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

Third metacarpal condylar fatigue fractures in equine athletes occur within previously modelled subchondral bone

Bone modelling and remodelling reduce the risk of fatigue fractures; the former by adapting bone to its loading circumstances, the latter by replacing fatigued bone. Remodelling transiently increases porosity because of the normal delay in onset of the formation phase of the remodelling sequence. Protracted intense loading suppresses remodelling leaving modelling as the only means of maintaining bone strength. We therefore hypothesized that race horses with fatigue fractures of the distal third metacarpal bone (MC3) will have reduced porosity associated with suppressed remodelling while continued adaptive modelling will result in higher volume fraction (BV/TV) at this site. Using high resolution peripheral quantitative computed tomography (HR-pQCT), we measured the distal aspect of the MC3 obtained at postmortem from 13 thoroughbred race horses with condylar fractures of the MC3 (cases), 8 horses without fractures (training controls), 14 horses with a fracture at another site (fractured controls) and 9 horses resting from training (resting controls). Porosity of the subchondral bone of MC3 was lower in cases than resting controls (12 +/- 1.4% vs. 18 +/- 1.6%, P=0.017) although areas of focal porosity were observed adjacent to fractures in 6/13 horses. BV/TV of the distal metacarpal epiphysis tended to be higher in horses with condylar fractures (0.79 +/- 0.015) than training controls (0.74 +/- 0.019, P=0.070), but also higher in controls with a fracture elsewhere (0.79 +/- 0.014) than the training controls (0.74 +/- 0.019, P=0.040). BV/TV was higher in horses over three years of age than those aged two or three years (0.79 +/- 0.01 vs. 0.74 +/- 0.01, P=0.016). All metacarpal condylar fractures occurred within focal areas of high BV/TV. We infer that intense training in equine athletes suppresses remodelling of third metacarpal subchondral bone limiting damage repair while modelling increases regional bone volume in an attempt to minimise local stresses but may fail to offset bone fragility

Genetic and linguistic borders in the Himalayan region.

There are a number of competing theories about the origins of the Himalayan peoples. These theories are largely based on linguistic and/or archaeological findings. A large-scale, ethnolinguistically informed genetic study of the greater Himalayan region might provide a definitive model for historical population events in this region, and that is why the current study was undertaken. The geographical area of the present states of Nepal and Bhutan could have served as ancient corridors for human migration through the Himalayas, despite their geographic position immediately south of the highest land barrier. The findings also raise the question as to whether the southern slopes of the himalayas could have harboured refuge areas for the ancestral Tibeto-Burman population(s) during the last glacial maximum

L'image personnelle dans l'espace collectif = Personal Image for Social Space

In an introductory text, Reid emphasizes the need to explore the use of glass in architecture. Assessing individual architectural glass projects, jury members discuss the role of art in architecture. Includes a documentation of the seven selected proposals. Biographical notes. 1 bibl. ref