title: A distinct four-value blood signature of pyrexia under combination therapy of malignant melanoma with BRAF/MEK-inhibitors evidenced by an algorithm defined pyrexia score

abstract:
Pyrexia is a frequent adverse event of BRAF/MEK-inhibitor combination therapy in patients with metastasized malignant melanoma (MM). The studys objective was to identify laboratory changes which might correlate with the appearance of pyrexia. Initially, data of 38 MM (14 with pyrexia) patients treated with dabrafenib plus trametinib were analysed retrospectively. Graphical visualization of time series of laboratory values suggested that a rise in C-reactive-protein, in parallel with a fall of leukocytes and thrombocytes, were indicative of pyrexia. Additionally, statistical analysis showed a significant correlation between lactate dehydrogenase (LDH) and pyrexia. An algorithm based on these observations was designed using a deductive approach in order to calculate a pyrexia score (PS) for each laboratory assessment in treated patients. A second independent data set with 28 MM patients (8 with pyrexia) was used for the validation of the algorithm. PS based on the four parameters CRP, LDH, leukocyte and thrombocyte numbers, were statistically significantly higher in pyrexia patients, differentiated between groups (F=20,8; p=<0,0001) and showed a significant predictive value for the development of pyrexia (F=6,24; p=0,013). We provide first evidence that pyrexia in patients treated with BRAF/MEK-blockade can be identified and predicted by an algorithm that calculates a score.

SUMMARY STATEMENTPyrexia is a severe side effect of BRAF/MEK-inhibitor therapy of malignant melanoma. An algorithm based on the four laboratory values, leukocyte and thrombocyte counts, CRP and LDH, was designed for detecting pyrexia. The used heuristic approach might serve as a blueprint for analysing unevenly sampled or even incomplete clinical data.


title: Androgen receptor polyQ alleles and COVID-19 severity in men: a replication study

abstract: Ample evidence indicates a sex-related difference in severity of COVID-19, with less favorable outcomes observed in men. Genetic factors have been proposed as candidates to explain this difference. The polyQ polymorphism in the androgen receptor gene has been recently described as a genetic biomarker of COVID-19 severity. In this study, we analyzed this association in a large cohort of 1136 men classified into three groups according to their degree of COVID-19 severity, finding a similar distribution of polyQ alleles among severity groups. Therefore, our results do not support the role of this polymorphism as a biomarker of COVID-19 severity.

category: genetic and genomic medicine


title: A proposed de-identification framework for a cohort of children presenting at a health facility in Uganda

abstract:
Data sharing has enormous potential to accelerate and improve the accuracy of research, strengthen collaborations, and restore trust in the clinical research enterprise. Nevertheless, there remains reluctancy to openly share raw datasets, in part due to concerns regarding research participant confidentiality and privacy. Statistical data de-identification is an approach that can be used to preserve privacy and facilitate open data sharing. We have proposed a standardized framework for the de-identification of data generated from cohort studies in children in a low- and-middle income country.

Variables were labeled as direct and quasi-identifiers based on conditions of replicability, distinguishability, and knowability with consensus from two independent evaluators. Direct identifiers were removed from the dataset, while a statistical risk-based de-identification approach using the k-anonymity model was applied to quasi-identifiers. Qualitative assessment of the level of privacy invasion associated with data set disclosure was used to determine an acceptable re-identification risk threshold, and corresponding k-anonymity requirement. A de-identification model using generalization, followed by suppression was applied using a logical stepwise approach to achieve k-anonymity. The utility of the de-identified data was demonstrated using a typical clinical regression example. The de-identified dataset was published on the Pediatric Sepsis Data CoLaboratory Dataverse which provides moderated data access.

Researchers are faced with many challenges when providing access to clinical data. We provide a standardized de-identification framework that can be adapted and refined based on specific context and risks. This process will be combined with moderated access to foster coordination and collaboration in the clinical research community.

AUTHOR SUMMARYOpen Data is data that anyone can access, use, and share. Open Data has the potential to facilitate collaboration, enrich research, and advance the analytic capacity to inform decisions. Importantly, Open Data plays a role in fulfilling obligations to research participants and honoring the nature of medical research as a public good. Leaders in industry, academia, and regulatory agencies recognize the value in increased transparency and are focusing on how to openly share data while minimizing the safety risks to research participants. For example, making data open can pose a privacy risk to research participants who have shared personal health information. This risk can be mitigated using data de-identification, a process of removing personal information from a dataset so that an individuals identity is no longer apparent or cannot be reasonably ascertained from the data. We introduce a simple, statistical risk-based framework for de-identification of clinical data that can be followed by any researcher. This framework will guide open data sharing while improving the protection of research participants.

category: health informatics


title: Estimating epidemiological quantities from repeated cross-sectional prevalence measurements

abstract:
BackgroundRepeated measurements of cross-sectional prevalence of Polymerase Chain Reaction (PCR) positivity or seropositivity provide rich insight into the dynamics of an infection. The UK Office for National Statistics (ONS) Community Infection Survey publishes such measurements for SARS-CoV-2 on a weekly basis based on testing enrolled households, contributing to situational awareness in the country. Here we present estimates of time-varying and static epidemiological quantities that were derived from the estimates published by ONS.

MethodsWe used a gaussian process to model incidence of infections and then estimated observed PCR prevalence by convolving our modelled incidence estimates with a previously published PCR detection curve describing the probability of a positive test as a function of the time since infection. We refined our incidence estimates using time-varying estimates of antibody prevalence combined with a model of antibody positivity and waning that moved individuals between compartments with or without antibodies based on estimates of new infections, vaccination, probability of seroconversion and waning.

ResultsWe produced incidence curves of infection describing the UK epidemic from late April 2020 until early 2022. We used these estimates of incidence to estimate the time-varying growth rate of infections, and combined them with estimates of the generation interval to estimate time-varying reproduction numbers. Biological parameters describing seroconversion and waning, while based on a simple model, were broadly in line with plausible ranges from individual-level studies.

ConclusionsBeyond informing situational awareness and allowing for estimates using individual-level data, repeated cross-sectional studies make it possible to estimate epidemiological parameters from population-level models. Studies or public health surveillance methods based on similar designs offer opportunities for further improving our understanding of the dynamics of SARS-CoV-2 or other pathogens and their interaction with population-level immunity.

category: epidemiology


title: Cancer diagnosis in primary care after second pandemic year in Catalonia: a time-series analysis of primary care electronic health records covering about five million people

abstract:
BackgroundDuring COVID-19 pandemic, incidence of chronic disease had drastically been reduced due to health care interruptions. The aim of this study is to analyze cancer diagnosis during the two years of the COVID-19 pandemic.

MethodsTime-series study of malignant neoplasms, using data from the primary care electronic health records from January 2014 to December 2021. We obtained the expected monthly incidence using a temporary regression adjusted by trend and seasonality. We additionally compared cancer incidence in 2019 with those of 2020 and 2021 using the T-Test. We performed analysis globally, by sex and by type of cancer.

ResultsDuring 2020, the incidence of cancer had reduced by -21% compared to 2019 (p-value <0.05). Greater reductions were observed during lockdown in early 2020 (>40%) and with some types of cancers, especially prostate and skin cancers (-29.6% and -26.9% respectively, p-value<0.05). Lung cancers presented statistically non-significant reductions in both years. Cancer diagnosis returned to expected around March 2021, and incidence in 2021 was similar to that of 2019 (overall difference of 0.21%, p=0.967). However, -11% reduction still was found when comparing pandemic months of 2020-2021 with pre-pandemic months (2019-2020)

ConclusionsAlthough primary care cancer diagnostic capacity in 2021 has returned to pre-pandemic levels, missing diagnoses during the last two years have not been fully recovered.

Key messagesO_LICancer diagnoses have dramatically dropped during 2020 worldwide.
C_LIO_LIWe observe a -21% decline in 2020, but a return to pre-pandemic diagnosis capacity in 2021.
C_LIO_LIA -11% outstanding drop was still found comparing pre-pandemic to pandemic months.
C_LIO_LIReductions were greater during the lockdown (>40%).
C_LIO_LILung and breast cancers presented fewer reductions while prostate and skin cancers had greater drops.
C_LIO_LIMissing diagnoses during the last two years have not been fully recovered
C_LI


title: Association of Mass Distribution of Rapid Antigen Tests and SARS-CoV-2 Prevalence: Results from NIH-CDC funded Say Yes! Covid Test program in Michigan

abstract:
ImportanceWide-spread distribution of diagnostics is an integral part of the United States COVID-19 strategy; however, few studies have assessed the effectiveness of this intervention at reducing transmission of community COVID-19.

ObjectiveTo assess the impact of the Say Yes! Covid Test (SYCT!) Michigan program, a population-based program that distributed 20,000 free rapid antigen tests within Ann Arbor and Ypsilanti, Michigan in June-August 2021, on community prevalence of SARS-CoV-2.

DesignThis ecological study analyzed cases of SARS-CoV-2 from March to October 2021 reported to the Washtenaw County Health Department.

SettingWashtenaw County, Michigan

ParticipantsAll residents of Washtenaw County

InterventionsCommunity-wide distribution of 500,000 rapid antigen tests for SARS-CoV-2 to residents of Ann Arbor and Ypsilanti, Michigan. Each household was limited to one test kit containing 25 rapid antigen tests.

Main Outcome and MeasuresCommunity prevalence of SARS-CoV-2, as measured through 7-day average cases, in Ann Arbor and Ypsilanti was compared to the rest of Washtenaw County. A generalized additive model was fitted with non-parametric trends for control and relative differences of trends in the pre-intervention, intervention, and post-intervention periods to compare intervention municipalities of Ann Arbor and Ypsilanti to the rest of Washtenaw County. Model results were used to calculate average cases prevented in the post-intervention period.

ResultsIn the post-intervention period, there were significantly lower standardized average cases in the intervention communities of Ann Arbor/Ypsilanti compared to the rest of Washtenaw County (p<0.001). The estimated standardized relative difference between Ann Arbor/Ypsilanti and the rest of Washtenaw County was -0.016 cases per day (95% CI: -0.020 to -0.013), implying that the intervention prevented 40 average cases per day two months into the post-intervention period if trends were consistent.

Conclusions and RelevanceMass distribution of rapid antigen tests may be a useful mitigation strategy to combat community transmission of SARS-CoV-2, especially given the recent relaxation of social distancing and masking requirements.

category: public and global health


title: Using DeepLabCut for tracking body landmarks in videos of children with dyskinetic cerebral palsy: a working methodology

abstract:
Markerless motion tracking is a promising technique to capture human movements and postures. It could be a clinically feasible tool to objectively assess movement disorders within severe dyskinetic cerebral palsy (CP). Here, we aim to evaluate tracking accuracy on clinically recorded video data.

Method94 video recordings of 33 participants (dyskinetic CP, 8-23 years; GMFCS IV-V, i.e. non-ambulatory) from a previous clinical trial were used. Twenty-second clips were cut during lying down as this is a postion for this group of children and young adults allows to freely move. Video image resolution was 0.4 cm per pixel. Tracking was performed in DeepLabCut. We evaluated a model that was pre-trained on a human healthy adult data set with an increasing number of manually labeled frames (0, 1, 2, 6, 10, 15 and 20 frames per video). To assess generalizability, we used 80% of videos for the model development and evaluated the generalizability of the model using the remaining 20%. For evaluation the mean absolute error (MAE) between DeepLabCuts prediction of the position of body points and manual labels was calculated.

ResultsUsing just the pre-trained adult human model yielded a MAE of 121 pixels. An MAE of 4.5 pixels (about 1.5 cm) could be achieved by adding 15-20 manual labels. When applied to unseen video clips (i.e. generalization set), the MAE was 33 pixels with a dedicated model trained on 20 frames per videos.

ConclusionAccuracy of tracking with a standard pre-trained model is insufficiently to automatically assess movement disorders in dyskinetic CP. However, manually adding labels improves the model performance substantially. In addition, the methodology proposed within our study is applicable to check the accuracy of DeepLabCut application within other clinical data set.

category: rehabilitation medicine and physical therapy


title: The relationship of major diseases with childlessness: a sibling matched case-control and population register study in Finland and Sweden

abstract:
BackgroundApproximately 20% of men and 15% of women remain childless at the end of their reproductive lifespan, with childlessness increasing over time, yet we lack a comprehensive understanding of the role and relative importance of diseases associated with childlessness, particularly among men.

MethodsWe examined all individuals born in Finland (n=1,035,928) and Sweden (n=1,509,092) between 1956 and 1968 (men) or 1956 and 1973 (women) and followed them up until the end of 2018. Socio-demographic, health, and reproductive information was obtained from nationwide registers. We assessed the association of 414 diseases across 16 categories with having no children by age 45 (women) and 50 (men) using a matched pair case-control design based on 71,524 pairs of full-sisters and 77,622 full-brothers who were discordant for childlessness as well as a population-based approach.

FindingsMental-behavioral, congenital anomalies, and endocrine-nutritional-metabolic disorders had the strongest associations with childlessness. Novel associations were discovered with inflammatory (eg. myocarditis) and autoimmune diseases (eg. juvenile idiopathic arthritis). Mental-behavioral disorders had stronger associations amongst men, particularly for schizophrenia and acute alcohol intoxication, while congenital anomalies, obesity-related diseases such as diabetes, and inflammatory diseases had stronger associations amongst women. Associations were dependent on the age at onset of the disease, with the strongest association observed earlier in women (21-25 years old) than men (26-30 years old). For most diseases, the association with childlessness was mediated by singlehood, especially in men. Some diseases, however, remained associated with childlessness among partnered individuals, including some mood- and endocrine-nutritional-metabolic disorders. All results can be explored in an interactive online dashboard.

InterpretationWe provide evidence that disease burden across multiple domains is associated with childlessness, identifying modifiable mental-behavioral disorders and novel autoimmune and inflammatory diseases. Evidence can be used for targeted health interventions to counter decreasing fertility, reproductive health, involuntary childlessness, and shrinking populations.

FundingEuropean Research Council (835079, 945733) and The Leverhulme Trust.

Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSThe majority of research on infertility and childlessness has focused on socio-environmental factors, diseases related to reproduction, and examined predominantly women. Diseases are often considered separately, without a yardstick of their relative importance, and rarely examined within an entire population.

Added value of this studyThis is the first large-scale population study examining the association of 414 diseases across 16 broad categories with remaining childless, examining the entire reproductive and disease histories of 2.5 million men and women.

Implications of all the available evidenceOur study provides evidence that childlessness is associated with multiple diseases that are potentially modifiable with targeted public health interventions, particularly mental-behavioral disorders such as alcohol dependence in men or endocrine-nutritional-metabolic disorders linked to obesity and diabetes. Our broader approach revealed hitherto unknown links of childlessness with autoimmune (eg. juvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus) and inflammatory diseases (eg. myocarditis), warranting future studies examining the mechanisms underlying these associations.

category: sexual and reproductive health


title: The predictive significance of prognostic nutritional index and serum albumin/globulin ratio on the overall survival of penile cancer patients undergoing penectomy

abstract:
ObjectiveTo assess the value of using the prognostic nutritional index (PNI) and serum albumin/globulin ratio (AGR) in predicting the overall survival (OS) of patients with penile cancer (PC) undergoing penectomy.

Materials and methodsA retrospective analysis of 123 patients who were admitted to our hospital due to PC from April 2010 to September 2021 and underwent penectomy were included in the study. The optimal cut-off value of PNI and AGR was determined by receiver operating characteristic curve analysis. Kaplan-Meier analysis and the Cox proportional hazard model were used to evaluate the correlation between PNI, AGR, and OS in patients with PC.

ResultsThe best cut-off values of PNI and AGR were set to 49.03 (95% confidence interval 0.705-0.888, Youden index=0.517, sensitivity=57.9%, specificity=93.7%, P<0.001) and 1.28 (95% confidence interval 0.610-0.860, Youden index=0.404, sensitivity=84.1%, specificity=56.2%, P=0.003). Kaplan-Meier analysis showed that the OS of the patients in the high PNI group and the high AGR group was significantly higher than that of the patients in the low PNI group and the low AGR group (P<0.001). Univariate analysis showed that patient age, clinical N stage, pathological stage, PNI, and SII are all predictors of OS in patients with PC (P<0.05). Multivariate analysis showed that pathological stage (P=0.005), PNI (P=0.021), and AGR (P=0.004) are independent prognostic factors for predicting OS in patients with PC undergoing penectomy.

ConclusionsBoth PNI score and serum AGR are independent prognostic factors for predicting OS in patients with PC undergoing penectomy.

category: urology


title: Mechanisms of central brain atrophy in multiple sclerosis

abstract:
Background and objectivesThe measurement of longitudinal change in ventricular volume has been suggested as an accurate and reliable surrogate of central brain atrophy (CBA), potentially applicable to the everyday management of patient with multiple sclerosis (MS). To better understand mechanisms underlying central brain atrophy in RRMS patients we investigated the contribution of inflammatory activity in different lesion compartments to the enlargement of ventricular CSF volume. In addition, we investigated the role of the severity of lesional tissue damage in CBA progression.

MethodsPre- and post-gadolinium 3D-T1, 3D fluid-attenuated inversion recovery (FLAIR) and diffusion tensor images were acquired from 50 patients with relapsing MS. Lesional activity between baseline and 48 months was analysed on FLAIR images using custom-build software, which independently segmented expanding part of the chronic lesions, new confluent lesions and new free-standing lesions. The degree of lesional tissue damage was assessed by change in Mean Diffusivity (MD). Volumetric change of lateral ventricles was used as a measure of central brain atrophy.

ResultsDuring follow-up ventricles expanded on average by 12.6+/-13.7%. There was significant increase of total lesion volume, 69.3% of which was due to expansion of chronic lesions and 30.7%-to new (confluent and free-standing) lesional activity. There was high degree of correlation between volume of combined lesional activity and CBA (r2=0.67), which became considerably stronger when lesion volume was adjusted by the degree of tissue damage severity (r2=0.81). Linear regression analysis explained 90% of CBA variability and revealed that chronic lesion expansion was by far the largest contributor to ventricular enlargement (Standardized Coefficient Beta 0.68 (p<0.001) for expansion of chronic lesions compared to 0.29 (p=<0.001) for confluent lesions and 0.23 (p=0.001) for free-standing new lesions). Age and baseline ventricular volume also provided significant input to the model.

DiscussionOur data suggest that central brain atrophy is almost entirely explained by the combination of the volume and severity of lesional tissue activity. Furthermore, the expansion of chronic lesions plays a central role in this process.

category: neurology


title: Risk models based on non-cognitive measures may identify presymptomatic Alzheimer's disease

abstract:
ObjectiveExamine if non-cognitive metrics alone can be used to construct risk models to identify adults at risk for Alzheimers dementia and cognitive impairment, thus enabling early interventions.

MethodsClinical data from older adults without dementia from two harmonized cohort studies, the Memory and Aging Project (MAP, n=1179) and Religious Orders Study (ROS, n=1103), were analyzed using Cox proportional hazard models with backward variable selection to develop risk prediction models for Alzheimers dementia and cognitive impairment. Models using only non-cognitive covariates of physical function, psychosocial, health conditions and medications were compared to models that added cognitive covariates of Mini-Mental Status Examination (MMSE) and composite cognition score summarizing 17 cognitive tests. All models were trained in MAP and tested in ROS. Model performance was evaluated by the area under the curves (AUC) of receiver operating characteristic (ROC) curve.

ResultsModels based on non-cognitive covariates alone achieved AUC (0.800, 0.785) for predicting Alzheimers dementia (3, 5) years from baseline. Including additional cognitive covariates improved AUC to (0.916, 0.881). A model with a single covariate of composite cognition score achieved AUC (0.905, 0.863). Models based on non-cognitive covariates alone achieved AUC (0.717, 0.714) for predicting cognitive impairment (3, 5) years from baseline. Including additional cognitive covariates improved AUC to (0.783, 0.770). A model with a single covariate of composite cognition score achieved AUC (0.754, 0.730).

ConclusionsRisk models based on non-cognitive metrics predict both Alzheimers dementia and cognitive impairment. However, non-cognitive covariates do not provide incremental predictivity for models that include cognitive metrics in predicting Alzheimers dementia, but do in models predicting cognitive impairment. Risk models of Alzheimers dementia show more accurate predictions than the models of cognitive impairment. To ensure early interventions, it will be necessary to derive improved risk prediction models in particular for cognitive impairment.


title: Double burden of malnutrition and its social disparities among rural Sri Lankan adolescents

abstract: In Sri Lanka, the double burden of nutrition is often neglected, and increase of adolescent obesity is not well investigated. This study determines the double burden of malnutrition among adolescents in Anuradhapura district exploring the differences of prevalence based on different definitions. Students aged 13 to 16 years were selected from 74 schools using probability proportionate to size sampling. Anthropometry was done according to WHO guidelines. Obesity was defined according to body mass index (BMI) based definitions of WHO, International Obesity Task Force and Indian growth references. Central obesity was defined using Indian and British waist circumference cut-offs. Prevalence estimates from different definitions were compared using McNemars test. Socio-demographic determinants of nutritional issues were assessed using Chi-square test for independence. A total of 3105 students (47.7% boys) were studied (mean age 14.8+ 0.8 years). According to WHO definitions, 73 (2.4%, 95% CI; 1.9-2.9) were obese, 222 (7.2%, 95% CI; 6.3-8.1) were overweight, 673 (21.7%, 95% CI; 20.2-23.1,) were thin and 396 (12.8%, 95% CI; 11.6-14.0) were stunted. More boys (3.1%) than girls (1.7%) were obese as well as thin (29.0% compared to 15.0%). Prevalence of overweight/obesity was higher among students in larger, urban schools, and belonging to high social class and more educated parents. Prevalence of overweight/obesity estimated using IOTF-Asian and Indian thresholds were significantly higher than that from WHO and IOTF-international thresholds. Double burden of malnutrition is affecting the adolescents in rural Sri Lanka. Prevalence estimates of obesity largely depend on the definition used.

category: nutrition


title: Demonstration of antibodies against SARS-CoV-2, neutralizing or binding, in seroconversion panels after mRNA-1273, BNT-162b2 and Ad26.COV2.S vaccine administration.

abstract: Seroconversion panels were collected before and after vaccination with three COVID-19 vaccines: two mRNA vaccines (mRNA-1273 and BNT-162b2) and one adenovirus vector vaccine (Ad26.COV2.S). The panels were tested for antibody activity by chemiluminescent immunoassay, ELISA and one was tested in a pseudovirus neutralization assay. Participants positive for anti-SARS-CoV-2 antibodies before vaccination (18.6%) had a higher response to the first vaccine dose than participants who tested negative. For two-dose vaccines, older participants showed a lower response to the first dose than younger participants. All participants showed positive antibody responses after the second vaccine. For the adenovirus vector vaccine, two participants did not generate antibody responses two weeks and two months after vaccination. Three participants were negative at two weeks but positive at two months. Pseudovirus neutralization showed good correlation with antibody activity (correlation coefficient =0.78, p<0.0001). Antibody responses in participants over 45 years old tended to be less robust.

category: infectious diseases


title: Phase 3, multicentre, double-blind, randomised, parallel-group, placebo-controlled study of camostat mesilate (FOY-305) for the treatment of COVID-19 (CANDLE study)

abstract:
BackgroundIn vitro drug-screening studies have indicated that camostat mesilate (FOY-305) may prevent SARS-CoV-2 infection into human airway epithelial cells. This study was conducted to investigate whether camostat mesilate is an effective treatment for SARS-CoV-2 infection (COVID-19).

MethodsThis was a phase 3, multicentre, double-blind, randomised, parallel-group, placebo-controlled study. Patients were enrolled if they were admitted to a hospital within 5 days of onset of COVID-19 symptoms or within 5 days of a positive test for asymptomatic patients. Severe cases (e.g., those requiring oxygenation/ventilation) were excluded. Patients were administered camostat mesilate (600 mg qid; four to eight times higher than the clinical doses in Japan) or placebo for up to 14 days. The primary efficacy endpoint was the time to the first two consecutive negative tests for SARS-CoV-2.

FindingsOne-hundred and fifty-five patients were randomised to receive camostat mesilate (n=78) or placebo (n=77). The median time to the first test was 11 days in both groups, and conversion to negative status was observed in 60{middle dot}8% and 63{middle dot}5% of patients in the camostat mesilate and placebo groups, respectively. The primary (Bayesian) and secondary (frequentist) analyses found no significant differences in the primary endpoint between the two groups. No additional safety concerns beyond those already known for camostat mesilate were identified.

InterpretationCamostat mesilate is no more effective, based on upper airway viral clearance, than placebo for treating patients with mild to moderate SARS-CoV-2 infection with or without symptoms.

FundingOno Pharmaceutical Co., Ltd.

RESEARCH IN CONTEXT PANELO_ST_ABSEvidence before this studyC_ST_ABSSARS-CoV-2 infection (COVID-19), as a significant global health threat, is characterised by broad symptoms and varying disease severity. At the time of planning this study, there were no specific treatments for COVID-19 beyond the use of antiviral drugs, steroids and, in severe cases, ventilation with oxygen. Pre-clinical screening studies revealed the spike (S) protein of SARS-CoV-2 bind to angiotensin converting enzyme II (ACE2) on the host cell membrane. The S protein is then cleaved by a type II transmembrane serine protease (TMPRSS2) as an essential enzyme for the viral entry into host cells. In vitro drug-screening studies have shown that drugs that block binding of the S protein to ACE2 can prevent viral entry into a cell line derived from human airway epithelium. The studies identified 4-(4-guanidinobenzoyloxy)phenylacetic acid, the active metabolite of a serine protease inhibitor (camostat mesilate, FOY-305), as a candidate inhibitor of SARS-CoV-2 entry into humans. A retrospective study of critically ill COVID-19 patients with organ failure revealed a decline in disease activity within 8 days of admission among patients treated with camostat mesilate. In consideration of the preclinical and early clinical evidence, it was hypothesised that camostat mesilate is an effective treatment for patients with COVID-19. Therefore, we planned and executed a phase 3, randomised, double-blind, placebo-controlled study to investigate the efficacy and safety of camostat mesilate for the treatment of patients with mild to moderate COVID-19 infection with or without symptoms. The primary endpoint was the time to the first two consecutive negative tests for SARS-CoV-2. No controlled clinical studies of camostat mesilate had been conducted at the time of planning this study.

Added value of this studyThe results of this randomised controlled trial revealed that camostat mesilate, administered at a dose of 600 mg qid for up to 14 days, was no more effective than placebo, based on upper airway viral clearance in patients with mild to moderate SARS-CoV-2 infection with or without symptoms. Furthermore, there were no differences between the study groups in terms of other efficacy endpoints. This study used a dose that was four to eight times higher than the clinical doses of camostat mesilate used in Japan for the acute symptoms of chronic pancreatitis and postoperative reflux oesophagitis. The study identified no additional safety concerns beyond those already known for camostat mesilate.

Implications of all available evidenceAfter starting this study, another randomised, placebo-controlled study reported the efficacy and safety of camostat mesilate for the treatment of patients with COVID-19, albeit at a lower dose of 200 mg three times daily. That study also found no difference between camostat mesilate and placebo for the primary endpoint (the time to discharge or a clinical improvement in clinical severity of at least two points on a seven-point ordinal scale). Along with this evidence, our study did not support the use of camostat mesilate as a treatment option for COVID-19. However, since the administration of camostat mesilate was started after the onset of symptoms and presumably the peak viral load, we cannot exclude the possibility that camostat mesilate may be effective if administration is started earlier in the course of infection, or perhaps as prophylactic use in close contacts.


title: Dupilumab use is associated with protection from COVID-19 mortality: A retrospective analysis.

abstract: We previously found that type 2 immunity promotes COVID-19 pathogenesis in a mouse model. To test relevance to human disease we used electronic health record databases and determined that patients on dupilumab (anti-IL-4R monoclonal antibody that blocks IL-13 and IL-4 signaling) at the time of COVID-19 infection had lower mortality.


title: Acceptability and associated factors of indoor residual spraying for Malaria control by households in Luangwa district of Zambia: A multilevel analysis

abstract:
BackgroundThe global burden of malaria has increased from 227 million cases in 2019 to 247 million cases in 2020. Indoor residual spraying (IRS) remains one of the most effective control strategies for malaria. The current study sought to measure the acceptability level and associated factors of indoor residual spraying.

MethodsA cross sectional study was conducted from October to November 2020 in sixteen urban and rural communities of Luangwa district using a cluster sampling method, Multilevel analysis was used to account for the hierarchical structure of the data.

ResultsThe acceptability level of indoor residual spraying among household heads was relatively high at 87%. Individuals who felt the timing was not appropriate were associated with decreased odds of accepting IRS (AOR = 0.55, 95% CI: 0.20 - 0.86). Positive attitude was associated with increased odds of accepting IRS (AOR = 29.34, 95% CI: 11.14 - 77.30). High acceptability level was associated with unemployment (AOR = 1.92, 95% CI: 1.07 - 3.44). There were no associations found between acceptability levels and community-level factors such as information, education, communication dissemination, awareness achieved through door-to-door sensitization, and public address system.

ConclusionAcceptability level of indoor residual spraying was relatively high among households of Luangwa District suggesting that the interventions are more acceptable which is essential in reaching malaria elimination by 2030. Finding that community factors known to influence acceptability such as information, education and communication as well as awareness were not important to influencing acceptability suggests need for reinforcing messages related to indoor residual spraying and redefining the community sensitization approaches to make indoor residual spraying more acceptable.


title: COVID-19 vaccination coverage by company size and the effects of socioeconomic factors and workplace vaccination in Japan: a cohort study

abstract:
BackgroundVaccination is considered the most effective control measure against COVID-19. Vaccine hesitancy and equitable vaccine allocation are important challenges to disseminating developed vaccines. To promote COVID-19 vaccination coverage, the government of Japan established the workplace vaccination program. However, while it appears that the program was effective in overcoming vaccine hesitancy, the program may have hindered the equitable allocation of vaccines because it mainly focused on employees of large companies. We investigated the relationship between company size and COVID-19 vaccination completion status of employees and the impact of the workplace vaccination program on this relationship.

MethodsWe conducted an internet-based prospective cohort study from December 2020 (baseline) to December 2021. The data were collected using a self-administered questionnaire survey. Briefly, 27,036 workers completed the questionnaire at baseline and 18,560 at follow-up. After excluding ineligible respondents, we finally analyzed the data from 15,829 participants. At baseline, the participants were asked about the size of the company they worked for, and at follow-up they were asked about the month in which they received their second COVID-19 vaccine dose and the availability of a company-arranged vaccination opportunity.

ResultsIn each month throughout the observation period, the odds of having received a second COVID-19 vaccine dose were significantly lower for small-company employees than for large-company employees in the sex- and age-adjusted model. This difference decreased after adjusting for socioeconomic factors, and there was no significant difference after adjusting for the availability of a company-arranged vaccination opportunity.

ConclusionsThe workplace vaccination program implemented in Japan to control the COVID-19 pandemic may have been effective in overcoming vaccine hesitancy in workers; however, it may have caused an inequitable allocation of vaccines between companies of different sizes. Because people who worked for small companies were less likely to be vaccinated, it will be necessary to enhance support of vaccination for this population in the event of future infectious disease outbreaks.

Trial registrationNot applicable.


title: Adapted "Break The Cycle for Avant Garde" Intervention to Reduce Injection Assisting and Promoting Behaviours in People Who Inject Drugs in Tallinn, Estonia: A Pre- Post Trial.

abstract: In the context of established and emerging injection drug use epidemics, there is a need to prevent and avert injection drug use. We tested the hypothesis that an individual motivation and skills building counselling, adapted and enhanced from Hunts Break the Cycle intervention targeting persons currently injecting drugs would lead to reduction in injection initiation-related behaviours among PWID in Tallinn, Estonia. For this quasi-experimental study, pre-post outcome measures included self-reported promoting behaviours (speaking positively about injecting to non-injectors, injecting in front of non-injectors, offering to give a first injection) and injection initiation behaviours (assisting with or giving a first injection) during the previous 6 months. Of 214 PWID recruited, 189 were retained (88.3%) for the follow-up at 6 months. The proportion of those who had injected in front of non-PWID significantly declined from 15.9% to 8.5%, and reporting assisting with 1st injection from 6.4% to 1.06%. Of the current injectors retained in the study, 17.5% reported not injecting drugs at the follow up. The intervention adapted for the use in the setting of high prevalence of HIV and relatively low prevalence of injection assisting, tested proved to be effective and safe.

category: addiction medicine


title: Visualising Emergency Department Wait Times; Rapid Iterative Testing to Determine Patient Preferences for Displays

abstract: Visualising patient wait times in emergency departments for patients and families is increasingly common, following the development of prediction models using routinely collected patient demographic, urgency and flow data. Consumers of an emergency department wait time display will have culturally and linguistically diverse backgrounds, are more likely to be from under-served populations and will have varied data literacy skills. The wait times are uncertain, the information is presented when people are emotionally and physically challenged, and the predictions may inform high stakes decisions. In such a stressful environment, simplicity is crucial and the visual language must cater to the diverse audience. When wait times are conveyed well, patient experience improves. Designers must ensure the visualisation is patient-centred and that data are consistently and correctly interpreted. In this article, we present the results of a design study at three hospitals in Melbourne, Australia, undertaken in 2021. We used rapid iterative testing and evaluation methodology, with patients and families from diverse backgrounds as participants, to develop and validate a wait time display. We present the design process and the results of this project. Patients, families and staff were eligible to participate if they were awaiting care in the emergency department, or worked in patient reception and waiting areas. The patient-centred approach taken in our design process varies greatly from past work led by hospital administrations, and the resulting visualisations are very distinct. Most currently displayed wait time visualisations could be adapted to better meet end-user needs. Also of note, we found that techniques developed by visualisation researchers for conveying temporal uncertainty tended to overwhelm the diverse audience rather than inform. There is a need to balance precise and comprehensive information presentation against the strong need for simplicity in such a stressful environment.

category: emergency medicine


title: Motor signatures in digitized cognitive and memory tests enhances characterization of Parkinson's disease

abstract:
BackgroundAlthough there is a growing interest in using wearable sensors to characterize movement disorders, there is a lack of methodology for developing clinically interpretable kinematics biomarkers. Such digital biomarkers would provide a more objective diagnosis, capturing finer degrees of motor deficits, while retaining the information of traditional clinical tests.

ObjectivesWe aim at digitizing traditional tests of cognitive and memory performance to derive motor biometrics of pen-strokes and voice, thereby complementing clinical tests with objective criteria, while enhancing the overall motor characterization of Parkinsons disease (PD).

Methods35 participants including patients with PD, healthy young and age-matched controls performed a series of drawing and memory tasks, while their pen movement and voice were digitized. We examined the moment-to-moment variability of time-series reflecting the pen speed and voice amplitude.

ResultsThe stochastic signatures of the fluctuations in pen drawing speed and voice amplitude of patients with PD show lower noise-to-signal ratio compared to those derived from the younger and age-matched neurotypical controls. It appears that contact motions of the pen strokes on the tablet evokes sensory feedback for more immediate and predictable control in PD, compared to controls, while voice amplitude loses its neurotypical richness.

ConclusionsWe offer new standardized data types and analytics to help advance our understanding of hidden motor aspects of cognitive and memory clinical assays commonly used in Parkinsons disease.


title: Prediction of serious complications in patients with cancer and pulmonary thromboembolism: validation of the EPIPHANY Index in a prospective cohort of patients from the PERSEO Study

abstract:
IntroductionThere is currently no validated score capable of classifying cancer-associated pulmonary embolism (PE) in its full spectrum of severity. This study has validated the EPIHANY Index, a new tool to predict serious complications in cancer patients with suspected or unsuspected PE.

MethodThe PERSEO Study prospectively recruited individuals with PE and cancer from 22 Spanish hospitals. The estimation of the relative frequency {theta} of complications based on the EPIPHANY Index categories was made using the Bayesian alternative for the binomial test.

ResultsNine hundred patients diagnosed with PE between 2017/2020 were recruited. The rate of serious complications at 15 days was 11.8%, 95% highest density interval [HDI], 9.8-14.1%. Of the EPIPHANY low-risk patients, 2.4% (95% HDI, 0.8-4.6%) had serious complications, as did 5.5% (95% HDI, 2.9-8.7%) of the moderate-risk participants and 21.0% (95% HDI, 17.0-24.0%) of those with high-risk episodes. The EPIPHANY Index correlated with overall survival. Both the EPIPHANY Index and the Hestia criteria exhibited greater negative predictive value and a lower negative likelihood ratio than the remaining models. The incidence of bleeding at 6 months was 6.2% (95% HDI, 2.9-9.5%) in low/moderate-risk vs 12.7% (95% HDI, 10.1-15.4%) in high-risk (p-value=0.037) episodes. Of the outpatients, complications at 15 days were recorded in 2.1% (95% HDI, 0.7-4.0%) of the cases with EPIPHANY low/intermediate-risk vs 5.3% (95% HDI, 1.7-11.8%) in high-risk cases.

ConclusionWe have validated the EPIPHANY Index in patients with incidental or symptomatic cancer-related PE. This model can contribute to standardize decision-making in a scenario lacking quality evidence.

SummaryWe have validated the EPIPHANY Index in patients with acute, incidental, or symptomatic cancer-related PE. This predictive model of complications can contribute to standardize decision-making in a scenario lacking quality evidence.

category: oncology


title: Spatial prediction of COVID-19 pandemic dynamics in the United States

abstract:
BackgroundThe impact of COVID-19 across the United States has been heterogeneous, with some areas demonstrating more rapid spread and greater mortality than others. We used geographically-linked data to test the hypothesis that the risk for COVID-19 is spatially defined and sought to define which features are most closely associated with elevated COVID-19 spread and mortality.

MethodsLeveraging geographically-restricted social, economic, political, and demographic information from U.S. counties, we developed a computational framework using structured Gaussian processing to predict county-level case and death counts during both the initial and the nationwide phases of the pandemic. After identifying the most predictive spatial features, we applied an unsupervised clustering algorithm, topic modelling, to identify groups of features that are most closely associated with COVID-19 spread.

FindingsWe found that the inclusion of spatial features modeled case counts very well, with overall Pearsons correlation coefficient (PCC) and R2of 0.96 and 0.84 during the initial phase and 0.95 and 0.87, respectively, during the nationwide phase. The most frequently selected features were associated with urbanicity and 2020 presidential vote margins. When trained using death counts, models revealed similar performance metrics, with the addition of aging metrics to those most frequently selected. Topic modeling showed that counties with similar socioeconomic and demographic features tended to group together, and some feature sets were associated with COVID-19 dynamics. Unsupervised clustering of counties based on these topics revealed groups of counties that experienced markedly different COVID-19 spread.

InterpretationSpatial features explained most of the variability in COVID-19 dynamics between counties. Topic modeling can be used to group collinear features and identify counties with similar features in epidemiologic research.


title: Detection of a BA.1/BA.2 recombinant in travelers arriving in Hong Kong, February 2022

abstract: We studied SARS-CoV-2 genomes from travelers arriving in Hong Kong from November-2021 to February-2022. Apart from detecting Omicron (BA.1, BA1.1. and BA.2) and Delta variants, we detected a BA.1/BA.2 recombinant in two epidemiologically linked cases. This recombinant has a breakpoint near the 5 end of Spike gene (nucleotide position 20055-21618).


title: Socioeconomic inequality in the double burden of child malnutrition in the Eastern and Southern African Region

abstract: Socioeconomic inequalities in the double burden of child malnutrition threatens global nutrition targets 2025, especially in Eastern and Southern Africa. We aimed to quantify these inequalities from nationally representative household surveys in 13 Eastern and Southern African countries between 2000 and 2018. 13 of the latest Demographic and Health Surveys including 72,231 children under five year olds were studied. Prevalence of stunting, wasting and overweight (including obesity) were disagregated by wealth quintiles, maternal education categories and urban-rural residence for visual inspection of inequalities, and the slope index of inequality (SII) and the relative index of inequality (RII) were estimated for each country. Country-specific estimates were pooled using random-effects meta-analyses. Regional stunting and wasting prevalence was higher among children living in the poorest households, with mothers with the lowest educational level and in rural areas. In contrast, regional overweight (including obesity) prevalence was higher among children living in the richest households, with mothers with the highest educational level and urban areas. Tackling social inequalities in the distribution of the double burden of malnutrition among children in the Eastern and Southern African region will require strategies that address the reasons socially disadvantaged children become more exposed to stunting or wasting.


title: Acute respiratory distress syndrome after SARS-CoV-2 infection on young adult population: international observational federated study based on electronic health records through the 4CE consortium ARDS after SARS-CoV-2 infection on young adult

abstract:
PurposeIn young adults (18 to 49 years old), investigation of the acute respiratory distress syndrome (ARDS) after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been limited. We evaluated the risk factors and outcomes of ARDS following infection with SARS-CoV-2 in a young adult population.

MethodsA retrospective cohort study was conducted between January 1st, 2020 and February 28th, 2021 using patient-level electronic health records (EHR), across 241 United States hospitals and 43 European hospitals participating in the Consortium for Clinical Characterization of COVID-19 by EHR (4CE). To identify the risk factors associated with ARDS, we compared young patients with and without ARDS through a federated analysis. We further compared the outcomes between young and old patients with ARDS.

ResultsAmong the 75,377 hospitalized patients with positive SARS-CoV-2 PCR, 1001 young adults presented with ARDS ( 7.8% of young hospitalized adults). Their mortality rate at 90 days was 16.2% and they presented with a similar complication rate for infection than older adults with ARDS. Peptic ulcer disease, paralysis, obesity, congestive heart failure, valvular disease, diabetes, chronic pulmonary disease and liver disease were associated with a higher risk of ARDS. We described a high prevalence of obesity (53%), hypertension (38%-although not significantly associated with ARDS), and diabetes (32%).

ConclusionTrough an innovative method, a large international cohort study of young adults developing ARDS after SARS-CoV-2 infection has been gather. It demonstrated the poor outcomes of this population and associated risk factor.

category: intensive care and critical care medicine


title: Multi-task deep autoencoder to predict Alzheimer's disease progression using temporal DNA methylation data in peripheral blood

abstract:
MotivationTraditional approaches for diagnosing Alzheimers disease (AD) such as brain imaging and cerebrospinal fluid are invasive and expensive. It is desirable to develop a useful diagnostic tool by exploiting biomarkers obtained from peripheral tissues due to their noninvasive and easily accessible characteristics. However, the capacity of using DNA methylation data in peripheral blood for predicting AD progression is rarely known. It is also challenging to develop an efficient prediction model considering the complex and high-dimensional DNA methylation data in a longitudinal study.

ResultsWe develop two multi-task deep autoencoders, which are based on convolutional autoencoder and long short-term memory autoencoder to learn the compressed feature representations by jointly minimizing the reconstruction error and maximizing the prediction accuracy. By benchmarking on longitudinal methylation data collected from peripheral blood in Alzheimers Disease Neuroimaging Initiative, we demonstrate that the multi-task deep autoencoders outperform state-of-the-art machine learning approaches for both predicting AD progression and reconstructing the temporal methylation profiles. In addition, the proposed multi-task deep autoencoders can predict AD progression accurately using only historical data and the performance is further improved by including all temporal data.

Availabilityhttps://github.com/lichen-lab/MTAE


title: Telehealth versus Self-Directed Lifestyle Intervention to Promote Healthy Blood Pressure: a Randomized Controlled Trial

abstract:
IntroductionLifestyle behavior modification interventions, delivered using telehealth, have been shown to be effective in reducing weight. However, limited data exists on the benefits of lifestyle behavior change delivered using telehealth and web-based applications on blood pressure (BP).

MethodsWe conducted a 2-site randomized controlled trial in the Geisinger Health System (January 2019 to March 2021) to compare the efficacy of a self-guided vs. a dietitian telehealth approach using web-based applications in 187 participants with 24-hour systolic BP 120-160 mmHg and body mass index [≥] 25 kg/m2. Both arms received recommendations to improve diet based on a web-based food frequency questionnaire, and access to an online weight management program. The telehealth arm received weekly telephone calls with a dietitian who used motivational interviewing. The primary outcome was 12-week change in 24-hour systolic BP. Secondary outcomes included changes in sleep/awake systolic BP and diastolic BP, self-reported physical activity, healthy eating index (HEI)-2015 score, and weight.

ResultsA total of 187 participants (mean age 54.6 [SD 13.2] years, 52% female, 23% on BP medications, mean body mass index 34.5 [6.5] kg/m2, mean HEI-2015 score 60.8 [11.1] units) were randomized with 156 (83.4%) completing the trial. Mean 24-hour systolic BP improved from baseline to 12 weeks similarly in the dietitian (-6.73 mmHg, 95% CI: -8.64, -4.82) and the self-directed arm (-4.92, 95% CI: -7.01, -2.77; p comparing groups=0.2). The dietitian telehealth arm had greater 12-week improvements in sleep systolic BP (mean -6.92 vs. -1.45; p=0.004), sleep diastolic BP (-3.31 vs. 0.73; p=0.001), and self-reported physical activity (866 vs. -243 metabolic equivalent of task minutes/week; p=0.01). The dietitian telehealth arm also tended to have greater 12-week improvements in weight loss (-5.11 vs. -3.89 kg; p=0.1) and HEI-2015 score (9.23 vs. 6.43 units; p=0.09), though these differences were not statistically significant.

ConclusionsDietitian-led telehealth supported by web-based applications resulted in a similar reduction in 24-hour systolic BP as a self-directed approach, with secondary improvements in sleep BP and physical activity.

Trial registration numberClinicalTrials.gov Identifier NCT03700710

category: cardiovascular medicine


title: Transmission of SARS-CoV-2 in standardised First Few X cases and household transmission investigations: a systematic review and meta-analysis

abstract:
We aimed to estimate the household secondary infection attack rate (hSAR) of SARS-CoV-2 in investigations aligned with the WHO Unity Studies Household Transmission Investigations (HHTI) protocol. We conducted a systematic review and meta-analysis according to PRISMA 2020 guidelines.

We searched Medline, Embase, Web of Science, Scopus and medRxiv/bioRxiv for  Unity-aligned First Few X cases (FFX) and HHTIs published between 1 December 2019 and 26 July 2021. Standardised early results were shared by WHO Unity Studies collaborators (to 1 October 2021). We used a bespoke tool to assess investigation methodological quality. Values for hSAR and 95% confidence intervals (CIs) were extracted or calculated from crude data. Heterogeneity was assessed by visually inspecting overlap of CIs on forest plots and quantified in meta-analyses.

Of 9988 records retrieved, 80 articles (64 from databases; 16 provided by Unity Studies collaborators) were retained in the systematic review and 62 were included in the primary meta-analysis. hSAR point estimates ranged from 2%-90% (95% prediction interval: 3%-71%; I2=99.7%); I2 values remained >99% in subgroup analyses, indicating high, unexplained heterogeneity and leading to a decision not to report pooled hSAR estimates.

FFX and HHTI remain critical epidemiological tools for early and ongoing characterisation of novel infectious pathogens. The large, unexplained variance in hSAR estimates emphasises the need to further support standardisation in planning, conduct and analysis, and for clear and comprehensive reporting of FFX and HHTIs in time and place, to guide evidence-based pandemic preparedness and response efforts for SARS-CoV-2, influenza and future novel respiratory viruses.


title: Chronotype and mortality - a 37-year follow-up study in Finnish adults

abstract:
BackgroundThe only study on chronotype and mortality suggested small increases of all-cause and cardiovascular mortality in a 6.5-year follow-up. Our aim was to constructively replicate findings from it in a longer follow-up.

MethodsA questionnaire was administered to the population-based Finnish Twin Cohort in 1981 (response rate 84%, age 24-101 years). The study population included 23,854 participants who replied to the question: "Try to assess to what extent you are a morning person or an evening person", with four response alternatives (clearly a morning person, to some extent a morning person, to some extent an evening person, and clearly an evening person). Vital status and cause of death data were provided by nationwide registers up to the end of 2018. Hazard ratios and their 95% confidence intervals for mortality were computed; there were 8728 deaths over the follow-up period. Adjustments were made for education, alcohol, smoking, body mass index, and sleep length.

ResultsThe model adjusted for all covariates showed a 9% increase in risk of all-cause mortality for the evening-type group (1.09, 1.01-1.18), with attenuation mainly due to smoking and alcohol, as they had larger consumption than those with morningness chronotypes. We observed no increase in cardiovascular mortality by chronotype. No increase in mortality was seen among the non-smokers who were at most light drinkers.

ConclusionsOur results from this 37-year follow-up study suggest that there is little or no independent contribution of chronotype to all-cause and cardiovascular mortality.

Key messagesO_LIThere is little or no independent contribution of chronotype to mortality.
C_LIO_LIThe increased risk of mortality associated with eveningness appears to be mainly mediated by a larger consumption of tobacco and alcohol than in those with a morningness chronotype.
C_LIO_LIIt is important to be aware of the increased health risks of evening-type persons.
C_LI


title: Inferring the true number of SARS-CoV-2 infections in Japan

abstract:
IntroductionIn Japan, as of December 31, 2021, more than 1.73 million laboratory-confirmed cases have been reported. However, the actual number of infections is likely to be under-ascertained due to the epidemiological characteristics such as mild and subclinical infections and limited testing availability in the early days of the pandemic. In this study, we infer the true number of infections in Japan between January 16, 2020, and December 31, 2021, using a statistical modelling framework that combines data on reported cases and fatalities.

MethodsWe used reported daily COVID-19 deaths stratified into 8 distinct age-groups and age-specific infection fatality ratios (IFR) to impute the true number of infections. Estimates of IFR were informed from published studies as well seroprevalence studies conducted in Japan. To account for the uncertainty in IFR estimates, we sampled values from relevant distributions.

ResultsWe estimated that as of December 31, 2021, 2.90 million (CrI: 1.77 to 4.27 million) people had been infected in Japan, which is 1.68 times higher than the 1.73 million reported cases. Our meta-analysis confirmed that these findings were consistent with the intermittent seroprevalence studies conducted in Japan.

ConclusionsWe have estimated that a substantial number of COVID-19 infections in the country were unreported, particularly in adults. Our approach provides a more realistic assessment of the true underlying burden of COVID-19. The results of this study can be used as fundamental components to strengthen population health control and surveillance measures.


title: Association of history of metformin use with delirium and mortality: A retrospective cohort study

abstract:
ObjectiveTo investigate the relationship between history of metformin use and delirium risk, as well as long-term mortality.

MethodsIn this retrospective cohort study, subjects recruited between January 2016 and March 2020 were analyzed. Logistic regression analysis was performed to investigate the relationship between metformin use and delirium. Log-rank analysis and Cox proportional hazards model were used to investigate the relationship between metformin use and 3-year mortality.

ResultsThe data from 1404 subjects were analyzed. 242 subjects were categorized into a DM-without-metformin group, and 264 subjects were categorized into a DM-with-metformin group. Prevalence of delirium was 36.0% in the DM-without-metformin group, and 29.2% in the DM-with-metformin group. A history of metformin use reduced the risk of delirium in patients with DM (OR, 0.50 [95% CI, 0.32 to 0.79]) after controlling for age, sex, and dementia status, body mass index (BMI), and insulin use. The 3-year mortality in the DM-without-metformin group (survival rate, 0.595 [95% CI, 0.512 to 0.669]) was higher than in the DM-with-metformin group (survival rate, 0.695 [95% CI, 0.604 to 0.770]) (p=0.035). A history of metformin use decreased the risk of 3-year mortality after adjustment for age, sex, Charlson Comorbidity Index, BMI, history of insulin use, and delirium status (HR, 0.69 [95% CI, 0.48 to 0.98]).

ConclusionsIt was found that metformin usage was associated with decreased delirium prevalence and lower 3-year mortality. The potential benefit of metformin on delirium risk and mortality were shown.

category: psychiatry and clinical psychology


title: The spatial-temporal risk profiling of Clonorchis sinensis infection in South Korea: A geostatistical modeling study

abstract: Clonorchiasis is one of the major parasitic diseases in South Korea. Spatially explicit estimates of the infection risk are important for control and intervention. We did a systematic review of collected prevalence data on Clonorchis sinensis infection in South Korea. Data of potential influencing factors (e.g., environmental and social-economic factors) was obtained from open-access databases. Bivariate Bayesian geostatistical joint modeling approaches were applied to analyze disease data, within a logit regression in combination of potential influencing factors and spatial-temporal random effects. We identified surveys of C. sinensis infection done at 1362 unique locations, and presented the first spatial-temporal risk maps at high spatial resolution (5x5km) in South Korea. High infection risk areas shrunk significantly from 1970 to 2017. The overall risk decreased since the start of the national deworming program in 1969, and then slightly increased since the year 1995 when the program suspended, and maintained stable since 2005 when the Clonorchiasis Eradication Program begun. The population-weighted prevalence was estimated as 3.87% (95% BCI: 3.04-4.82%) in 2017, accounting to 1.92 (95% BCI: 1.51-2.40) million infected people. Although the prevalence over the country has been low, C. sinensis infection was still endemic in areas of eastern and southern regions, particularly the five major river basins. We also defined factors significantly correlated, such as, distance to the nearest open water bodies, annual precipitation, and land surface temperature at night. All findings above provide important information on spatial-targeting control and preventive strategies of C. sinensis infection in South Korea.


title: Blood flow restriction added to usual care exercise in patients with early weight bearing restrictions after cartilage or meniscus repair in the knee joint: A feasibility study

abstract:
PurposeIn musculoskeletal rehabilitation, blood flow restriction - low load strength training (BFR-LLST) is theoretically indicated - as opposed to traditional heavy strength training - in patients who can or may not heavily load tissues healing from recent surgery. The main purpose was to examine the feasibility of BFR-LLST added to usual care exercise early after cartilage or meniscus repair in the knee joint.

MethodsWe included 42 patients with cartilage (n=21) or meniscus repair (n=21) in the knee joint. They attended 9 weeks of BFR-LLST added to a usual care exercise at an outpatient rehabilitation center. Outcome measures were assessed at different time points from 4 (baseline) to 26 weeks postoperatively. They included: Adherence, harms, knee joint and thigh pain, perceived exertion, thigh circumference (muscle size proxy), isometric knee-extension strength, self-reported disability and quality of life.

ResultsOn average, patients with cartilage and meniscus repair performed >84 % of the total BFR-LLST supervised sessions. Thirty-eight patients reported 146 adverse events (e.g., dizziness) - none considered serious. A decrease in thigh circumference of the operated leg was not found in both groups from baseline to the end of the intervention period with no exacerbation of knee joint or quadriceps muscle pain.

ConclusionsBFR-LLST added to usual care exercise initiated early after cartilage or meniscus repair seems feasible and may prevent disuse thigh muscle atrophy during a period of weight bearing restrictions. Harms were reported, but no serious adverse events were found. Our findings are promising but need replication using RCT-design.


title: Pharmacokinetics/pharmacodynamics by Race: Analysis of a Peginterferon Beta-1a Phase I Study

abstract:
BackgroundBlack/African-American participants are underrepresented in clinical trials but can experience a greater burden of disease, such as multiple sclerosis, than other racial groups in the United States. A phase 1, open-label, 2-period crossover study that demonstrated bioequivalence of subcutaneous (SC) and intramuscular (IM) injection of peginterferon beta-1a in healthy volunteers enrolled a similar proportion of Black/African-American and White participants, enabling a subgroup analysis comparing these groups.

MethodsPeginterferon beta-1a 125 g was administered by SC or IM (1:1) injection, followed by a 28-day washout period before a second injection using the alternate method. Primary endpoints were maximum observed concentration (Cmax) and area under the concentration-time curve from Hour 0 to infinity (AUCinf). Secondary endpoints included safety, tolerability, and additional pharmacokinetic and pharmacodynamic parameters.

FindingsThis analysis included 70 (51.5%) Black and 59 (43.3%) White participants. Black participants exhibited a 29.8% higher geometric mean Cmax of peginterferon beta-1a than White participants following SC administration and demonstrated similar values following IM administration. Black participants displayed 31.0% versus 11.8% higher geometric mean AUCinf values than White participants with SC versus IM administration. Neopterin dynamics and safety signals were similar between groups, with numerically fewer adverse events reported among Black participants.

ConclusionsNo clinically meaningful differences were identified between Black and White participants in pharmacokinetics/pharmacodynamics or safety related to peginterferon beta-1a administration, indicating that no change in dosing regimen is warranted for Black patients with MS.

FundingFunding for medical writing support was provided by Biogen Inc. (Cambridge, MA, USA).


title: Ablation of Apparent Diffusion Coefficient Hyperintensity Clusters and Mesial Temporal Lobe Epilepsy Improves Seizure Outcomes after Laser Interstitial Thermal Therapy

abstract:
ObjectiveMR-guided Laser Interstitial Thermal Therapy (LiTT) is a minimally invasive surgical procedure for intractable mesial temporal epilepsy (mTLE). LiTT is safe and effective but seizure outcomes are highly variable due to patient variability, suboptimal targeting, and incomplete ablation of epileptogenic zone. Apparent Diffusion Coefficient (ADC) is an MRI sequence that can identify potential epileptogenic foci in the mesial temporal lobe to improve ablation and seizure outcome. The objective of this study was to investigate whether ablation of tissue clusters with high ADC values in the mesial temporal structures is associated with seizure outcome in mTLE after LiTT.

MethodsThirty mTLE patients who underwent LiTT at our institution were analyzed. Seizure outcome was categorized as complete seizure freedom (ILAE Class I) and residual seizures (ILAE Class II - VI). Volumes of hippocampus and amygdala were segmented from preoperative T1 MRI sequence. Spatially distinct hyperintensity clusters were identified in the preoperative ADC map. Percent cluster volume and number ablated were associated with seizure outcomes.

ResultsThe mean age at surgery was 36.6 years and mean follow-up duration was 1.9 years. Proportions of hippocampal cluster volume (35.20% vs. 16.5 %, p = 0.014) and cluster number (27.1 % vs 4.2 %, p = 0.0007) ablated were significantly higher in patients with seizure freedom. For amygdala clusters, only proportion of cluster number ablated was significantly associated with seizure outcome (13.2 % vs. 0 %, p = 0.016). Ablation of hippocampal clusters predicted seizure outcome, both by volume (AUC = 0.7679) and number (AUC = 0.8086) ablated.

SignificanceSeizure outcome after LiTT in mTLE patients was significantly associated with the extent of cluster ablation in the hippocampus and amygdala. The results suggest that preoperative ADC analysis may help identify high-yield pathological tissue clusters that represent epileptogenic foci. ADC based cluster analysis can potentially assist ablation targeting and improve seizure outcome after LiTT in mTLE.


title: Predicting the future development of diabetic retinopathy using a deep learning algorithm for the analysis of non-invasive retinal imaging

abstract: Diabetic retinopathy (DR) is the most common cause of vision loss in the working age. While over 90% of sight-threatening cases may be treated if detected early, prevalence of yearly detective screening is low until advanced presentation of the disease. We developed a machine learning algorithm for the prediction of future DR development using fundus photography of otherwise healthy eyes. Our algorithm achieves 0.81 Area Under Receiver Operating Curve (AUC) averaging scores from multiple images on the task of predicting development of referrable DR, and 0.76 AUC when using a single image. In conclusion, risk of DR may be predicted from fundus photography alone. Prediction of personalized risk of DR may become key in treatment and contribute to patient compliance across the board. Further prospective research is necessary.

category: ophthalmology


title: Assessing the potential cost-effectiveness of centralized vs point-of-care testing for hepatitis C virus in Pakistan: a model-based comparison

abstract:
BackgroundPakistan has a hepatitis C virus (HCV) infection prevalence of 6-9% and aims to achieve World Health Organization (WHO) targets for elimination of HCV by the year 2030 through scaling HCV diagnosis and accelerating access to care. The clinical and economic benefits of various HCV testing strategies have not yet been evaluated in Pakistan.

ObjectiveTo evaluate the potential cost-effectiveness of a reference laboratory-based (CEN) confirmatory testing approach vs a molecular near-patient point-of-care (POC) confirmatory approach to screen the general population for HCV in Pakistan.

MethodsWe developed a decision-analytic model comparing HCV testing under two scenarios: screening with an anti-HCV antibody test (Anti-HCV) followed by either POC nucleic acid testing (NAT) (Anti-HCV-POC), or reference laboratory NAT (Anti-HCV-CEN), using data from published literature, the Pakistan Ministry of Health, and expert judgment. Outcome measures included: number of HCV infections identified per year, percentage of individuals correctly classified, total costs, average costs per individual tested, and cost-effectiveness. Sensitivity analysis was also performed.

ResultsAt a national level for a tested population of 25 million, the Anti-HCV-CEN strategy would identify 142,406 more HCV infections in one year and increase correct classification of individuals by 0.57% compared with the Anti-HCV-POC strategy. The total annual cost of HCV testing was reduced using the Anti-HCV-CEN strategy by $7.68 million ($0.31 per person). Thus, incrementally, the Anti-HCV-CEN strategy costs less and identifies more HCV infections than Anti-HCV-POC.

ConclusionsAnti-HCV-CEN would provide the best value for money when scaling up HCV testing in Pakistan.

Significance statementO_LIHepatitis C virus (HCV) infection constitutes a major medical and public health burden in Pakistan
C_LIO_LIWidespread testing is important to identify those that are chronically infected in order to link them to treatment services
C_LIO_LIThe optimal and most cost-effective testing approach to scale up HCV testing to support elimination efforts in Pakistan has not been established
C_LIO_LIHigh throughput reference laboratory testing would provide the best value for money when scaling-up HCV testing in Pakistan
C_LI

category: health economics


title: Epidemiological topology data analysis links severe COVID-19 to RAAS andhyperlipidemia associated metabolic syndrome conditions

abstract: The emergence of COVID19 created incredible worldwide challenges but offers unique opportunities to understand the physiology of its risk factors and their interactions with complex disease conditions, such as metabolic syndrome. Epidemiological analysis powered by topological data analysis (TDA) is a novel approach to uncover these clinically relevant interactions. Here TDA utilized Explorys data to discover associations among severe COVID19 and metabolic syndrome, and it explored the probative value of drug prescriptions to capture the involvement of RAAS and hypertension with COVID19 as well as modification of risk factor impact by hyperlipidemia on severe COVID19.

category: health informatics


title: High rate of BA.1, BA.1.1 and BA.2 in triple vaccinated

abstract:
BackgroundBooster vaccine doses offer protection against severe COVID-19 caused by omicron but are less effective against infection. Characteristics such as serological correlates of protection, viral abundance and clearance of omicron infections in triple vaccinated individuals are scarce.

MethodsWe conducted a 4-week twice-weekly SARS-CoV-2 qPCR screening shortly after an mRNA vaccine booster in 375 healthcare workers. Anti-Spike IgG levels and neutralization titers were determined at study start. qPCR-positive participants were sampled repeatedly for two weeks and monitored for symptoms.

ResultIn total 82 (cumulative incidence 22%) omicron infections were detected, divided between BA.1, BA.1.1 and BA.2. Only 10% of infected participants remained asymptomatic. Viral load peaked at day 3 and live virus could be detected for up to 9 days after first PCR-positive sample. Presence of symptoms correlated to elevated viral load (p<0.0001), but despite resolution of symptoms most participants showed Ct levels <30 at day 9. While post-booster antibody titers were similar in those with and without subsequent breakthrough infection (p>0.05), high antibody titers were linked to reduced viral load (p<0.01) and time to viral clearance (p<0.01). No significant differences were observed for viral load and time to viral clearance between BA.1, BA.1.1 and BA.2 infected individuals.

ConclusionWe report high incidence of omicron infections despite recent booster vaccination in triple vaccinated individuals. Vaccine-induced antibody titres seem to play a limited role in risk of omicron infection. High viral load and secretion of live virus for up to nine days may increase transmission in a triple vaccinated population.


title: Predictors of all-cause mortality among patients hospitalized with influenza, respiratory syncytial virus, or SARS-CoV-2

abstract:
BackgroundShared and divergent predictors of clinical severity across respiratory viruses may support clinical and community responses in the context of a novel respiratory pathogen.

MethodsWe conducted a retrospective cohort study to identify predictors of 30-day all-cause mortality following hospitalization with influenza (N=45,749; 2011-09 to 2019-05), respiratory syncytial virus (RSV; N=24,345; 2011-09 to 2019-04), or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; N=8,988; 2020-03 to 2020-12; pre-vaccine) using population-based health administrative data from Ontario, Canada. Multivariable modified Poisson regression was used to assess associations between potential predictors and mortality. We compared the direction, magnitude, and confidence intervals of risk ratios to identify shared and divergent predictors of mortality.

Results3,186 (7.0%), 697 (2.9%) and 1,880 (20.9%) patients died within 30 days of hospital admission with influenza, RSV, and SARS-CoV-2, respectively. Shared predictors of increased mortality included: older age, male sex, residence in a long-term care home, and chronic kidney disease. Positive associations between age and mortality were largest for patients with SARS-CoV-2. Few comorbidities were associated with mortality among patients with SARS-CoV-2 as compared to those with influenza or RSV.

ConclusionsOur findings may help identify patients at greatest risk of illness secondary to a respiratory virus, anticipate hospital resource needs, and prioritize local prevention and therapeutic strategies to communities with higher prevalence of risk factors.


title: Unravelling the transcriptome of the human tuberculosis lesion and its clinical implications

abstract:
Tuberculosis (TB) disease causes up to 1.5 million deaths every year and represents an important problem of public health at worldwide level. Here, we quantified the gene expression signatures of granuloma biopsies across human TB pulmonary lesions, and validated the best gene candidates using NanoString technology, profiling 157 samples from 40 TB patients who underwent surgery.

We characterised the transcriptional profile of the TB granuloma in comparison to healthy tissue, described an 11-gene signature and measured 7 proteins in plasma associated with it. We demonstrated a gradient of immune-related transcript abundance across the granuloma substructure and evidenced metabolically-active Mycobacterium tuberculosis in the lesions. Patients who converted to sputum negative after two months of starting treatment, showed enriched inflammatory pathways in the lesion several months after, supporting use of sputum culture conversion (SCC) as a prognostic biomarker during clinical management and as a factor to prioritise patients when considering lung surgery.


title: Clinical and Economic Impact of Differential COVID-19 Vaccine Effectiveness in the United States

abstract:
BackgroundIn the United States (US), three vaccines are currently available for primary vaccination and booster doses to prevent coronavirus disease 2019 (COVID-19), including the 2-dose messenger ribonucleic acid (mRNA) BNT162b2 (COMIRNATY(R), Pfizer Inc) and mRNA-1273 (SPIKEVAX(R), Moderna Inc) vaccines, which are preferred by the Centers for Disease Control and Preventions (CDC) Advisory Committee on Immunization Practice (ACIP), and the adenovirus vector Ad26.COV2.S (Johnson & Johnson) vaccine. A substantial body of evidence has now been published on the real-world effectiveness and waning of the primary series and booster doses against specific SARS-CoV2-variants. The study objective was to determine the clinical and economic impact of differences in effectiveness between mRNA-1273 and BNT162b2 booster vaccinations over one year (2022) in US adults [≥]18 years.

MethodsA decision analytic model was used to compare three mRNA booster market share scenarios: (1) Current Scenario, where the booster mix observed in December 2021 continues throughout 2022; (2) mRNA-1273 Scenario, where the only booster administered in 2022 is mRNA-1273, and (3) BNT162b2 Scenario, where the only booster administered in 2022 is BNT162b2. Analyses were performed from the US healthcare system perspective. Sensitivity analyses were performed to explore the impact of COVID-19 incidence in the unvaccinated population and vaccine effectiveness (VE) on model results.

ResultsIn the Current Scenario, the model predicts 65.2 million outpatient visits, 3.4 million hospitalizations, and 636,100 deaths from COVID-19 in 2022. The mRNA-1273 Scenario reduced each of these outcomes compared to the Current Scenario. Specifically, 684,400 fewer outpatient visits, 48,700 fewer hospitalizations and 9,500 fewer deaths would be expected. Exclusive of vaccine costs, the mRNA-1273 Scenario is expected to decrease direct medical costs by $1.3 billion. Conversely, the BNT162b2 Scenario increased outcomes compared to the Current Scenario: specifically, 391,500 more outpatient visits, 34,500 more hospitalizations and 7,200 more deaths would be expected in 2022, costing an additional $946 million in direct medical costs. For both the mRNA-1273 and BNT162b2 booster scenarios, the percent change in direct treatment costs for COVID-19 is similar to the percent change in hospitalizations as the rate of hospitalizations is the driver of the overall costs.

Changing the number of projected COVID-19 cases in 2022 by varying the incidence rate has a direct effect on model outcomes. Higher incidence rates leads to higher outpatient visits, hospitalizations and deaths for all scenarios. Varying VE has an inverse effect on model outcomes. All outcomes increase when VE is lower for all vaccines and decrease when VE is higher. In all cases, additional use of mRNA-1273 leads to fewer infection outcomes while additional use of BNT126b2 results to higher infection outcomes.

ConclusionAs the real-world effectiveness evidence to date indicates that mRNA-1273 may be more effective at preventing COVID-19 infection and hospitalization over time than BNT-162b2, increasing the proportion of people receiving this as a booster are expected to reduce COVID-19-related outcomes and costs in 2022, regardless of COVID-19 incidence or variant.


title: Does Metformin Decrease Mortality in Patients with Type 2 Diabetes Mellitus Hospitalized for COVID-19? A Multivariable and Propensity Score-adjusted Meta-analysis

abstract:
AimsCoronavirus disease 2019 (COVID-19) is a new pandemic that the entire world is facing since December of 2019. Increasing evidence has shown that metformin is linked to favorable outcomes in patients with COVID-19. The aim of this study was to address whether outpatient or inpatient metformin therapy offers low in-hospital mortality in patients with type 2 diabetes mellitus hospitalized for COVID-19.

MethodsWe searched studies published in PubMed, Embase, Google Scholar and Cochrane Library up to October 1, 2021. Raw event data extracted from individual study were pooled using the Mantel-Haenszel approach. Odds ratio (OR) or hazard ratio (HR) adjusted for covariates that potentially confound the association using multivariable regression or propensity score matching was pooled by the inverse-variance method. Random effect models were applied for meta-analysis due to variation among studies.

ResultsNineteen retrospective observational studies were selected. The pooled unadjusted OR for outpatient metformin therapy and in-hospital mortality was 0.54 (95% CI, 0.42-0.68), whereas the pooled OR adjusted with multivariable regression or propensity score matching was 0.72 (95% CI, 0.47-1.12). The pooled unadjusted OR for inpatient metformin therapy and in-hospital mortality was 0.19 (95% CI, 0.10-0.36), whereas the pooled adjusted HR was 1.10 (95% CI, 0.38-3.15).

ConclusionsOur results suggest that there is a significant reduction of in-hospital mortality with metformin therapy in patients with type 2 diabetes mellitus hospitalized for COVID-19 in the unadjusted analysis, but this mortality benefit does not retain after adjustments for confounding bias.

category: endocrinology


title: Variation in National COVID-19 Mortality Rates Across Asian Subgroups in the United States, 2020

abstract: Provisional U.S. national COVID-19 mortality data for the year 2020 analyzed by the CDC in March 2021 indicated that non-Hispanic Asians fared markedly better overall than other racial/ethnic minority groups-and marginally better than non-Hispanic Whites-in terms of age-adjusted mortality rates. However, Asians in the United States are composed of diverse array of origin subgroups with highly varying social, economic, and environmental experiences, which influence health outcomes. As such, lumping all Asians together into a single category can mask meaningful health disparities among more vulnerable Asian subgroups. To date, there has not been a national-level analysis of COVID-19 mortality outcomes between Asian subgroups. Utilizing final multiple cause of death data for 2020 and population projections from the U.S. Census Bureaus Current Population Survey Annual Social and Economic Supplement for 2020, crude and age-adjusted national COVID-19 mortality rates, both overall and stratified by sex, were calculated for the six major single-race Asian origin subgroups (Asian Indian, Chinese, Filipino, Japanese, Korean, and Vietnamese) and a catch-all seventh category that comprises the remaining Asian subgroups (Other Asians), contrasting them to the corresponding mortality rates of other racial/ethnic groups. A substantially more nuanced picture emerges when disaggregating Asians into its diverse origin subgroups and stratifying by sex, with Filipino males and Asian males outside of the six major Asian subgroups in particular experiencing markedly higher age-adjusted mortality rates than their White male counterparts, whether comparisons were restricted to their non-Hispanic subsets or not. During the COVID-19 pandemic and in the post-pandemic recovery, it is imperative not to overlook the health needs of vulnerable Asian populations. Public health strategies to mitigate the effects of COVID-19 must avoid viewing Asians as a monolithic entity and recognize the heterogeneous risk profiles within the U.S. Asian population.

category: public and global health


title: Safety, Immunologic Effects and Clinical Response in a Phase I Trial of Umbilical Cord Mesenchymal Stromal Cells in Patients with Treatment Refractory Systemic Lupus Erythematosus

abstract:
BackgroundReports of clinical improvement following mesenchymal stromal cell (MSC) infusions in refractory lupus patients at a single center in China led us to perform an explorative Phase I trial of umbilical cord derived MSCs in patients refractory to six months of immunosuppressive therapy.

MethodsSix women with a SLEDAI>6, having failed standard of care therapy, received one IV infusion of 1x106 MSCs/kg of body weight. They maintained their current immunosuppressives, but their physician was allowed to adjust corticosteroids initially for symptom management. The clinical endpoint was an SRI of 4 with no new BILAG As and no increase in Physician Global Assessment score of >0.3 with tapering of prednisone to 10mg or less by 20 weeks.

ResultsOf 6 patients, 5 (83.3%; 95% CI = 35.9% to 99.6%) achieved the clinical endpoint of an SRI of 4. Adverse events were minimal. Mechanistic studies revealed significant reductions in CD27IgD negative B cells, switched memory B cells and activated naive B cells with increased transitional B cells in the 5 patients who met the endpoint. There was a trend towards decreased autoantibody levels in specific patients. One patient had an increase in their Helios+Treg cells, but no other significant T cell changes were noted. GARP-TGF{beta} complexes were significantly increased following the MSC infusions. The B cell changes and the GARP-TGF{beta} increase were significantly correlated with SLEDAI scores.

ConclusionThis pilot trial suggests that UC MSC infusions are safe and may have efficacy in lupus. The B cell and GARP-TGF{beta} changes provide insight into mechanisms by which MSCs may impact disease.

Trial RegistrationNCT03171194

FundingThis study was funded by a grant from the Lupus Foundation of America and NIH UL1 RR029882

category: rheumatology


title: Associations of current and childhood socioeconomic status and health outcomes amongst patients with knee or hip osteoarthritis in a Mexico City family-practice setting.

abstract:
ObjectivesTo examine the association of current and childhood socioeconomic status (SES) with patient-reported functional status, quality of life and disability in patients with knee osteoarthritis (OA)

MethodsWe conducted a cross-sectional study amongst individuals seeking care for any medical reason in a primary care family-practice clinic in Mexico City. We included individuals with self-reported doctor-diagnosed arthritis and administered a survey using validated Spanish language versions of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), the Osteoarthritis of Lower Limbs and Quality of Life (AMICAL), and the Stanford Health Assessment Questionnaire-Disability Index (HAQ-DI). To estimate current and childhood SES, we and used a validated tool to estimate income quintile, as well as education level and occupation type, for both the patient and their parents.

ResultsWe recruited 154 patients and excluded 8 patients. Estimated income and education levels were correlated with WOMAC, AMICAL and HAQ-DI scores, and significant differences were found in all scores by occupation type. The association for estimated income and all scores remained significant independently of age, sex, BMI, and presence of diabetes or hypertension. Maternal education was best correlated with AMICAL scores, though its effect seemed largely mediated by its association with current SES measures.

ConclusionsCurrent and - to a lesser extent - childhood Socioeconomic Status impacts functional status, quality of life and disability amongst OA patients in Mexico City. Awareness of life-course SES can help identify patients at risk for worse outcomes.


title: Decoding mitochondrial genes in pediatric AML and development of a novel prognostic mitochondrial gene signature

abstract:
BackgroundGene expression profile of mitochondrial-related genes is not well deciphered in pediatric acute myeloid leukaemia (AML). We aimed to identify mitochondria-related differentially expressed genes (DEGs) in pediatric AML with their prognostic significance.

MethodsChildren with de novo AML were included prospectively between July 2016-December 2019. Transcriptomic profiling was done for a subset of samples, stratified by mtDNA copy number. Top mitochondria-related DEGs were identified and validated by real-time PCR. A prognostic gene signature risk score was formulated using DEGs independently predictive of overall survival (OS) in multivariable analysis. Predictive ability of the risk score was estimated along with external validation in The Tumor Genome Atlas (TCGA) AML dataset.

ResultsIn 143 children with AML, twenty mitochondria-related DEGs were selected for validation, of which 16 were found to be significantly dysregulated. Upregulation of SDHC (p<0.001), CLIC1 (p=0.013) and downregulation of SLC25A29 (p<0.001) were independently predictive of inferior OS, and included for developing prognostic risk score. The risk score model was independently predictive of survival over and above ELN risk categorization (Harrells c-index: 0.675). High-risk patients (risk score above median) had significantly inferior OS (p<0.001) and event free survival (p<0.001); they were associated with poor-risk cytogenetics (p=0.021), ELN intermediate/poor risk group (p=0.016), absence of RUNX1-RUNX1T1 (p=0.027), and not attaining remission (p=0.016). On external validation, the risk score also predicted OS (p=0.019) in TCGA dataset.

ConclusionWe identified and validated mitochondria-related DEGs with prognostic impact in pediatric AML and also developed a novel 3-gene based externally validated gene signature predictive of survival.


title: Associations between e-cigarette use and e-cigarette flavors with cigarette smoking quit attempts and quit success: Evidence from a US large, nationally representative 2018-2019 survey

abstract:
ObjectivesWhile many studies have examined the association between e-cigarette use and smoking cessation, fewer have considered the impact of e-cigarette flavors on cessation outcomes. This study extends previous studies by examining the effects of e-cigarette use and e-cigarette flavors on smoking quit attempts and quit success.

MethodsWe used data from the 2018-2019 Tobacco Use Supplement-Current Population Survey (TUS-CPS) survey. Multivariate logistic regression analyses were used to investigate the associations between e-cigarette and flavor use with quit attempts among individuals who smoked 12 months ago and quit success. Two current e-cigarette use definitions were considered; currently use every day or some days vs. 20+ days in the past 30-days.

ResultsCompared to those not using e-cigarettes, current everyday or someday e-cigarette use with all non-tobacco flavors had an adjusted odds ratio (AOR) of 2.9 (95% CI: 2.4-3.5) for quit attempts and 1.7 (95% CI: 1.3-2.2) for quit success. 20+ days e-cigarette use with flavors had stronger associations with quit attempts (AOR=4.2, 95% CI: 3.1-5.5) and quit success (AOR=4.0, 95% CI: 2.9-5.4). E-cigarette users with non-tobacco flavors were more likely to succeed in quitting compared to those exclusively using non-flavored or tobacco-flavored e-cigarettes. Menthol/mint flavor users had slightly higher odds of quit attempts and success than users of other non-tobacco flavors.

ConclusionsE-cigarette use is positively associated with both making a smoking quit attempt and quit success. Those using flavored e-cigarettes, particularly menthol/mint, are more likely to quit successfully.

ImplicationsE-cigarette use is positively associated with both making a quit attempt and quit success, and those using flavored e-cigarettes are more likely to successfully quit smoking, with no statistically significant differences between use of menthol or mint flavored e-cigarettes versus use of other non-tobacco flavored products. This suggests that the potential for e-cigarettes to help people who currently smoke quit could be maintained with the availability of menthol or mint flavored e-cigarettes, even if other non-tobacco flavored products, which are associated with e-cigarette use among youth, were removed from the market.

category: epidemiology


title: Cardiac impairment in Long Covid 1-year post-SARS-CoV-2 infection

abstract:
BackgroundLong Covid is associated with multiple symptoms and impairment in multiple organs. Cardiac impairment has been reported to varying degrees by varying methodologies in cross-sectional studies. Using cardiac magnetic resonance (CMR), we investigated the 12-month trajectory of cardiac impairment in individuals with Long Covid.

Methods534 individuals with Long Covid underwent baseline CMR (T1 and T2 mapping, cardiac mass, volumes, function, and strain) and multi-organ MRI at 6 months (IQR 4.3,7.3) since first post-COVID-19 symptoms and 330 were rescanned at 12.6 (IQR 11.4, 14.2) months if abnormal findings were reported at baseline. Symptoms, standardised questionnaires, and blood samples were collected at both timepoints. Cardiac impairment was defined as one or more of: low left or right ventricular ejection fraction (LVEF and RVEF), high left or right ventricular end diastolic volume (LVEDV and RVEDV), low 3D left ventricular global longitudinal strain (GLS), or elevated native T1 in [≥]3 cardiac segments. A significant change over time was reported by comparison with 92 healthy controls.

ResultsThe technical success of this multiorgan assessment in non-acute settings was 99.1% at baseline, and 98.3% at follow up, with 99.6% and 98.8% for CMR respectively. Of individuals with Long Covid, 102/534 [19%] had cardiac impairment at baseline; 71/102 had complete paired data at 12 months. Of those, 58% presented with ongoing cardiac impairment at 12 months. High sensitivity cardiac troponin I and B-type natriuretic peptide were not predictive of CMR findings, symptoms, or clinical outcomes. At baseline, low LVEF, high RVEDV and low GLS were associated with cardiac impairment. Low LVEF at baseline was associated with persistent cardiac impairment at 12 months.

ConclusionCardiac impairment, other than myocarditis, is present in 1 in 5 individuals with Long Covid at 6 months, persisting in over half of those at 12 months. Cardiac-related blood biomarkers are unable to identify cardiac impairment in Long COVID. Subtypes of disease (based on symptoms, examination, and investigations) and predictive biomarkers are yet to be established. Interventional trials with pre-specified subgroup analyses are required to inform therapeutic options.