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 hospitalization2–4 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

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

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Seamless Collaborative Learning Method to Learn Business Japanese with eBook and Chat System

7th International Conference, DAPI 2019, Held as Part of the 21st HCI International Conference, HCII 2019, Orlando, FL, USA, July 26–31, 2019, ProceedingsThe breakthrough of information technology has accelerated the evolutionary change in teaching and learning methodologies. In particular, pervasion of high-efficiency smartphones has raised the potential to generate a new learning environment called seamless learning, which has been drawing much attentions from researchers in pedagogy of any domains. The Japanese government, in 2016, declared “Japan Revitalization Strategy 2016”. It includes the increasing of the number of foreign workers who gain employment in Japan after graduation. They set the goal from 30% to 50% of the international job hunting students find jobs in Japan. Therefore, career education for international students has become an urgent issue to tackle with in Japan. In fact, many universities in Japan have started providing international students with career education such as business Japanese, business communication and career design. Since Japanese job hunting process is very unique, most foreign students have anxieties about it. The objective of this study is to propose an effective business Japanese learning support system. Our ultimate goal is to contribute to the enhancement of their employment rate in Japan

Gender and career advancement Women managers in the UK

SIGLEAvailable from British Library Document Supply Centre-DSC:9350.151(32) / BLDSC - British Library Document Supply CentreGBUnited Kingdo

SeMatching: using semantics to perform pair matching processes

Proceedings of: Second World Summit on the Knowledge Society (WSKS 2009), Chania, Crete, Greece, September 16-18, 2009.The importance of the human factor in 21st century organizations means that the competent development of professionals has become a key aspect. In this environment, mentoring has emerged as a common and efficient practice for the development of knowledge workers. Following the surge of concepts such as eMentoring, advancements of the Internet and its evolution towards a Semantic Web, such developments present novel opportunities for the improvement of the different characteristics of mentoring. Basing itself on such advancements, this paper presents SeMatching, a semantics-based platform which utilizes different personal and professional information to carry out pair matching of mentors and mentees.Publicad

Being female doing gender. Narratives of women in education management

The paper explores gender relations in academia and discusses how gender is constructed within academic institutions. It is based upon the study of a business school, part of a British university. The construction of gender relations within this institution was of special interest because the majority of managerial roles were occupied by women. All female academic managers (dean, associate deans and heads of department) and a random selection of female and male academics were interviewed. The process of construction of gender relations is investigated through the analysis of the discrepancy between the ‘masculine culture’ of high education institutions and the dominance of women managers within this organization. It is suggested that the numerical dominance of women managers may create tensions between their individual identities as women and their managerial identities, due to the predominance of masculine practices and values within the organization. Additionally, it emerged that the maintenance of masculine ideals and practices is also associated with downplaying women’s achievements