5 research outputs found
Global On-line, Interactive and Simulated Learning Techniques via BIRS
Role-playing simulations have been effective techniques to encourage global skills in the engineering and design classrooms. May, Wold and Moore (2014), defined global skills as student display of respect, recognition, adjustment and integration. Gray, Debs, Exter, and Krause (2016), took this one step further and looked-for empathy in the design classroom. This has yet to be realized in the regulatory science education realm. Therefore, there is a need for on-line, interactive regulatory science education focusing on global skill outcomes. To assess the gap, four sets of data are collected. The first set was a review of evaluations from a regulatory science course teaching documents and dialogues necessary for drug and device approvals. The evaluations stated that more global skills, problem-solving and innovation needed to be a part of the curricula. The course was reformatted and an interactive simulation called the BIRS Experience included. The second data set came from the studentâs final assignments after the BIRS Experience was delivered. The assignments were analyzed for global skills and creative inquiry movements. The students participating in the BIRS Experience were both from the United States and Tanzania. Both sets of participants again answered questions after a regulatory intelligence workshop. This was the third data set. The comments from the questionnaire were analyzed for global skills and creative inquiry movements. The fourth data set was answers to a world cafĂ© experience delivered at a quality and regulatory affairs summit. In this case, the participants were working professionals asked what competencies were needed for the regulatory science discipline moving forward, again, comments were analyzed for global skills and creative inquiry movements. The theme of needing both global skills and creative inquiry movements was consistent in all four data sets
Genetic mechanisms of critical illness in COVID-19.
Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, PÂ =Â 1.65Â ĂÂ 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, PÂ =Â 2.3Â ĂÂ 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, PÂ =Â 3.98Â ĂÂ Â 10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, PÂ =Â 4.99Â ĂÂ 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice
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Differential relationships of hepatic and epicardial fat to body composition in HIV
Abstract HIVâinfected patients commonly experience changes in central and peripheral fat content as well as ectopic fat accumulation. However, whether hepatic and epicardial fat stores relate differentially to body composition or how these associations are modified by HIV status has not been well explored. A previously recruited sample of 124 HIVâinfected patients and 58 healthy controls had undergone dual energy Xâray absorptiometry (DEXA) and computed tomography (CT) from which body composition measures, liverâspleen ratio, and epicardial fat volume were obtained. Unique to the HIVâinfected group, there was a parabolic association between abdominal subcutaneous adipose tissue (SAT) area and liverâspleen ratio (P = 0.03, inflection point 324 cm2) such that hepatic fat content was greatest at the extremes of low and high SAT. A quadratic model also closely described the relationship between mean leg fat and liverâspleen ratio among patients with HIV (P = 0.02, inflection point 4.7 kg), again suggesting greater liver fat content with both low and high leg fat. Notably, an analogous relationship of epicardial fat with SAT was not evident among HIVâinfected individuals or healthy controls. In contrast, visceral adipose tissue (VAT) linearly related to both liverâspleen ratio in HIV and epicardial fat volume irrespective of HIV status in multivariable models. In conclusion, our analyses implicate both low and high SAT as risk factors for hepatic fat accumulation in HIV. These findings add to growing evidence of SAT dysfunction in the setting of HIV infection, and highlight key physiologic differences between hepatic and epicardial fat depots
Whole-genome sequencing reveals host factors underlying critical COVID-19
Altres ajuts: Department of Health and Social Care (DHSC); Illumina; LifeArc; Medical Research Council (MRC); UKRI; Sepsis Research (the Fiona Elizabeth Agnew Trust); the Intensive Care Society, Wellcome Trust Senior Research Fellowship (223164/Z/21/Z); BBSRC Institute Program Support Grant to the Roslin Institute (BBS/E/D/20002172, BBS/E/D/10002070, BBS/E/D/30002275); UKRI grants (MC_PC_20004, MC_PC_19025, MC_PC_1905, MRNO2995X/1); UK Research and Innovation (MC_PC_20029); the Wellcome PhD training fellowship for clinicians (204979/Z/16/Z); the Edinburgh Clinical Academic Track (ECAT) programme; the National Institute for Health Research, the Wellcome Trust; the MRC; Cancer Research UK; the DHSC; NHS England; the Smilow family; the National Center for Advancing Translational Sciences of the National Institutes of Health (CTSA award number UL1TR001878); the Perelman School of Medicine at the University of Pennsylvania; National Institute on Aging (NIA U01AG009740); the National Institute on Aging (RC2 AG036495, RC4 AG039029); the Common Fund of the Office of the Director of the National Institutes of Health; NCI; NHGRI; NHLBI; NIDA; NIMH; NINDS.Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care or hospitalization 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