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

Fitotoxicidade de três antibióticos na cultura in vitro de abacateiro Phytotoxicity of three antibiotics to avocado tissue culture

Desenvolveram-se dois experimentos para verificar o efeito do ácido nalidíxico, do cloranfenicol e da estreptomicina sobre a cultura in vitro do abacateiro 'Ouro Verde'. No primeiro, testou-se a influência de diversas concentrações (0, 12,5, 25, 50, 100 e 200 mg/L) desses antibióticos sobre a calogênese de discos foliares e, no segundo, o efeito sobre a brotação de gemas de segmentos nodais. Enquanto a formação de calos foi reduzida à metade com o uso de 50 mg/L de cloranfenicol, sua massa foi drasticamente reduzida já na concentração de 12,5 mg/L. Restringiu-se o comprimento das brotações, adicionando os antibióticos ao meio de cultura, concluindo-se que os três foram tóxicos para o abacateiro, sendo recomendados apenas em casos de extrema necessidade, dependendo da suscetibilidade do microorganismo contaminante e da concentração necessária para seu controle.<br>Two experiments were carried out in order to verify the toxicity of nalidixic acid, chloramphenicol and streptomycin to avocado 'Ouro Verde' in vitro culture. In the first experiment, it was tested the effect of the antibiotics to callus initiation on leave explants, using a concentration range of 0, 12.5, 25, 50, 100 and 200 mg/L. In the second experiment, sprouting from nodal segments were tested. The callus formation was reduced by 50% with 50 mg/L of chloramphenicol and the highest reduction in callus weight was observed with 12.5 mg/L. The length of sprouts was reduced by incorporating antibiotics into plant growth medium. Results showed that the three antibiotics were toxic to avocado, and they must be used only in real necessity cases, depending on the bacterial susceptibility and the adequate concentration to control the contaminants

When Can We Rely on Real‐World Evidence to Evaluate New Medical Treatments?

Concerns regarding both the limited generalizability and the slow pace of traditional randomized trials have led to calls for greater use of real-world evidence (RWE) in the evaluation of new treatments or products. The RWE label has been used to refer to a variety of departures from the methods of traditional randomized controlled trials. Recognizing this complexity and potential confusion, the National Academies of Science, Engineering, and Medicine convened a series of workshops to clarify and address questions regarding the use of RWE to evaluate new medical treatments. Those workshops identified three specific dimensions in which RWE studies might differ from traditional clinical trials: use of real-world data (data extracted from health system records or data captured by mobile devices), delivery of real-world treatment (open-label treatments delivered in community settings by community practitioners), and real-world treatment assignment (including nonrandomized comparisons and variations on random assignment such as before-after or stepped-wedge designs). For any RWE study, decisions regarding each of these dimensions depends on the specific research question, characteristics of the potential study settings, and characteristics of the settings where study results would be applied