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

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    BackgroundWe 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 similar to 80% of cases.MethodsWe 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.ResultsNo 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=1.1x10(-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=2.1x10(-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=3.4x10(-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=7.7x10(-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=1.68x10(-5)).ConclusionsRare 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

    Zur Entwicklung von praxisorientierten, forschungsbasierten, inklusionssensiblen und phasenĂŒbergreifenden Lehrkonzepten und Materialien in BiProfessional

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    Das Editorial zum Themenheft des Projekts BiProfessional zeigt die konzeptionelle Ausrichtung und Weiterentwicklung der Bielefelder LehrkrĂ€ftebildung im Rahmen der „QualitĂ€tsoffensive Lehrerbildung“ auf. Dabei wird die forschungsbasierte Entwicklung von Lehrkonzepten und -materialien als ein zentrales Element des Transfers der Projektergebnisse markiert. Die 23 BeitrĂ€ge des Themenheftes, in denen in BiProfessional erarbeitete Lehrmaterialien zur Nachnutzung aufbereitet sind, werden kurz vorgestellt. DarĂŒber hinaus werden im Editorial die Strukturentwicklungen an der Bielefeld School of Education als weiteres Element der Transferstrategie erlĂ€utert und auf die Zeit nach der Programmförderung bezoge

    Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries