Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown1 to be highly efficient for discovery of genetic associations2. Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group3. Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).
In the version of this article initially published, the name of Ana Margarita Baldión-Elorza, of the SCOURGE Consortium, appeared incorrectly (as Ana María Baldion) and has now been amended in the HTML and PDF versions of the article.
Due to the importance of laboratory analyses in clinical studies, whether for toxicity monitoring, assessment of plasma levels, or eficacy assessments, a suitable infrastructure should be created at the investigational site to ensure adherence to the specified protocol requirements for these laboratory parameters. This will ensure meaningful and quality data at the end of the study. Thus, there are certain requirements to consider when selecting investigational sites such as feasibility, equipment, expertise, and personnel. This article will discuss the ways in which a sponsor can develop this infrastructure, the role and responsibilities of the investigator, and the means of maintaining the infrastructure.
The general capabilities encompass the knowledge, skills, behaviours and dispositions that will assist students to live and work successfully in the 21st century. Teachers may find opportunities to incorporate the capabilities into the teaching and learning program for the Humanities and Social Sciences. The general capabilities are not assessed unless they are identified within the core content.
LITERACYAcross the Western Australian Curriculum, students become literate as they develop the knowledge, skills and dispositions to interpret and use language confidently for learning and communicating in and out of school and for participating effectively in society. Literacy involves students in listening to, reading, viewing, speaking, writing and creating oral, print, visual and digital texts, and using and modifying language for different purposes in a range of contexts.Humanities and Social Sciences Curriculum -Pre-Primary to Year 10
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