41 research outputs found

    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

    Brain potential responses involved in decision-making in weightlessness

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    The brain is essential to human adaptation to any environment including space. We examined astronauts’ brain function through their electrical EEG brain potential responses related to their decision of executing a docking task in the same virtual scenario in Weightlessness and on Earth before and after the space stay of 6 months duration. Astronauts exhibited a P300 component in which amplitude decreased during, and recovered after, their microgravity stay. This effect is discussed as a post-value-based decision-making closing mechanism; The P300 amplitude decrease in weightlessness is suggested as an emotional stimuli valence reweighting during which orbitofrontal BA10 would play a major role. Additionally, when differentiating the bad and the good docks on Earth and in Weightlessness and keeping in mind that astronauts were instantaneously informed through a visual cue of their good or bad performance, it was observed that the good dockings resulted in earlier voltage redistribution over the scalp (in the 150–250 ms period after the docking) than the bad dockings (in the 250–400 ms) in Weightlessness. These results suggest that in Weightlessness the knowledge of positive or negative valence events is processed differently than on Earth.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

    The risk of COVID-19 death is much greater and age dependent with type I IFN autoantibodies

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    International audienceSignificance There is growing evidence that preexisting autoantibodies neutralizing type I interferons (IFNs) are strong determinants of life-threatening COVID-19 pneumonia. It is important to estimate their quantitative impact on COVID-19 mortality upon SARS-CoV-2 infection, by age and sex, as both the prevalence of these autoantibodies and the risk of COVID-19 death increase with age and are higher in men. Using an unvaccinated sample of 1,261 deceased patients and 34,159 individuals from the general population, we found that autoantibodies against type I IFNs strongly increased the SARS-CoV-2 infection fatality rate at all ages, in both men and women. Autoantibodies against type I IFNs are strong and common predictors of life-threatening COVID-19. Testing for these autoantibodies should be considered in the general population

    The risk of COVID-19 death is much greater and age dependent with type I IFN autoantibodies

    No full text
    International audienceSignificance There is growing evidence that preexisting autoantibodies neutralizing type I interferons (IFNs) are strong determinants of life-threatening COVID-19 pneumonia. It is important to estimate their quantitative impact on COVID-19 mortality upon SARS-CoV-2 infection, by age and sex, as both the prevalence of these autoantibodies and the risk of COVID-19 death increase with age and are higher in men. Using an unvaccinated sample of 1,261 deceased patients and 34,159 individuals from the general population, we found that autoantibodies against type I IFNs strongly increased the SARS-CoV-2 infection fatality rate at all ages, in both men and women. Autoantibodies against type I IFNs are strong and common predictors of life-threatening COVID-19. Testing for these autoantibodies should be considered in the general population

    Caudate and cerebellar involvement in altered P2 and P3 components of GO/NoGO evoked potentials in children with attention-deficit/hyperactivity disorder

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    Previous studies showed reduced activity of the anterior cingulate cortex (ACC) and supplementary motor area during inhibition in children with attention-deficit/hyperactivity disorder (ADHD). This study aimed to investigate deep brain generators underlying alterations of evoked potential components triggered by visual GO/NoGO tasks in children with ADHD compared with typically developing children (TDC). Standardized weighted low-resolution electromagnetic tomography (swLORETA) source analysis showed that lower GO-P3 component in children with ADHD was explained not only by a reduced contribution of the frontal areas but also by a stronger contribution of the anterior part of the caudate nucleus in these children compared with TDC. While the reduction of the NoGO-P3 component in children with ADHD was essentially explained by a reduced contribution of the dorsal ACC, the higher NoGO-P2 amplitude in these children was concomitant to the reduced contribution of the dorsolateral prefrontal cortex, the insula, and the cerebellum. These data corroborate previous findings showed by fMRI studies and offered insight relative to the precise time-related contribution of the caudate nucleus and the cerebellum during the automatic feature of inhibition processes in children with ADHD. These results were discussed rega