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

Rights discourses in relation to people with intellectual disability: towards an ethics of relations, critique and care

In this paper we argue that human rights approaches for intellectually disabled people have failed to recognise the complexity of rights claims made by and on behalf of this group. Drawing on a research project into discourses of education for intellectually disabled people in the Eastern Cape, South Africa we discern three rights discourses; namely, rights to full participation, rights to special services and rights to protection. These draw off a social model, a medical model and a protective model, respectively. We note that these discourses may be set up in contestation with each other. However, we argue that they can be seen as complementary if viewed within an ethics of care that enables participation. Within this conceptualisation, participation is viewed within relations of care but is subject to a critique that examines the role of context and disciplinary power in constructing dependency

Overview of mast results

Significant progress has been made on the Mega Ampere Spherical Tokamak (MAST) towards a fundamental understanding of transport, stability and edge physics and addressing technological issues for future large devices. Collaborative studies of the L-H transition with NSTX and ASDEX Upgrade confirm that operation in a connected double-null configuration significantly reduces the threshold power, Pthr. The MAST data provide support for a theory for the transition based on finite β drift wave turbulence suppression by self-generated zonal flows. Analysis of low and high field side density gradients in the H-mode pedestal provides support for an analytical model of the density pedestal width dependent on the neutral penetration depth. Adding MAST data to international confinement databases has enhanced confidence in scalings for ITER by significantly expanding the range of β and ε explored and indicates a slightly stronger ε dependence than in current scalings. Studies of core transport have been conducted for well-diagnosed L-mode, H-mode and internal transport barrier (ITB) discharges using TRANSP, and microstability and turbulence studies have been carried out using GS2. Linear micro-stability analysis indicates that ITG modes are typically unstable on all flux surfaces with growth rates that are comparable to the equilibrium E × B flow shearing rate. Mixing length estimates of transport coefficients from ITG (neglecting flow shear) give diffusion coefficients that are broadly comparable with observed thermal diffusivities. Non-linear, collisionless ETG calculations have been performed and suggest radially extended electrostatic streamers up to 100ρe across in radius. Transport from ITG could easily be suppressed in regions where the E × B shear flow rate, ωSE, exceeds the ITG growth rate, possibly contributing to ITBs. Toroidal rotation, driven by neutral beam torque, is the dominant contribution to ωSE via the vBθ term in the radial electric field. Early edge localized mode activity on MAST is associated with the formation of narrow filamentary structures following field lines in the edge. These filaments rotate toroidally with the edge plasma and, away from the X-points, accelerate radially outwards from the edge up to 20 cm. Studies of disruptions on MAST demonstrate a complex evolution of core energy loss and resultant divertor power loads, including phases where the target heat flux width is broadened by a factor of 8. Observations of energetic particle modes driven by super-Alfvénic beam ions provide support for a model for the non-linear evolution of toroidal Alfvén eigenmodes (AEs) forming Bernstein-Green-Krushal waves. The AE activity reduces to low levels with increasing β. Plasma start-up without a central solenoid and in a manner compatible with future large spherical tokamak (ST) devices has been demonstrated using breakdown at a quadrupole magnetic null. Closed flux surface plasmas with peak plasma currents up to 370 kA have been generated and sustained for 0.3 s. New error field correction coils have extended the operational space for low density plasmas and enabled scaling studies of error field induced locked mode formation in the ST

Stratified analyses refine association between TLR7 rare variants and severe COVID-19

Summary: Despite extensive global research into genetic predisposition for severe COVID-19, knowledge on the role of rare host genetic variants and their relation to other risk factors remains limited. Here, 52 genes with prior etiological evidence were sequenced in 1,772 severe COVID-19 cases and 5,347 population-based controls from Spain/Italy. Rare deleterious TLR7 variants were present in 2.4% of young (<60 years) cases with no reported clinical risk factors (n = 378), compared to 0.24% of controls (odds ratio [OR] = 12.3, p = 1.27 × 10−10). Incorporation of the results of either functional assays or protein modeling led to a pronounced increase in effect size (ORmax = 46.5, p = 1.74 × 10−15). Association signals for the X-chromosomal gene TLR7 were also detected in the female-only subgroup, suggesting the existence of additional mechanisms beyond X-linked recessive inheritance in males. Additionally, supporting evidence was generated for a contribution to severe COVID-19 of the previously implicated genes IFNAR2, IFIH1, and TBK1. Our results refine the genetic contribution of rare TLR7 variants to severe COVID-19 and strengthen evidence for the etiological relevance of genes in the interferon signaling pathway

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