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

Principles of low PIM hardware design

In space RF communications payloads, it is increasingly required that high-power multi-channel transmitters and broadband receivers have shared, or closely adjacent RF feeds. Because of the large power level difference between the transmit and receive signals and the limitation of frequency allocation, passive intermodulation (PIM) interference due to passive non-linearities in the high-power transmission path can be serious problem. One of the main sources of PIM in RF microwave systems is the metal-to-metal contact. A contact model regardless of the suspected non-linear mechanisms, i.e. semiconductor, electron tunnelling and microdischarge, has been used to explain the non-linear effect at metallic contacts. The model requires that the non-linear effect is current dependent and the PIM level is proportional to the current density at the contacts. Because metal-to-metal contact in an RF coaxial connector is unavoidable, an alternative has to be developed. The work reported represents some of our efforts toward developing a demountable RF coaxial connector which does not involve metal-to-metal contact in any electrically significant part, i.e. a "contactless connector". The novel design of the coaxial contactless connector and the theoretical analysis are described