Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

Background: We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15–20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases. Methods: We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded. Results: No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5–528.7, P = 1.1 × 10−4) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR = 3.70[95%CI 1.3–8.2], P = 2.1 × 10−4). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR = 19.65[95%CI 2.1–2635.4], P = 3.4 × 10−3), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR = 4.40[9%CI 2.3–8.4], P = 7.7 × 10−8). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD] = 43.3 [20.3] years) than the other patients (56.0 [17.3] years; P = 1.68 × 10−5). Conclusions: Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old

The Human Phenotype Ontology in 2017.

Deep phenotyping has been defined as the precise and comprehensive analysis of phenotypic abnormalities in which the individual components of the phenotype are observed and described. The three components of the Human Phenotype Ontology (HPO; www.human-phenotype-ontology.org) project are the phenotype vocabulary, disease-phenotype annotations and the algorithms that operate on these. These components are being used for computational deep phenotyping and precision medicine as well as integration of clinical data into translational research. The HPO is being increasingly adopted as a standard for phenotypic abnormalities by diverse groups such as international rare disease organizations, registries, clinical labs, biomedical resources, and clinical software tools and will thereby contribute toward nascent efforts at global data exchange for identifying disease etiologies. This update article reviews the progress of the HPO project since the debut Nucleic Acids Research database article in 2014, including specific areas of expansion such as common (complex) disease, new algorithms for phenotype driven genomic discovery and diagnostics, integration of cross-species mapping efforts with the Mammalian Phenotype Ontology, an improved quality control pipeline, and the addition of patient-friendly terminology

A trial of nurse practitioner scope of practice

Aims. The aim of this paper is to report a trial to investigate the feasibility of the nurse practitioner role in local health service delivery and to provide information about the educational and legislative requirements for nurse practitioner practice. Background. Nurse practitioners have been shown to offer a beneficial service and fill a gap in health care provision. However, the lack of publications describing, critiquing, or defending the way that existing nurse practitioner roles have been developed may lead to a lack of clarity in comparing the nurse practitioner scope of practice internationally. In Australia, credible exploratory research is needed to realize the potential of nurse practitioners to bridge the divide of inequitable distribution of health services. A trial of nurse practitioner services in the Australian Capital Territory provided an excellent opportunity to investigate these scope and continuity issues. Methods. This was an observational analytic study using multiple data sources. Four models of nurse practitioner service were chosen from a competitive field of applications that were evaluated according to efficacy, feasibility, and sustainability across specified selection criteria. Each model in the trial included a clinical support team, with the nurse practitioner candidate 'working-into-the-role' and collecting demographic, clinical practice, patient outcome, and health service and consumer survey data over a 10 month period. Findings. The trial identified the broad potential of the nurse practitioner role, its breadth and limitations, and its impact on selected health services in the Australian Capital Territory. Data from individual models were compared highlighting generic elements, and formed the basis for the development of the scope of practice for the Australian Capital Territory nurse practitioner models. Conclusions. This study has validated a research-based, iterative process for initial development of nurse practitioner scope of practice for any Australian specialization. Importantly, the study concluded with the scope of practice as a finding, rather than commencing with it a priori. Although general areas of health care need and under-servicing were identified at the outset, the process tested both the expansion and parameters of the roles. What is already known about this topic: • Nurse practitioners offer a beneficial service and fill a gap in health care provision. • The nurse practitioner scope of practice varies from country to country. • Australian nurse practitioners are well positioned to bridge the divide of inequitable distribution of health services not only between metropolitan and rural/remote areas, but also within metropolitan areas. What this paper adds: • Research-based, iterative processes for development of clinical protocols that define the scope of practice for diverse nurse practitioner models. • A test of both the expansion and parameters of the roles applicable for any Australian specialization. • Systems and processes to inform health policy deliberations

UN EVENEMENT MARQUEUR DE LA DIFFERENCIATION MUSCULAIRE : LA TRANSITION DE L'ENOLASE EMBRYONNAIRE αα VERS L'ENOLASE ββ SPECIFIQUE DU MUSCLE. ETUDE A L'AIDE DES SONDES cDNAs

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