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

The Risk of Diarrhea and Colitis in Patients with Lung Cancer Treated with Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis

Background: Immune checkpoint inhibitors (icis), including inhibitors of PD-1, PD-L1, and ctla-4, are relatively novel therapies for lung cancer, although their use might be limited by gastrointestinal toxicity. The aim of the present study was to determine the risk of diarrhea and colitis associated with icis in lung cancer and the rates of discontinuation because of those toxicities. Methods: Electronic databases were searched for prospective trials reporting the risk of diarrhea and colitis in patients with lung cancer treated with PD-1, PD-L1, and ctla-4 inhibitors. The incidences of diarrhea and colitis and their grades were assessed clinically using standardized reporting criteria. Pooled incidence and weighted relative risk estimates for diarrhea and colitis with 95% confidence intervals (cis) were estimated using a random effects model. The incidence of discontinuations for gi toxicity was also calculated. Results: Twenty-seven studies were included: sixteen studies with PD-1 inhibitors, nine studies with PD-L1 inhibitors, and four studies combining PD-based strategies with ctla-4 inhibitors. The incidence of all-grade diarrhea was 9.1% (95% ci: 7.8% to 10.5%) for anti–PD-1 therapy and 11.0% (95% ci: 7.5% to 14.5%) for anti–PD-L1 therapy. The incidence of all-grade colitis was 0.9% (95% ci: 0.4% to 1.3%) for anti–PD-1 therapy and 0.4% (95% ci: 0.0% to 0.8%) for anti–PD-L1 therapy. The relative risk for all-grade diarrhea was higher with combination anti–PD-1 and anti–ctla-4 than with anti–PD-1 monotherapy (relative risk: 1.61; 95% ci: 1.14 to 2.29). Anti–PD-1 therapy was discontinued in 4.1% of patients with diarrhea (95% ci: 0.7% to 7.4%) and in 35.7% of those with colitis (95% ci: 0.0% to 81.1%); combination therapy was discontinued in 10.1% of patients with diarrhea (95% ci: 4.8% to 15.4%) and in 39.9% of those with colitis (95% ci: 3.9% to 75.9%). Conclusions: Diarrhea is a relatively frequently encountered gi toxicity when ici therapy is used in lung cancer treatment. Colitis is less frequently encountered, although when it does occur, it often results in therapy discontinuation

A comparison of medical physics training and education programs: Canada and Australia

An overview and comparison of medical physics clinical training, academic education, and national certification/accreditation of individual professionals in Canada and Australia is presented. Topics discussed include program organization, funding, fees, administration, time requirements, content, program accreditation, and levels of certification/accreditation of individual Medical Physicists. Differences in the training, education, and certification/accreditation approaches between the two countries are highlighted. The possibility of mutual recognition of certified/accredited Medical Physicists is examined

Herbicide-Resistance in Turf Systems: Insights and Options for Managing Complexity

Due to complex interactions between social and ecological systems, herbicide resistance has classic features of a “wicked problem.” Herbicide-resistant (HR) Poa annua poses a risk to sustainably managing U.S. turfgrass systems, but there is scant knowledge to guide its management. Six focus groups were conducted throughout the United States to gain understanding of socio-economic barriers to adopting herbicide-resistance management practices. Professionals from major turfgrass sectors (golf courses, sports fields, lawn care, and seed/sod production) were recruited as focus-group participants. Discussions emphasized challenges of the weed management of turfgrass systems as compared to agronomic crops. This included greater time constraints for managing weeds and more limited chemical control options. Lack of understanding about the proper use of compounds with different modes of action was identified as a threat to sustainable weed management. There were significant regional differences in perceptions of the existence, geographic scope, and social and ecological causes of HR in managing Poa annua. Effective resistance management will require tailoring chemical and non-chemical practices to the specific conditions of different turfgrass sectors and regions. Some participants thought it would be helpful to have multi-year resistance management programs that are both sector- and species-specific. © 2022 by the authors.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]