A th an as ios Kousathanas, Erola Pairo-Castineira, Konrad Rawlik, Alex S tu ck ey , C hr is to ph er A. Odhams,

Critical illness in COVID-19 is caused by inflammatory lung injury, mediated by the host immune system. We and others have shown that host genetic variation influences the development of illness requiring critical care or hospitalisation following SARS-Co-V2 infection. The GenOMICC (Genetics of Mortality in Critical Care) study is designed to compare genetic variants in critically-ill cases with population controls in order to find underlying disease mechanisms. Here, we use whole genome sequencing and statistical fine mapping in 7,491 critically-ill cases compared with 48,400 population controls to discover and replicate 22 independent variants that significantly predispose to life-threatening COVID-19. We identified 15 new independent associations with severe COVID-19, including variants within genes involved in interferon signalling (IL10RB, PLSCR1), leucocyte differentiation (BCL11A), and blood type secretor status (FUT2). Using transcriptome-wide association and colocalisation to infer the effect of gene expression on disease severity, we find evidence implicating expression of multiple genes, including reduced expression of a membrane flippase (ATP11A), and increased mucin expression (MUC1), in severe disease. We show that comparison between critically-ill cases and population controls is highly efficient for genetic association analysis and enables detection of therapeutically-relevant mechanisms of disease. Therapeutic predictions arising from these findings require testing in clinical trials.

If institutional systems that provide end-of-life care are to survive the demands of managed care, they will need to tie together methods of assessing the needs of the dying, leading to a new understanding of the functioning of a patient's existing helping networks. This paper presents the preliminary findings of a research project conducted at a Midwest hospice. The study utilized a cross sectional correlational survey of patients' needs via the Early Risk and Resiliency Inventory (ERRI), while mapping their helping networks with a Circles of Care Ecomap. It addressed the question, "What is the relationship between the needs of the dying and the formal and informal support provided?" Study findings supported the contention that higher need patients utilized the more expensive institutional services rather than relying on available natural networks; and statistical analysis of the study instrument suggested the creation of a new conceptual domain of psychospiritual need.

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The stability of steady, plane, one-dimensional, trans-Alfvénic shocks to small normal disturbances (i.e. those in which the perturbed quantities are functions only of time and the distance from the plane of the shock wave) is discussed. The magnetic diffusivity of the ambient gas is taken to be very much greater than each of the viscous diffusivities and the thermal diffusivity.It is confirmed in detail that all plane-polarized trans-Alfvénic shocks, except the 2–3 type (which is the only type that has no steady-state structure), are unstable to disturbances in those components of the magnetic field and velocity which are transverse to the plane of polarization. An incident Alfvénic wave, consisting of a weak, diffusing current-sheet would initially cause the shock profiles of these transverse quantities to grow linearly with time, while outside this shock region steady, uniform states would be reached. An integral condition is obtained which, together with the relevant boundary conditions; determines the asymptotic shock profiles of the transverse quantities whenever the disturbance is such that a steady state is reached. This removes the puzzling arbitrariness of these profiles.It is also shown that the ‘1–4’ trans-Alfvénic shock is unstable to magnetoacoustic waves and contact fronts. A qualitative description of how it may be broken up is given. If the disturbance is of finite extent, a steady state is reached. An integral equation is obtained which, together with the relevant boundary conditions, determines the asymptotic steady-state shock-profiles for this case. This removes the apparent arbitrariness of these profiles.The behaviour of ‘2–3’ trans-Alfvénic shocks and of switch-on and switch-off shocks is discussed.