Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Qual Pedagogia para os alunos em dificuldade escolar ?

Repetir o ano não ajuda os alunos com dificuldades. Numerosas pesquisas sobre os efeitos da repetência mostram que em regra geral os alunos fracos que recomeçam o mesmo ano progridem menos que os alunos fracos que são promovidos. Que medidas pedagógicas são necessárias para combater o fracasso escolar? O objetivo deste artigo é proceder a uma revisão do que as pesquisas empíricas revelam sobre os procedimentos mais freqüentemente mencionados como meios de obter um aperfeiçoamento pedagógico. Os primeiros dizem respeito à composição e ao manejo de turmas homogêneas e heterogêneas, de classes grandes ou pequenas, e de grupos de alunos com necessidades específicas; os segundos remetem aos dispositivos de individualização da aprendizagem ou à estratégia oposta, de aprendizagem cooperativa e tutoral; os terceiros são relativos à avaliações formativas, seguidas ou não de ações corretivas. Discutindo o conjunto dos resultados, o autor defende um redirecionamento das pesquisas pedagógicas no sentido de investigar prioritariamente os procedimentos mais genéricos, deixando para casos extremos a mobilização de dispositivos baseados num diagnóstico fino das dificuldades de aprendizagem.<br>To repeat the year does not help students with difficulties. Several studies about the effects of grade repetition show that in general students who do poorly and start again the same school year progress less than weak students who are promoted. Which pedagogical measures are necessary to combat school failure? The aim of this article is to review what empirical studies reveal about the most often mentioned procedures as a means to attain pedagogical improvement. The first procedures relate to the composition and management of homogeneous and heterogeneous groups, small or big classes, and groups of students with specific needs; the second procedures relate to the learning individualization devices or to the opposite strategy of cooperative and tutorial learning; the third procedures relate to the formative evaluations, either followed or not by corrective actions. When discussing the results, the author defends to redirect the pedagogical studies so as to investigate primarily the most generic procedures, leaving for the most extreme cases the mobilization of devices based on a fine diagnosis of the learning difficulties

Whole-genome sequencing reveals host factors underlying critical COVID-19

Altres ajuts: Department of Health and Social Care (DHSC); Illumina; LifeArc; Medical Research Council (MRC); UKRI; Sepsis Research (the Fiona Elizabeth Agnew Trust); the Intensive Care Society, Wellcome Trust Senior Research Fellowship (223164/Z/21/Z); BBSRC Institute Program Support Grant to the Roslin Institute (BBS/E/D/20002172, BBS/E/D/10002070, BBS/E/D/30002275); UKRI grants (MC_PC_20004, MC_PC_19025, MC_PC_1905, MRNO2995X/1); UK Research and Innovation (MC_PC_20029); the Wellcome PhD training fellowship for clinicians (204979/Z/16/Z); the Edinburgh Clinical Academic Track (ECAT) programme; the National Institute for Health Research, the Wellcome Trust; the MRC; Cancer Research UK; the DHSC; NHS England; the Smilow family; the National Center for Advancing Translational Sciences of the National Institutes of Health (CTSA award number UL1TR001878); the Perelman School of Medicine at the University of Pennsylvania; National Institute on Aging (NIA U01AG009740); the National Institute on Aging (RC2 AG036495, RC4 AG039029); the Common Fund of the Office of the Director of the National Institutes of Health; NCI; NHGRI; NHLBI; NIDA; NIMH; NINDS.Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care or hospitalization after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes-including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)-in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease