longer-term stability of its protective effect and effectiveness against Delta variants.

DesignCohort study of newly Ad26.COV2.S-vaccinated and unvaccinated individuals.

SettingU.S. insurance claims data through July 2021.

ParticipantsIndividuals 18 years and older newly vaccinated with Ad26.COV2.S and up to 10 unvaccinated individuals matched exactly by age, sex, date, location, comorbidity index plus 17 COVID-19 risk factors via propensity score (PS) matching.

InterventionVaccination with Ad26.COV2.S versus no vaccination.

Main outcomesWe estimated vaccine effectiveness (VE) for observed COVID-19 infection and COVID-19-related hospitalization, nationwide and stratified by age, immunocompromised status, calendar time, and states with high incidence of the Delta variant. We corrected VE estimates for under-recording of vaccinations in insurance data.

ResultsAmong 390,517 vaccinated and 1,524,153 matched unvaccinated individuals, VE was 79% (95% CI, 77% to 80%) for COVID-19 and 81% (79% to 84%) for COVID-19-related hospitalizations. VE was stable over calendar time. Among states with high Delta variant incidence, VE during June/July 2021 was 78% (73% to 82%) for infections and 85% (73% to 91%) for hospitalizations. VE for COVID-19 was higher in individuals <50 years (83%; 81% to 85%) and lower in immunocompromised patients (64%; 57% to 70%). All estimates were corrected for under-recording; uncorrected VE was 69% (67% to 71%) and 73% (69% to 76%), for COVID-19 and COVID-19-related hospitalization, respectively.

ConclusionsThese non-randomized data across U.S. clinical practices show high and stable vaccine effectiveness of Ad26.COV2.S over time before the Delta variant emerged to when the Delta variant was dominant.


title: Analysis of SARS-CoV-2 variants from 24,181 patients exemplifies the role of globalisation and zoonosis in pandemics

abstract: After the end of the first epidemic episode of SARS-CoV-2 infections, as cases began to rise again during the summer of 2020, we at IHU Mediterranee Infection in Marseille, France, intensified the genomic surveillance of SARS-CoV-2, and described the first viral variants. In this study, we compared the incidence curves of SARS-CoV-2-associated deaths in different countries and reported the classification of SARS-CoV-2 variants detected in our institute, as well as the kinetics and sources of the infections. We used mortality collected from a COVID-19 data repository for 221 countries. Viral variants were defined based on [≥]5 hallmark mutations shared by [≥]30 genomes. SARS-CoV-2 genotype was determined for 24,181 patients using next-generation genome and gene sequencing (in 47% and 11% of cases, respectively) or variant-specific qPCR (in 42% of cases). Sixteen variants were identified by analysing viral genomes from 9,788 SARS-CoV-2-diagnosed patients. Our data show that since the first SARS-CoV-2 epidemic episode in Marseille, importation through travel from abroad was documented for seven of the new variants. In addition, for the B.1.160 variant of Pangolin classification (a.k.a. Marseille-4), we suspect transmission from mink farms. In conclusion, we observed that the successive epidemic peaks of SARS-CoV-2 infections are not linked to rebounds of viral genotypes that are already present but to newly-introduced variants. We thus suggest that border control is the best mean of combating this type of introduction, and that intensive control of mink farms is also necessary to prevent the emergence of new variants generated in this animal reservoir.


title: Exposures to different SARS-CoV-2 spike variants elicit neutralizing antibody responses with differential specificity towards established and emerging strains

abstract:
The wide spectrum of SARS-CoV-2 variants with phenotypes impacting transmission and antibody sensitivity necessitates investigation of the immune response to different spike protein versions. Here, we compare the neutralization of variants of concern, including B.1.617.2 (Delta) and B.1.1.529 (Omicron) in sera from individuals exposed to variant infection, vaccination, or both. We demonstrate that neutralizing antibody responses are strongest against variants sharing certain spike mutations with the immunizing exposure. We also observe that exposure to multiple spike variants increases the breadth of variant cross-neutralization. These findings contribute to understanding relationships between exposures and antibody responses and may inform booster vaccination strategies.

SUMMARYThis study characterizes neutralization of eight different SARS-CoV-2 variants, including Delta and Omicron, with respect to nine different prior exposures, including vaccination, booster, and infections with Delta, Epsilon, and others. Different exposures were found to confer substantially differing neutralization specificity.


title: SARS-CoV-2 variant exposures elicit antibody responses with differential cross-neutralization of established and emerging strains including Delta and Omicron


title: Reduced magnitude and durability of humoral immune responses by COVID-19 mRNA vaccines among older adults

abstract:
BackgroundmRNA vaccines reduce COVID-19 incidence and severity, but the durability of vaccine-induced immune responses, particularly among the elderly, remains incompletely characterized.

MethodsAnti-spike RBD antibody titers, ACE2 competition and virus neutralizing activities were longitudinally assessed in 151 healthcare workers and older adults (overall aged 24-98 years) up to three months after vaccination.

ResultsOlder adults exhibited lower antibody responses after one and two vaccine doses for all measures. In multivariable analyses correcting for sociodemographic, chronic health and vaccine-related variables, age remained independently associated with all response outcomes. The number of chronic health conditions was additionally associated with lower binding antibody responses after two doses, and male sex with lower ACE2 competition activity after one dose. Responses waned universally at three months after the second dose, but binding antibodies, ACE2 competition and neutralizing activities remained significantly lower with age. Older adults also displayed reduced ability to block ACE2 binding by the Delta variant.

ConclusionsThe humoral immune response to COVID-19 mRNA vaccines is significantly weaker with age, and universally wanes over time. This will likely reduce antibody-mediated protection against SARS-CoV-2 and the Delta variant as the pandemic progresses. Older adults may benefit from additional immunizations as a priority.


title: Evaluating strategies for spatial allocation of vaccines based on risk and centrality

abstract: When vaccinating a large population in response to an invading pathogen, it is often necessary to prioritise some individuals to be vaccinated first. One way to do this is to choose individuals to vaccinate based on their location. Methods for this prioritisation include strategies which target those regions most at risk of importing the pathogen, and strategies which target regions with high centrality on the travel network. We use a simple infectious disease epidemic model to compare a risk-targeting strategy to two different centrality-targeting strategies based on betweenness centrality and random walk percolation centrality, respectively. We find that the relative effectiveness of these strategies in reducing the total number of infections varies with the basic reproduction number of the pathogen, travel rates, structure of the travel network, and vaccine availability. We conclude that, when a pathogen has high spreading capacity, or when vaccine availability is limited, centrality-targeting strategies should be considered as an alternative to the more commonly used risk-targeting strategies.


title: High risk landscapes of Japanese encephalitis virus outbreaks in India converge on wetlands, rainfed agriculture, wild Ardeidae, and domestic pigs

abstract: Japanese encephalitis constitutes a significant burden of disease across Asia, particularly in India, with high mortality in children. This zoonotic mosquito-borne disease is caused by the Flavivirus, Japanese encephalitis virus (JEV), and circulates in wild ardeid bird and domestic pig reservoirs both of which generate sufficiently high viremias to infect vector mosquitoes, which can then subsequently infect humans. The landscapes of these hosts, particularly in the context of anthropogenic ecotones and resulting wildlife-livestock interfaces, are poorly understood and thus significant knowledge gaps in the epidemiology and infection ecology of JEV persist, which impede optimal control and prevention of outbreaks. The current study investigated the landscape epidemiology of JEV outbreaks in India over the period 2010 to 2020 based on national human disease surveillance data. Outbreaks were modelled as an inhomogeneous Poisson point process. Outbreak risk was strongly associated with the habitat suitability of ardeid birds and pig density, and shared landscapes between fragmented rainfed agriculture and both river and freshwater marsh wetlands. Moreover, risk scaled with Ardeidae habitat suitability, but was consistent across scale with respect to pig density and rainfed agriculture-wetland mosaics. The results from this work provide a more complete understanding of the landscape epidemiology and infection ecology of JEV in India and suggest important priorities for control and prevention across fragmented terrain comprised of wildlife-livestock interface that favours spillover to humans.


title: The efficiency of dynamic regional lockdown approach in controlling the COVID-19 epidemic. Insights from the agent-based epidemiological model for Poland

abstract: In this work properties of the dynamic regional lockdown approach to suppress the COVID-19 epidemic spread in Poland were investigated. In particular, an agent based model was used with the aim to indicate an optimal lockdown strategy, defined here as the one which minimizes mean lockdown time over regional unit provided health service is not overwhelmed. With this approach the lockdown extent was also considered by varying restrictions between complete regional school closure and/or significant social distancing in semi-public spaces. In result, a cooperative effect was discovered in the case when closure of schools was accompanied by severe restrictions of social contacts in semi-public spaces. Moreover, the regional lockdown approach implemented here on the level of counties (units of population around 100k) proofed to be successful, that is allowed to identify optimal entrance and release thresholds for lockdown. The authors believe that until significant portion of population is vaccinated such a strategy might be applied.


title: Incidence of COVID-19 reinfection among Midwestern healthcare employees

abstract:
ImportanceGiven the overwhelming worldwide rate of infection and the disappointing pace of vaccination, addressing reinfection is critical. Understanding reinfection, including protection longevity after natural infection, will allow us to better know the prospect of herd immunity, which hinges on the assumption that natural infection generates sufficient, protective immunity. The primary aim of this paper is to provide data on SARS-CoV-2 reinfection over a 10-month period.

ObjectiveThe primary objective of this study is to establish the incidence of reinfection of COVID-19 among healthcare employees who experienced a prior COVID-19 infection.

DesignThis observational cohort study followed a convenience sample of 2,625 participants who experienced a COVID-19 infection for subsequent COVID-19 infection.

SettingHealthcare employees were recruited across a large Midwestern healthcare system. Positive PCR test results were administered and recorded by the system-affiliated lab serving Illinois and Wisconsin.

ParticipantsAdult healthcare system employees who enrolled in a research study focused on SARS-CoV-2 antibodies (N = 16,357) and had at least one positive PCR test result between March 1, 2020 and January 10, 2021 were included (N = 2,625).

ExposurePositive PCR test for SARS-CoV-2

Main Outcome(s) and Measure(s)The primary outcome is incidence of COVID-19 reinfection, defined by current CDC guidelines (i.e. subsequent COVID-19 infection [≥] 90 days from prior infection). COVID-19 recurrence, defined as subsequent COVID-19 infection after prior infection irrespective of time, is also described.

ResultsOf 2,625 participants who experienced at least one COVID-19 infection during the 10-month study period, 156 (5.94%) experienced reinfection and 540 (20.57%) experienced recurrence after prior infection. Median days were 126.50 (105.50-171.00) to reinfection and 31.50 (10.00-72.00) to recurrence. Incidence rate of COVID-19 reinfection was 0.35 cases per 1,000 person-days, with participants working in COVID-clinical and clinical units experiencing 3.77 and 3.57 times, respectively, greater risk of reinfection relative to those working in non-clinical units. Incidence rate of COVID-19 recurrence was 1.47 cases per 1,000 person-days.

Conclusions and RelevanceThis study supports the consensus that COVID-19 reinfection, defined as subsequent infection [≥] 90 days after prior infection, is rare, even among a sample of healthcare workers with frequent exposure.


title: Street images classification according to COVID-19 risk in Lima, Peru: A convolutional neural networks analysis

abstract:
BackgroundDuring the COVID-19 pandemic, convolutional neural networks (CNNs) have been used in clinical medicine (e.g., to classify chest X-rays for COVID-19 diagnosis). Whether CNNs could also inform the epidemiology of COVID-19 analysing street images has been understudied, though it could identify high-risk places and relevant features of the built environment. We trained CNNs to classify bus stops (Lima, Peru) into moderate or extreme COVID-19 risk.

MethodsWe used five images per bus stop. The outcome label (moderate or extreme) for each bus stop was extracted from the local transport authority. We used transfer learning and updated the output layer of five CNNs: NASNetLarge, InceptionResNetV2, Xception, ResNet152V2, and ResNet101V2. We chose the best performing network which was further tuned to increase performance.

ResultsThere were 1,788 bus stops (1,173 moderate and 615 extreme), totalling 8,940 images. NASNetLarge outperformed the other CNNs except in the recall metric for the extreme label: 57% versus 59% in NASNetLarge and ResNet152V2, respectively. NASNetLarge was further tuned and reached: training loss of 0.50; training accuracy of 75%; precision, recall and F1 score for the moderate label of 80%, 83% and 82%, respectively; these metrics for the extreme label were 65%, 51% and 63%.

ConclusionsCNNs has the potential to accurately classify street images into levels of COVID-19 risk. In addition to applications in clinical medicine, CNNs and street images could also advance the epidemiology of COVID-19 at the population level.


title: Four-week forecasts of COVID-19 epidemic trajectories in South Africa, Chile, Peru and Brazil: a model evaluation

abstract:
IntroductionFrom the beginning of the COVID-19 pandemic, epidemiological models have been used in a number of ways to aid governments and organizations in efficient planning of resources and decision making. These models have elucidated important epidemiological transmission parameters, in addition to making short-term projections.

MethodsWe constructed a compartmental mathematical model for the transmission, detection and prevention of SARS-CoV-2 infections for regions where Anglo American has mining operations. We fitted the model to publicly available data and used it to make short-term projections. Finally, we evaluated how the model performed by comparing short-term projections to actual confirmed cases, retrospectively.

FindingsThe average forecast errors for four-week-ahead projections ranged between 1% and 8% in all the countries and regions considered in this study. All but one region had more than 75% of the true values falling within the range of four-week-ahead projections. The quality of the projections improved with time as expected due to increased historical data.

ConclusionOur model produced four-week forecasts with a sufficiently high level of accuracy to guide operational and strategic planning for business continuity and COVID-19 responses in Anglo American mining sites.


title: The statistical analysis of daily data associated with different parameters of the New Coronavirus COVID-19 pandemic in Georgia and their two-week interval prediction in summer 2021

abstract:
The lockdown introduced in Georgia on November 28, 2020 brought positive results. There were clearly positive tendencies in the spread of COVID-19 to February - first half of March 2021. However, in April-May 2021 there was a significant deterioration in the epidemiological situation. From June to August 2021, the epidemiological situation with Covid-19 in Georgia became very difficult.

In this work results of the next statistical analysis of the daily data associated with New Coronavirus COVID-19 infection of confirmed (C), recovered (R), deaths (D) and infection rate (I) cases of the population of Georgia in the period from June 01, 2021 to August 31, 2021 are presented. It also presents the results of the analysis of two-week forecasting of the values of C, D and I. As earlier, the information was regularly sent to the National Center for Disease Control & Public Health of Georgia and posted on the Facebook page https://www.facebook.com/Avtandil1948/.

The analysis of data is carried out with the use of the standard statistical analysis methods of random events and methods of mathematical statistics for the non-accidental time-series of observations. In particular, the following results were obtained.

Georgias ranking in the world for Covid-19 monthly mean values of infection and deaths cases in summer 2021 (per 1 million population) was determined. Among 159 countries with population [≥] 1 million inhabitants in August 2021 Georgia was in the 1 place on new infection cases and on Death.

A comparison between the daily mortality from Covid-19 in Georgia in summer 2021 with the average daily mortality rate in 2015-2019 shows, that the largest share value of D from mean death in 2015-2019 was 66.0 % (26.08.2021 and 31.08.2021), the smallest 6.0 % (09.07.2021).

The statistical analysis of the daily and decade data associated with coronavirus COVID-19 pandemic of confirmed, recovered, deaths cases and infection rate of the population of Georgia are carried out. Maximum daily values of investigation parameters are following: C = 6208 (17.08.2021), R = 6177 (29.08.2021), D = 79 (26.08.2021 and 31.08.2021), I = 13.0 % (17.08.2021). Maximum mean decade values of investigation parameters are following: C = 5019 (2 Decade of August 2021), R = 4822 (3 Decade of August 2021), D = 69 (3 Decade of August 2021), I = 10.88 % (2 Decade of August 2021).

It was found that as with September 2020 to February 2021 and in spring 2021 [7,8], from June to August 2021 the regression equations for the time variability of the daily values of C, R and D have the form of a tenth order polynomial.

Mean values of speed of change of confirmed -V(C), recovered - V(R), deaths - V(D) and infection rate V(I) coronavirus-related cases in different decades of months in the summer 2021 were determined. Maximum mean decade values of investigation parameters are following: V(C) = +134 cases/day (1 Decade of August 2021), V(R) = +134 cases/day (2 Decade of August 2021), V(D) = +2.4 cases/day (3 Decade of August 2021), V(I) = + 0.25 %/ day (1 decades of August 2021).

Cross-correlations analysis between confirmed COVID-19 cases with recovered and deaths cases shows, that the maximum effect of recovery is observed 19 days after infection (RC=0.95), and deaths - after 16 and 18 days (RC=0.94). In Georgia in the summer 2021, the duration of the impact of the delta variant of the coronavirus on people (recovery, mortality) could be up to two months.

Comparison of real and calculated predictions data of C, D and I in Georgia are carried out. It was found that in summer 2021 two-week daily and mean two-week real values of C, D and I practically fall into the 67% - 99.99% confidence interval of these predicted values.

With September 1, 2021, it is started monthly forecasting of C, D and I values.

As earlier, the comparison of data about C and D in Georgia (GEO) with similar data in Armenia (ARM), Azerbaijan (AZE), Russia (RUS), Turkey (TUR) and in the World (WRL) is also carried out.


title: The Histological Diagnosis of Breast Cancer by Employing scale invariant ResNet 18 With Spatial Supervised Technique

abstract:
BackgroundBreast cancer is one of the most prevalent cause of morbidity and mortality in women all over the world. Histopathological diagnosis is a vital component in the management of breast cancer. The application of artificial intelligence is yielding promising results for the better patient care.

AimThe main aim of the present research project is to explore the potential of spatial supervised technique to develop scale invariant system for the histological diagnosis of breast cancer.

Materials and MethodsThe anonymized images of hematoxylin and eosin stained section of the dataset, which has been acquired from the website. The slides were taken at different zoom (magnification) levels. Spatial supervised learning has been employed to make a scale invariant system. We used 400x and 40x to generate the results. For the 400x, we trained our network on a dataset of 200x,100x, and 40x images. The datasets were split into training and validation sets. The training set contained 80% digital slides of the respected dataset, and the validation set contained 20% digital slides of the respected dataset. The final result was generated by splitting the dataset of 400x into the training and test dataset. The training set contained 50% digital slides, and the test set also contained 50% digital slides. This unusual split is done to show how good spatial supervised learning works. Similarly, for 40x, we trained our networks on a dataset of 400x,200x, and 100x. The same steps were followed to obtain the 40x results.

ResultsThe result analysis revealed that the ResNet 18 with spatial supervised learning on dataset of 40x yielded the F-1 score of 1.0, while ResNet 18 with supervised learning only, on dataset of 40x yielded F-1 score of 0.9823. ResNet 18 with spatial supervised learning on dataset of 400x revealed F-1 score of 0.9957, and ResNet 18 with supervised learning only, on dataset of 400x showed the F-1 score of 0.9591. For supervised learning dataset is spited into training (80%) and testing (20% of dataset).

ConclusionThe analysis of digitized pathology images with the application of convolutional neural network Resnet -18 architecture with spatial supervised learning revealed excellent results, which is demonstrated by a very high F-1 score of 1.0.

The development of scale invariant system with application of spatial supervised technique solved the problem of images with variable magnifications. The finding would further pave the pathway for application of deep learning for the histological diagnosis of pathological lesions.

category: pathology


title: Perceptions and experiences of rare diseases among General Practitioners: an exploratory study

abstract:
BackgroundGeneral Practitioners (GPs) play an important role in healthcare delivery for people living with a rare disease and their families. Managing long-term multisystem diseases that often have no cure and sub-optimal treatment options can be extremely challenging.

AimTo gain an understanding of GPs perception and experience of rare diseases.

Design and SettingThis is an exploratory study with GPs from Northern Ireland.

MethodAn online survey was hosted within SmartSurvey, available for 6 weeks in early 2019, which queried: GPs career to date, interactions with rare disease patients, challenges faced, the exchange of information with patients, priorities for the future, support for such patients and finally training.

ResultsSixty-six GPs engaged with the survey with 15 completing the survey. Many frustrations were mentioned by GPs when caring for such patients including finding a diagnosis, lack of specialist services and lack of awareness. Seventy-nine percent of GPs responding did not feel adequately trained to care for patients with a rare disease, while 93% were interested in undertaking training to enable them to improve their care for rare disease patients.

ConclusionMore effective and convenient  rare disease focused training programs would help GPs manage patients with rare diseases. Enabling efficient, effective communication between GPs and individual medical specialists is of paramount importance to give GPs access to information on how to effectively manage patients living with a rare disease. Awareness should be raised for effective support mechanisms such as charities and support groups for rare disease patients.

How this fits inMany GPs have reported feeling overwhelmed when caring for rare disease patients. Their lack of knowledge forces them to turn to the internet but finding reliable information is often difficult. This study acknowledges the difficult task GPs face when caring for this population and highlights the need for training development, improved communication, and better awareness.


title: Analysis of Respiratory Kinematics: a method to characterize breaths from motion signals

abstract:
RationaleBreathing motion (respiratory kinematics) can be characterized by the interval and depth of each breath, and by magnitude-synchrony relationships between locations. Such characteristics and their breath-by-breath variability might be useful indicators of respiratory health.

ObjectivesTo enable breath-by-breath characterization of respiratory kinematics, we developed a method to detect breaths using motion sensor signals.

MethodsIn 34 volunteers who underwent maximal exercise testing, we used 8 motion sensors to record upper rib, lower rib and abdominal kinematics at 3 exercise stages (rest, lactate threshold and exhaustion). We recorded volumetric air flow signals using clinical exercise laboratory equipment and synchronized them with kinematic signals. Using instantaneous phase landmarks from the analytic representation of kinematic and flow signals, we identified individual breaths and derived respiratory rate signals at 1Hz. To evaluate the fidelity of kinematics-derived respiratory rate signals, we calculated their cross-correlation with the flow-derived respiratory rate signals. To identify coupling between kinematics and flow, we calculated the Shannon entropy of the relative frequency with which kinematic phase landmarks were distributed over the phase of the flow cycle.

Measurements and Main ResultsWe found good agreement in the kinematics-derived and flow-derived respiratory rate signals, with cross-correlation coefficients as high as 0.94. In some individuals, the kinematics and flow were significantly coupled (Shannon entropy < 2) but the relationship varied within (by exercise stage) and between individuals. The final result was that the phase landmarks from the kinematic signal were uniformly distributed over the phase of the air flow signals (Shannon entropy close to the theoretical maximum of 3.32).

ConclusionsThe Analysis of Respiratory Kinematics method can yield highly resolved respiratory rate signals by separating individual breaths. This method will facilitate characterization of clinically significant breathing motion patterns on a breath-by-breath basis. The relationship between respiratory kinematics and flow is much more complex than expected, varying between and within individuals.

category: respiratory medicine


title: OpenClinicalAI: enabling AI to diagnose diseases in real-world clinical settings

abstract:
This paper quantitatively reveals the state-of-the-art and state-of-the-practice AI systems only achieve acceptable performance on the stringent conditions that all categories of subjects are known, which we call closed clinical settings, but fail to work in real-world clinical settings. Compared to the diagnosis task in the closed setting, real-world clinical settings pose severe challenges, and we must treat them differently. We build a clinical AI benchmark named Clinical AIBench to set up real-world clinical settings to facilitate researches. We propose an open, dynamic machine learning framework and develop an AI system named OpenClinicalAI to diagnose diseases in real-world clinical settings. The first versions of Clinical AIBench and OpenClinicalAI target Alzheimers disease. In the real-world clinical setting, OpenClinicalAI significantly out-performs the state-of-the-art AI system. In addition, OpenClinicalAI develops personalized diagnosis strategies to avoid unnecessary testing and seamlessly collaborates with clinicians. It is promising to be embedded in the current medical systems to improve medical services.

One-Sentence SummaryWe propose a clinical AI benchmark and an open, dynamic machine learning framework to enable AI diagnosis systems to land in real-world clinical settings.

category: health systems and quality improvement


title: Determinants of early antibody responses to COVID-19 mRNA vaccines in exposed and naive healthcare workers

abstract:
BackgroundTwo doses of mRNA vaccination have shown >94% efficacy at preventing COVID-19 mostly in naive adults, but it is not clear if the second dose is needed to maximize effectiveness in those previously exposed to SARS-CoV-2 and what other factors affect responsiveness.

MethodsWe measured IgA, IgG and IgM levels against SARS-CoV-2 spike (S) and nucleocapsid (N) antigens from the wild-type and S from the Alpha, Beta and Gamma variants of concern, after BNT162b2 (Pfizer/BioNTech) or mRNA-1273 (Moderna) vaccination in a cohort of health care workers (N=578). Neutralizing capacity and antibody avidity were evaluated. Data were analyzed in relation to COVID-19 history, comorbidities, vaccine doses, brand and adverse events.

FindingsVaccination induced robust IgA and IgG levels against all S antigens. Neutralization capacity and S IgA and IgG levels were higher in mRNA-1273 vaccinees, previously SARS-CoV-2 exposed, particularly if symptomatic, and in those experiencing systemic adverse effects. A second dose in pre-exposed did not increase antibody levels. Smoking and comorbidities were associated with lower neutralization and antibody levels. Among fully vaccinated, 6.3% breakthroughs were detected up to 189 days post-vaccination. Among pre-exposed non-vaccinated, 90% were IgG seropositive more than 300 days post-infection.

InterpretationOur data support administering a single-dose in pre-exposed healthy individuals. However, heterogeneity of responses suggests that personalized recommendations may be necessary depending on COVID-19 history and life-style. Higher mRNA-1273 immunogenicity would be beneficial for those expected to respond worse to vaccination. Persistence of antibody levels in pre-exposed unvaccinated indicates maintenance of immunity up to one year.

FundingThis work was supported by Institut de Salut Global de Barcelona (ISGlobal) internal funds, in-kind contributions from Hospital Clinic de Barcelona, the Fundacio Privada Daniel Bravo Andreu, and European Institute of Innovation and Technology (EIT) Health (grant number 20877), supported by the European Institute of Innovation and Technology, a body of the European Union receiving support from the H2020 Research and Innovation Programme. We acknowledge support from the Spanish Ministry of Science and Innovation and State Research Agency through the "Centro de Excelencia Severo Ochoa 2019-2023" Program (CEX2018-000806-S), and support from the Generalitat de Catalunya through the CERCA Program. L. I. work was supported by PID2019-110810RB-I00 grant from the Spanish Ministry of Science & Innovation. Development of SARS-CoV-2 reagents was partially supported by the National Institute of Allergy and Infectious Diseases Centers of Excellence for Influenza Research and Surveillance (contract number HHSN272201400008C). The funders had no role in study design, data collection and analysis, the decision to publish, or the preparation of the manuscript.


title: Autoantibodies against IL-1-receptor-antagonist in multisystem inflammatory syndrome in children

abstract:
Multisystem inflammatory syndrome in children (MIS-C or PIMS) is a rare but serious complication after an infection with SARS-CoV-2. A possible involvement of pathogenetically relevant autoantibodies has been discussed. Recently neutralizing autoantibodies against anti-inflammatory receptor antagonists progranulin (PGRN) and IL-1-receptor antagonist (IL-1-Ra) were discovered in adult patients with critical COVID-19.

Plasma of an index case with severe PIMS/MIS-C was analyzed for autoantibodies against IL-1-Ra and PGRN. The study was extended by a case series of 12 additional patients. In addition to ELISA for of antibodies, IL-1-Ra plasma levels were determined and IL-1-Ra was analyzed by Western-blot and isoelectric focusing. Functional activity of the autoantibodies was examined in vitro with IL-1{beta} reporter assays.

Antibodies against IL-1-Ra could be detected in 10 of 13 (76.9%) patients with PIMS/MIS-C, but not in controls. In contrast to critical COVID-19 in adults, no IL-1-Ra antibodies of the IgM class were detected in PIMS/MIS-C. IL-1-Ra-antibodies exclusively belonged to IgG1. No antibodies directed against PGRN were detected. Western blots and ELISA showed a concomitant reduction of free IL-1-Ra plasma levels in the presence of IL-1-Ra-antibodies. The antibodies inhibited IL-1-Ra function in IL-1{beta} reporter cell assays. Notably, an additional, hyperphosphorylated, transiently occurring atypical isoform of IL-1-Ra was observed in all IL-1-Ra autoantibody-positive patients.

To conclude, IL-1-Ra autoantibodies were observed in high frequency in children with PIMS/MIS-C. They may represent a diagnostic and pathophysiologically relevant marker for PIMS/MIS-C. Their generation is likely to be triggered by an atypical, hyperphosphorylated isoform of IL-1-Ra.

category: allergy and immunology


title: Persistence of child marriage in rural Bangladesh and impact on maternal and perinatal health: findings from a health and demographic surveillance system

abstract:
ObjectivesTo describe temporal trends in child marriage between 1990 and 2019 in a rural sub-district of Bangladesh and characterize relationships between age, time to pregnancy, complications during delivery, and perinatal mortality.

DesignHealth and demographic surveillance system.

SettingBaliakandi sub-district, Bangladesh.

Participants56,155 female residents.

Main outcome measuresAnnual proportion of marriages to female residents under 18 years of age, time between first marriage and pregnancy, proportion of births with complications during delivery, and odds of perinatal mortality.

ResultsBetween 1990 and 2010, the proportion of marriages to female residents under 18 years of age decreased from 71% to 57%. Most notably, marriages to females aged 10 to 12 years dropped from 22% of all marriages to 3%. In 2019, 53% of all marriages were to females under 18 years. The estimated time between first marriage and pregnancy did not differ by female age at marriage. By 365 days after marriage, the cumulative incidence of pregnancy was approximately 50% for each age group. Adolescent girls were more likely to experience complications during delivery with at least one complication reported for 36% of mothers aged 13 to 15 years, 32% of mothers aged 16 to 17 years, and 23% of mothers aged 18 to 34 years ({chi}2 test, P<0.001). Compared to adults, births among females aged 13 to 15 years were more likely to result in stillbirths (odds ratio 2.23, 95% confidence interval 1.19 to 4.16) and births among females 16-17 years were more likely to result in early neonatal deaths (odds ratio 1.57, 95% confidence interval 1.01 to 2.42).

ConclusionsChild marriage persists in Baliakandi. Over half of all marriages were to child brides and only minor reductions were seen over the past decade. Pregnancies were common among adolescent girls with no evidence of delayed pregnancy after marriage. Compared to adults, adolescents were more likely to experience complications during delivery and perinatal death. Preventing child marriage has substantial social and health benefits for girls and, by doing so, will also contribute to Bangladeshs commitment to reduce child mortality.

category: obstetrics and gynecology