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

Gender and critical realism: a critique of Sayer

In a recent article in this journal, Andrew Sayer has argued that much feminist research on the gendered nature of organisations, such as bureaucracy and the market, confuses a contingent association of gender and organisational forms with a stronger claim that they are intrinsically gendered. Sayer accepts that this research has shown that the empirically found, concrete forms of organisations are gendered. However, deeper theoretical reflection, he suggests, reveals that, when considered as `abstract realist models', bureaucracy and the market are, in fact, identity-blind. He makes two claims, one concerned with explanation, the other concerned with the political consequences of social inquiry. The first is that the construction of abstract models, rather than the `associational' thinking concerned with the delineation of empirical regularities, is necessary to the proper understanding of the operation of causal mechanisms and their mode of determination in social life. The second is that this will enable a more progressive and positive politics beyond a fatalism which he attributes to associational thinking. This paper takes issue with both claims arguing that the abstract theory he defends has no positive role in social inquiry and that his political critique is misplaced

Acute toxicity related to misuse (nonmedical use) of tramadol: Experience of the European Drug Emergencies Network Plus

International audienceFollowing the development of the tramadol crisis currently affecting countries in the Middle East, and Africa, there has been increasing international interest in the regulation of tramadol. This study investigates the misuse of tramadol in patients presenting to emergency departments across Europe. Data from 32 emergency departments in 21 countries were extracted from the Euro-DEN Plus database for the 4-year period from 1 January 2014 to 31 December 2017. Of the reported 24,957 emergency department presentations, tramadol misuse was reported in 105 (0.4% presentations). Tramadol misuse was most common in Bratislava (Slovakia; n = 11, 7.5% of all presentations to this centre), Riga (Latvia; n = 4, 4.9%) and Munich (Germany; n = 17, 2.9%). On arrival, 14 (13.3%) of presentations were in coma/Glasgow coma score ≤ 8 and 9 of these had a respiratory rate <12 breaths/min. These presentations potentially pose a significant burden on emergency departments with a large proportion requiring admission to hospital for ongoing care