title: Mutational landscape of high-grade B-cell lymphoma with MYC-, BCL2 and/or BCL6 rearrangements characterized by whole-exome sequencing

abstract:
High-grade B-cell lymphoma accompanied with MYC and BCL2 and/or BCL6 rearrangements (HGBL-DH/TH) poses a cytogenetically-defined provisional entity among aggressive B-cell lymphomas that is traditionally associated with unfavorable prognosis.

To better understand the mutational and molecular landscape of HGBL-DH/TH we here performed whole-exome sequencing and deep panel next-generation-sequencing (NGS) of 47 clinically annotated cases. Oncogenic drivers, mutational signatures and perturbed pathways were compared with data from follicular lymphoma (FL), diffuse large-B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL).

We find an accumulation of oncogenic mutations in NOTCH, IL6/JAK/STAT and NF{kappa}B signaling pathways and delineate the mutational relationship within the continuum between FL/DLBCL, HGBL-DH/TH and BL. Further, we provide evidence of a molecular divergence between BCL2 and BCL6 rearranged HGBL-DH. Beyond a significant congruency with the C3/EZB DLBCL cluster in BCL2 rearranged cases on an exome-wide level, we observe an enrichment of the SBS6 mutation signature in BCL6 rearranged cases. Differential gene set enrichment and subsequent network propagation analysis according to cytogenetically defined subgroups revealed an impairment of TP53 and MYC pathway signaling in BCL2 rearranged cases, whereas BCL6 rearranged cases lacked this enrichment, but instead exhibited showed impairment of E2F targets. Intriguingly, HGBL-TH displayed intermediate mutational features in all three aspects.

This study elucidates a recurrent pattern of mutational events driving FL into MYC-driven BCL2 rearranged HGBL, unveiling the mutational pathogenesis of this provisional entity. Through this refinement of the molecular taxonomy for aggressive, germinal-center derived B-cell lymphomas, this calls into question the current WHO classification system, especially regarding the status of MYC/BCL6 rearranged HGBL.

category: hematology


title: Vaccination with BNT162b2 reduces transmission of SARS-CoV-2 to household contacts in Israel

abstract:
The individual-level effectiveness of vaccines against clinical disease caused by SARS-CoV-2 is well-established. However, few studies have directly examined the effect of COVID-19 vaccines on transmission. We quantified the effectiveness of vaccination with BNT162b2 (Pfizer-BioNTech mRNA-based vaccine) against household transmission of SARS-CoV-2 in Israel. We fit two time-to-event models - a mechanistic transmission model and a regression model - to estimate vaccine effectiveness against susceptibility to infection and infectiousness given infection in household settings. Vaccine effectiveness against susceptibility to infection was 80-88%. For breakthrough infections among vaccinated individuals, the vaccine effectiveness against infectiousness was 41-79%. The overall vaccine effectiveness against transmission was 88.5%. Vaccination provides substantial protection against susceptibility to infection and slightly lower protection against infectiousness given infection, thereby reducing transmission of SARS-CoV-2 to household contacts.

One-Sentence SummaryVaccination reduced both the rate of infection with SARS-CoV-2 and transmission to household contacts in Israel.

category: infectious diseases


title: THE COMPARISON OF THREE REAL-TIME PCR KITS FOR SARS-COV-2 DIAGNOSIS REVEALS DISCREPANCIES ON THE IDENTIFICATION OF POSITIVE COVID-19 CASES AND DISPERSION ON THE VALUES OBTAINED FOR THE DETECTION OF SARS-COV-2 VARIANTS

abstract: The COVID-19 pandemic has generated a huge challenge and threat to public health throughout the world population. Reverse transcription associated with real-time Polymerase Chain Reaction (RT-qPCR) has been the gold-standard molecular tool for diagnosis and detection of the SARS-CoV-2. Currently, it is used as the main strategy for testing, traceability, and control of positive cases For this reason, the on-top high demand for reagents has produced stock-out on several occasions and the only alternative to keep population diagnosis has been the use of different RT-qPCR kits. Therefore, we evaluate the performance of three of the commercial RT-qPCR kits currently in use for SARS-CoV-2 diagnosis in Chile, consisting in: TaqMan 2019-nCoV Assay Kit v1 (Thermo). Real-Time Fluorescent RT-PCR Kit for Detecting SARS-CoV-2 (BGI), and LightCycler(R) Multiplex RNA Virus Master (Roche). Results of quantification cycle (Cq) and relative fluorescence units (RFU) obtained from their RT-qPCR reactions revealed important discrepancies on the total RNA required for the identification of SARS-CoV-2 genes and diagnosis. Marked differences between kits in samples with 30>Cq value< 34 was observed. Samples with positive diagnoses for Covid-19 using the Thermo Fisher kit had different results when the same samples were evaluated with Roche and BGI kits. The displacement on the Cq value for SARS-CoV-2 identification between the three different RT-qPCR kits was also evident when the presence of single nucleotide variants was evaluated in the context of genomic surveillance. Taken together, this study emphasizes the special care adjusting RT-qPCR reaction conditions of the different kits must be taken by all the laboratories before carrying out the detection of SARS-CoV-2 genes from total RNA nasopharyngeal swab (NPS) samples.


title: Structural Neuroplasticity Following Cognitive Behavioral Therapy for the Treatment of Chronic Musculoskeletal Pain: A Randomized Controlled Trial with Secondary MRI Outcomes

abstract:
The extent of white matter (WM) and Grey matter (GM) structural neuroplasticity following cognitive behavioral therapy for chronic pain management remains undetermined. In the current study, we investigated structural alterations in GM morphometry, as well as WM complexity and connectivity, before and after an 11-week group CBT for the treatment of chronic musculoskeletal pain. We hypothesized that effective pain management would influence WM structural metrics indicative of brain plasticity, particularly within cognitive and limbic circuitry as well as GM volume within pain matrix structures. To determine this, patients were randomized into two groups: 1) CBT group that received CBT once-weekly for 11-weeks, or 2) EDU group consisting of an active patient control group that received educational materials by mail. All subjects completed behavioral assessments and underwent neuroimaging at: baseline prior to any intervention (TP1), 11-weeks following either CBT or EDU (TP2), and four months following completion of the intervention (TP3). CBT resulted in significant clinical improvements, assessed via behavioral self-reports, compared to EDU. Compared to EDU, region of interest WM analysis revealed several fiber tracts that had significantly increased WM complexity following CBT intervention, including the bilateral posterior internal capsule and the left cingulum within the temporal lobe. Conversely, several tracts exhibited a decrease in WM complexity including the right external capsule, the left posterior internal capsule, and the right cingulum within the temporal lobe. Changes in clinical outcomes were predictive of alterations in WM complexity metrics immediately following intervention and at long-term follow-up. No between-group differences were observed in either WM connectivity or GM volume. In conclusion, psychotherapeutic interventions such as group CBT influence coping strategies for effective pain relief that influence WM microstructure, however, the mechanisms of these changes remain undetermined. Future studies will be required to uncover the biological underpinnings of these alterations in pain populations.

ClinicaltrialsgovCan Therapy Alter CNS Processing of Chronic Pain: A Longitudinal Study (https://clinicaltrials.gov/ct2/show/NCT01794988?term=naylor&cntry=US&state=US%3AVT&draw=2&rank=1;NCT01794988). The study protocol was registered in the Clinical Trials Database.

category: pain medicine


title: Quantitative magnetisation transfer imaging in relapsing-remitting multiple sclerosis: a systematic review and meta-analysis.

abstract:
Myelin-sensitive MRI such as magnetisation transfer imaging has been widely used in the clinical context of multiple sclerosis. The influence of methodology and differences in disease subtype on imaging findings is, however, not well established. Here, we aim to review systematically the use of quantitative magnetisation transfer imaging in the brain in relapsing- remitting multiple sclerosis. We examine how methodological differences, disease effects and their interaction influence magnetisation transfer imaging measures.

Articles published before 06/01/2021 were retrieved from online databases (PubMed, EMBASE and Web of Science) with search terms including  magnetisation transfer and  brain for systematic review. Only studies which used human in vivo quantitative magnetisation transfer imaging in adults with relapsing-remitting multiple sclerosis (with or without healthy controls) were included.

Data including sample size, magnetic field strength, MRI acquisition protocol parameters, treatments and clinical findings were extracted and qualitatively synthesised. Where possible, effect sizes were calculated for meta-analyses to determine magnetisation transfer (1) differences between patients and healthy controls; (2) longitudinal change; and, (3) relationships with clinical disability in relapsing-remitting multiple sclerosis.

Eighty-six studies met the inclusion/exclusion criteria. MRI acquisition parameters varied widely, and were also underreported. The majority of studies examined MTR (magnetisation transfer ratio) in white matter, but magnetisation transfer metrics, brain regions and results were heterogeneous. Analysis demonstrated a risk of bias due to selective reporting and small sample sizes.

A random-effects meta-analysis revealed MTR was 1.1 percent units [95% CI -1.47pu to -0.73pu] lower in relapsing-remitting multiple sclerosis than healthy controls (z-value: -6.04, p<0.001, n=23). Linear mixed-model analysis did not show a significant longitudinal change in MTR across all brain regions ({beta}=-0.14 [-0.9 to 0.61], t-value=-0.38, p=0.71, n=13) or normal-appearing white matter alone ({beta}=-0.082 [-0.13 to -0.29], t-value=0.78, p=0.44, n=7). There was a significant negative association between MTR and clinical disability, as assessed by the Expanded Disability Status Scale (r=-0.30 [95% CI -0.48 to -0.08]; z-value=-2.91, p=0.01, n=8).

Evidence suggests that magnetisation transfer imaging is sensitive to pathological changes in relapsing-remitting multiple sclerosis, although the effect of relapsing-remitting multiple sclerosis on magnetisation transfer metrics in different brain tissue types was small in comparison to the inter-study variability. Recommended improvements include: the use of techniques such as MTsat (magnetisation transfer saturation) or ihMTR (inhomogeneous MTR) which provide more robust and specific microstructural measures within clinically feasible acquisition times; detailed methodological reporting standards; and larger, demographically diverse cohorts for comparison, including healthy controls.

Abbreviated SummaryYork et al. systematically reviewed 86 studies of magnetisation transfer (MT) brain imaging in relapsing-remitting multiple sclerosis. MT was reduced in patients compared with controls, but results were highly variable, longitudinal change subtle, and associations with clinical disability weak. Use of better harmonised MT acquisition in large cohorts is warranted.

category: radiology and imaging


title: Breaching the curation bottleneck with human-machine reading symbiosis

abstract:
PurposeThe explosion of molecular biomarker and treatment information in the precision medicine era drastically exacerbated difficulty in identifying patient-relevant knowledge for clinical researchers and practitioners. Curated knowledgebases, such as the JAX Clinical Knowledgebase (CKB) are tools to organize and display knowledge in a readily accessible format; however, curators face the same challenges in comprehensively identifying clinically relevant information for curation. Natural language processing (NLP) has emerged as a promising direction for accelerating manual curation, but prior applications were often conceived as stand-alone efforts to automate curation, and the scope is often limited to simple entity and relation extraction. In this paper, we study the alternative paradigm of assisted curation and identify key desiderata to scale up knowledge curation with human-computer symbiosis.

MethodsWe chose precision oncology for a case study and introduced self-supervised machine reading, which can automatically generate noisy training examples from unlabeled text. We developed a curation user interface (UI) for precision oncology and through iterative "curathons" (curation hackathons), conducted retrospective and prospective user studies for head-to-head comparison between manual and machine-assisted curation.

ResultsContrary to the prevailing assumption, we showed that high recall is more important for end-to-end assisted curation. In extensive user studies, we showed that assisted curation can double the curation speed and increase the number of findings by an order of magnitude for previously scarcely curated drugs.

ConclusionWe demonstrated that an iterative and thoughtful collaboration between professional curators and NLP researchers can facilitate rapid advances in assisted curation for precision medicine. Human-machine reading symbiosis can potentially be applicable to clinical care and research scenarios where curation is a major bottleneck.

category: health informatics


title: SARS-CoV-2 Antibody Lateral Flow Assay for antibody prevalence studies following vaccine roll out: a Diagnostic Accuracy Study

abstract:
BackgroundLateral flow immunoassays (LFIAs) have the potential to deliver affordable, large scale antibody testing and provide rapid results without the support of central laboratories. As part of the development of the REACT programme extensive evaluation of LFIA performance was undertaken with individuals following natural infection. Here we assess the performance of the selected LFIA to detect antibody responses in individuals who have received at least one dose of SARS-CoV-2 vaccine.

MethodsThis is a prospective diagnostic accuracy study.

SettingSampling was carried out at renal outpatient clinic and healthcare worker testing sites at Imperial College London NHS Trust. Laboratory analyses were performed across Imperial College London sites and university facilities.

ParticipantsTwo cohorts of patients were recruited; the first was a cohort of 108 renal transplant patients attending clinic following SARS-CoV-2 vaccine booster, the second cohort comprised 40 healthcare workers attending for first SARS-CoV-2 vaccination, and 21 day follow up. A total of 186 paired samples were collected.

InterventionsDuring the participants visit, capillary blood samples were analysed on LFIA device, while paired venous sampling was sent for serological assessment of antibodies to the spike protein (anti-S) antibodies. Anti-S IgG were detected using the Abbott Architect SARS-CoV-2 IgG Quant II CMIA.

Main outcome measuresThe accuracy of Fortress LFIA in detecting IgG antibodies to SARS-CoV-2 compared to anti-spike protein detection on Abbott Assay.

ResultsUsing the threshold value for positivity on serological testing of [≥]7.10 BAU/ml, the overall performance of the test produces an estimate of sensitivity of 91.94% (95% CI 85.67% to 96.06%) and specificity of 93.55% (95% CI 84.30% to 98.21%) using the Abbott assay as reference standard.

ConclusionsFortress LFIA performs well in the detection of antibody responses for intended purpose of population level surveys, but does not meet criteria for individual testing.


title: Predictors of Arterial Stiffness in Adolescents and Adults with Type 1 Diabetes: A Cross-Sectional Study

abstract:
IntroductionIndividuals with type 1 diabetes have increased arterial stiffness compared to age-matched healthy controls. Our aim was to determine which hemodynamic and demographic factors predict arterial stiffness in this population.

Research Design and MethodsCarotid-femoral pulse wave velocity (cfPWV) was examined in 41 young adults and adolescents with type 1 diabetes without microvascular complications. Two ordinary least squares regression analyses were performed to determine multivariate relationships between cfPWV [loge] and: 1) age, duration of diabetes, sex, and HbA1c, and 2) augmentation index (AIx), mean arterial pressure, flow-mediated dilation (FMD), and heart rate. We also examined differences in macrovascular outcome measures between sexes.

ResultsAge, sex, and FMD provided unique predictive information about cfPWV in these participants with type 1 diabetes. Despite having similar cardiovascular risk factors, males had higher cfPWV compared to females but no differences were observed in other macrovascular outcomes (including FMD and AIx).

ConclusionsOnly age, sex, and FMD were uniquely associated with arterial stiffness in adolescents and adults with uncomplicated type 1 diabetes. Females had less arterial stiffness and similar nitric-oxide dependent endothelial function compared to males. Larger, prospective investigation is warranted to determine the temporal order of and sex-differences in arterial dysfunction in type 1 diabetes.

Significance of this studyO_ST_ABSWhat is already known about this subject?C_ST_ABSO_LIA measure of central artery stiffness, carotid-femoral pulse wave velocity (cfPWV) predicts renal outcomes, cardiovascular events, and mortality in persons with type 1 diabetes.
C_LIO_LIAge, race, mean arterial pressure, waist-to-height ratio/body mass index, presence of microalbuminuria have all been uniquely associated with cfPWV in populations with type 1 diabetes.
C_LIO_LIThe relationship between cfPWV and flow mediated dilation (FMD), a measure of nitric oxide dependent endothelial function at the brachial artery, has not been defined in type 1 diabetes, and the relationship between diabetes duration and these vascular measures are unclear.
C_LI

What are the new findings?O_LIArterial stiffness and NO-dependent endothelial dysfunction were highly prevalent even within 5 years of diabetes diagnosis (16.7% and 83.3% respectively) in this cohort of adolescents and adults with uncomplicated type 1 diabetes.
C_LIO_LIFMD was uniquely associated with cfPWV.
C_LIO_LIAugmentation index (AIx), mean arterial pressure, and diabetes duration were not predictive of cfPWV.
C_LIO_LIDespite a greater excess cardiovascular risk associated with type 1 diabetes in females compared to males, macrovascular function was no worse in females when examining sex differences. Females had a lower cfPWV and similar AIx and FMD compared to males.
C_LI

How might these results change the focus of research or clinical practice?O_LILarger, prospective clinical investigation is needed in type 1 diabetes to determine the temporal order of and sex-differences in arterial dysfunction.
C_LI

category: endocrinology


title: Emergence of SARS-CoV-2 Alpha (B.1.1.7) variant, infection rates, antibody seroconversion and seroprevalence rates in secondary school students and staff: active prospective surveillance, December 2020 to March 2021, England

abstract:
BackgroundIn England, the rapid spread of the SARS-Cov-2 Alpha (B.1.1.7) variant from November 2020 led to national lockdown, including school closures in January 2021. We assessed SARS-CoV-2 infection, seroprevalence and seroconversion in students and staff when secondary schools reopened in March 2021.

MethodsPublic Health England initiated SARS-CoV-2 surveillance in 18 secondary schools across six regions in September 2020. Participants provided nasal swabs for RT-PCR and blood samples for SARS-CoV-2 antibodies at the beginning (September 2020) and end (December 2020) of the autumn term and at the start of the spring term (March 2021).

FindingsIn March 2021, 1895 participants (1100 students, 795 staff) were tested; 5.6% (61/1094) students and 4.4% (35/792) staff had laboratory-confirmed SARS-CoV-2 infection between December 2020 and March 2021. Nucleoprotein antibody seroprevalence was 36.3% (370/1018) in students and 31.9% (245/769) in staff, while spike protein antibody prevalence was 39.5% (402/1018) and 59.8% (459/769), respectively, similar to regional community seroprevalence. Between December 2020 and March 2021 (median 15.9 weeks), 14.8% (97/656; 95% CI: 12.2-17.7) students and 10.0% (59/590; 95% CI: 7.7-12.7) staff seroconverted. Weekly seroconversion rates were similar from September to December 2020 (8.0/1000) and from December 2020 to March 2021 (7.9/1000; students: 9.3/1,000; staff: 6.3/1,000).

InterpretationBy March 2021, a third of secondary school students and staff had serological evidence of prior infection based on N-antibody seropositivity, and an additional third of staff had evidence of vaccine-induced immunity based on S-antibody seropositivity. Further studies are needed to assess the impact of the Delta variant.

Research in ContextO_ST_ABSEvidence Before this studyC_ST_ABSThe Alpha variant is 30-70% more transmissible than previously circulating SARS-CoV-2 strains in adults and children. One outbreak investigation in childcare settings estimated similar secondary attack rates with the Alpha variant in children and adults. There are limited data on the impact of the Alpha variant in educational settings. In England, cases in primary and secondary school aged children increased rapidly from late November 2020 and peaked at the end of December 2020, leading to national lockdown including school closures.

Added Value of This StudySeroconversion rates in staff and students during December 2020 to March 2021, when the Alpha variant was the primary circulating strain in England, were similar to the period between September 2020 and December 2020 when schools were fully open for in-person teaching. By March 2021, a third of students overall and more than half the students in some regions were seropositive for SARS-CoV-2 antibodies. Among staff, too, around a third had evidence of prior infection on serological testing and a further third had vaccine-induced immunity.

Implications of all the Available EvidenceSARS-CoV-2 antibody seroprevalence was high among secondary school students in March 2021 and is likely to be higher following the emergence of an even more transmissible Delta variant in May 2021. Education staff are increasingly being protected by the national COVID-19 immunisation programme. These findings have important implications for countries that are considering vaccination of children to control the pandemic

category: epidemiology


title: The Specchio-COVID19 cohort study: a longitudinal follow-up of SARS-CoV-2 serosurvey participants in the canton of Geneva, Switzerland (Study protocol)

abstract:
BackgroundThe COVID-19 pandemic has affected billions of people around the world both directly through the infection itself and indirectly through its economic, social and sanitary impact. Collecting data over time is essential for the understanding of the disease spread, the incidence of COVID19-like symptoms, the level and dynamics of immunity, as well as the long-term impact of the pandemic.

ObjectiveThe objective of the study was to set up a longitudinal follow-up of adult participants of serosurveys carried out in the Canton of Geneva, Switzerland, during the COVID-19 pandemic.

MethodsSerosurvey participants were invited to create an account on the dedicated digital platform Specchio-COVID19 (https://www.specchio-covid19.ch/). Upon registration, an initial questionnaire assessed socio-demographic and lifestyle characteristics (including housing conditions, physical activity, diet, alcohol and tobacco consumption), anthropometry, general health, and experience related to COVID-19 (symptoms, COVID-19 test results, quarantines, hospitalizations). Weekly, participants were invited to fill in a short questionnaire with updates on self-reported COVID-19-compatible symptoms, SARS-CoV-2 infection testing and vaccination. A more detailed questionnaire about mental health, well-being, risk perception, and changes in working conditions was proposed monthly. Supplementary questionnaires were proposed at regular intervals to assess more in depth the impact of the pandemic on physical and mental health, vaccination adherence, health care consumption and changes in health behaviors. At baseline, serology testing allowed to assess the spread of SARS-CoV-2 infection among the general population and subgroups of workers. Additionally, seropositive participants and a sample of randomly selected participants were invited for serologic testing at regular intervals in order to monitor both the seropersistance of anti-SARS-CoV-2 antibodies and the seroprevalence of anti-SARS-CoV-2 antibodies in the population of the Canton of Geneva.

Ethics and disseminationThe study was approved by the Cantonal Research Ethics Commission of Geneva, Switzerland (CCER Project ID 2020-00881). Results will be disseminated in a variety of ways, via the Specchio-COVID19 platform, social media posts, press releases, and through regular scientific dissemination methods (open-access articles, conferences).

Article summaryO_ST_ABSStrengths and limitationsC_ST_ABSO_LIThis is a large study with a diversified recruitment among the general population and mobilized workers. It will contribute to obtain a clearer picture of the impact of the COVID-19 pandemic, for both the general population and targeted subpopulations.
C_LIO_LIA major strength of the study is the combined use of serological testing and questionnaires. While regular serological testing will help us to model evolution of the pandemic, self-reported data on socioeconomic characteristics, COVID-19-compatible symptoms, and general and mental health will allow us to monitor the progression of the COVID-19 pandemic as well as to thoroughly analyze its effects on several dimensions of health.
C_LIO_LIThe longitudinal component of the study will provide insight into the extent and duration of immunity, as well as the long-term impact of the pandemic and the sanitary, social and economic measures associated with it.
C_LIO_LIThe main limitation is that Specchio-COVID19 is based on self-reports with a risk of information bias. However, considering the pandemic context, participants are generally engaged to participate and to contribute to COVID-19 research. Further, at least half of the sample is based on random selection in the general population.
C_LIO_LIThe study is primarily being conducted online, which may limit the generalizability of the findings, especially for the elderly and vulnerable populations, although internet access is extensive in Switzerland. Nonetheless, participants can use paper questionnaires to contribute to the major assessments.
C_LI


title: SARS-CoV-2 variants of concern, Gamma (P.1) and Delta (B.1.617), sensitive detection and quantification in wastewater employing direct RT-qPCR

abstract: SARS-CoV-2 variants of concern present a worldwide threat. Demonstrating higher infection rate and durability to antibodies when compared to the original SARS-CoV-2 virus, the variants of concern are responsible for continuing global outbreaks. Prompt identification of the infecting SARS-CoV-2 variant is essential for pandemic assessment and containment. However, variant identification is mainly being performed using expensive, time-consuming next generation sequencing. Rapid identification methodology for variants of concern is of great need and various variant-specific assays are being developed. Amongst the variants of concern that have recently appeared, the Gamma variant (P.1, Brazilian) and Delta variant (B.1.617, Indian) are the most prominent. Here we describe the development of a sensitive RT-qPCR assay for the quick direct detection of the Gamma and Delta variants as part of a methodical characterization and detection in municipal wastewater.


title: London Ramadan Fasting Study (LORANS): Rationale, design, and methods

abstract:
BackgroundHundreds of millions of Muslims fast during the month of Ramadan. The London Ramadan Fasting Study (LORANS) aims to assess the lifestyle changes during this month and investigate the effect of Ramadan fasting on health.

MethodsLORANS is an observational study of participants that follow religious fasting in Ramadan. We advertised, recruited, and visited participants in five mosques in London, United Kingdom. In total, 146 individuals were recruited before Ramadan in May 2019 of which 85 participated in the follow up visit after Ramadan. The study protocol was approved by the ethics committee affiliated to Imperial College London. A written informed consent was signed by all the participants. Every participant completed a questionnaire, a physical examination, and gave blood samples at each visit. Moreover, they completed a 3-day food diary before Ramadan and once again during Ramadan to record dietary changes during the month of fasting.

ResultsThe mean age of participants was 45.6{+/-} 15.9 years. 47.1% of the participants were females, 25.5% were obese, 4.7% were smokers, 14% were diabetic, 24% were hypertensive, and 5.2% had cardiovascular diseases. Data collection covered demographics, lifestyle, food intake, blood pressure, anthropometric measurements, body composition, and metabolic biomarker profiling.

ConclusionBy engaging with mosques, proper introduction of the study aims and convenient recruitment in the mosque, we were able to recruit a balanced population regarding age and sex and collected valuable data on Ramadan fasting using high-quality techniques.

category: public and global health


title: Quantifying within-school SARS-CoV-2 transmission and the impact of lateral flow testing in secondary schools in England

abstract:
BackgroundTo control within-school SARS-CoV-2 transmission in England, secondary school pupils have been encouraged to participate in twice weekly mass testing via lateral flow device tests (LFTs) from 8th March 2021, to complement an isolation of close contacts policy in place since 31st August 2020. Strategies involving the isolation of close contacts can lead to high levels of absences, negatively impacting pupils.

MethodsWe fit a stochastic individual-based model of secondary schools to both community swab testing data and secondary school absences data. By simulating epidemics in secondary schools from 31st August 2020 until 21st May 2021, we quantify within-school transmission of SARS-CoV-2 in secondary schools in England, the impact of twice weekly mass testing on within-school transmission, and the potential impact of alternative strategies to the isolation of close contacts in reducing pupil absences.

FindingsThe within-school reproduction number, Rschool, has remained below 1 from 31st August 2020 until 21st May 2021. Twice weekly mass testing using LFTs have helped to control within-school transmission in secondary schools in England. A strategy of serial contact testing alongside mass testing substantially reduces absences compared to strategies involving isolating close contacts, with only a marginal increase in within-school transmission.

InterpretationSecondary school control strategies involving mass testing have the potential to control within-school transmission while substantially reducing absences compared to an isolation of close contacts policy.


title: On the forecastability of food insecurity

abstract: Food insecurity, defined as the lack of physical or economic access to safe, nutritious and sufficient food, remains one of the main challenges included in the 2030 Agenda for Sustainable Development. Near real-time data on the food insecurity situation collected by international organizations such as the World Food Programme can be crucial to monitor and forecast time trends of insufficient food consumption levels in countries at risk. Here, using food consumption observations in combination with secondary data on conflict, extreme weather events and economic shocks, we build a forecasting model based on gradient boosted regression trees to create predictions on the evolution of insufficient food consumption trends up to 30 days in to the future in 6 countries (Burkina Faso, Cameroon, Mali, Nigeria, Syria and Yemen). Results show that the number of available historical observations is a key element for the forecasting model performance. Among the 6 countries studied in this work, for those with the longest food insecurity time series, the proposed forecasting model makes it possible to forecast the prevalence of people with insufficient food consumption up to 30 days into the future with higher accuracy than a naive approach based on the last measured prevalence only. The framework developed in this work could provide decision makers with a tool to assess how the food insecurity situation will evolve in the near future in countries at risk. Results clearly point to the added value of continuous near real-time data collection at sub-national level.

category: nutrition


title: Vaccine Confidence and Hesitancy at the start of COVID-19 vaccine deployment in the UK: An embedded mixed-methods study

abstract:
IntroductionApproval for the use of COVID-19 vaccines has been granted in a number of countries but there are concerns that vaccine uptake may be low amongst certain groups.

MethodsThis study used a mixed methods approach based on online survey and an embedded quantitative/qualitative design to explore perceptions and attitudes that were associated with intention to either accept or refuse offers of vaccination in different demographic groups during the early stages of the UKs mass COVID-19 vaccination programme (December 2020). Analysis used multivariate logistic regression, structural text modelling and anthropological assessments.

ResultsOf 4,535 respondents, 85% (n=3,859) were willing to have a COVID-19 vaccine. The rapidity of vaccine development and uncertainties about safety were common reasons for COVID-19 vaccine hesitancy. There was no evidence for the widespread influence of mis-information, although broader vaccine hesitancy was associated with intentions to refuse COVID-19 vaccines (OR 20.60, 95% CI 14.20-30.30, p<0.001). Low levels of trust in the decision-making (OR 1.63, 95% CI 1.08, 2.48, p=0.021) and truthfulness (OR 8.76, 95% CI 4.15-19.90, p<0.001) of the UK government were independently associated with higher odds of refusing COVID-19 vaccines. Compared to political centrists, conservatives and liberals were respectively more (OR 2.05, 95%CI 1.51-2.80, p<0.001) and less (OR 0.30, 95% CI 0.22-0.41, p<0.001) likely to refuse offered vaccines. Those who were willing to be vaccinated cited both personal and public protection as reasons, with some alluding to having a sense of collective responsibility.

ConclusionDominant narratives of COVID-19 vaccine hesitancy are misconceived as primarily being driven by misinformation. Key indicators of UK vaccine acceptance include prior behaviours, transparency of the scientific process of vaccine development, mistrust in science and leadership and individual political views. Vaccine programmes should leverage the sense of altruism, citizenship and collective responsibility that motivated many participants to get vaccinated.


title: Biallelic TET2 mutation sensitizes to 5-azacitidine in acute myeloid leukemia

abstract:
Precision medicine can significantly improve outcomes for cancer patients, but implementation requires comprehensive characterization of tumor cells to identify therapeutically exploitable vulnerabilities. Here we describe somatic biallelic TET2 mutation (focal deletion and nonsense mutation) in an elderly patient with acute myeloid leukemia (AML) that was chemoresistant to anthracycline and cytarabine, but acutely sensitive to 5-azacitidine (5-Aza) hypomethylating monotherapy, resulting in long-term morphological remission (overall survival (OS) 850 days). Given the role of TET2 as a regulator of genomic methylation, we hypothesized that mutant TET2 allele dosage affects response to 5-Aza. Using an isogenic cell model system and an orthotopic mouse xenograft, we demonstrate that biallelic TET2 mutations confer sensitivity to 5-Aza compared to cells with monoallelic mutation. We subsequently identified 29 additional patients from the Study Alliance Leukemia biobank with chromosome 4 abnormalities and identified two further patients with complex biallelic TET2 mutations, including one with trisomy 4, homozygosity across the long arm and an inactivating point mutation. We also screened patients recruited to the PETHEMA FLUGAZA phase 3 clinical trial and identified three patients with biallelic TET2 mutations, two of whom had responded very well to single agent 5-Aza (OS 767 and 579 days) despite having adverse risk AML and poor performance status. Our data argue in favor of using hypomethylating agents for chemoresistant disease or as first line therapy in patients with biallelic TET2-mutated AML and demonstrate the importance of considering mutant allele dosage in the implementation of precision medicine for cancer patients.

Key PointsO_LIMutant TET2 allele dosage affects response to 5-azacitidine in acute myeloid leukemia in vitro and in a xenograft model.
C_LIO_LIOur data highlight the importance for screening of biallelic mutations to predict response to therapy in acute myeloid leukemia.
C_LI


title: Sequencing SARS-CoV-2 in Slovakia: An Unofficial Genomic Surveillance Report

abstract: We present an unofficial SARS-CoV-2 genomic surveillance report from Slovakia based on approximately 3500 samples sequenced between March 2020 and May 2021. Early samples show multiple independent imports of SARS-CoV-2 from other countries. In Fall 2020, three virus variants (B.1.160, B.1.1.170, B.1.258) dominated as the number of cases increased. In November 2020, B.1.1.7 (alpha) variant was introduced in Slovakia and quickly became the most prevalent variant in the country (> 75% of new cases by early February 2021 and > 95% in mid-March).


title: The integration of genetically-regulated transcriptomics and electronic health records highlights a pattern of medical outcomes related to increased hepatic Transthyretin expression

abstract:
BackgroundTransthyretin (TTR) is a multi-function protein involved in the systemic transport of retinol and thyroxine. It also participates in the neuronal response to stress and proteolysis of few specific substrates. TTR is also the precursor of the fibrils that compromise organ function in the familial and sporadic systemic amyloidoses (ATTR). RNA-interference and anti-sense therapeutics targeting TTR hepatic transcription have been shown to reduce TTR amyloid formation. The goal of our study was to investigate the role of genetic regulation of TTR transcriptomic variation in human traits and diseases.

Methods and FindingsWe leveraged genetic and phenotypic information from the UK Biobank and transcriptomic profiles from the GTEx (Genotype-Tissue Expression) project to test the association of genetically regulated TTR gene expression with 7,149 traits assessed in 420,531 individuals. We conducted a joint multi-tissue analysis of TTR transcription regulation and identified an association with a specific operational procedure related to secondary open reduction of fracture of bone (p=5.46x10-6, false discovery rate q=0.039). Using tissue-specific TTR cis expression quantitative trait loci, we demonstrated that the association is driven by the genetic regulation of TTR hepatic expression (odds ratio [OR] = 3.46, 95% confidence interval [CI] = 1.85-6.44, p = 9.51x10-5). Although there is an established relationship of retinol and thyroxine abnormalities with bone loss and the risk of bone fracture, this is the first evidence of a possible effect of TTR transcriptomic regulation. Investigating the UK Biobank electronic health records available, we investigated the comorbidities affecting individuals undergoing the specific surgical procedure. Excluding medical codes related to bone fracture events, we identified a pattern of health outcomes that have been previously associated with ATTR manifestations. These included osteoarthritis (OR=3.18, 95%CI=1.93-4.25, p=9.18x10-8), carpal tunnel syndrome (OR=2.15, 95%CI=1.33-3.48, p=0.002), and a history of gastrointestinal diseases (OR=2.01, 95%CI=1.33-3.01, p=8.07x10-4).

ConclusionsThe present study supports the notion that TTR hepatic expression can affect health outcomes linked to physiological and pathological processes presumably related to the encoded protein. Our findings highlight how the integration of omics information and electronic health records can successfully dissect the complexity of multi-function proteins such as TTR.

category: genetic and genomic medicine


title: Validation of a Novel Molecular Assay to the Diagnostic of COVID-19 Based on Real Time PCR with High Resolution Melting

abstract: With the emergence of the Covid-19 pandemic, the world faced an unprecedented need for RT-qPCR-based molecular diagnostic tests, leading to a lack of kits and inputs, especially in developing countries. Hence, the costs for commercial kits and inputs were overrated, stimulating the development of alternative methods to detect SARS-CoV-2 in clinical specimens. The availability of the complete SARS-CoV-2 genome at the beginning of the pandemic facilitated the development of specific primers and standardized laboratory protocols for Covid-19 molecular diagnostic. High-sensitive and cost-effective molecular biology technique based on the Melting Temperature differences between purine and pyrimidine bases can be used to the detection and genotyping of pathogens in clinical specimens. Here, a RT-qPCR assays with High Resolution Melting (HRM-RTqPCR) was developed for different regions of the SARS-CoV-2 genome (RdRp, E and N) and an internal control (human RNAse P gene). The assays were validated using synthetic sequences from the viral genome and clinical specimens (nasopharyngeal swabs, serum and saliva) of sixty-five patients with severe or moderate COVID-19 from different states in Brazil, in comparison to a commercial TaqMan RT-qPCR assay, as gold standard. The sensitivity of the HRM-RTqPCR assays targeting N, RdRp and E were 94.12, 98.04 and 92.16%, with 100% specificity to the 3 targets, and diagnostic accuracy of 95.38, 98.46 and 93.85%, respectively. Thus, the HRM-RTqPCR emerges as an alternative and low-cost methodology to increase the molecular diagnostic of patients suspicious for Covid-19, especially in restricted-budget laboratories.


title: Racial Inequalities in Alcohol Use Disorder Diagnosis in a Sample of 700,000 Veterans

abstract:
BackgroundStudies show that Black and Hispanic Veterans have a higher prevalence of alcohol use disorder (AUD) than White Veterans. We examined whether the relationship between self-reported race/ethnicity and AUD diagnosis varies by self-reported alcohol consumption.

MethodsThe sample included 700,013 Black, Hispanic, and White Veterans enrolled in the Million Veteran Program cohort. Alcohol consumption was defined as an individuals maximum score on the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) questionnaire, a screen for hazardous or harmful drinking. The primary outcome, AUD, was defined by the presence of ICD-9/10 codes in the electronic health record. We used logistic regression with interactions to assess the association between race/ethnicity and AUD by maximum AUDIT-C score.

ResultsBlack and Hispanic Veterans were more likely to have an AUD diagnosis than White Veterans despite similar levels of alcohol consumption. The difference was greatest between Black and White men. At all but the lowest and highest levels of alcohol consumption, Black men had 24%-111% greater odds of an AUD diagnosis. The association between race/ethnicity and AUD diagnosis remained after adjustment for alcohol consumption, alcohol-related disorders, and other potential confounders.

ConclusionsThe large discrepancy in AUD diagnosis across groups despite a similar distribution of alcohol consumption measures suggests that Veterans are differentially assigned an AUD diagnosis by race/ethnicity. Efforts are needed to examine the causes of the observed differences and to implement changes, such as structured diagnostic methods, to address a likely contributor to racial differences (i.e., bias) in AUD diagnosis.


title: Sex-specific differences in resting-state functional brain activity in pediatric concussion.

abstract:
ImportancePediatric concussion has a rising incidence and can lead to long-term symptoms in nearly 30% of children. Resting state functional magnetic resonance imaging (rs-fMRI) disturbances are a common pathological feature of concussion, though no studies have examined sex-differences with respect to this outcome. Despite known sex-differences in how pediatric concussion presents, females have remained understudied in rs-fMRI studies, precluding a sex-specific understanding of the functional neuropathology of pediatric concussion.

ObjectiveTo provide the first insights into sex-specific rs-fMRI differences in pediatric concussion.

Design, setting, and participantsSecondary data analysis of rs-fMRI data collected on children with concussion recruited from in a pediatric hospital setting, with control data accessed from the open-source ABIDE-II database. In total, 27 children with concussion (14 females) approximately one-month post-injury and 1:1 age- and sex-matched healthy controls comprised our sample.

ExposurePatients received a physician diagnosis of concussion. ABIDE-II healthy controls were typically developing.

Main outcomes & measuresSeed-based (which permitted an examination of whole-brain connectivity, fitting with the exploratory nature of the present study) and region of interest (ROI) analyses were used to examine sex-based rs-fMRI differences. Threshold-free cluster enhancement (TFCE) and a family-wise error (FWE) corrected p-values were used to identify significantly different clusters.

ResultsIn comparing females with concussion to healthy females, seed-based analyses (in order of largest effect) showed hypo-connectivity between the anterior cingulate cortex of the salience network and the precuneus (TFCE=1173.6, p=FWE=0.002) and cingulate gyrus (TFCE=1039.7, p-FWE=0.008), and the posterior cingulate cortex (PCC) of the default mode network and the paracingulate gyrus (TFCE=870.1, p-FWE=0.015) and sub-callosal cortex (TFCE=795.4, p-FWE=0.037); hyper-connectivity was observed between the lateral pre-frontal cortex and inferior frontal gyrus (TFCE=1215.4, p-FWE=0.002) and lateral occipital cortex (TFCE=854.9, p-FWE=0.020) and between the PCC and cerebellum (TFCE=791.0, p-FWE=0.038). ROI analyses showed primarily patterns of hyper-connectivity in females. No differences were observed between males with concussion and healthy males on seed-based or ROI analyses.

Conclusions and relevanceThere are alterations in rs-fMRI in females with concussion at one-month post-injury that are not present in males, which provides further evidence that recovery timelines in pediatric concussion may differ by sex.

KEY FINDINGSO_ST_ABSQuestionC_ST_ABSAre there sex-differences in resting state functional brain activity in pediatric concussion?

FindingsFemales with concussion show both hyper- and hypo-connectivity between multiple brain regions when compared to healthy age- and sex-matched controls. The same analyses revealed no differences in resting state brain activity when comparing males with concussion to their age- and sex-matched healthy peers.

MeaningThere are sex-differences in resting state brain activity in pediatric concussion. This suggests that the functional neuropathology of the injury differs between males and females, which may account for sex-differences in the clinical presentation of pediatric concussion.

category: pediatrics


title: Sequencing SARS-CoV-2 from Antigen Tests

abstract: Genomic surveillance empowers agile responses to SARS-CoV-2 by enabling scientists and public health analysts to issue recommendations aimed at slowing transmission, prioritizing contact tracing, and building a robust genomic sequencing surveillance strategy. Since the start of the pandemic, real time RT-PCR diagnostic testing from upper respiratory specimens, such as nasopharyngeal (NP) swabs, has been the standard. Moreover, respiratory samples in viral transport media are the ideal specimen for SARS-CoV-2 whole-genome sequencing (WGS). In early 2021, many clinicians transitioned to antigen-based SARS-CoV-2 detection tests, which use anterior nasal swabs for SARS-CoV-2 antigen detection. Despite this shift in testing methods, the need for whole-genome sequence surveillance remains. Thus, we developed a workflow for whole-genome sequencing with antigen test-derived swabs as an input rather than nasopharyngeal swabs. In this study, we use excess clinical specimens processed using the BinaxNOW COVID-19 Ag Card. We demonstrate that whole-genome sequencing from antigen tests is feasible and yields similar results from RT-PCR-based assays utilizing a swab in viral transport media.


title: Powerful gene-based testing by integrating long-range chromatin interactions and knockoff genotypes

abstract:
Gene-based tests are valuable techniques for identifying genetic factors in complex traits. Here we propose a novel gene-based testing framework that incorporates data on long-range chromatin interactions, several recent technical advances for region-based tests, and leverages the knockoff framework for synthetic genotype generation for improved gene discovery. Through simulations and applications to GWAS and whole-genome sequencing data for multiple diseases and traits we show that the proposed test increases the power over state-of-the-art gene-based tests in the literature, identifies genes that replicate in larger studies, and can provide a more narrow focus on the possible causal genes at a locus by reducing the confounding effect of linkage disequilibrium. Furthermore, our results show that incorporating genetic variation in distal regulatory elements tends to improve power over conventional tests. Results for UK Biobank and BioBank Japan traits are also available in a publicly accessible database that allows researchers to query gene-based results in an easy fashion.

SignificanceGene-based tests are important tools for elucidating the genetic basis of complex traits. Despite substantial recent efforts in this direction, the existing tests are still limited owing to low power and detection of false positive signals due to the confounding effects of linkage disequilibrium. In this paper we describe a novel gene-based test that attempts to address these limitations by incorporating data on long-range chromatin interactions, several recent technical advances for region-based testing, and the knockoff framework for synthetic genotype generation. Through extensive simulations and applications to multiple diseases and traits, we show that the proposed test increases the power over state-of-the-art gene-based tests and provides a narrower focus on the possible causal genes involved at a locus.


title: Trans Cohorts Metabolomic Modulation Following Long-Term Successful Therapy in HIV-Infection

abstract: Despite successful combination antiretroviral therapy (cART), persistent low-grade immune activation together with inflammation and toxic antiretroviral drugs can lead to long-lasting metabolic adaptation in people living with HIV (PLWH). The successful short-term cART reported abnormalities in the metabolic reprogramming in PLWH, but the long-term consequences are unknown. This study investigated alterations in the plasma metabolic profiles by comparing PLWH and matched HIV-negative controls (HC) from Cameroon and India. We used untargeted and targeted LC-MS/MS-based metabolic profiling in PLWH with long-term (>5years) successful therapy in a trans cohorts approach. Advanced statistical and bioinformatics analyses showed altered amino acid metabolism, more specifically to glutaminolysis in PLWH with therapy than HIV-negative controls that can lead to excitotoxicity in both the cohorts. A significantly lower level of neurosteroids was observed in both cohorts and could potentiate neurological impairments in PLWH. The modulation of cellular glutaminolysis promoted increased cell death and latency reversal in pre-monocytic HIV-1 latent cell model U1, which may be essential for the clearance of the inducible reservoir in HIV-integrated cells. Our patient-based metabolomics and in vitro study, therefore, highlight the importance of altered glutaminolysis in PLWH that can be linked accelerated neurocognitive aging and metabolic reprogramming in latently infected cells.

category: hiv aids


title: Impact of circulating SARS-CoV-2 variants on mRNA vaccine-induced immunity in uninfected and previously infected individuals

abstract: The emergence of SARS-CoV-2 variants with mutations in major neutralizing antibody-binding sites can affect humoral immunity induced by infection or vaccination1-6. We analysed the development of anti-SARS-CoV-2 antibody and T cell responses in previously infected (recovered) or uninfected (naive) individuals that received mRNA vaccines to SARS-CoV-2. While previously infected individuals sustained higher antibody titers than uninfected individuals post-vaccination, the latter reached comparable levels of neutralization responses to the ancestral strain than previously infected individuals 7 days after the second vaccine dose. T cell activation markers measured upon spike or nucleocapsid peptide in vitro stimulation showed a progressive increase after vaccination in the time-points analysed. Comprehensive analysis of plasma neutralization using 16 authentic isolates of distinct locally circulating SARS-CoV-2 variants revealed a range of reduction in the neutralization capacity associated with specific mutations in the spike gene: lineages with E484K and N501Y/T (e.g., B.1.351 and P.1) had the greatest reduction, followed by lineages with L452R (e.g., B.1.617.2) or with E484K (without N501Y/T). While both groups retained neutralization capacity against all variants, plasma from previously infected vaccinated individuals displayed overall better neutralization capacity when compared to plasma from uninfected individuals that also received two vaccine doses, pointing to vaccine boosters as a relevant future strategy to alleviate the impact of emerging variants on antibody neutralizing activity.


title: Vaccine uptake and SARS-CoV-2 antibody prevalence among 207,337 adults during May 2021 in England: REACT-2 study

abstract:
BackgroundThe programme to vaccinate adults in England has been rapidly implemented since it began in December 2020. The community prevalence of SARS-CoV-2 anti-spike protein antibodies provides an estimate of total cumulative response to natural infection and vaccination. We describe the distribution of SARS-CoV-2 IgG antibodies in adults in England in May 2021 at a time when approximately 7 in 10 adults had received at least one dose of vaccine.

MethodsSixth round of REACT-2 (REal-time Assessment of Community Transmission-2), a cross-sectional random community survey of adults in England, from 12 to 25 May 2021; 207,337 participants completed questionnaires and self-administered a lateral flow immunoassay test producing a positive or negative result.

ResultsVaccine coverage with one or more doses, weighted to the adult population in England, was 72.9% (95% confidence interval 72.7-73.0), varying by age from 25.1% (24.5-25.6) of those aged 18 to 24 years, to 99.2% (99.1-99.3) of those 75 years and older. In adjusted models, odds of vaccination were lower in men (odds ratio [OR] 0.89 [0.85-0.94]) than women, and in people of Black (0.41 [0.34-0.49]) compared to white ethnicity. There was higher vaccine coverage in the least deprived and highest income households. People who reported a history of COVID-19 were less likely to be vaccinated (OR 0.61 [0.55-0.67]). There was high coverage among health workers (OR 9.84 [8.79-11.02] and care workers (OR 4.17 [3.20-5.43]) compared to non-key workers, but lower in hospitality and retail workers (OR 0.73 [0.64-0.82] and 0.77 [0.70-0.85] respectively) after adjusting for age and key covariates.

The prevalence of antibodies (weighted to the adult population of England and adjusted for test characteristics) was 61.1% (95% CI 60.9-61.4), up from 6.6% (5.4-5.7) in round 4 (27 October to 10 November 2020) and 13.9% (13.7-14.1) in round 5 (26 January to 8 February 2021). Prevalence (adjusted and weighted) increased with age, from 35.8% (35.1-36.5) in those aged 18 to 24 years, to 95.3% (94.6-95.9) in people 75 and over. Antibodies were 30% less likely to be detected in men than women (adjusted OR 0.69, 0.68-0.70), and were higher in people of Asian (OR 1.67 [1.58-1.77]), Black (1.55 [1.41-1.69]), mixed 1.17 [1.06-1.29] and other (1.37 [1.23-1.51]) ethnicities compared with white ethnicity. Workers in hospitality (OR 0.69 [0.63-0.74]) and retail (0.71 [0.67-0.75]) were less likely to have antibodies.

Following two doses of Pfizer-BioNTech vaccine, antibody positivity (adjusted for test performance) was 100% (100-100) at all ages except 80 years and older when it was 97.8% (95.9-99.6). For AstraZeneca positivity was over 90% up to age 69, and then 89.2% (88.5-89.9) in 70-79 year olds and 83.6% (78.5-88.3) in those aged 80 and over. Following a single dose of Pfizer-BioNTech positivity ranged from 100.0% (91.1-100.0) in those aged 18-29 to 32.2% (18.2-51.1) in those aged 70-79 years. For AstraZeneca this was 72.2% (68.5-75.9) in the youngest and 46.2% (40.0-52.7) in the oldest age group.

DiscussionThe successful roll out of the vaccination programme in England has led to a high proportion of individuals having detectable antibodies, particularly in older age groups and those who have had two doses of vaccine. This is likely to be associated with high levels of protection from severe disease, and possibly from infection. Nonetheless, there remain some key groups with a lower prevalence of antibody, notably unvaccinated younger people, certain minority ethnic groups, those living in deprived areas and workers in some public facing employment. Obtaining improved rates of vaccination in these groups is essential to achieving high levels of protection against the virus through population immunity.

FundingDepartment of Health and Social Care in England.


title: Cortical function and sensorimotor plasticity predict future low back pain after an acute episode: the UPWaRD prospective cohort study

abstract: Predicting the development of chronic low back pain (LBP) at the time of an acute episode remains challenging. The Understanding persistent Pain Where it ResiDes (UPWaRD) study aimed to identify neurobiological and psychological risk factors for chronic LBP. Individuals with acute LBP (N=120) participated in a prospective cohort study with six-month follow-up. Candidate predictors were selected from the neurobiological (e.g. sensorimotor cortical excitability assessed by sensory and motor evoked potentials, Brain Derived Neurotrophic Factor genotype), psychological (e.g. depression and anxiety), symptom-related (e.g. LBP history) and demographic domains. Analyses involved multivariable linear regression models with pain intensity or disability degree as continuous variables. Secondary analyses involved a multivariable logistic model with presence of low back pain at six months (thresholding pain intensity and disability degree) as a dichotomous variable. Lower sensory cortex and corticomotor excitability, higher baseline pain intensity, higher depression, stress and pain catastrophizing were the strongest predictors (R2=0.47) of pain intensity at six months. Older age and higher pain catastrophizing were the strongest predictors (R2=0.30) of disability at six months. When LBP outcome was dichotomised, sensory cortex and corticomotor excitability, BDNF genotype, depression and anxiety, LBP history and baseline pain intensity, accurately discriminated those who did and did not report LBP at six months (c-statistic 0.91). This study identifies novel risk factors for future LBP after an acute episode that can predict an individuals pain intensity and level of disability at six-month follow-up, and accurately discriminate between those who will and will not report LBP at six months.


title: The DiSCover Project: Protocol and Baseline Characteristics of a Decentralized Digital Study Assessing Chronic Pain Outcomes and Behavioral Data

abstract:
BackgroundChronic pain affects approximately 50 million adults in the United States and impacts mood, everyday functioning, and quality of life. The challenges of analgesic clinical trials and, therefore, the approval of new non-opioid analgesics, are based in part on a fundamental lack of understanding of those outcomes that are relevant to an individuals overall functioning.

ObjectivesTo determine the behaviors and health outcomes associated with chronic pain. This manuscript presents an overview of the study design, baseline health and behavioral characteristics of our sample, and preliminary findings of how behavioral characteristics differ between individuals with and without chronic pain.

MethodsThe study is a decentralized digital longitudinal cohort study of 10,036 individuals (5,832 with chronic pain [CP] and 4,204 with no chronic pain [NCP]), age 18 years or older, living in the United States. The study period was one year. Data were collected from wearable activity trackers and health or fitness mobile applications to capture passively collected behavioral data including steps, sleep, and heart rate. Patient-reported outcomes on mood and pain, including the BPI-SF, PHQ-9, and GAD-7, were collected at various timepoints during the study.

ResultsThe data suggest greater levels of depression and anxiety, lower quality of life, less physical activity, more variable sleep, and higher resting heart rate are associated with CP.

ConclusionsThe longitudinal data from the larger study will yield substantial contributions to the body of literature in chronic pain, particularly in delineating relational and causal factors relevant to the impact of chronic pain, and potential development of a digital biomarker to assess and monitor patients everyday experience with chronic pain.


title: A Poisson binomial based statistical testing framework for comprehensive comorbidity discovery across massive Electronic Health Record datasets

abstract: Discovery of comorbidities (the concomitant occurrence of distinct medical conditions in the same patient) is a prerequisite for creating forecasting tools for downstream outcomes research. Current comorbidity discovery applications are designed for small datasets and use stratification to control for confounding variables such as age, sex, or ancestry. Stratification lowers false positive rates, but reduces power, as the size of the study cohort is decreased. Here, we describe a Poisson Binomial based approach to comorbidity discovery (PBC) designed for big-data applications that circumvents the need for stratification. PBC adjusts for confounding demographic variables on a per-patient basis, and models temporal relationships. We benchmark PBC using two datasets, the publicly available MIMIC-IV; and the entire Electronic Health Record (EHR) corpus of the University of Utah Hospital System, encompassing over 1.6 million patients, to compute comorbidity statistics on 4,623,841 pairs of potentially comorbid medical terms. The results of this computation are provided as a searchable web resource. Compared to current methods, the PBC approach reduces false positive associations, while retaining statistical power to discover true comorbidities.


title: Inferring the multiplicity of founder variants initiating HIV-1 infection: a systematic review and individual patient data meta-analysis

abstract:
1.BackgroundHIV-1 infections initiated by multiple founder variants are characterised by a higher viral load and a worse clinical prognosis, yet little is known about the routes of exposure through which multiple variant transmission is most likely, and whether methods of quantifying the number of founder variants differ in their accuracy.

MethodsWe conducted a systematic review of studies that estimated founder variant multiplicity in HIV-1 infection, searching MEDLINE, EMBASE and Global Health databases for papers published between 1st January 1990 and 14th September 2020 (PROSPERO study CRD42020202672). Leveraging individual patient estimates from these studies, we performed a logistic meta-regression to estimate the probability that an HIV infection is initiated by multiple founder variants. We calculated a pooled estimate using a random effects model, subsequently stratifying this estimate across nine transmission routes in a univariable analysis. We then extended our model to adjust for different study methods in a multivariable analysis, recalculating estimates across the nine transmission routes.

FindingsWe included 71 publications in our analysis, comprising 1664 individual patients. Our pooled estimate of the probability that an infection is initiated by multiple founder variants was 0{middle dot}25 (95% CI: 0{middle dot}21-0{middle dot}30), with moderate heterogeneity (Q = 137{middle dot}1, p < {middle dot}001, I2 = 65{middle dot}3%). Our multivariable analysis uncovered differences in the probability of multiple variant infection by transmission route. Relative to a baseline of male-to-female transmission, the probability for female-to-male multiple variant transmission was significantly lower at 0{middle dot}10 (95% CI: 0{middle dot}05-0{middle dot}21), while the probability for people-who-inject-drugs (PWID) transmission was significantly higher at 0{middle dot}29 (0{middle dot}13-0{middle dot}52). There was no significant difference in the probability of multiple variant transmission between male-to-female transmission (0{middle dot}16 (0{middle dot}08-0{middle dot}29)), post-partum mother-to-child (0{middle dot}12 (0{middle dot}02-0{middle dot}51)), pre-partum mother-to-child (0{middle dot}13 (0{middle dot}05-0{middle dot}32)), intrapartum mother-to-child (0.21 (0{middle dot}08-0{middle dot}44)) and men-who-have-sex-with-men (MSM) transmission (0{middle dot}23 (0{middle dot}03-0{middle dot}7)).

InterpretationWe identified PWID transmissions are significantly more likely to result in an infection initiated by multiple founder variants, whilst female-to-male infections are significantly less likely. Quantifying how the routes of HIV infection impact the transmission of multiple variants allows us to better understand how the evolution and epidemiology of HIV-1 determine the clinical picture.

FundingThis study was supported by the MRC Precision Medicine Doctoral Training Programme (ref: 2259239) and a ERC Starting Grant awarded to KEA (award number 757688).

2. Panel: Research in contextO_ST_ABSEvidence before this studyC_ST_ABSThe majority of HIV-1 infections are initiated by a single, genetically homogeneous founder variant. Infections initiated by multiple founders, however, are associated with a significantly faster decline of CD4+ T Cells in untreated individuals, ultimately leading to an earlier onset of AIDS. Through our systematic search of MEDLINE, EMBASE and Global Health databases, we identified 82 studies that classify the founder variant multiplicity of acute HIV infections. As these studies vary in the methodology used to calculate the number of founder variants, it is difficult to evaluate the multiplicity of founder variants across routes of exposure.

Added value of this studyUsing meta-regression, we estimated the probability of multiple founder infections across exposure routes by accounting for variability in methodology between studies. Our multivariable meta-regression adjusted for heterogeneity across study methodology and uncovered differences in the probability that an infection is initiated by multiple founder variants by transmission route, with the probability for female-to-male transmission significantly lower than for male-to-female transmission. By contrast, the probability for transmission among people-who-inject-drugs (PWID) was significantly higher. There was no difference in the probability of multiple founder variant transmission for mother-to-child transmission or men-who-have-sex-with-men (MSM) when compared with male-to-female.

Implications of all the available evidenceBecause HIV-1 infections initiated by multiple founders are associated with a poorer prognosis, determining whether the route of infection affects the probability of transmission of multiple variants will facilitate an improved understanding of how the evolution and epidemiology of HIV-1 determine clinical progression. Our results identify that PWID transmissions are significantly more likely to result in an infection initiated by multiple founder variants compared to male-to-female. This reiterates the need for focussed public health programmes that reduce the burden of HIV-1 in this vulnerable risk group.


title: Predicting Infectivity: Comparing Four PCR-based Assays to Detect Culturable SARS-CoV-2 in Clinical Samples

abstract: With the COVID-19 pandemic caused by SARS-CoV-2 now in its second year, there remains an urgent need for diagnostic testing that can identify infected individuals, particularly those who harbor infectious virus. Various RT-PCR strategies have been proposed to identify specific viral RNA species that may predict the presence of infectious virus, including detection of transcriptional intermediates (e.g. subgenomic RNA [sgRNA]) and replicative intermediates (e.g. negative-strand RNA species). Using a novel primer/probe set for detection of subgenomic (sg)E transcripts, we successfully identified 100% of specimens containing culturable SARS-CoV-2 from a set of 126 clinical samples (total sgE CT values ranging from 12.3-37.5). This assay showed superior performance compared to a previously published sgRNA assay and to a negative-strand RNA assay, both of which failed to detect target RNA in a subset of samples from which we isolated live virus. In addition, total levels of viral RNA (genome, negative-strand, and sgE) detected with the WHO/Charite primer-probe set correlated closely with levels of infectious virus. Specifically, infectious virus was not detected in samples with a CT above 31.0. Clinical samples with higher levels of viral RNA also displayed cytopathic effect (CPE) more quickly than those with lower levels of viral RNA. Finally, we found that the infectivity of SARS-CoV-2 samples is significantly dependent on the cell type used for viral isolation, as Vero E6 cells expressing TMRPSS2 extended the analytical sensitivity of isolation by more than 3 CT compared to parental Vero E6 cells and resulted in faster isolation. Our work shows that using a total viral RNA Ct cut-off of >31 or specifically testing for sgRNA can serve as an effective rule-out test for viral infectivity.


title: Comparison of kinetics of immune responses to SARS-CoV-2 proteins in individuals with varying severity of infection and following a single dose of the AZD1222

abstract:
BackgroundWhile there have been many studies characterizing the IgG and IgA responses to different SARS-CoV-2 proteins in individuals with natural infection, the induction of IgG and IgA to different viral proteins in vaccinees have not been extensively studied. Therefore, we sought to investigate the antibody responses to SARS-CoV-2 following natural infection and following a single dose of AZD2221, in Sri Lankan individuals.

MethodsUsing Luminex assays, we characterized the IgG and IgA responses in patients with varying severity of illness and following a single dose of the vaccine at 4 weeks and 12 weeks since onset of illness or following vaccination. Haemagglutination test (HAT) was used to assess the antibodies to the receptor binding domain of SARS-CoV-2 wild type (WT), B.1.1.7, B.1.351 and B.1.617.2 (VOCs) and surrogate neutralizing test to measure ACE2 receptor blocking antibodies.

ResultsThose with mild illness and in vaccinees, the IgG responses to S1, S2, RBD and N protein increased from 4 weeks to 12 weeks, while it remained unchanged in those with moderate/severe illness. Those who had a febrile illness in 2017 and 2018 (controls) also gave IgG and IgA high responses to the S2 subunit. In the vaccinees, the most significant rise was seen for the IgG antibodies to the S2 subunit (p<0.0001). Vaccinees had several fold lower IgA antibodies to all the SARS-CoV-2 proteins tested than those with mild and moderate/severe illness at 4 weeks and 12 weeks. At 12 weeks the HAT titres were significantly lower to the B.1.1.7 in vaccinees and significantly lower in those with mild illness, and in vaccinees to B.1.351 and for B.1.617.2. No such difference was seen in those with moderate/severe illness.

ConclusionsVaccinees had significantly less IgA to SARS-CoV-2, but comparable IgG responses to those with natural infection. However, following a single dose, vaccinees had reduced antibody levels to the variants of concern (VOC), which further declined with time, compared to natural infection.

category: allergy and immunology


title: Lives saved and hospitalizations averted by COVID-19 vaccination in New York City

abstract: Despite the emergence of highly transmissible variants, the number of cases in NYC has fallen from over 5,500 average daily cases in January, 2020 to less than 350 average daily cases in July, 2021. The impact of vaccination in saving lives and averting hospitalizations in NYC has not been formally investigated yet. We used an age-stratified agent-based model calibrated to COVID-19 transmission and vaccination in NYC to evaluate the impact of the vaccination campaign in suppressing the COVID-19 burden. We found that the vaccination campaign has prevented over 250,000 COVID-19 cases, 44,000 hospitalizations and 8,300 deaths from COVID-19 infection since the start of vaccination through July 1, 2021. Notably, the swift vaccine rollout suppressed another wave of COVID-19 that would have led to sustained increase in cases, hospitalizations and deaths during spring triggered by highly transmissible variants. As the Delta variant sweeps across the city, the findings of this study underscore the urgent need to accelerate vaccination and close the vaccine coverage gaps across the city.


title: Gender Based Differences in Risks and Comorbidities in Patients Hospitalized with Acute Exacerbation of COPD: A Retrospective Observational study in Eastern-Nepal

abstract:
BackgroundAcute Exacerbation of Chronic Obstructive Pulmonary Disease (AECOPD) share a complex relationship with gender, risk, and co-morbidities. There is paucity of data on the gender-based differences in the prevalence of risks and co-morbidities in AECOPD in Nepal.

MethodsWe performed a retrospective cross-sectional study where data were collected from medical records of adult patients (age >40 years), hospitalized with clinical diagnosis of AECOPD in a tertiary level University hospital in eastern Nepal from April 15, 2014 to October 15, 2014 were included. Data analysis was performed by using SPSS software (Version 26.0, 2020; SPSS Inc., Chicago, IL).

ResultsOf the 256 patients with the primary diagnosis of AECOPD, mean age was 69 years and 65.63% (n=168) of hospitalizations were female population. Compared to males, 64.32 % (n=137) of active smokers were females p= 0.299, 76.19% (n=32) of diabetics were females p= 0.155, 72.86% (n=51) of hypertensive were females, p= 0.143, 50% (n= 6) of underlying Atrial fibrillation were in females p= 0.350, 57.50% (n= 23) of anemics were females p= 0.278, 100% (n= 3) of asthmatics were females p= 0.553, 44.44% (n= 8) of Pulmonary tuberculosis were in females p= 0.070, and 78.76% (n= 89) of indoor air pollution exposure was in females p <0.001.

ConclusionFemales have higher association to indoor air pollution exposure compared to male and this association was found to be statistically significant. The higher incidence of AECOPD hospitalization in females can be explained by these findings. We need larger studies to validate these findings.


title: Benefit-finding and self-compassion promote psychological well-being in caregivers of individuals with mental illness: a cross-sectional study

abstract:
BackgroundResilience factors that promote psychological well-being amongst caregivers of individuals with a mental illness are understudied. Coping strategies (problem-focused coping, emotion-focused coping and benefit-finding) have been found to influence the relation between stress and psychological outcomes, but their relative contribution to psychological well-being has not been tested. Self-compassion reduces caregiver burden in caregivers, yet no research has examined its contribution to psychological well-being nor the mechanisms via which it could do so. The aim of this study was to examine benefit-finding and self-compassion as resilience factors that could promote psychological well-being amongst caregivers of individuals with mental illnesses.

MethodsThis cross-sectional study was conducted between June 2019 to October 2019 in Singapore. 107 informal caregivers of individuals with various diagnosed mental illnesses completed an online questionnaire. COPE, General Benefit Finding Scale (GBFS), Self-Compassion Scale -Short (SCS-SF), Psychological Well-Being Scale -Brief (PWBS-B), and Hospital Anxiety and Depression Scale (HADS) were used. Hierarchical multiple regression and mediation analyses were conducted.

ResultsBenefit-finding was a more important predictor of psychological well-being compared to problem-focused and emotion-focused coping. Self-compassion was positively associated with psychological well-being amongst caregivers, and this is partially due to an increased use of problem-focused coping strategies.

ConclusionsFuture interventions should cultivate caregivers benefit-finding and self-compassion and consider using psychological well-being as an additional outcome measure.

category: psychiatry and clinical psychology


title: Prospective genomic surveillance reveals cryptic MRSA outbreaks with local to international origins among NICU patients.

abstract: MRSA infections cause significant morbidity and mortality in neonates. Clinical testing and routine surveillance screening identified an increase in neonates with MRSA colonization and infection which triggered prospective genomic surveillance. Here we show the complex transmission dynamics of MRSA in a NICU setting. Analyses revealed concurrent transmission chains affecting 16 of 22 MRSA-colonized patients (68%), and 3.1% of all NICU patients (n=517). Prematurity and longer lengths of stay increased risks for colonization. Intervals of up to 7 months occurred among some cluster-related isolates. 3 of 22 MRSA-colonized patients developed invasive infections with the colonizing strain. Comparisons with 21,521 isolates in the NCBI Pathogen Detection Resource revealed NICU strains to be distinct from MRSA seen locally and internationally. Integration of international strain datasets in analyses increased the resolution of strain clusters and helped rule-out suspected transmission events. Analyses also identified sequence type 1535 isolates, emergent in the Middle East, carrying a unique SCCmec with fusC and aac(6)-Ie/aph(2)-1a that provided a multi-drug resistant phenotype. NICU genomic surveillance identified cryptic MRSA colonization events, including NICU-endemic strains not linked with local hospital or international clusters, and has rich potential to guide improvements in infection prevention for this vulnerable patient population.


title: T cell receptor sequencing specifies psoriasis as a systemic and atopic dermatitis as a skin-focused, allergen-driven disease

abstract:
Atopic dermatitis (AD) and psoriasis represent two of the most common inflammatory skin diseases in developed countries. A hallmark of both diseases is T cell infiltration into the skin. However, it is still not clarified to what extent these infiltrating T cells are antigen-specific skin-homing T cells or unspecific heterogeneous bystander cells. To elucidate this, T cells from lesional skin and from blood of 10 AD and 11 psoriasis patients were compared by receptor (TCR) sequencing. Therefore, peripheral blood mononuclear cells (PBMC) were cell-sorted according to expression of the cutaneous leukocyte antigen (CLA) into skin-homing (CLA+) and non-skin-homing (CLA-) subfractions. Aeroallergen-specific T cell lines were grown from AD patients s PBMC in parallel. Intra-individual comparison of TCRB CDR3 regions revealed that clonally expanded T cells in skin lesions of both AD and psoriasis patients corresponded to skin-homing circulating T cells. However, in psoriasis patients, these T cell clones were also detectable to a larger extent among CLA- circulating T cells. Up to 28% of infiltrating cells were identified as allergen-specific by overlapping TCR sequences. Our data shows that in line with the systemic nature of psoriasis, T cells infiltrating psoriatic skin lesions do not exclusively home to the skin and are therefore not specific to antigens that are exclusively encountered at the skin. T cells driving AD skin inflammation appear to home nearly exclusively to the skin and are, to a certain extent, specific to aeroallergens.

One Sentence SummaryIn contrast to psoriasis, T cells driving atopic dermatitis are predominantly skin-homing and are to a certain extent allergen-specific

Key Message / Significance StatementT cells that encounter their cognate antigen proliferate clonally and share the same T cell receptor (TCR). Here we describe that clonally expanded T cells from lesional skin in patients with psoriasis and atopic dermatitis (AD) can also be detected within the circulation. While in AD these are mostly homing to the skin, psoriasis-driving T cells do not appear to be exclusively skin-directed. The fact that several co-morbidities are associated with psoriasis matches this observation. In contrast, AD is commonly accompanied by allergic sensitizations. Here we demonstrate that allergen-specific T cells do indeed infiltrate lesional skin and allow a concrete estimate of their frequency.

category: dermatology


title: Comparison of Pandemic Intervention Policies in Several Building Types Using Heterogeneous Population Model

abstract: In a world where pandemics are a matter of time and increasing urbanization of the worlds population, governments should be prepared with pandemic intervention policies (IPs) to minimize the crisis direct and indirect adverse effects while keeping normal life as much as possible. Successful pandemic IPs have to take into consideration the heterogeneous behavior of individuals in different types of buildings and social contexts. In this study, we propose a spatio-temporal, heterogeneous population model and in silico simulation to evaluate pandemic IPs in four types of buildings - home, office, school, and mall. We show that indeed each building type has a unique pandemic spread and therefore a different optimal IP. Moreover, we show that temporal-based IPs (such as mask wearing) have a similar influence on the pandemic spread in all four building types while spatial-based IPs (such as social distance) highly differ.


title: Study protocol: Assessing the association between corporate political influence and implementation of policies to tackle commercial determinants of non-communicable diseases: a cross-sectional analysis of 172 countries

abstract:
ObjectivesTo assess the association between corporate political influence and implementation of WHO-recommended policies to constrain sales, marketing and consumption of tobacco, alcohol, and unhealthy foods.

DesignCross-sectional analysis using national datasets from 2015, 2017, and 2020.

SettingGlobal analysis of data from 172 of the 194 WHO Member States

Main outcome measuresWe will use random effects multivariate regression to test the association between implementation status of 12 WHO-recommended tobacco, alcohol, and diet policies and corporate political influence, a metric that combines disclosure of campaign donations, public campaign finance, corporate campaign donations, legislature corrupt activities, disclosure by politicians, and executive oversight. We will control for GDP per capita, population aged >65 years, urbanization, level of democracy, continent, ethno-linguistic fractionalization, legal origin, Small Island Developing States, and Muslim population (to capture alcohol policy differences). We will include year dummies to address the possibility of a spurious relationship between the outcome variable and the independent variables of interests. For example, there may be an upward global trend in policy implementation that coincides with an upward global trend in in the regulation of lobbying and campaign finance.

Ethics and disseminationAs this study uses publicly available data, ethics approval is not required. The authors have no conflicts of interest to declare. Findings will be submitted to a peer-reviewed journal for publication in the academic literature. All data, code, and syntax will be made publicly available on GitHub.


title: "Learn from the lessons and don't forget them": Identifying transferable lessons for COVID-19 from meningitis A, yellow fever, and Ebola virus disease vaccination campaigns

abstract:
IntroductionCOVID-19 vaccines are now being distributed to low- and middle-income countries (LMICs), with global urgency surrounding national vaccination plans. LMICs have significant experience implementing vaccination campaigns to respond to epidemic threats but are often hindered by chronic health system challenges. We sought to identify transferable lessons for COVID-19 vaccination from the rollout of three vaccines that targeted adult groups in Africa and South America: MenAfriVac (meningitis A); 17D (yellow fever); and rVSV-ZEBOV (Ebola virus disease).

MethodsWe conducted a rapid literature review and 24 semi-structured interviews with technical experts who had direct implementation experience with the selected vaccines in Africa and South America. We identified barriers, enablers, and key lessons from the literature and from participants experiences. Interview data were analysed thematically according to seven implementation domains.

ResultsParticipants highlighted multiple components of vaccination campaigns that are instrumental for achieving high coverage. Community engagement is an essential and effective tool, requiring dedicated time, funding and workforce. Involving local health workers is a key enabler, as is collaborating with community leaders to map social groups and tailor vaccination strategies to their needs. Vaccination team recruitment and training strategies need to be enhanced to support vaccination campaigns. Although recognised as challenging, integrating vaccination campaigns with other routine health services can be highly beneficial if well planned and coordinated across health programmes and with communities.

ConclusionAs supplies of COVID-19 vaccines become available to LMICs, countries need to prepare to efficiently roll out the vaccine, encourage uptake among eligible groups, and respond to potential community concerns. Lessons from the implementation of these three vaccines that targeted adults in LMICs can be used to inform best practice for COVID-19 and other epidemic vaccination campaigns.

O_TEXTBOXKEY QUESTIONSO_ST_ABSWhat is already known?C_ST_ABSO_LILow- and middle-income countries (LMICs) have substantial experience conducting vaccination campaigns as a part of epidemic responses.
C_LIO_LIVaccination campaigns in LMICs are impacted by a number of systemic challenges, including poor infrastructure, limited resources, and an overstretched health workforce.
C_LIO_LIMeningitis A, yellow fever and Ebola virus disease vaccines have been recently rolled out in LMICs to respond to epidemic threats. These campaigns share some of the same challenges anticipated for COVID-19 vaccination, including the focus on adult target groups.
C_LI

What are the new findings?O_LIExtensive community engagement is crucial when targeting adults for vaccination in LMICs to shift community perceptions that vaccination is only associated with children.
C_LIO_LIWorking with community leaders to map social groups and plan effective vaccination strategies is vital to achieving high vaccination coverage.
C_LIO_LIRecruiting local health workers who have established links to the community, can speak the local language, and can leverage existing rapport to increase vaccination uptake, is preferred over bringing in staff from other regions.
C_LIO_LIVaccination training quality is reduced as information is transmitted down to lower levels using the  cascade or  training-of-trainers model. Training for vaccination campaigns in LMICs has been further affected by COVID-19 and the move to remote learning. Where access to training is limited, a greater emphasis is placed on resource-intensive supervision to ensure the effectiveness of vaccination campaigns.
C_LI

What do the new findings imply?O_LIPrevious vaccination campaigns conducted during epidemics are an important source of transferable lessons that can assist countries in their COVID-19 vaccine rollouts and future epidemic preparedness.
C_LIO_LIOur findings suggest that countries can strengthen vaccination campaigns during epidemics by recruiting local health workers to assist vaccination teams, by providing operational funding for pre-campaign community engagement and social mobilisation activities, and by examining the effectiveness of vaccination training and developing new models where needed.
C_LIO_LIImplementing these lessons for COVID-19, however, relies on countries having sufficient vaccine supply.
C_LI

C_TEXTBOX


title: Older adults experiences of supervised hardstyle kettlebell training: A qualitative study from the BELL pragmatic controlled trial

abstract:
ObjectivesThis study examined older adults experiences of participating in the BELL trial, involving 12-weeks of group-based hardstyle kettlebell training.

MethodsIn the BELL trial, 28 insufficiently active older adults (15 women, 13 men, 59-79 years) completed 6 weeks of face-to-face group training, and 6 weeks of home-based training. In-depth semi-structured interviews were audio recorded and transcribed, inductively coded, with themes constructed thematically from patterns of shared meaning.

ResultsFour higher-order themes were developed that reflect older adults experiences participating in a group-exercise program of hardstyle kettlebell training. These included: (1) "Its one of the best things weve done" - enjoying the physical and psychosocial benefits, (2) "Its improved it tremendously!" - change in a long-term health condition, (3) "It put me on a better course" - overcoming challenges, (4) "I wasnt just a number" - feeling part of a group/community.

DiscussionFindings highlight the perceived physical and psychological benefits of participating in hardstyle group kettlebell training, the value attributed to being part of an age-matched community of like-minded people engaged in group-exercise, as well as the challenges participants faced, and the sense of achievement in overcoming them. Implications for program design and delivery, and future research are discussed.


title: "If somebody had told me I'd feel like I do now, I wouldn't have believed them"    Older adults' experiences of the BELL trial: a qualitative study


title: Identification of genetic loci associated with antibodies to specific sets of citrullinated peptides in rheumatoid arthritis patients

abstract:
ObjectivesProduction of anti-citrullinated peptide/protein antibodies (ACPA) is characteristic for rheumatoid arthritis (RA) and may inform about biological pathways involved in disease development in specific subgroups. Since multiple loci in genome wide association screens have been implicated in RA risk, we investigated the association between genetic variations and the development of multiple types of ACPA in three big cohorts of RA patients from Sweden, USA and UK (EIRA, NARAC and WTCCC) with overall 6,127 individuals with RA.

MethodsWe combined genotyping data from Illumina Immunochip with serological data for 16 ACPA specificities from a custom-made multiplex microarray (Thermo Fisher Scientific, ImmunoDiagnostic division). A logistic regression-based association test in each cohort was followed by meta-analysis.

ResultsWe report several loci, harbouring three or more variants associated with ACPA, reaching study-wide significance (FDR<0.1) - PTPN22, LINC02341_TNFSF11, THADA and TMEM174. Most of these loci are not known to be associated with RA. Stratification by "shared epitope" (SE) alleles indicated an association between the PTPN22 locus and levels of antibodies binding to the vimentin peptide, Cit-Vim60-75, in SE positive cases, but not in SE negative cases.

ConclusionOur data identifies several new loci which associate with subsets of RA characterized by presence of specific ACPA and indicate unknown disease heterogeneity.

Key messagesO_ST_ABSWhat is already known about this subject?C_ST_ABSO_LIACPA define two subgroups within RA, and has been an important biomarker included in diagnostic criteria
C_LIO_LICommonly used ACPA test, anti-CCP, accumulate signals from autoantibodies to several peptides and does not discriminate between multiple autoantibody specificities.
C_LI

What does this study add?O_LIOur study demonstrates that different sets of ACPAs in RA have distinct genetic associations. Associated variants from our study localize in known regulatory regions and have transcriptomic effects beyond the associated locus
C_LIO_LIWe find that PTPN22 locus can drive positivity for multiple APCAs, while other found loci associate with specific autoantibody positivities
C_LI

How might this impact on clinical practice?O_LIOur study will extend personalized approach in handling of rheumatoid arthritis with focus on serologically defined subgroups of the disease.
C_LI

category: rheumatology


title: Financial burden of Chronic Kidney Disease Patients on Maintenance Hemodialysis in Chittagong, Bangladesh

abstract:
BackgroundChronic kidney disease (CKD) is an important public health problem. Renal replacement therapy (RRT) is needed to patients who goes to end stage renal disease(ESRD). Most of the evidence on its costs relates to patients receiving dialysis or kidney trans-plants, which shows that, in these phases, CKD poses a high burden to payers. The aim of this study was to estimate the financial burden of patients with CKD on maintenance hemodialysis.

MethodsIt is one -year observational study, carried out to collect data on 105 patients with CKD on dialysis taking from different centers of Chittagong Bangladesh. After collection of sociodemographic informations financial status were collected from patients who gave informed written consent to be included in the study. Data were analyzed by SPSS 20.

ResultsRegarding gender distribution, male was 73(69.5%) and female was 32(30.5%). Male to female ratio was 2.28:1. Age group distribution revealed 10(9.5%) patients were at <30 years, 18(17.1%) were at 31-40 years, 23(21.9%) were at 41-50 years, 26(24.8%) were at 51-60 years, 20(19.0%) were at 61-70 years and 8(7.6%) were >71 years age. Among all most were involved in service 40(38.1%) and business 23(21.9%). Socio economic status of the patients revealed 42(40.0%) patients were from upper middle class, 50(47.6%) were from lower middle class. Among all, 33(31.4%) patients took treatment from abroad. Regarding bearing of cost of the dialysis 24(22.9%) were self financed and 35(33.3%) got help from others(non family member), 11(10.5%) took loan and 13(12.4%) sold their stable land property. Regarding tenure of dialysis 31(29.5% patients are getting dialysis <1 year and 74(70.5%) were getting it for 1-2 years. Previous monthly income before start of dialysis was zero(0) in 33(31.4%) patients and it was >30000 taka/month in 34(32.4%) patients and after start of dialysis present monthly income was zero(o) per month in 67(63.8%) patients and >30000 taka/month in 13(12.4%) patients. Regarding expenditure for each dialysis showed 2(1.9%) had zero(0) taka and 46(43.8%) patients needed 1000-2000 taka/session and 41(39.0%) needed 2000-3000 taka /session.

ConclusionDialysis in CKD patients is a huge financial burden to the patients himself and the family. Government assistance should be provided to all patients who are unable to bear the cost.

category: nephrology


title: Association of polycyclic aromatic hydrocarbons in moss with blood biomarker among nearby residents in Portland, Oregon

abstract:
Polycyclic aromatic hydrocarbons (PAHs) are a component of air pollutants that are costly to measure using traditional air-quality monitoring methods. We used an epiphytic bio-indicator (moss genus: Orthotrichum) to cost-effectively evaluate atmospheric deposition of PAHs in Portland, Oregon in May 2013. However, it is unclear if measurements derived from these bioindicators are good proxies for human exposure. To address this question, we simultaneously, measured PAH-DNA adducts in blood samples of non-smokers residing close to the sites of moss measurements. We accounted for individual determinants of PAH uptake that are not related to environmental air quality through questionnaires, e.g., wood fires, consumption of barbecued and fried meats. Correlation and linear regression (to control for confounders from the lifestyle factors) evaluated the associations. We did not observe evidence of an association between PAH levels in moss and PAH-DNA adducts in blood of nearby residents, but higher level of adduct were evident in those who used wood fire in their houses in the last 48 hours. It remains to be determined whether bio-indicators in moss can be used for human health risk assessment.

HighlightsO_LIConcentration of PAH in moss do not relate to DNA adducts of PAH in blood of nearby residents in our sample.
C_LIO_LIContent of moss may not be suitable for assessing exposure to PAH among humans.
C_LI

category: occupational and environmental health