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

Problem solving for breast health care delivery in low and middle resource countries (LMCs): consensus statement from the Breast Health Global Initiative.

Item does not contain fulltextInternational collaborations like the Breast Health Global Initiative (BHGI) can help low and middle income countries (LMCs) to establish or improve breast cancer control programs by providing evidence-based, resource-stratified guidelines for the management and control of breast cancer. The Problem Solving Working Group of the BHGI 2010 Global Summit met to develop a consensus statement on problem-solving strategies addressing breast cancer in LMCs. To better assess breast cancer burden in poorly studied populations, countries require accurate statistics regarding breast cancer incidence and mortality. To better identify health care system strengths and weaknesses, countries require reasonable indicators of true health system quality and capacity. Using qualitative and quantitative research methods, countries should formulate cancer control strategies to identify both system inefficiencies and patient barriers. Patient navigation programs linked to public advocacy efforts feed and strengthen functional early detection and treatment programs. Cost-effectiveness research and implementation science are tools that can guide and expand successful pilot programs.1 april 201

Breast cancer management in middle-resource countries (MRCs): consensus statement from the Breast Health Global Initiative.

In middle resource countries (MRCs), cancer control programs are becoming a priority as the pattern of disease shifts from infectious diseases to non-communicable diseases such as breast cancer, the most common cancer among women in MRCs. The Middle Resource Scenarios Working Group of the BHGI 2010 Global Summit met to identify common issues and obstacles to breast cancer detection, diagnosis and treatment in MRCs. They concluded that breast cancer early detection programs continue to be important, should include clinical breast examination (CBE) with or without mammography, and should be coupled with active awareness programs. Mammographic screening is usually opportunistic and early detection programs are often hampered by logistical and financial problems, as well as socio-cultural barriers, despite improved public educational efforts. Although multidisciplinary services for treatment are available, geographical and economic limitations to these services can lead to an inequity in health care access. Without adequate health insurance coverage, limited personal finances can be a significant barrier to care for many patients. Despite the improved availability of services (surgery, pathology, radiology and radiotherapy), quality assurance programs remain a challenge. Better access to anticancer drugs is needed to improve outcomes, as are rehabilitation programs for survivors. Focused and sustained government health care financing in MRCs is needed to improve early detection and treatment of breast cancer