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

Induction of Hypersensitivity Reactions to <i>Lactobacillus fermentum</i> and Lipoteichoic Acid in Rabbits

Regimens of intravenous injections of saline-washed &lt;i&gt;Lactobacillus fermentum&lt;/i&gt; elicited hypersensitivity reactions in rabbits. Pathological investigation revealed evidence consistent with induction of aggregate anaphylaxis, characterised by acute cor pulmonale. Additional evidence of similar tissue injury was observed in livers of rabbits which had received several intravenous injections of&lt;i&gt; L. fermentum&lt;/i&gt;. Deposition of immune complexes in kidney glomeruli was demonstrated in only 1 out of 11 animals. Skin testing experiments revealed that lipoteichoic acid was involved in type I and type III antibody-mediated hypersensitive states. The involvement of bacterial cell surface components and extracellular products in such reactions implies a potential role in host tissue injury.</jats:p

Analysis of Helicopter Rotor Nonlinear Dynamics by Numerical Continuation Method

The capability of numerical continuation to trace branches of periodic solutions is exploited in order to investigate the behavior of an articulated rotor blade as design and flight parameters are varied. The aim of the paper is to demonstrate the use of Dynamical System Theory and bifurcation analysis as an innovative tool for supporting rotor design, an approach based on the determination of critical thresholds for motion variables and rotor design parameters that determine unstable or simply undesirable behaviors of the coupled, flap-lag motions. In spite of the relative simplicity of the model presently implemented, the potential of the method is fully demonstrated. The reported results show a reasonable trend in the evolution of blade motion as different parameters are varied with continuity