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

Microbiological growth testing and cytotoxic reaction testing for the assessment of water quality arising from its contact with non-metallic materials

The application of a microbiological growth test and a cytotoxic reaction test are reviewed as biological methods for the assessment of water quality.The microbiological growth test is based on the determination of oxygen consumption and micro-organism numbers following a period of incubation of the test material with a standard biological inoculum ; in the cytotoxic reaction test materials are examined for the release into water of substances that can give rise to a toxic reaction against an African Green Monkey Kidney (VERO) cell line. Both procedures have been developed as part of the United Kingdom Water Fittings Byelaws Scheme (UKWFBS) as requirements for the testing of non-metallic materials for use in contact with potable water. Test rationale and methodology are described, with regard to both practical and theoretical considerations. Test performance data covering a range of material types are presented and, where possible, comparisons made between the two methods and other tests (also used to assess water quality), including organoleptic and physical tests and chemical analysis of toxic elements. Future development and application of these biological assay procedures are briefly discussed

BET inhibitors synergize with venetoclax to induce apoptosis in MYC-driven lymphomas with high BCL-2 expression

Although the MYC oncogenic network represents an attractive therapeutic target for lymphoma, MYC inhibitors have been difficult to develop. Alternatively, inhibitors of epigenetic/ transcriptional regulators, particularly the bromodomain and extraterminal (BET) family, have been used to modulate MYC. However, current benzodiazepine-derivative BET inhibitors (BETi) elicit disappointing responses and dose-limiting toxicity in relapsed/refractory lymphoma, potentially because of enrichment of high-risk molecular features and chemical backbone-associated toxicities. Consequently, novel nonbenzodiazepine BETi and improved mechanistic understanding are required. Here we characterize the responses of aggressive MYC-driven lymphomas to 2 nonbenzodiazepine BETi: PLX51107 and PLX2853. Both invoked BIM-dependent apoptosis and in vivo therapy, associated with miR-17∼92 repression, in murine Eµ-myc lymphomas, with PLX2853 exhibiting enhanced potency. Accordingly, exogenous BCL-2 expression abrogated these effects. Because high BCL-2 expression is common in diffuse large B-cell lymphoma (DLBCL), BETi were ineffective in driving apoptosis and in vivo therapy of DLBCL cell lines, mirroring clinical results. However, BETi-mediated BIM upregulation and miR-17∼92 repression remained intact. Consequently, coadministration of BETi and ABT199/venetoclax restored cell death and in vivo therapy. Collectively, these data identify BIM-dependent apoptosis as a critical mechanism of action for this class of BETi that, via coadministration of BH3 mimetics, can deliver effective tumor control in DLBCL.</p

Treatment preferences for medication or surgery in patients with deep endometriosis and bowel involvement – a discrete choice experiment

Objective: To study the preferences of women with deep endometriosis (DE) with bowel involvement when they have to choose between conservative (medication) or surgical treatment. Design: Labelled discrete choice experiment (DCE). Setting: Dutch academic and non-academic hospitals and online recruitment. Population or Sample: A total of 169 women diagnosed with DE of the bowel. Methods: Baseline characteristics and the fear of surgery were collected. Women were asked to rank attributes and choose between hypothetical conservative or surgical treatment in different choice sets (scenarios). Each choice set offered different levels of all treatment attributes. Data were analysed by using multinomial logistic regression. Main Outcome Measures: The following attributes – effect on/risk of pain, fatigue, pregnancy, endometriosis lesions, mood swings, osteoporosis, temporary stoma and permanent intestinal symptoms – were used in this DCE. Results: In the ranking, osteoporosis was ranked with low importance, whereas in the DCE, a lower chance of osteoporosis was one of the most important drivers when choosing a conservative treatment. Women with previous surgery showed less fear of surgery compared with women without surgery. Low anterior resection syndrome was almost equally important for patients as the chance of pain reduction. Pain reduction had higher importance than improving fertility chances, even in women with desire for a future child. Conclusions: The risk of developing low anterior resection syndrome as a result of treatment is almost equally important as the reduction of pain symptoms. Women with previous surgery experience less fear of surgery compared with women without a surgical history. Tweetable Abstract: First discrete choice experiment in patients with deep endometriosis.Medical Instruments & Bio-Inspired Technolog

Fitase na alimentação da tilápia do Nilo (Oreochromis niloticus). Desempenho e digestibilidade Phytase as feeding for Nile tilapia (Oreochromis niloticus). Performance and digestibility

Este experimento foi realizado para avaliar os efeitos da adição de diferentes níveis de fitase (0, 500, 1500 e 3000 unidades de fitase ativa [UFA]/kg de ração) em dietas para a tilápia do Nilo (8,88 ± 0,02 g). Todas as rações foram fornecidas até saciedade durante 45 dias. O nível de fitase baseou-se nos parâmetros de desempenho e digestibilidade e foi estimado pelos modelos quadrático e/ou LRP ("broken line"). De acordo com os resultados obtidos com os níveis de fitase, o modelo LRP apresentou o melhor ajustamento de dados. A suplementação de fitase aumentou o desempenho, a retenção de minerais nos ossos, a digestibilidade da proteína e a disponibilidade de cálcio e fósforo. Os melhores resultados de desempenho, retenção de minerais nos ossos e digestibilidade foram obtidos com 700 UFA/kg de ração.<br>This experiment was carried out to evaluate the effects of addition of different levels of phytase (0, 500, 1500 and 3000 units of active phytase [UFA]/kg diet) in the diets for Nile tilapia (8.88 ± 0.02 g). All diets were fed to satiation daily for 45 days. The phytase level determination was based on the performance and digestibility parameters and was estimated by the quadratic and/or the broken line models. The broken line model showed a better adjustment for phytase levels according to the observed results. Phytase supplementation increased performence, bone minerals, protein digestibility and calcium and phosphorus availability. The best results of performance, bone mineral retentions and digestibility were obtained with 700 UFA/kg of diet