title: CNN for a Connectivity Based Epilepsy Diagnosis with Resting-state EEG

abstract:
ObjectiveThis study investigates the performance of a CNN algorithm on epilepsy diagnosis. Without pathology, diagnosis involves long and costly electroencephalographic (EEG) monitoring. Novel approaches may overcome this by comparing brain connectivity using graph metrics. This study, however, uses deep learning to learn connectivity patterns directly from easily acquired EEG data.

MethodsA convolutional neural network (CNN) algorithm was applied on directed Granger causality (GC) connectivity measures, derived from 50 seconds of resting-state surface EEG recordings from 30 subjects with epilepsy and a 30 subject control group.

ResultsThe learned CNN filters reflected reduced delta band connectivity in frontal regions and increased left lateralized frontal-posterior gamma band connectivity. A diagnosis accuracy of 85% (F1-score 85%) was achieved by an ensemble of CNN models, each trained on differently prepared data from different electrode combinations.

ConclusionsAppropriate preparation of connectivity data enables generic CNN algorithms to be used for detection of multiple discriminative epileptic features. Differential patterns revealed in this study may help to shed light on underlying altered cognitive abilities in epilepsy patients.

SignificanceThe accuracy achieved in this study shows that, in combination with other methods, this approach could prove a valuable clinical decision support system for epilepsy diagnosis.

category: health informatics


title: Estimation of country-specific tuberculosis antibiograms using genomic data

abstract:
BackgroundGlobal tuberculosis (TB) drug resistance (DR) surveillance is largely focused on the drug rifampicin. We leveraged public and surveillance M. tuberculosis (Mtb) whole genome sequencing (WGS) data, to generate more comprehensive country-level resistance prevalence estimates (antibiograms) using in silico resistance prediction.

MethodsWe curated and quality-controlled Mtb WGS data. We used a validated random forest model to predict phenotypic resistance to twelve drugs and bias-corrected for model performance, outbreak sampling, and resistance oversampling. We validated our estimates using a national DR survey conducted in South Africa.

ResultsMtb isolates from 29 countries (n=19,149) met sequence quality criteria. Marginal genotypic resistance estimates overlapped with the South African DR survey for all drugs except isoniazid and second-line injectables that were underestimated (n=3,134); among multi-drug resistant (MDR) TB, estimates overlapped for pyrazinamide and the fluoroquinolones. Globally, mono-resistance to isoniazid was estimated at 10.9% (95% CI: 10.2-11.7%, n = 14,012. Mono-levofloxacin resistance rates were highest in South Asia (Pakistan 3.4% [0.1-11%], n=111 and India 2.8% [0.08-9.4%], n=114). Rates of resistance discordance between isoniazid and ethionamide were high with 74.4% (IQR: 64.5-79.7%) of isoniazid resistant isolates predicted to be ethionamide susceptible. The global susceptibility rate to pyrazinamide and levofloxacin among MDR was 15.1% (95% CI: 10.2-19.9%, n=3,964).

ConclusionsThis is the first attempt at global Mtb antibiogram estimation. DR prevalence in Mtb can be reliably estimated using public WGS and phenotypic resistance prediction for key antibiotics. Our results raise concerns about the empiric use of short-course fluoroquinolone regimens for drug susceptible TB in South Asia and suggest that ethionamide is an under-utilized drug in MDR treatment.

category: infectious diseases


title: FastMix: A Versatile Multi-Omics Data Integration Pipeline for Cell Type-Specific Biomarker Inference

abstract: We developed a novel analytic pipeline - FastMix - to integrate flow cytometry, bulk transcriptomics, and clinical covariates for statistical inference of cell type-specific gene expression signatures. FastMix addresses the "large p, small n" problem via a carefully designed linear mixed effects model (LMER), which is applicable for both cross-sectional and longitudinal studies. With a novel moment-based estimator, FastMix runs and converges much faster than competing methods for big data analytics. The pipeline also includes a cutting-edge flow cytometry data analysis method for identifying cell population proportions. Simulation studies showed that FastMix produced smaller type I/II errors with more accurate parameter estimation than competing methods. When applied to real transcriptomics and flow cytometry data in two vaccine studies, FastMix-identified cell type-specific signatures were largely consistent with those obtained from the single cell RNA-seq data, with some unique interesting findings.

category: allergy and immunology


title: Stress signaling and STAT1 activation characterize the keratinocytic gene expression pattern in Hidradenitis suppurativa

abstract:
BackgroundThe underlying pathogenetic factors generating the innate immune signal necessary for T cell activation, initiation and chronification of Hidradenitis suppurativa (HS, also known as Acne inversa) are still poorly understood. Emerging evidence suggests that defective keratinocyte function critically contributes to HS disease development and progression.

ObjectivesTo elucidate the role of keratinocytes in HS lesion formation, we compared the transcriptomes of isolated lesional and perilesional HS epidermis by RNA sequencing.

MethodsLesional and perilesional HS skin samples of at least 3 different donors were obtained. Isolated epidermal keratinocytes were further processed for cell culture, protein extraction, immunostaining procedures or RNA isolation and RNA sequencing. For large scale promotor site analysis, DEGs were analyzed for overrepresented transcription factor binding sites. Functional annotation clustering for analyzing enriched functional-related gene groups was performed employing the DAVID Bioinformatics Resources.

ResultsWe show that HS is characterized by a strong epidermal stress state as evident by a significant overrepresentation of an AP-1-driven stress signature in the overall gene expression pattern of lesional keratinocytes and a substantial activation of the stress-activated cJun N-terminal kinase (JNK) pathway in lesional HS epidermis. Additionally, our data reveal a strong induction of STAT1 activation in lesional HS epidermis that likely results from IFN{gamma} production and governs the expression of key inflammatory genes that coordinate activation of innate immunity and the adaptive T cell response in HS.

ConclusionsTaken together, these data implicate a new role of combined stress signaling and JAK/STAT1 pathway activation in disease progression of HS suggesting interference with JAK/STAT1 signaling as a potentially promising therapeutic approach for HS.

category: dermatology


title: The mathematics of erythema: Development of machine learning models for artificial intelligence assisted measurement and severity scoring of radiation induced dermatitis

abstract: Although significant advancements in computer-aided diagnostics using artificial intelligence (AI) have been made, to date, no viable method for radiation-induced skin reaction (RISR) analysis and classification is available. The objective of this single-center study was to develop machine learning and deep learning approaches using deep convolutional neural networks (CNNs) for automatic classification of RISRs according to the Common Terminology Criteria for Adverse Events (CTCAE) grading system. Scarletred(R) Vision, a novel and state-of-the-art digital skin imaging method capable of remote monitoring and objective assessment of acute RISRs was used to convert 2D digital skin images using the CIELAB color space and conduct SEV* measurements. A set of different machine learning and deep convolutional neural network-based algorithms has been explored for the automatic classification of RISRs. A total of 2263 distinct images from 209 patients were analyzed for training and testing the machine learning and CNN algorithms. For a 2-class problem of healthy skin (grade 0) versus erythema (grade[≥] 1), all machine learning models produced an accuracy of above 70%, and the sensitivity and specificity of erythema recognition were 67-72% and 72-83%, respectively. The CNN produced a test accuracy of 74%, sensitivity of 66%, and specificity of 83% for predicting healthy and erythema cases. For the severity grade prediction of a 3-class problem (grade 0 versus 1 versus 2), the test accuracy was 60-67%, and the sensitivity and specificity were 56-82%, 35-59%, and 65-72%, respectively. For estimating the severity grade of each class, the CNN obtained an accuracy of 73%, 66%, and 82%, respectively. Ensemble learning combines several individual predictions to obtain a better generalization performance. Furthermore, we exploited ensemble learning by deploying a CNN model as a meta-learner. The ensemble CNN based on bagging and majority voting shows an accuracy, sensitivity and specificity of 87%, 90%, and 82% for a 2-class problem, respectively. For a 3-class problem, the ensemble CNN shows an overall accuracy of 66%, while for each grade (0, 1, and 2) accuracies were 0.76%, 0.69%, and 0.87%, sensitivities were 0.70%, 0.57%, and 0.71%, and specificities were 0.78%, 0.75%, and 0.95%, respectively. This study is the first to focus on erythema in radiation-dermatitis and produces benchmark results using machine learning models. The outcome of this study validates that the proposed system can act as a pre-screening and decision support tool for oncologists or patients to provide fast, reliable, and efficient assessment of erythema grading.


title: Rapid replacement of the Beta variant by the Delta variant in South Africa

abstract: The Beta variant of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in South Africa in late 2020 and rapidly became the dominant variant, causing over 95% of infections in the country during and after the second epidemic wave. Here we show rapid replacement of the Beta variant by the Delta variant, a highly transmissible variant of concern (VOC) that emerged in India and subsequently spread around the world. The Delta variant was imported to South Africa primarily from India, spread rapidly in large monophyletic clusters to all provinces, and became dominant within three months of introduction. This was associated with a resurgence in community transmission, leading to a third wave which was associated with a high number of deaths. We estimated a growth advantage for the Delta variant in South Africa of 0.089 (95% confidence interval [CI] 0.084-0.093) per day which corresponds to a transmission advantage of 46% (95% CI 44-48) compared to the Beta variant. These data provide additional support for the increased transmissibility of the Delta variant relative to other VOC and highlight how dynamic shifts in the distribution of variants contribute to the ongoing public health threat.

category: epidemiology


title: Effectiveness of rectal artesunate as pre-referral treatment for severe malaria in children <5 years of age

abstract:
BackgroundTo prevent child deaths from severe malaria, early parenteral treatment is essential. Yet, in remote rural areas, higher-level facilities offering parenteral antimalarials are often difficult to access. A randomised controlled trial found pre-referral rectal artesunate (RAS) to reduce death and disability in children who delay arriving at a referral facility. This study examined the effectiveness of pre-referral RAS treatment in established community-based health care systems.

MethodsAn observational study accompanied the roll-out of RAS in the Democratic Republic of the Congo, Nigeria and Uganda. Children < 5 years presenting to a community-based health provider with a positive malaria test and signs of severe malaria were followed-up during admission and after 28 days to assess their health status and treatment history. The primary outcome was death; covariates of interest included RAS use, referral completion, and post-referral treatment.

FindingsPost-roll-out, RAS was administered to 88% of patients in DRC, 52% in Nigeria, and 70% in Uganda. The overall case fatality rate (CFR) was 6.7% (135/2011) in DRC, 11.7% (69/589) in Nigeria, and 0.5% (19/3686) in Uganda; 865/6286 patients were sick at follow-up. In all countries, the CFR was higher after RAS-roll-out (6.7 vs. 6.6% in DRC, 16.1 vs. 4.2% in Nigeria, 0.7 vs. 0.3% in Uganda). In DRC and Nigeria, children receiving RAS were more likely to die than those not receiving RAS (aOR = 3.31, 95% CI 1.43-7.65 and aOR = 2.42, 95% CI 1.25-4.70, respectively). In Uganda, RAS users were less likely to be dead or sick at follow-up (aOR = 0.61, 95% CI 0.46-0.80). Post-referral parenteral antimalarials were protective in all countries; however, the effect of ACT administration was inconsistent.

InterpretationRAS pre-referral treatment had no beneficial effect on child survival in three highly malaria endemic settings. RAS is unlikely to reduce malaria deaths unless health system shortfalls such as referral and post-referral treatment are addressed.

category: public and global health


title: The International Sexual Health And Reproductive Health Survey (I-SHARE-1): A Cross-Sectional Multi-Country Analysis of Adults from 30 Countries Prior to and During the Initial COVID-19 Wave

abstract:
BackgroundThe COVID-19 pandemic forced billions of people to shelter in place, altering social and sexual relationships worldwide. In many settings, COVID-19 threatened already precarious health services. However, there is limited evidence to date about changes to sexual and reproductive health (SRH) during the initial wave of COVID-19 disease. To address this gap, our team organized a multi-country, cross-sectional online survey as part of a global consortium.

MethodsConsortium research teams conducted online surveys in 30 countries. Sampling methods included convenience, online panels, and population-representative. Primary outcomes included sexual behaviors, partner violence, and SRH service utilization, and we compared three months prior to and three months after policy measures to mitigate COVID-19. We used established indicators and analyses pre-specified in our protocol. We conducted meta-analyses for primary outcomes and graded the certainty of the evidence using Cochrane methods. Descriptive analyses included 22,724 individuals in 25 countries. Five additional countries with sample sizes <200 were included in descriptive meta-analyses.

ResultsRespondents were mean age 34 years; most identified as women (15160; 66.7%), cis-gender (19432; 86.6%) and heterosexual (16592; 77.9%). Among 4546 respondents with casual partners, condom use stayed the same for 3374 (74.4%) people and 640 (14.1%) people reported a decline. Fewer respondents reported physical or sexual partner violence during COVID-19 measures (1063/15144, 7.0%) compared to the period before COVID-19 measures (1469/15887, 9.3%). COVID-19 measures impeded access to condoms (933/10790, 8.7%), contraceptives (610/8175, 7.5%), and HIV/STI testing (750/1965, 30.7%). Pooled estimates from meta-analysis indicate during COVID-19 measures, 32.3% (95% CI 23.9-42.1) of people needing HIV/STI testing had hindered access, 4.4% (95% CI 3.4-5.4) experienced partner violence, and 5.8% (95% CI 5.4-8.2) decreased casual partner condom use (moderate certainty of evidence for each outcome). Meta-analysis findings were robust in sensitivity analyses that examined country income level, sample size, and sampling strategy.

ConclusionOpen science methods are feasible to organize research studies as part of emergency responses. The initial COVID-19 wave impacted SRH behaviors and access to services across diverse global settings.


title: Analysis of modular gene co-expression networks reveals molecular pathways underlying Alzheimer's disease and progressive supranuclear palsy

abstract: A comprehensive understanding of the pathological mechanisms involved at different stages of neurodegenerative diseases is key for the advance of preventive and disease-modifying treatments. Gene expression alterations in the diseased brain is a potential source of information about biological processes affected by pathology. In this work, we performed a systematic comparison of gene expression alterations in the brains of human patients diagnosed with Alzheimers disease (AD) or Progressive Supranuclear Palsy (PSP) and animal models of amyloidopathy and tauopathy. Using a systems biology approach to uncover biological processes associated with gene expression alterations, we could pinpoint processes more strongly associated with tauopathy/PSP and amyloidopathy/AD. We show that gene expression alterations related to immune-inflammatory responses preponderate in younger, whereas those associated to synaptic transmission are mainly observed in older AD patients. In PSP, however, changes associated with immune-inflammatory responses and synaptic transmission overlap. These two different patterns observed in AD and PSP brains are fairly recapitulated in animal models of amyloidopathy and tauopathy, respectively. Moreover, in AD, but not PSP or animal models, gene expression alterations related to RNA splicing are highly prevalent, whereas those associated with myelination are enriched both in AD and PSP, but not in animal models. Finally, we identify 12 AD and 4 PSP genetic risk factors in cell-type specific co-expression modules, thus contributing to unveil the possible role of these genes to pathogenesis. Altogether, this work contributes to unravel the potential biological processes affected by amyloid versus tau pathology and how they could contribute to the pathogenesis of AD and PSP.

category: neurology


title: N-acetyl-L-leucine improves symptoms and functioning in GM2 Gangliosidosis (Tay-Sachs & Sandhoff)

abstract:
Background and ObjectiveGM2 gangliosidosis (Tay-Sachs and Sandhoff diseases) are rare, inherited neurodegenerative disorders with no available symptomatic or disease modifying treatments. This clinical trial aimed to investigate the safety and efficacy of N-acetyl-L-leucine (NALL) on symptoms of pediatric ([≥] 6 years) and adult patients with GM2 gangliosidosis.

Methods\We conducted an 8-center, multi-national, open-label, rater-blinded Phase IIb study (IB1001-201). Patients with a genetically confirmed diagnosis of GM2 gangliosidosis were assessed during a baseline period, a 6-week treatment period (orally administered NALL 4 g/day in patients [≥]13 years, weight-tiered doses for patients 6-12 years), and a 6-week post-treatment washout period. The primary Clinical Impression of Change in Severity (CI-CS) endpoint (based on a 7-point Likert scale) was assessed by blinded, centralized raters who compared randomized video pairs of each patient performing a pre-defined primary anchor test (8-Meter Walk Test or 9-Hole Peg Test) during each study periods. Secondary outcomes included cerebellar rating scales (namely Scale for the Assessment and Rating of Ataxia), clinical global impression, and quality of life assessments.

Results30 patients aged 6 to 55 years with a confirmed diagnosis of GM2 gangliosidosis (Tay-Sachs or Sandhoffs disease) were enrolled. 29 patients were included in the primary modified intention-to-treat analysis. NALL met the CI-CS primary endpoint (mean difference 0.71, SD=2.09, 90% CI 0.00, 1.50, p=0.044), as well as secondary endpoints. No treatment-related serious adverse events occurred.

ConclusionsThis study showed NALL led to a statistically significant improvement in symptoms, functioning, and quality of life in patients with GM2 gangliosidosis. It is a safe, well-tolerated, easily administered oral therapy, therefore offering a favorable risk/benefit profile for this serious, debilitating disorder. NALL is a new therapeutic option for the treatment of this rare disease that has no other approved therapies worldwide.

Classification of EvidenceThis study provides Class IV evidence NALL is safe, well-tolerated, and improves neurological symptoms and quality of life in patients with GM2 gangliosidosis.

Trial Registration InformationThe trial is registered with ClinicalTrials.gov (NCT03759665; registered 30-Nov-2018), EudraCT (2018-004406-25), and DRKS (DRKS00017539). The first patient was enrolled 07-June-2019.


title: First trimester gut microbiome induces Inflammation-dependent gestational diabetes phenotype in mice

abstract: Gestational diabetes mellitus (GDM) is a condition in which non-diabetic women are diagnosed with glucose intolerance during pregnancy, typically in the second trimester. GDM can lead to a wide range of obstetrical and metabolic complications for both mother and neonate1. Early identification of GDM risk, along with a better understanding of its pathophysiology during the first trimester of pregnancy, may be effective in reducing GDM incidence, as well as its associated short and long term morbidities2. Here, we comprehensively profiled the gut microbiome, metabolome, inflammatory cytokines, nutrition and clinical records of 394 women during the first trimester of pregnancy. We found elevated levels of proinflammatory serum cytokines in those who later developed GDM. The womens stool samples were also characterized by decreased levels of several fecal short-chain fatty acids and altered microbiome. We next tested the hypothesis that differences in GDM-associated microbial composition during the first trimester drove inflammation and insulin-resistance. Stool samples collected early in pregnancy from women from three populations who did and did not later develop GDM were transplanted to germ-free mice and confirmed that both inflammation and insulin-resistance are induced by the microbiome of pregnant women more than 10 weeks prior to GDM diagnosis. Following these observations, we used a machine-learning approach to predict GDM based on first trimester clinical, microbial and inflammatory markers. Our model showed high predictive accuracy. Overall, our results suggest that the gut microbiome of women in the first trimester plays a remarkable role in inflammation-induced GDM pathogenesis and point to dozens of GDM markers during the first trimester of pregnancy, some of which may be targets for therapeutic intervention.

category: obstetrics and gynecology


title: Diagnostic surveillance of high-grade gliomas: towards automated change detection using radiology report classification

abstract: Natural Language Processing (NLP) on electronic health records (EHRs) can be used to monitor the evolution of pathologies over time to facilitate diagnosis and improve decision-making. In this study, we designed an NLP pipeline to classify Magnetic Resonance Imaging (MRI) radiology reports of patients with high-grade gliomas. Specifically, we aimed to distinguish reports indicating changes in tumors between one examination and the follow-up examination (treatment response/tumor progression versus stability). A total of 164 patients with 361 associated reports were retrieved from routine imaging, and reports were labeled by one radiologist. First, we assessed which embedding is more suitable when working with limited data, in French, from a specific domain. To do so, we compared a classic embedding techniques, TF-IDF, to a neural embedding technique, Doc2Vec, after hyperparameter optimization for both. A random forest classifier was used to classify the reports into stable (unchanged tumor) or unstable (changed tumor). Second, we applied the post-hoc LIME explainability tool to understand the decisions taken by the model. Overall, classification results obtained in repeated 5-fold cross-validation with TF-IDF reached around 89% AUC and were significantly better than those achieved with Doc2Vec (Wilcoxon signed-rank test, P = 0.009). The explainability toolkit run on TF-IDF revealed some interesting patterns: first, words indicating change such as progression were rightfully frequent for reports classified as unstable; similarly, words indicating no change such as not were frequent for reports classified as stable. Lastly, the toolkit discovered misleading words such as T2 which are clearly not directly relevant for the task. All the code used for this study is made available.

category: oncology


title: The Report on China-Spain Joint Clinical Testing for Rapid COVID-19 Risk Screening by Eye-region Manifestations

abstract:
BackgroundThe worldwide surge in coronavirus cases has led to the COVID-19 testing demand surge. Rapid, accurate, and cost-effective COVID-19 screening tests working at a population level are in imperative demand globally.

MethodsBased on the eye symptoms of COVID-19, we developed and tested a COVID-19 rapid prescreening model using the eye-region images captured in China and Spain with cellphone cameras. The convolutional neural networks (CNNs)-based model was trained on these eye images to complete binary classification task of identifying the COVID-19 cases. The performance was measured using area under receiver-operating-characteristic curve (AUC), sensitivity, specificity, accuracy, and F1. The application programming interface was open access.

FindingsThe multicenter study included 2436 pictures corresponding to 657 subjects (155 COVID-19 infection, 23{middle dot}6%) in development dataset (train and validation) and 2138 pictures corresponding to 478 subjects (64 COVID-19 infections, 13{middle dot}4%) in test dataset. The image-level performance of COVID-19 prescreening model in the China-Spain multicenter study achieved an AUC of 0{middle dot}913 (95% CI, 0{middle dot}898-0{middle dot}927), with a sensitivity of 0{middle dot}695 (95% CI, 0{middle dot}643-0{middle dot}748), a specificity of 0{middle dot}904 (95% CI, 0{middle dot}891 -0{middle dot}919), an accuracy of 0{middle dot}875(0{middle dot}861-0{middle dot}889), and a F1 of 0{middle dot}611(0{middle dot}568-0{middle dot}655).

InterpretationThe CNN-based model for COVID-19 rapid prescreening has reliable specificity and sensitivity. This system provides a low-cost, fully self-performed, non-invasive, real-time feedback solution for continuous surveillance and large-scale rapid prescreening for COVID-19.

FundingThis project is supported by Aimomics (Shanghai) Intelligent

category: ophthalmology


title: Diagnostic Yield of Screening for SARS-CoV-2 among Patients Admitted for Alternate Diagnoses

abstract:
ObjectivesTo determine the diagnostic yield of screening patients for SARS-CoV-2 who were admitted with a diagnosis unrelated to COVID-19, and identify risk factors for positive tests.

DesignCohort from the Canadian COVID-19 Emergency Department Rapid Response Network (CCEDRRN) registry

Setting30 acute care hospitals across Canada

ParticipantsPatients hospitalized for non-COVID-19 related diagnoses who were tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) between March 1, and December 29, 2020

Main outcomePositive nucleic acid amplification test (NAAT) for SARS-CoV-2

Outcome measureDiagnostic yield

ResultsWe enrolled 15,690 consecutive eligible adults who were admitted to hospital without clinically suspected COVID-19. Among these patients, 122 tested positive for COVID-19, resulting in a diagnostic yield of 0.8% (95% CI 0.64% - 0.92%). Factors associated with a positive test included presence of a fever, being a healthcare worker, having a positive household contact or institutional exposure, and living in an area with higher 7-day average incident COVID-19 cases.

ConclusionsUniversal screening of hospitalized patients for COVID-19 across two pandemic waves had a low diagnostic yield and should be informed by individual-level risk assessment in addition to regional COVID-19 prevalence.

Trial registrationNCT04702945

SUMMARY BOXESSection 1: Universal screening of admitted patients for SARS-CoV-2 was implemented in many hospitals at the beginning of the pandemic. The Infections Diseases Society of America (IDSA) recommended avoiding universal screening of asymptomatic hospitalized patients in areas and times of low-COVID prevalence (defined as <2% prevalence) with very low certainty of evidence, based on studies of COVID-19 prevalence among asymptomatic individuals in the community.

Section 2: This study supports IDSA recommendations to avoid universal screening for COVID-19 in times and areas of low COVID prevalence and identifies patient-level risk factors strongly associated with positive testing that should be considered for screening.

category: emergency medicine


title: Geographic partitioning of dengue virus transmission risk in Florida

abstract: Dengue viruses (DENVs) cause the greatest public health burden globally among the arthropod-borne viruses. DENV transmission risk has also expanded from tropical to subtropical regions due to the increasing range of its principal mosquito vector, Aedes aegypti. Focal out-breaks of dengue fever (dengue) in the state of Florida (FL) in the USA have increased since 2009. However, little is known about the competence of Ae. aegypti populations across different regions of FL to transmit DENVs. To understand the effects of DENV genotype and serotype variations on vector susceptibility and transmission potential in FL, we orally infected a colony of Ae. aegypti (Orlando/ORL) with laboratory and wild type DENV-1 through -4. Wild type DENVs were more infectious to and transmissible by ORL mosquitoes. We used these same DENVs to examine natural Ae. aegypti populations to determine whether spatial distributions correlated with differential vector competence. Vector competence across all DENV serotypes was greater for mosquitoes from areas with the highest dengue incidence in south FL compared to north FL. Vector competence for wild type DENVs was significantly higher, revealing that transmission risk is influenced by virus/vector combinations. These data support a targeted mosquito-plus-pathogen screening approach to more accurately estimate DENV transmission risk.


title: Prediction of long-term kinetics of vaccine-elicited neutralizing antibody and time-varying vaccine-specific efficacy against the SARS-CoV-2 Delta variant by clinical endpoint

abstract: Evidence on vaccine-specific protection over time and boosting impact against the Delta variant across different clinical endpoints and age groups is urgently needed. To address this, we used a previously published model, combined with neutralization data for four vaccines - mRNA-1273, BNT162b2, NVX-CoV2373, and CoronaVac - to evaluate long-term dynamics of neutralizing antibody and to predict time-varying efficacy against the Delta variant by specific vaccine, age group, and clinical severity. We found that booster vaccination produces higher neutralization titers compared with titers observed following primary-series vaccination for all vaccines studied. We estimate the efficacies of mRNA-1273 and BNT162b2 against Delta variant infection to be 63.5% (95%CI: 51.4-67.3%) and 78.4% (95%CI: 72.2-83.5%), respectively, 14-30 days after the second dose, and that efficacies decreased to 36.0% (95%CI: 24.1-58.0%) and 38.5% (95%CI: 28.7-49.1%) 6-8 months later. After administration of booster doses, efficacies against the Delta variant would be 97.0% (95%CI: 96.4-98.5%) and 97.2% (95.7-98.1%). All four vaccines are predicted to provide good protection against severe illness from the Delta variant after both primary and booster vaccination. Long-term monitoring and surveillance of antibody dynamics and vaccine protection, as well as further validation of neutralizing antibody or other markers that can serve as correlates of protection against SARS-CoV-2 and its variants are needed to inform COVID-19 pandemic preparedness.


title: CD19 B cell repopulation after ocrelizumab, alemtuzumab and cladribine: Implications for SARS-CoV-2 vaccinations in multiple sclerosis

abstract:
BackgroundCD20 depletion is a highly-effective treatment for relapsing multiple sclerosis that maintains B cells at low levels through six monthly dosing of 600mg ocrelizumab. This dosing schedule is associated with inhibition of seroconversion following SARS-CoV-2 vaccination, in contrast to the high levels of seroconversion following treatment with alemtuzumab and cladribine tablets. A number of emerging reports suggest that repopulation of 1-3% B cells facilitates seroconversion after CD20-depletion. The frequency of this occurring following repeated ocrelizumab treatment, after other DMT, and after treatment cessation is largely unknown.

MethodsRelapse data, lymphocyte and CD19 B cell numbers were extracted from phase II ocrelizumab extension study (NCT00676715) data supplied by the manufacturer via the Vivli Inc, trial data-request portal. Repopulation data of oral cladribine from the phase III CLARITY study (NCT00213135) was supplied by the European Medicines Agency; and the alemtuzumab phase III CARE-MS I (NCT00530348) and CARE-MS II (NCT00548405) trial data were supplied by the manufacturer via the clinicalstudydatarequest.com portal.

ResultsOnly 3-5% of people with MS exhibit 1% B cells at 6 months after the last infusion following 3-4 cycles of ocrelizumab, compared to 50-55% at 9 months, and 85-90% at 12 months. During this time relapses occurred at consistent disease breakthrough rates compared to people during standard therapy. In contrast most people (90-100%) exhibited more than 1% B cells during treatment with either cladribine or alemtuzumab.

ConclusionsFew people repopulate peripheral B cells with standard ocrelizumab dosing, however an extending the dosing interval by 3-6 months may allow many more people to potentially seroconvert in the relative absence of excess relapse-activity. Most people demonstrate B cell repletion within 3 months of the last treatment of alemtuzumab and cladribine. This may help protect against severe COVID-19.


title: The kinetic of SARS-CoV-2 antibody (Ab) decline determines the threshold for Ab persistence up to one year

abstract: Twelve subjects with positive SARS-CoV-2 neutralization test (NT) titers (>1:10) identified in a seroprevalence study with 1655 working adults were followed up for one year. Here we report that 7 of these 12 individuals (58%) still had NT titers [≥]1:50, S1-specific IgG concentrations [≥]50 BAU/ml and [≥]26% ACE2 receptor binding inhibition, measured with surrogate virus NT one year after mild COVID infection. Furthermore, NT_50 titers >1:10 and S1-specific IgG levels >60 BAU/ml present at three months post-infection persisted at detectable levels for 1 year and correlated with circulating S1-specific memory B-cells. Vaccine-induced SARS-CoV2 immune responses decline at similar rates as those after infection; thus the describes threshold of 60 BAU/ml at three months post infection might also be relevant for assessment of Ab persistence after vaccination.


title: Quality control and removal of technical variation of NMR metabolic biomarker data in ~120,000 UK Biobank participants

abstract: Metabolic biomarker data quantified by nuclear magnetic resonance (NMR) spectroscopy has recently become available in UK Biobank. Here, we describe procedures for quality control and removal of technical variation for this biomarker data, comprising 249 circulating metabolites, lipids, and lipoprotein sub-fractions on approximately 121,000 participants. We identify and characterise technical and biological factors associated with individual biomarkers and find that linear effects on individual biomarkers can combine in a non-linear fashion for 61 composite biomarkers and 81 biomarker ratios. We create an R package, ukbnmr, for extracting and normalising the metabolic biomarker data, then use ukbnmr to remove unwanted variation from the UK Biobank data. We make available code for re-deriving the 61 composite biomarkers and 81 ratios, and for further derivation of 76 additional biomarker ratios of potential biological significance. Finally, we demonstrate that removal of technical variation leads to increased signal for genetic and epidemiological studies of the NMR metabolic biomarkers in UK Biobank.

category: cardiovascular medicine


title: PathProfiler: Automated Quality Assessment of Retrospective Histopathology Whole-Slide Image Cohorts by Artificial Intelligence, A Case Study for Prostate Cancer Research

abstract:
Research using whole slide images (WSIs) of scanned histopathology slides for the development of artificial intelligence (AI) algorithms has increased exponentially over recent years. Glass slides from large retrospective cohorts with patient follow-up data are digitised for the development and validation of AI tools. Such resources, therefore, become very important, with the need to ensure that their quality is of the standard necessary for downstream AI development. However, manual quality control of such large cohorts of WSIs by visual assessment is unfeasible, and whilst quality control AI algorithms exist, these focus on bespoke aspects of image quality, e.g. focus, or use traditional machine-learning methods such as hand-crafted features, which are unable to classify the range of potential image artefacts that should be considered.

In this study, we have trained and validated a multi-task deep neural network to automate the process of quality control of a large retrospective cohort of prostate cases from which glass slides have been scanned several years after production, to determine both the usability of the images for research and the common image artefacts present.

Using a two-layer approach, quality overlays of WSIs were generated from a quality assessment undertaken at patch-level at 5X magnification. From these quality overlays the slide-level quality scores were predicted and then compared to those generated by three specialist urological pathologists, with a Pearson correlation of 0.89 for overall  usability (at a diagnostic level), and 0.87 and 0.82 for focus and H&E staining quality scores respectively. We subsequently applied our quality assessment pipeline to the TCGA prostate cancer cohort and to a colorectal cancer cohort, for comparison.

Our model, designated as PathProfiler, indicates comparable predicted usability of images from the cohorts assessed (86-90%), and perhaps more significantly is able to predicts WSIs that could benefit from re-scanning or re-staining for quality improvement.

We have shown in this study that AI can be used to automate the process of quality control of large retrospective cohorts to maximise research outputs and conclusions.

category: pathology


title: Dissecting the Epigenomic Differences between Smoking and Nicotine Dependence in a Veteran Cohort

abstract:
BackgroundSmoking is a serious public health issue linked to more than 8 million deaths per year worldwide. It also may lead to nicotine dependence (ND). Smoking can induce long-lasting epigenetic changes. Although epigenetic alterations related to tobacco smoke have been largely studied, few works have investigated ND and its interaction with smoking status (SS).

ObjectiveWe investigated the peripheral epigenomic profile of SS and ND in a U.S. male veteran cohort.

MethodsDNA from saliva was collected from 1,135 European American (EA) male U.S. military veterans. DNAm was assessed using the Illumina Infinium Human MethylationEPIC BeadChip array. SS was evaluated as: current smokers (n=137; 12.1%) and non-current smokers (never and former smokers; n=998; 87.9%). ND was assessed using the Fagerstrom Test for Nicotine Dependence (FTND). EWAS and co-methylation analyses were conducted for SS and ND.

ResultsA total of 450 and 22 genome-wide significant differentially methylated sites (DMS) were associated with SS and ND, respectively (fifteen overlapped sites). We identified 97 DMS (43 genes) in SS-EWAS previously reported in the literature, including AHRR, and F2RL3 genes (p-value range: 1.95x10-83 to 4.5x10-33). ND novel DMS mapped to NEUROG1, ANPEP, and SLC29A1. Co-methylation analysis identified 386 modules (11 SS-related and 19 ND-related). SS-related modules showed enrichment for alcoholism, chemokine signaling pathway, and neurogenesis; while ND-related modules were enriched for cellular adhesion, and nicotine addiction.

ConclusionsThis study confirms previous findings and identifies novel and -potentially specific - epigenetic signatures for SS and ND in a sample of EA male veterans.

category: psychiatry and clinical psychology


title: Non-invasive Vagus Nerve Stimulation for Respiratory Symptoms of COVID-19: Results From a Randomized Controlled Trial (SAVIOR I)

abstract:
BackgroundSevere coronavirus disease 2019 (COVID-19) is characterized, in part, by an excessive inflammatory response. Evidence from animal and human studies suggests that vagus nerve stimulation can lead to reduced levels of various pro-inflammatory cytokines. We conducted a prospective randomized controlled study (SAVIOR-I) to assess the feasibility, efficacy, and safety of non-invasive vagus nerve stimulation (nVNS) for the treatment of respiratory symptoms and inflammatory markers among patients who were hospitalized for COVID-19 (ClinicalTrials.gov identifier: NCT04368156).

MethodsParticipants were randomly assigned in a 1:1 allocation to receive either the standard of care (SoC) alone or nVNS therapy plus the SoC. The nVNS group received 2 consecutive 2-minute doses of nVNS 3 times daily as prophylaxis. Efficacy and safety were evaluated via the incidence of specific clinical events, inflammatory biomarker levels, and the occurrence of adverse events.

ResultsOf the 110 participants who were enrolled and randomly assigned, 97 (nVNS, n=47; SoC, n=50) had sufficient available data and comprised the evaluable population. C-reactive protein (CRP) levels decreased from baseline to a significantly greater degree in the nVNS group than in the SoC group at day 5 and overall (ie, all postbaseline data points collected through day 5, combined). Procalcitonin level also showed significantly greater decreases from baseline to day 5 in the nVNS group than in the SoC group. D-dimer levels were decreased from baseline for the nVNS group and increased from baseline for the SoC group at day 5 and overall, although the difference between the treatment groups did not reach statistical significance. No significant treatment differences were seen for clinical respiratory outcomes or any of the other biochemical markers evaluated. No serious nVNS-related adverse events occurred during the study.

ConclusionsnVNS therapy led to significant reductions in levels of inflammatory markers, specifically CRP and procalcitonin. Because nVNS has multiple mechanisms of action that may be relevant to COVID-19, additional research into its potential to be used earlier in the course of COVID-19 and possibly mitigate some of the symptoms associated with post-acute COVID-19 syndrome is warranted.

category: respiratory medicine


title: Acquired peripheral nerve injuries associated with severe COVID-19

abstract: We diagnosed 66 peripheral nerve injuries in 34 patients who survived severe COVID-19. We combine our latest data with published case series re-analyzed here (117 nerve injuries; 58 patients) to provide a comprehensive accounting of lesion sites. The most common are ulnar (25.1%), common fibular (15.8%), sciatic (13.1%), median (9.8%), brachial plexus (8.7%) and radial (8.2%) nerves at sites known to be vulnerable to mechanical loading. Protection of peripheral nerves should be prioritized in the care of COVID-19 patients. To this end, we report proof of concept data of a wearable, wireless pressure sensor to provide real time monitoring in the intensive care unit setting.


title: Evaluating a polygenic hazard score to predict risk of developing metastatic or fatal prostate cancer in the multi-ancestry Million Veteran Program cohort

abstract:
BackgroundGenetic scores may provide an objective measure of a mans risk of prostate cancer and thus inform screening decisions. We evaluated whether a polygenic hazard score based on 290 genetic variants (PHS290) is associated with risk of prostate cancer in a diverse population, including Black men, who have higher average risk of prostate cancer death but are often treated as a homogeneous, high-risk group

MethodsThis was a retrospective analysis of Million Veteran Program (MVP), a national, population-based cohort study of United States military veterans conducted 2011-2021. Cox proportional hazards analyses tested for association of genetic and other risk factors (including self-reported race/ethnicity and family history) with age at death from prostate cancer, age at diagnosis of metastatic (nodal or distant) prostate cancer, and age at diagnosis of any prostate cancer.

Results590,750 male participants were included. Median age at last follow-up was 69 years. PHS290 was associated with fatal prostate cancer in the full cohort and for each racial/ethnic group (p<10-10). Comparing men in the highest 20% of PHS290 to those in the lowest 20%, the hazard ratio for fatal prostate cancer was 4.42 [95% CI: 3.91-5.02]. When accounting for guideline-recommended risk factors (family history, race/ethnicity), PHS290 remained the strongest independent predictor of any, metastatic, and fatal prostate cancer.

ConclusionsPHS290 stratified US veterans of diverse ancestry for lifetime risk of prostate cancer, including metastatic and fatal cancer. Predicting genetic risk of lethal prostate cancer with PHS290 might inform individualized decisions about prostate cancer screening.


title: Prediction of Life-threatening and Disabling Bleeding in Patients with Acute Myeloid Leukemia Receiving Intensive Induction Chemotherapy

abstract:
Bleeding in patients with acute myeloid leukemia (AML) receiving intensive induction chemotherapy is multifactorial and contributes to early death. We sought to define incidence and risk factors of grade 4 bleeding to support strategies for risk mitigation. Bleeding events were assessed according to the WHO bleeding assessment scale, which includes grade 4 bleeding as fatal, life-threatening, retinal with visual impairment, or involving the central nervous system. Using multivariable competing-risk regression analysis with grade 4 bleeding as the primary outcome, we identified risk factors in the development cohort (n=341), which were tested in an independent cohort (n=143). Grade 4 bleeding occurred in 5.9% and 9.8% of patients in the development and validation cohort, respectively. Risk factors that were independently associated with grade 4 bleeding included baseline platelet count [≤]40 x109/L compared with >40 x109/L, and baseline PT-INR >1.5 or >1.3-1.5 compared with [≤]1.3. These variables were allocated points, which allowed for stratification of patients with low- and high-risk for grade 4 bleeding. Cumulative incidence of grade 4 bleeding at day+60 was significantly higher among patients with high- versus low-risk (development: 31{+/-}7% vs. 2{+/-}1%, P<0.001, validation: 25{+/-}9% vs. 7{+/-}2%, P=0.008). In both cohorts, high bleeding risk was associated with disseminated intravascular coagulation (DIC) and proliferative disease. We developed and validated a simple risk model for grade 4 bleeding, which enables development of rational risk mitigation strategies to improve early mortality of intensive induction treatment.

KEY POINTSO_LIRisk factors predicting grade 4 bleeding were consistent with DIC-like coagulopathy, including prolonged PT-INR and thrombocytopenia.
C_LIO_LIThe grade 4 bleeding score was externally validated and allows for preventive strategies to improve early mortality in high-risk patients.
C_LI


title: Multi-omics approach identifies novel age-, time- and treatment-related immunopathological signatures in MIS-C and pediatric COVID-19

abstract: Pediatric COVID-19 (pCOVID-19) is rarely severe, however a minority of SARS-CoV-2-infected children may develop MIS-C, a multisystem inflammatory syndrome with significant morbidity. In this longitudinal multi-institutional study, we used multi-omics to identify novel time- and treatment-related immunopathological signatures in children with COVID-19 (n=105) and MIS-C (n=76). pCOVID-19 was characterized by enhanced type I IFN responses, and MIS-C by type II IFN- and NF-{kappa}B dependent responses, matrisome activation, and increased levels of Spike protein. Reduced levels of IL-33 in pCOVID-19, and of CCL22 in MIS-C suggested suppression of Th2 responses. Expansion of TRBV11-2 T-cell clonotypes in MIS-C was associated with inflammation and signatures of T-cell activation, and was reversed by glucocorticoids. The association of MIS-C with the combination of HLA A*02, B*35, C*04 alleles suggests genetic susceptibility. MIS-C B cells showed higher mutation load. Use of IVIG was identified as a confounding factor in the interpretation of autoantibody levels.


title: Reddit discussions about buprenorphine associated precipitated withdrawal in the era of fentanyl

abstract:
BackgroundBuprenorphine is an evidence-based treatment for Opioid Use Disorder (OUD). Standard buprenorphine induction requires a period of opioid abstinence to minimize risk of precipitated opioid withdrawal (POW). Our objective was to study the impact of the increasing presence of fentanyl and its analogs in the opioid supply of the United States, on buprenorphine induction and POW, using social media data from Reddit.

MethodsThis is a data-driven, mixed methods study of opioid-related forums, called subreddits, on Reddit to analyze posts related to fentanyl, POW, and buprenorphine induction. The posts were collected from seven subreddits using an application programming interface for Reddit. We applied natural language processing to identify subsets of salient posts relevant to buprenorphine induction, and performed manual, qualitative, thematic analyses of them.

Results267,136 posts were retrieved from seven subreddits. Fentanyl mentions increased from 3 in 2013 to 3870 in 2020, and POW mentions increased from 2 (2012) to 332 (2020). Manual review of 384 POW-mentioning posts and 106  Bernese method (a microdosing induction strategy) mentioning posts revealed common themes and peoples experiences. Specifically, presence of fentanyl caused POWs despite long abstinence durations, and alternative induction via microdosing were frequently recommended in peer-to-peer discussions.

ConclusionsThis study found that increased social media chatter on Reddit about POW correlated with fentanyl mentions. A subset of posts described microdosing as a self-management strategy to avoid POW. Reddit posts suggest that people are utilizing these strategies to initiate buprenorphine due to challenges arising from fentanyl prevalence in the opioid supply.

HighlightsO_LIIncrease in mentions of precipitated opioid withdrawal (POW) on Reddit from 2012 to 2021 was closely correlated with the increase in fentanyl mentions.
C_LIO_LIExperiences of precipitated opioid withdrawal (POW) were described by individuals who reported sufficient periods of abstinence by standard buprenorphine induction protocols.
C_LIO_LIPeople with Opioid Use Disorder (OUD) on Reddit are using and recommending microdosing strategies with buprenorphine to avoid POW.
C_LIO_LIPeople who used fentanyl report experiencing POW following statistically longer periods of abstinence than people who use heroin.
C_LI

category: addiction medicine


title: Is Mycobacterium avium subspecies paratuberculosis (MAP) associated with Crohn's Disease?

abstract:
ObjectiveThis retroactive meta-analysis assesses the relationship between Mycobacterium avium subspecies paratuberculosis (MAP) and Crohns Disease (CD).

MethodsA meta-analysis of PCR- and culture-based studies was conducted to determine if there is a relationship between MAP and Crohns Disease. The chi-squared test of independence was also conducted to determine if MAP infection and Crohns disease onset are independent events.

ResultsThe studies analyzed were able to provide evidence that Mycobacterium avium subspecies paratuberculosis is highly associated with Crohns disease. It is also shown that, regardless of detection method, MAP can effectively be detected in Crohns patients.

ConclusionMAP is strongly connected with Crohns Disease.

SummaryThis paper examines the incidence of MAP in the tissue of Crohns disease patients. We found evidence to support MAP being strongly associated with Crohns disease.

category: gastroenterology


title: Perilipin-1 autoantibodies linked to idiopathic lipodystrophy in the setting of two distinct breaks in immune tolerance

abstract:
BackgroundAcquired lipodystrophy is often characterized as an idiopathic subtype of lipodystrophy. Despite suspicion of an immune-mediated pathology, biomarkers such as autoantibodies are generally lacking.

MethodsHere, we used an unbiased proteome-wide screening approach to identify autoantibodies to the adipocyte specific lipid droplet protein Perilipin-1 in a murine model of Autoimmune Polyendocrine Syndrome 1 (APS1). We then tested for PLIN1 autoantibodies in human subjects with lipodystrophy with two independent severe breaks in immune tolerance (including APS1) along with controls using a specific Radioligand Binding Assay and indirect immunofluorescence on fat tissue.

ResultsWe identified autoantibodies to the lipid-droplet protein Perilipin-1 (PLIN1) in two human case reports including the first reported case of human APS1 with acquired lipodystrophy. Further, we extend PLIN1 autoantibodies to a second non-APS1 patient who acquired lipodystrophy as an immune-related adverse event following cancer immunotherapy.

ConclusionThese data suggest that PLIN1 autoantibodies may represent a unifying marker of autoimmune lipodystrophy.


title: "The vaccination is positive; I don't think it's the panacea": A qualitative study on COVID-19 vaccine attitudes among ethnically diverse healthcare workers in the United Kingdom

abstract:
BackgroundGlobally, healthcare workers (HCWs) are prioritised for receiving vaccinations against the coronavirus disease-2019 (COVID-19). Previous research has shown disparities in COVID-19 vaccination uptake among HCWs based on ethnicity, job role, sex, age, and deprivation. However, vaccine attitudes underpinning these variations are yet to be fully explored.

MethodsWe conducted a qualitative study with 164 HCWs from different ethnicities, sexes, job roles, migration statuses, and regions in the United Kingdom (UK). Interviews and focus groups were conducted using Microsoft Teams or telephone, and recorded with participants permission. Recordings were transcribed and thematically analysed following an inductive approach.

FindingsWe conducted an in-depth analysis of 53 randomly selected transcripts (involving 82 participants) to generate rapid evidence. Four different vaccine attitudes were identified: Active Acceptance, Passive Acceptance, Passive Decline, and Active Decline. Factors influencing vaccine acceptance include: knowledge of vaccine; risk perception; positive attitude towards other vaccines; social influences; and considerations about the future. Correspondingly, barriers to vaccine acceptance were identified as, low trust in the vaccine and historical (mis)trust, inadequate communication, and inequities in delivery and access. Opinion on mandatory vaccination was divided.

InterpretationOur data show that vaccine attitudes are diverse and elements of hesitancy may remain even after vaccine acceptance. This has implications for the sustainability of the vaccine programme, particularly as new components (e.g. boosters) are being added. Based on our findings we recommend trust-building, designing inclusive and accessible information, and addressing structural inequities for improving vaccine uptake among HCWs.

FundingUKRI-MRC and NIHR.


title: Improved survival by Helicobacter pylori-modulated immunity in gastric cancer patients with S-1 adjuvant chemotherapy

abstract:
BackgroundParadoxically, Helicobacter pylori-positive (HP+) advanced gastric cancer patients have a better prognosis than those who are HP-negative (HP-). Immunologic and statistical analyses can be used to verify whether systematic mechanisms modulated by HP are involved in this more favorable outcome.

MethodsA total of 658 advanced gastric cancer patients who underwent gastrectomy were enrolled. HP infection, mismatch repair, programmed death-ligand 1 (PD-L1), and CD4/CD8 proteins, and microsatellite instability were analyzed. Overall survival (OS) and relapse free survival (RFS) rates were analyzed after stratifying clinicopathological factors. Cox proportional hazards regression analysis was performed to identify independent prognostic factors.

ResultsAmong 491 cases that were analyzed, 175 (36%) and 316 (64%) cases were HP+ and HP-, respectively. Analysis of RFS indicated an interaction of HP status among the subgroups for S-1 Dose (P=0.0487) and PD-L1 (P=0.016). HP+ patients in the PD-L1 group had significantly higher five-year OS and RFS than HP- patients (81% vs. 68%; P=0.0011; HR 0.477; and 76% vs. 63%; P=0.0011; HR 0.508, respectively). The five-year OS and RFS was also significantly higher for HP+ compared to HP- patients in the PD-L1-/S-1-reduced group (86% vs. 46%; p=0.0014; HR 0.205; 83% vs. 34%; p=0.001; HR 0.190, respectively). Thus, HP status was identified as one of the most potentially important independent factors to predict prolonged survival.

ConclusionModulation of host immune system function by HP may contribute to prolonged survival in the absence of immune escape mechanisms of gastric cancer.


title: Sub-Saharan African Countries' COVID-19 Research: An analysis of the External and Internal Contributions, Collaboration Patterns and Funding Sources

abstract: This study aims at providing some evidence-based insight into Sub-Saharan Africas first eighteen months of COVID-19 research by evaluating its research contributions, patterns of collaboration, and funding sources. Eighteen months (2020 January 1-2021 June 30) COVID-19 publication data of 46 Sub-Saharan African countries was collected from Scopus for analysis. Country of affiliation of the authors and funding agencies data was analyzed to understand country contributions, collaboration pattern and funding sources. USA (23.08%) and the UK (19.63%), the top two external contributors, collaborated with Sub-Saharan African countries about three times more than other countries. Collaborative papers between Sub-Saharan African countries - without contributions from outside the region-made up less than five percent of the sample, whereas over 50% of the papers were written in collaboration with researchers from outside the region. Organizations that are in USA and the UK funded 45% of all the COVID-19 research from Sub-Saharan Africa. 53.44% of all the funding from Sub-Saharan African countries came from South African organizations. This study provides evidence that pan-African COVID-19 research collaboration is low, perhaps due to poor funding and lack of institutional support within Sub-Saharan Africa. This mirrors the collaborative features of science in Sub-Saharan Africa before the COVID-19 pandemic. The high volume of international collaboration during the pandemic is a good development. There is also a strong need to forge more robust pan-African research collaboration networks, through funding from Africas national and regional government organizations, with the specific objective of meeting local COVID-19 and other healthcare needs.


title: Basal cell carcinoma treated with HeberFERON. A real world retrospective study

abstract:
BackgroundBasal cell carcinoma is the most common type of skin cancer with major impact in health-related quality of life. The use of the formulation based on the combination of IFN-alpha 2b and IFN-gamma (HeberFERON) is an effective alternative in the treatment of basal cell carcinoma, immunogenic tumor, potentially responsible to immunotherapies. The aim of this report is to record, retrospectively, the effect of HeberFERON patients with BCC in the Cuban real word condition.

MethodsThis is a retrospectively study of the use of HeberFERON in real world conditions. Eligible patients were adults with histologic diagnosis of single or multiple basal cell carcinoma of any skin phototype, lesions of any size, subtype, location, recurrent or not, with or without specific prior treatments. Adult patients, who signed the informed consent to receive the treatment with HeberFERON, were identified from the data bases. The evaluation of clinical effectiveness was carried out according to RECIST 1.1. Ethical committee of participating institutions approved the study.

ResultsIn clinical practice evaluated patients the nose was the region of higher frequency of tumors (36.3%) and the nodular clinical subtype was the predominant (45.3%). Clinical response rate differences (p=0. 000) were found, with complete response of 61.9%, and partial response of 32.7%; with an overall response rate of 94.2% The HeberFERON exerted a 100% disease control, with no progression reported in 640 treated patients. The best responder tumor subtypes to HeberFERON were the more aggressive tumors, morpheaform with complete response of 72% (overall response=96%), followed by the infiltrative with complete response of 66.7% (overall response=100%). Tumor with larger size and patients with more than four tumors had lesser response to the anti-tumor effect of HeberFERON.

ConclusionsHeberFERON was highly effective in basal cell carcinomas in real world conditions. In the context of resistance of skin tumors to hedgehog and immune check point inhibitors the combination of IFNs alpha 2b and IFN gamma appears as a plausible therapeutic option for a wide number of basal cell carcinomas.


title: Children Living with Disabilities Are Absent From Severe Malnutrition Guidelines

abstract:
PurposeChildren living with disabilities (CLWD) are at high risk of malnutrition but have long been marginalised in malnutrition treatment programmes and research. The 2013 World Health Organization (WHO) guidelines for Severe Acute Malnutrition (SAM) mention disability but do not contain specific details for treatment or support. This study assesses inclusion of CLWD in national and international SAM guidelines.

MethodsNational and international SAM guidelines were sourced online and via direct enquiries. Eight scoping key informant interviews were conducted with experts involved in guideline development to help understand possible barriers to formalising malnutrition guidance for CLWD.

Results71 malnutrition guidelines were reviewed (63 national, 8 international). Only 4% (3/71) had a specific section for CLWD, while the remaining lacked guidance on consistently including CLWD in programmes or practice. Only one guideline mentioned strategies to include CLWD during a nutritional emergency. Most (99%,70/71) did not link to other disability-specific guidelines. Of the guidelines that included CLWD, most only discussed disability in general terms despite the fact that different interventions are often needed for children with different conditions. Interviews pointed towards barriers related to medical complexity, resource constraints, epidemiology (e.g., unrecognised burden), lack of evidence, and difficulty of integration into existing guidelines.

ConclusionChildren living with disability are not recognised in most SAM guidelines. Where they are, recommendations are very limited. Better evidence is urgently needed to identify and manage CLWD in malnutrition programmes. More inclusion in the 2022 update of the WHO malnutrition guidelines could support this vulnerable group.

category: pediatrics


title: Effectiveness of the mRNA BNT162b2 vaccine against SARS-CoV-2 severe infections in the Israeli over 60 population: a temporal analysis done by using the national surveillance data.

abstract: Last August, when the delta variant became the dominant infection strain, Israel, one of the countries with the highest levels of vaccination in the world, faced a scary pandemic wave. The frighteningly increasing number of infections was seen as the perfect storm to test the effectiveness of the mRNA BNT162b2 vaccine. The new surge forced the government to use a booster shot to protect the most vulnerable age groups. Starting from the August national surveillance data, we analysed the temporal effectiveness of vaccination against severe infections in the Israeli over 60 population. The study shows that the two-dose vaccine still works in preventing people from getting seriously sick but not with the same effectiveness observed in the first months of 2021. However, the observed temporal increase of the vaccine effectiveness in Israel, during August, suggests a correlation with the increase of the population protected by the booster shot.


title: Four SARS-CoV-2 vaccines induce quantitatively different antibody responses against SARS-CoV-2 variants

abstract:
BackgroundEmerging and future SARS-CoV-2 variants may jeopardize the effectiveness of vaccination campaigns. Therefore, it is important to know how the different vaccines perform against diverse SARS-CoV-2 variants.

MethodsIn a prospective cohort of 165 SARS-CoV-2 naive health care workers, vaccinated with either one of four vaccines (BNT162b2, mRNA-1273, AZD1222 or Ad26.COV2.S), we performed a head-to-head comparison of the ability of sera to recognize and neutralize SARS-CoV-2 variants of concern (VOCs; Alpha, Beta, Gamma, Delta and Omicron). Repeated serum sampling was performed 5 times during a year (from January 2021 till January 2022), including before and after booster vaccination with BNT162b2.

FindingsFour weeks after completing the initial vaccination series, SARS-CoV-2 wild-type neutralizing antibody titers were highest in recipients of BNT162b2 and mRNA-1273 (geometric mean titers (GMT) of 197 [95% CI 149-260] and 313 [95% CI 218-448], respectively), and substantially lower in those vaccinated with the adenovirus vector-based vaccines AZD1222 and Ad26.COV2.S (GMT of 26 [95% CI 18-37] and 14 [95% CI 8-25] IU/ml, respectively). These findings were robust for adjustment to age and sex. VOCs neutralization was reduced in all vaccine groups, with the largest (9- to 80-fold) reduction in neutralization observed against the Omicron variant. The booster BNT162b2 vaccination increased neutralizing antibody titers for all groups with substantial improvement against the VOCs including the Omicron variant. Study limitations include the lack of cellular immunity data.

ConclusionsOverall, this study shows that the mRNA vaccines appear superior to adenovirus vector-based vaccines in inducing neutralizing antibodies against VOCs four weeks after initial vaccination and after booster vaccination.

category: infectious diseases


title: Antibody responses against SARS-CoV-2 variants induced by four different SARS-CoV-2 vaccines


title: Bayesian Inference of State-Level COVID-19 Basic Reproduction Numbers across the United States

abstract:
Although many persons in the United States have acquired immunity to COVID-19, either through vaccination or infection with SARS-CoV-2, COVID-19 will pose an ongoing threat to non-immune persons so long as disease transmission continues. We can estimate when sustained disease transmission will end in a population by calculating the population-specific basic reproduction number [R]0, the expected number of secondary cases generated by an infected person in the absence of any interventions. The value of [R]0 relates to a herd immunity threshold (HIT), which is given by 1 - 1/[R]0. When the immune fraction of a population exceeds this threshold, sustained disease transmission becomes exponentially unlikely (barring mutations allowing SARS-CoV-2 to escape immunity). Here, we report state-level [R]0 estimates obtained using Bayesian inference. Maximum a posteriori estimates range from 7.1 for New Jersey to 2.3 for Wyoming, indicating that disease transmission varies considerably across states and that reaching herd immunity will be more difficult in some states than others. [R]0 estimates were obtained from compartmental models via the next-generation matrix approach after each model was parameterized using regional daily confirmed case reports of COVID-19 from 21-January-2020 to 21-June-2020. Our [R]0 estimates characterize infectiousness of ancestral strains, but they can be used to determine HITs for a distinct, currently dominant circulating strain, such as SARS-CoV-2 variant Delta (lineage B.1.617.2), if the relative infectiousness of the strain can be ascertained. On the basis of Delta-adjusted HITs, vaccination data, and seroprevalence survey data, we find that no state has achieved herd immunity as of 20-September-2021.

Significance StatementCOVID-19 will continue to threaten non-immune persons in the presence of ongoing disease transmission. We can estimate when sustained disease transmission will end by calculating the population-specific basic reproduction number [R]0, which relates to a herd immunity threshold (HIT), given by 1 - 1/[R]0. When the immune fraction of a population exceeds this threshold, sustained disease transmission becomes exponentially unlikely. Here, we report state-level [R]0 estimates indicating that disease transmission varies considerably across states. Our [R]0 estimates can also be used to determine HITs for the Delta variant of COVID-19. On the basis of Delta-adjusted HITs, vaccination data, and serological survey results, we find that no state has yet achieved herd immunity.


title: OUTCOME AND ASSOCIATED FACTORS AMONG ROAD TRAFFIC ACCIDENT VICTIMS AT WOLAITA SODDO CHRISTIAN HOSPITAL, WOLAITA SODDO, SOUTH ETHIOPIA 2020, INSTITUTION-BASED CROSS-SECTIONAL STUDY.

abstract:
BackgroundIn today s world road traffic accident victims are treated as a major epidemic of non-communicable disease. Road traffic accidents caused numerous family tragedies such as serious economic loss to the community and the death of young people. The problem is more severe in low and middle-income countries. In Ethiopia, the largest proportion of series injuries comes from road traffic accidents and become major causes of death in the emergency room. Despite this, only a little is known about treatment outcomes of road traffic accident victims and its associated factors in Ethiopia.

MethodAn institution-based Cross-sectional study design was conducted at Wolaita Soddo Christian hospital with a sample of 400 road traffic accidents. The medical record was selected using a systematic sampling method. Data was entered using Epi-data version 4.1 and was exported to and analyzed using SPSS version 23. A multivariable logistic regression model was used to assess the association between the independent variables and dependent variables.

RESULTThe overall death rate was 9.5%. Being out of hospital catchment area [AOR= 2.16, 95% CI= (1.01-4.70)] presence of co-morbid condition [AOR= 6.77 95% CI= (2.44-18.81)] lack of first aid help [AOR= 2.77 95% CI= (1.17-6.52)] and severity of the injury [AOR= 3.85 95% CI= (1.50-9.89)] were found to be significantly associated with outcome of road traffic accident victims.

ConclusionThe study shows that the death rate from road traffic accidents was high. Therefore, designing strategies to decrease death from road traffic accidents by giving great emphasis to road traffic accident victims with co-morbid conditions and severe injury and focusing on the availability and accessibility of pre-hospital care service.


title: Global Burden of Covid-19 Restrictions: National, Regional and Global Estimates

abstract: A large literature has documented the high global mortality and mental health burden associated with the current Covid-19 pandemic. In this paper, we combine newly collected data on subjective reductions in the quality of life with the latest data on Covid-19 restrictions to quantify the total number of quality-adjusted life years (QALYs) lost due to government imposed restrictions globally. Our estimates suggest a total loss of 2980 (95% 2764, 3198) million QALYs as of September 6th 2021, with the highest burden absolute burden in lower and upper middle income countries. QALY losses appear to be particularly large for closures of schools and daycares as well as restaurants and bars, and seem relatively small for wearing masks in public and closure of fitness facilities.

category: health economics


title: The Kinetics of COVID-19 Vaccine Response in a Community Vaccinated Population

abstract:
We used a noninvasive electrochemical quantitative assay for IgG antibodies to SARS-CoV-2 S1 in saliva to investigate the kinetics of antibody response in a community-based population who had received either the Pfizer or Moderna mRNA-based vaccines. Samples were received from a total of 97 individuals including a subset of 42 individuals who collected samples twice-weekly for 3 months or longer. In all, 840 samples were collected and analyzed. In all individuals, salivary antibody levels rose sharply in the 2-week period following their second vaccination, with peak antibody levels being at 10-20 days post-vaccination. We observed that 20%, 10% and 2.4% of individuals providing serial samples had a 90%, 95%, and 99% drop respectively from peak levels during the duration of monitoring and two patients fell to pre-vaccination levels (5%). The use of non-invasive quantitative salivary antibody measurement can allow widespread, cost-effective monitoring of vaccine response.

Article Summary LineCOVID-19 antibodies were measured in saliva and 20% of vaccinated subjects experienced a 90% drop in peak antibody levels over the course of monitoring.

category: allergy and immunology


title: CD14 Positive Extracellular Vesicles in Broncho-Alveolar Lavage Fluid as a New Biomarker of Acute Respiratory Distress Syndrome

abstract: Recent studies have indicated that extracellular vesicles (EV) may play a role in the pathogenesis of Acute Respiratory Distress Syndrome (ARDS). EV have been identified as potential biomarkers of disease severity and prognosis in other pulmonary diseases. We sought to characterize the EV phenotype within ARDS patient broncho-alveolar lavage fluid (BAL), and to determine whether BAL EV could be utilized as a potential biomarker in ARDS. BAL was collected from sepsis patients with and without ARDS, and from esophagectomy patients post-operatively (of whom a subset later developed ARDS during hospital admission). BAL EV were characterized with regards to size, number and cell of origin. Sepsis patients with ARDS had significantly higher numbers of CD14+/CD81+ monocyte-derived BAL EV than sepsis patients without ARDS (p=0.015). However, the converse was observed in esophagectomy patients who later developed ARDS (p=0.003). Esophagectomy patients who developed ARDS also had elevated CD31+/CD63+ and CD31+/CD81+ endothelial-derived BAL EV (p[≤]0.02) compared to esophagectomy patients who did not develop ARDS. Further studies are required to determine whether CD31+ BAL EV may be a predictive biomarker for ARDS in esophagectomy patients. CD14+/CD81+ BAL EV numbers were significantly higher in those patients with sepsis-related ARDS who died during the 30 days following ICU admission (p=0.027). Thus, CD14+/CD81+ BAL EV are a potential biomarker for disease severity and mortality in sepsis-related ARDS. These findings provide the impetus to further elucidate the contribution of these EV to ARDS pathogenesis.


title: Donor clonal hematopoiesis and recipient outcomes after transplantation

abstract:
BackgroundClonal hematopoiesis (CH) can be transmitted from donor to recipient during allogeneic hematopoietic cell transplantation. Exclusion of candidate donors with CH is controversial since its impact on recipient outcomes and graft alloimmune function is uncertain.

MethodsWe performed targeted error-corrected sequencing on samples from 1727 donors aged 40 or older and assessed the effect of donor CH on recipient clinical outcomes. We measured long-term engraftment of 102 donor clones and cytokine levels in 256 recipients at 3 and 12 months after transplant.

ResultsCH was present in 22.5% of donors, with DNMT3A (14.6%) and TET2 (5.2%) mutations being most common; 85% of donor clones showed engraftment in recipients after transplantation, including clones with variant allele fraction (VAF)<0.01. DNMT3A-CH with VAF[≥]0.01, but not smaller clones, was associated with improved recipient overall (HR 0.79, P=0.042) and progression-free survival (HR 0.72, P=0.003) after adjustment for significant clinical variables. In patients receiving calcineurin-based GVHD prophylaxis, donor DNMT3A-CH was associated with reduced relapse (sHR 0.59, P=0.014), increased chronic GVHD (sHR 1.36, P=0.042), and higher IL-12p70 levels in recipients. No recipient of sole DNMT3A or TET2-CH developed donor cell leukemia (DCL). In 7 of 8 cases, DCL evolved from donor CH with rare TP53 or splicing factor mutations or from donors carrying germline DDX41 mutations.

ConclusionDonor CH is associated with clinical outcomes in transplant recipients, with differential impact on alloimmune function and potential for leukemic transformation related to mutated gene and clonal abundance. DNMT3A-CH is associated with improved recipient survival due to reduced relapse risk and an augmented network of inflammatory cytokines in recipients. Risk of DCL is driven by pre-existing somatic MDS-associated mutations or germline predisposition in donors.


title: Generation of realistic synthetic data using multimodal neural ordinary differential equations

abstract: Individual organizations, such as hospitals, pharma companies and health insurance providers are currently limited in their ability to collect data that is fully representative of a disease population. This can in turn negatively impact the generalization ability of statistical models and scientific insights. However, sharing data across different organizations is highly restricted by legal regulations. While federated data access concepts exist, they are technically and organizationally difficult to realize. An alternative approach would be to exchange synthetic patient data instead. In this work, we introduce the Multimodal Neural Ordinary Differential Equation (MultiNODE), a hybrid, multimodal AI approach, which allows for generating highly realistic synthetic patient trajectories on a continuous time scale, hence enabling smooth interpolation and extrapolation of clinical studies. Our proposed method can integrate both static and longitudinal data and implicitly handles missing values. We demonstrate the capabilities of our approach by applying it to real patient-level data from two independent clinical studies and simulated epidemiological data of an infectious disease.

category: health informatics


title: Bringing testing closer to you. Barriers and Facilitators in Implementing HIV Self-Testing among Filipino Men Having Sex with Men and Transgender Women in National Capital Region (NCR), Philippines: A Qualitative Study

abstract:
ObjectivesOur study identified barriers and facilitators in implementing HIV Self-Testing (HIVST), including the perceptions of men-having-sex-with-men (MSM) and transgender women on HIVST. Furthermore, we explored the current knowledge, practices, and potential of HIVST among the MSM and TGW populations.

DesignQualitative in-depth Key Informant Interviews (KIIs) were conducted using semi-structured interviews administered in both English and Filipino. Thematic analysis of the findings was done after transcribing all audio recordings.

SettingThe study was done in the National Capital Region (NCR), Philippines using online video conferencing platforms due to mobility restrictions and lockdowns caused by the COVID-19 pandemic.

ParticipantsAll study participants were either MSM or TGW, 18 to 49 years old, and residing/working in NCR. Exclusion criteria include biologically born female and/or currently on pre-exposure prophylaxis (PrEP), antiretroviral therapy (ART) medications, or an HIV-positive diagnosis.

ResultsTwenty informants were interviewed, of which 75% were MSM, and most of them preferred the use of HIVST. Facilitators and barriers to the use of HIVST were grouped into three main themes: Acceptability, distribution, and monitoring and tracking. Convenience and confidentiality, overcoming fears, and normalization of HIV testing services (HTS) in the country were why the participants preferred HIVST. In contrast, lack of privacy and maintenance of confidentiality during kit delivery were perceived as barriers in HIVST implementation. Moreover, social media was recognized as a powerful tool in promoting HIVST. The use of a welcoming tone and positive language should be taken into consideration due to the prevalent HIV stigma.

ConclusionsThe identified facilitators and barriers from the study may be considered by the Philippine HTS program implementers. The HIVST strategy may complement the current HTS. It will be very promising to involve the MSM and TGW communities and other key populations to know their HIV status by bringing testing closer to them.

STRENGTH AND LIMITATIONSO_LIGathering participants and building trust to give their insights did not pose any difficulty because the community-based organization is reputable among the key populations (MSM and TGW) and HIV advocacy in the Philippines.
C_LIO_LIOur study only involved respondents from the National Capital Region, which may limit its generalizability to other regions of the country where HIV cases are still increasing.
C_LIO_LIKey informant interviews were done online due to the COVID-19 pandemic; thus, some reactions to the questions of the participants are not noted due to the unavailability of video and weak internet connectivity.
C_LIO_LIThe perceived acceptability of HIVST from the informants is suggestive, and the majority of the participants had not used the HIVST before.
C_LIO_LIOur study only involved the MSM and TGW populations and did not include other at-risk and high-risk populations, limiting its applicability to different populations.
C_LI

category: hiv aids


title: Discovering disease-causing pathogens in resource-scarce Southeast Asia using a global metagenomic pathogen monitoring system

abstract:
Understanding the regional pathogen landscape and surveillance of emerging pathogens is key to mitigating epidemics. Challenges lie in resource-scarce settings, where outbreaks are likely to emerge, but where laboratory diagnostics and bioinformatics capacity are limited. Using unbiased metagenomic next generation sequencing (mNGS), we identified a variety of vector-borne, zoonotic and emerging pathogens responsible for undifferentiated fevers in a peri-urban population in Cambodia. From March 2019 to October 2020, we enrolled 473 febrile patients aged 6 months to 65 years of age presenting to a large peri-urban hospital in Cambodia. We collected sera and prepared sequencing libraries from extracted pathogen RNA for unbiased metagenomic sequencing and subsequent bioinformatic analysis on the global cloud-based platform, IDseq. We employed multivariate Bayesian models to evaluate specific pathogen risk causing undifferentiated febrile illness. mNGS identified vector-borne pathogens as the largest clinical category with dengue virus (124/489) as the most abundant pathogen.

Underappreciated zoonotic pathogens such as Plasmodium knowlesi, leptospirosis, and co-infecting HIV were also detected. Early detection of chikungunya virus presaged a larger national outbreak of more than 6,000 cases. Pathogen-agnostic mNGS investigation of febrile persons in resource-scarce Southeast Asia is feasible and revealing of a diverse pathogen landscape. Coordinated and ongoing unbiased mNGS pathogen surveillance can better identify the breadth of endemic, zoonotic or emerging pathogens and deployment of rapid public health response.

Clinical Trial NumbersNCT04034264 and NCT03534245.

Significance StatementPublic health authorities recently advocated for global expansion of sequencing capacity worldwide; however, the importance of genomics-based surveillance to detect emerging pathogens or variants in resource-limited settings is paramount, especially in a populous, biodiverse Southeast Asia. From 2019 to 2020, pathogen metagenomic next generation sequencing (mNGS) of febrile patients in Cambodia identified several vector-borne and zoonotic pathogens, both common and underappreciated, and resulted in a variety of actionable health interventions. Understanding these pathogen discoveries, and the attendant challenges of mNGS in these outbreak-prone settings, is critical for todays global society and decision-makers in order to implement sequencing-based pathogen or variant detection.

Significance StatementMetagenomic pathogen sequencing offers an unbiased approach to characterizing febrile illness. In resource-scarce settings with high biodiversity, it is critical to identify disease-causing pathogens in order to understand burden and to prioritize efforts for control. Here, mNGS characterization of the pathogen landscape in Cambodia revealed diverse vector-borne and zoonotic pathogens irrespective of age and gender as risk factors. Identification of key pathogens led to changes in national program surveillance. This study provides a recent  real world example for the use of mNGS surveillance in both identifying diverse microbial landscapes and detecting outbreaks of vector-borne, zoonotic, and other emerging pathogens in resource-scarce settings.

ClassificationBiological Sciences; microbiology; medical sciences


title: Large-scale seroepidemiologic surveillance of COVID-19 - Cross-sectional study in Hyogo prefecture of Japan in August, 2021

abstract: The situation of the COVID-19 pandemic in Japan is drastically changing in the 2nd year, 2021, due to the appearance of SARS-CoV-2 variants of concern and the roll-out of mass vaccination. In addition to PCR diagnosis, periodic seroepidemiologic surveillance is important to analyze the epidemic situation. In this study, we analyzed the rate of seropositivity for the SARS-CoV-2 N and S antigens in Hyogo prefecture, Japan in August 2021. Sera collected from people who received a health check-up in a clinic of the Hyogo Prefecture Health Promotion Association were subjected to analysis of reactivity to the SARS-CoV-2 N and S antigens by electrochemiluminescence immunoassay (ECLIA) and enzyme-linked immunosorbent assay (ELISA), respectively. For a total 1,000 sera, the positive rates to N and S antigens were 2.1% and 38.7%, respectively. The infectious rate estimated by serological analysis based on the presence of the anti-N antibody was 2.5-fold higher than the value reported based on PCR-based analysis, and it increased five-fold compared to the rate determined by our previous seroepidemiologic study in October, 2020. The anti-S positive rate was almost consistent with the vaccination rate in this area. The observed high anti-S antibody level in the seropositive population may indicate that the mass vaccination in Japan is being performed smoothly at this time point, although the infectious rate has also increased.


title: A standardized instrument quantifying risk factors associated with bi-directional transmission of SARS-CoV-2 and other zoonotic pathogens: The COVID-19 Human-Animal Interactions Survey (CHAIS)

abstract:
SARS-CoV-2 (CoV-2), which surfaced in late 2019 in Wuhan City, China, most likely originated in bats and rapidly spread among humans globally, harming and disrupting livelihoods worldwide. Early into the pandemic, reports of CoV-2 diagnoses in pets and other animals emerged, including dogs, cats, farmed mink and some large felids (tigers and lions) from various countries. While most CoV-2 positive animals were confirmed to have been in close contact with CoV-2 positive humans, there has been a paucity of published evidence to-date describing risk factors associated with CoV-2 transmission among humans and domestic and wild animals. The COVID-19 Human-Animal Interactions Survey (CHAIS) was developed through a cross-CEIRS Center collaboration to provide a standardized survey describing human-animal interaction during the pandemic and to evaluate behavioral, spatiotemporal, and biological risk factors associated with bi-directional zoonotic transmission of CoV-2 within households and other shared environments. CHAIS measures four broad domains of transmission risk; 1) intensity and risk of infection among human hosts, 2) spatial characteristics of shared environments, 3) behaviors and human-animal interactions, and 4) animal susceptibility to infection and propensity for onward spread. Following the development of CHAIS, with a One Health approach, a multidisciplinary group of experts (n=20) was invited to review and provide feedback on the survey for content validity. Expert feedback was incorporated into two final survey formats-a long-form and an abridged version for which specific core questions addressing zoonotic and reverse zoonotic transmission were identified. Both forms are modularized, with each section having the capacity to serve as independent instruments, allowing researchers to customize the survey based on context and research-specific needs. Further adaptations for studies seeking to investigate other zoonotic pathogens with similar routes of transmission (i.e. respiratory, direct contact) are also possible. The CHAIS instrument is a standardized human-animal interaction survey developed to provide important data on risk factors that guide transmission of CoV-2 from humans to animals, with great utility in capturing information of zoonotic transmission risk factors for CoV-2 and other similar pathogens.

ImpactsO_LIWe present a standardized survey instrument for evaluating risk factors associated with bi-directional zoonotic transmission of SARS-CoV-2 and other similarly transmitted pathogens in household and other settings where humans and animals share close contact.
C_LIO_LIThe CHAIS instrument evaluates behavioral, spatiotemporal, and host determinants of transmission risk of SARS-CoV-2 and is highly adaptable for use in studies seeking to investigate other zoonotic pathogens such as influenza viruses.
C_LIO_LIThis standardized instrument will enable pooling of data across studies for meta-analyses to improve predictive models of bi-directional transmission of SARS-CoV-2 among humans and animals and will inform public health prevention and mitigation measures.
C_LI


title: Induction of robust neutralizing antibodies against the COVID-19 Delta variant with ChAdOx1 nCoV-19 or BNT162b2 as a booster following a primary vaccination series with CoronaVac

abstract: We determined the antibody response among CoronaVac vaccinees who were boosted with either BNT162b2 or ChAdOx1 nCoV-19. Increase in anti-S-RBD antibodies and surrogate neutralizing antibodies against the Delta variant was higher in BNT162b2 recipients than in ChAdOx1 nCoV-19 recipients. High proportions of reactogenicity were seen for both booster regimens.


title: A prevaccination validated network that drives the breadth of the protective neutralizing antibody response following Dengue Vaccine TV003 immunization

abstract: Development of fully protective dengue virus (DV) vaccines has been problematic as infection with DV requires a broad antibody immune response that targets all 4 possible serotypes. Herein, we used an integrated systems vaccinology approach to identify prevaccination features that allow the development of fully protective DV-specific antibody responses. This approach allowed us to identify a transcription network in a subset of monocytes defined by the expression of CD68 and downstream of specific pro- and anti-inflammatory cytokines. Moreover, we identified metabolites as drivers of an immune response that induced neutralizing antibodies to the 4 DV serotypes. Specifically, PC/PE drove the production of TGF-B in CD68 low monocytes, which was a positive correlate of the protective antibody response. In contrast, primary and secondary bile acids triggered a proinflammatory response downstream of TGR5 signaling and inflammasome activation in CD68 high monocytes, which was associated to a non-protective antibody response. These features were validated in vitro in primary myeloid cells. Our results highlight the role of cell and systemic metabolism as regulators of protective immune responses to vaccination, and that systems vaccinology is a key tool to identify such mechanisms.


title: Bayesian approach to comparing the left ventricular volume in myocardial infarction and in normal cases

abstract:
IntroductionPost-contrast delayed-enhancement MRI helps to show the extent of myocardial infarction (MI), as well as allowing the morphometric analysis of the heart structure, e.g., left ventricular volume (LVV). Here the author deployed Bayesian implementation of statistical inference to determine the difference between the LVV in MI cases and in normal controls.

MethodsSixty-seven MI patients and thirty-three controls from the EMIDEC dataset challenge were used. These were acquired at the University Hospital of Dijon (France). A cardiologist with 10 years of experience in cardiology and MRI and a biophysicist with 20 years of experience of cardiovascular MRI supervised the acquisition and annotated the images. ITK-Snap was used to extract the LVV and Bayesian inference were used to investigate the data.

ResultsPatients with MI were younger than the controls (58.3 {+/-} 11.5 vs. 66.5 {+/-} 12.9 years; BF10 = 17.9). With age taken into consideration, the patients showed larger LVV relative to the controls (128.1 {+/-} 46.3 vs. 83.4 {+/-} 24.4 cm3; post-hoc BF10 = 12663.8).

SummaryUsing Bayesian approach, we can conclude decisively that there is volumetric difference or remodeling in individuals with MI.


title: COVID-19 Vaccination Strategies Considering Hesitancy Using Particle-Based Epidemic Simulation

abstract: Vaccine hesitancy is one of the critical factors in achieving herd immunity and suppressing the COVID-19 epidemic. Many countries face this as an acute public health issue that diminishes the efficacy of their vaccination campaigns. Epidemic modeling and simulation can be used to predict the effects of different vaccination strategies. In this work, we present an open-source particle-based COVID-19 simulator with a vaccination module capable of taking into account the vaccine hesitancy of the population. To demonstrate the efficacy of the simulator, we conducted extensive simulations for the province of Lecco, Italy. The results indicate that the combination of both high vaccination rate and low hesitancy leads to faster epidemic suppression.

category: epidemiology


title: Estimating the lagged effect of price discounting: a time-series study using transaction data of sugar sweetened beverages.

abstract:
BackgroundPrice discount is an unregulated obesogenic environmental risk factor for the purchasing of unhealthy food, including Sugar Sweetened Beverages (SSB). Sales of price discounted food items are known to increase during the period of discounting. However, the presence and extent of the lagged effect of discounting, a sustained level of sales after discounting ends, is previously unaccounted for. We investigated the presence of the lagged effect of discounting on the sales of five SSB categories, which are soda, fruits juice, sport and energy drink, sweetened coffee and tea, and sweetened drinkable yogurt.

MethodsWe fitted a distributed lag model to weekly volume-standardized sales and percent discounting generated by a supermarket in Montreal, Canada between 2008 and 2013.

ResultsWhile the sales of SSB increased during the period of discounting, there was no evidence of a prominent lagged effect of discounting in four of the five SSB; the exception was sports and energy drinks, where a posterior mean of 28,459 servings (95% credible interval: 2,661 to 67,253) of excess sales can be attributed to the lagged effect in the target store during the study period.

ConclusionsOur results indicate that previous studies may have underestimated the effect of price discounting for some food categories.

Key messagesO_ST_ABSWhat is already knownC_ST_ABSTemporary price discounting is an important component of obesogenic food environment, as it has been shown to increase the sales of discretionary food items during the period of discounting.

Novelty of findingsEven after a period of price discounting has ended, the sales of sports and energy drinks remain at a higher level relative to the sales before discounting.

Research and public health implicationsPrevious research focusing on the immediate effect (i.e., same time period) of price discounting may have systematically underestimated the impact of price discounting for some food categories.

The findings and analytical method in this study promote improved validity of future food environment research targeting the impact of discounting and other types of food promotions on the sales of energy-dense and nutrition-poor food items.


title: Functional Data Analysis: Transition from Daily Observation of COVID-19 Prevalence in France to Functional Curves

abstract: In this paper we use the technique of functional data analysis to model daily hospitalized, deceased, ICU cases and return home patient numbers along the COVID-19 outbreak, considered as functional data across different departments in France while our response variables are numbers of vaccinations, deaths, infected, recovered and tests in France. These sets of data were considered before and after vaccination started in France. We used some smoothing techniques to smooth our data set, then analysis based on functional principal components method was performed, clustering using k-means techniques was done to understand the dynamics of the pandemic in different French departments according to their geographical location on France map and we also performed canonical correlations analysis between variables. Finally, we made some predictions to assess the accuracy of the method using functional linear regression models.