Des determinants genetiques peuvent influencer la sensibilite et la gravite de la COVID-19.

Contexte: Sous la supervision du Dr. J. Brent Richards, chercheur a l'Institut de recherche medicale Lady Davis de l'Hopital general juif, la plus grande biobanque d'echantillons biologiques et de donnees cliniques a ete coordonnee pour repondre a la mission provinciale de la BQC19. Une collaboration internationale en science ouverte a egalement ete initiee. Cette initiative permet aux chercheurs de pouvoir travailler avec des prelevements humains provenant de personnes atteintes par le virus SRAS-CoV-2 et des temoins non atteints pour tenter d'en elucider les causes et les mecanismes de severite. Entre autres, deux publications recentes sont issues des analyses realisees a partir de cette source de donnees. Methodes: Une etude a utilise des analyses de randomisation mendelienne (RM) a deux echantillons pour fournir de nouvelles informations biologiques sur la physiopathologie de la COVID-19 en balayant rapidement des centaines de proteines en circulation. Une autre etude a ete menee toujours avec la methode RM a deux echantillons afin d'estimer l'effet causal des niveaux du marquer biologique 25-hydroxyvitamin D (25OHD) sur la sensibilite et la gravite de la COVID-19. Resultats: La premiere etude a pu identifier que l'OAS-1 (2'-5'-Oligoadenylate Synthetase 1) est un gene protecteur qui permet de ne pas faire de forme grave de la maladie. La deuxieme etude a permis de montrer plus precisement que la supplementation en vitamine D en tant que mesure de sante publique pour ameliorer les resultats de la COVID-19 n'est pas soutenue, suggerant que l'investissement dans d'autres voies therapeutiques ou preventives devrait etre priorisees. Discussion/Conclusion: Cette BQC19 soutient les efforts visant a decouvrir et a developper de nouveaux biomarqueurs de sensibilite et de progression de la COVID-19, des therapies et des vaccins ainsi que tout effort de recherche en lien avec la prevention, le traitement et la gestion epidemiologique et populationnelle de la maladie. Declaration de liens d'interets: Les auteurs declarent ne pas avoir de liens d'interets.Copyright © 2022

Sex-biased expression of the TLR7 gene in severe COVID-19 patients: Insights from transcriptomics and epigenomics.

There is abundant epidemiological data indicating that the incidence of severe cases of coronavirus disease (COVID-19) is significantly higher in males than females worldwide. Moreover, genetic variation at the X-chromosome linked TLR7 gene has been associated with COVID-19 severity. It has been suggested that the sex-biased incidence of COVID-19 might be related to the fact that TLR7 escapes X-chromosome inactivation during early embryogenesis in females, thus encoding a doble dose of its gene product compared to males. We analyzed TLR7 expression in two acute phase cohorts of COVID-19 patients that used two different technological platforms, one of them in a multi-tissue context including saliva, nasal, and blood samples, and a third cohort that included different post-infection timepoints of long-COVID-19 patients. We additionally explored methylation patterns of TLR7 using epigenomic data from an independent cohort of COVID-19 patients stratified by severity and sex. In line with genome-wide association studies, we provide supportive evidence indicating that TLR7 has altered CpG methylation patterns and it is consistently downregulated in males compared to females in the most severe cases of COVID-19.

Pan-ancestry exome-wide association analyses of COVID-19 outcomes in 586,157 individuals

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), a respiratory illness that can result in hospitalization or death. We used exome sequence data to investigate associations between rare genetic variants and seven COVID-19 outcomes in 586,157 individuals, including 20,952 with COVID-19. After accounting for multiple testing, we did not identify any clear associations with rare variants either exome wide or when specifically focusing on (1) 13 interferon pathway genes in which rare deleterious variants have been reported in individuals with severe COVID-19, (2) 281 genes located in susceptibility loci identified by the COVID-19 Host Genetics Initiative, or (3) 32 additional genes of immunologic relevance and/or therapeutic potential. Our analyses indicate there are no significant associations with rare protein-coding variants with detectable effect sizes at our current sample sizes. Analyses will be updated as additional data become available, and results are publicly available through the Regeneron Genetics Center COVID-19 Results Browser.

Characterizing moonlighting during pulmonary and critical care medicine fellowship

Rationale Moonlighting is defined as optional extra work for extra compensation. Moonlighting (ML) during medical training is likely variable among residency and fellowship types and programs. To our knowledge, there have been no studies of ML in Pulmonary and Critical Care Medicine or Critical Care Medicine (PCCM/CCM) trainees therefore we sought to understand the types of moonlighting being performed by current PCCM/CCM fellows, as well as their motivations, and the perceived educational and burnout impacts related to ML. Methods Fourteen academic, university-based PCCM fellowship programs distributed geographically across the United States (U.S.) were recruited to participate in an online survey. Eight of these programs also had CCM fellows, which were included. Due to delays from the COVID-19 pandemic, two programs were unable to participate so twelve programs ultimately continued in the study. Using an iterative process of editing among the authors, focus groups with clinician educators, and cognitive interviewing among fellows, a survey was created that focused on characterizing ML practices. Descriptive statistics were generated to characterize results. Results A total of 258 current PCCM/CCM fellows were recruited and 144 fellows completed the survey (response rate: 59%), from twelve U.S. programs across the U.S. (East: 2;South: 3;Midwest: 4;West: 3). Respondents were predominantly in PCCM fellowships (87%). The majority of all respondents were second-year fellows or higher (72%). More than half of respondents (54%) had participated in ML while in fellowship, predominantly providing critical care (82%). A minority of respondents had no interest in ML (9%). Among those that did moonlight, it frequently occurred at a different hospital from their training hospital (53% of respondents). The most common motivations were financial (97%), gaining extra clinical experience (72%), and practicing with more autonomy (56%). A majority agreed or strongly agreed that ML increased their confidence as a physician (89%), and helped establish professional identity (62%). However, a majority also reported that ML worsened sleep hygiene (70%) and reduced time or energy spent on personal activities (56%). Despite this, 100% stated they would do it again or recommend ML to a colleague. Conclusion Moonlighting among trainees in academic PCCM/CCM fellowship programs is a common activity. Fellows generally find ML a positive experience. Although motivated primarily by extra compensation, they note ML offers additional educational value to their training. Moonlighting might also contribute to symptoms of burnout. More research is needed to understand the impact of moonlighting on PCCM/CCM fellows.