A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers

European Society for Vascular Surgery (ESVS) Certification of Theoretical and Practical Competences in Basic Vascular Ultrasound: Validity Investigation of the Assessment Tools

Objective: The aim of this study was to gather validity evidence for the Assessment of basic Vascular Ultrasound Expertise (AVAUSE) tool, and to establish a pass/fail score for each component, to support decisions for certification. Methods: A cross sectional validation study performed during the European Society for Vascular Surgery’s annual meeting.Validity evidence was sought for the theoretical test and two practical tests based on Messick’s framework. The participants were vascular surgeons, vascular surgical trainees, sonographers, and nurses with varying experience levels. Five vascular ultrasound experts developed the theoretical and two practical test components of the AVAUSE tool for each test component. Two stations were set up for carotid examinations and two for superficial venous incompetence (SVI) examinations. Eight raters were assigned in pairs to each station. Three methods were used to set pass/fail scores: contrasting groups’ method; rater consensus; and extended Angoff. Results: Nineteen participants were enrolled. Acceptable internal consistency reliability (Cronbach’s alpha) for the AVAUSE theoretical (0.93), carotid (0.84), and SVI (0.65) practical test were shown. In the carotid examination, inter-rater reliability (IRR) for the two rater pairs was good: 0.68 and 0.78, respectively. The carotid scores correlated significantly with years of experience (Pearson’s r 1⁄4 0.56, p 1⁄4 .013) but not with number of examinations in the last five years. For SVI, IRR was excellent at 0.81 and 0.87. SVI performance scores did not correlate with years of experience and number of examinations. The pass/fail score set by the contrasting groups’ method was 29 points out of 50. The rater set pass/fail scores were 3.0 points for both carotid and SVI examinations and were used to determine successful participants. Ten of 19 participants passed the tests and were certified. Conclusion: Validity evidence was sought and established for the AVAUSE comprehensive tool, including pass/fail standards. AVAUSE can be used to assess competences in basic vascular ultrasound, allowing operators to progress towards independent practice

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