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

Green index in semigroups : generators, presentations and automatic structures

The Green index of a subsemigroup T of a semigroup S is given by counting strong orbits in the complement S n T under the natural actions of T on S via right and left multiplication. This partitions the complement S nT into T-relative H -classes, in the sense of Wallace, and with each such class there is a naturally associated group called the relative Schützenberger group. If the Rees index ΙS n TΙ is finite, T also has finite Green index in S. If S is a group and T a subgroup then T has finite Green index in S if and only if it has finite group index in S. Thus Green index provides a common generalisation of Rees index and group index. We prove a rewriting theorem which shows how generating sets for S may be used to obtain generating sets for T and the Schützenberger groups, and vice versa. We also give a method for constructing a presentation for S from given presentations of T and the Schützenberger groups. These results are then used to show that several important properties are preserved when passing to finite Green index subsemigroups or extensions, including: finite generation, solubility of the word problem, growth type, automaticity (for subsemigroups), finite presentability (for extensions) and finite Malcev presentability (in the case of group-embeddable semigroups).PostprintPeer reviewe

Developing practice in breastfeeding

This paper reports on an approach to practice development in breastfeeding as part of a national programme of work to address inequalities in maternal and child nutrition. The production and dissemination of evidence and guidelines is necessary but not sufficient on its own to effect change in practice, particularly when dealing with complex public health issues. In the case of breastfeeding, review evidence and national guidance have shown that multifaceted changes are essential if policy aspirations are to be realized. The objectives of the programme described here were to (1) inform and enable practice development in breastfeeding in low-income areas; (2) evaluate the impact of approaches used; and (3) develop robust approaches and appropriate material for use nationally. A conceptual framework was established, and a six-stage process is outlined. The recruitment of four sentinel sites across whole health economies, involving professionals and the voluntary sector, was an essential component of the programme. The strength of the model is that it provides a structured, cross-sectoral approach to practice development in public health. A key challenge is to identify whose responsibility it is to resource practice development when a number of disciplines and sectors are involved. This question needs to be addressed if public health guidance is to be of sustained benefit

3D meteoroid trajectories

Meteoroid modelling of fireball data typically uses a one dimensional model along a straight line triangulated trajectory. The assumption of a straight line trajectory has been considered an acceptable simplification for fireballs, but it has not been rigorously tested. The unique capability of the Desert Fireball Network (DFN) to triangulate discrete observation times gives the opportunity to investigate the deviation of a meteoroid's position to different model fits. Here we assess the viability of a straight line assumption for fireball data in two meteorite-dropping test cases observed by the Desert Fireball Network (DFN) in Australia – one over 21 s (DN151212_03), one under 5 seconds (DN160410_03). We show that a straight line is not valid for these two meteorite dropping events and propose a three dimensional particle filter to model meteoroid positions without any straight line constraints. The single body equations in three dimensions, along with the luminosity equation, are applied to the particle filter methodology described by Sansom et al. (2017). Modelling fireball camera network data in three dimensions has not previously been attempted. This allows the raw astrometric, line-of-sight observations to be incorporated directly. In analysing these two DFN events, the triangulated positions based on a straight line assumption result in the modelled meteoroid positions diverging up to 3.09 km from the calculated observed point (for DN151212_03). Even for the more typical fireball event, DN160410_03, we see a divergence of up to 360 m. As DFN observations are typically precise to < 100 m, it is apparent that the assumption of a straight line is an oversimplification that will affect orbit calculations and meteorite search regions for a significant fraction of events