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

Congruent Leadership: values in action

To discuss the significance of an appropriate leadership theory in order to develop an understanding of clinical leadership. Leadership theories developed from management and related paradigms, particularly transformational leadership, may be ineffective in supporting nurses to gain insights into clinical leadership or to develop and implement clinical leadership skills. Instead, congruent leadership theory, based on a match between the clinical leaders' actions and their values and beliefs about care and nursing, may offer a more firm theoretical foundation on which clinical nurses can build an understanding of and capacity to implement clinical leadership or become clinical leaders.It is important to recognize that leadership theories based on a management paradigm may not be appropriate for all clinical applications. Education should be aimed specifically at clinical leaders, recognizing that clinical leaders are followed not for their vision or creativity (even if they demonstrate these), but because they translate their values and beliefs about care into action