Physical activity, sedentary time and breast cancer risk: a Mendelian randomisation study

Objectives: Physical inactivity and sedentary behaviour are associated with higher breast cancer risk in observational studies, but ascribing causality is difficult. Mendelian randomisation (MR) assesses causality by simulating randomised trial groups using genotype. We assessed whether lifelong physical activity or sedentary time, assessed using genotype, may be causally associated with breast cancer risk overall, pre/post-menopause, and by case-groups defined by tumour characteristics. Methods: We performed two-sample inverse-variance-weighted MR using individual-level Breast Cancer Association Consortium case-control data from 130 957 European-ancestry women (69 838 invasive cases), and published UK Biobank data (n=91 105–377 234). Genetic instruments were single nucleotide polymorphisms (SNPs) associated in UK Biobank with wrist-worn accelerometer-measured overall physical activity (nsnps=5) or sedentary time (nsnps=6), or accelerometer-measured (nsnps=1) or self-reported (nsnps=5) vigorous physical activity. Results: Greater genetically-predicted overall activity was associated with lower breast cancer overall risk (OR=0.59; 95% confidence interval (CI) 0.42 to 0.83 per-standard deviation (SD;~8 milligravities acceleration)) and for most case-groups. Genetically-predicted vigorous activity was associated with lower risk of pre/perimenopausal breast cancer (OR=0.62; 95% CI 0.45 to 0.87,≥3 vs. 0 self-reported days/week), with consistent estimates for most case-groups. Greater genetically-predicted sedentary time was associated with higher hormone-receptor-negative tumour risk (OR=1.77; 95% CI 1.07 to 2.92 per-SD (~7% time spent sedentary)), with elevated estimates for most case-groups. Results were robust to sensitivity analyses examining pleiotropy (including weighted-median-MR, MR-Egger). Conclusion: Our study provides strong evidence that greater overall physical activity, greater vigorous activity, and lower sedentary time are likely to reduce breast cancer risk. More widespread adoption of active lifestyles may reduce the burden from the most common cancer in women

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

Lectures on extremal set systems and two-colorings of hypergraphs

The aim of these lectures is to give a short introduction to two developing areas of combinatorics concerning hypergraphs. In the first part we present the main classical results in the theory of extremal set systems. The basic question is that how large can a family H of subsets of an underlying set X with n elements be if it satisfies a given intersection, union or inclusion property. We are also interested in what the set systems having maximum size look like. We try to illustrate the most fruitful methods of the theory. Furthermore, in Section 3, we also deal with a nice application to geometric problem. In the second part we consider two approaches for 2-colorings of hypergraphs. On the one hand we look for conditions that guarantee the existence of blocking sets -2-colorings of X without monochromatic members of H. On the other hand we investigate the possibility of a balanced 2-coloring: we would likt to divide X into two parts such that these parts divide the elements of H as evenly as possible. Of course we cannot expect that every member of H contains the same number of elements of the two color classes. Instead of this we investigate the discrepancy of the hypergraph - the measure of inevitable irregularities. Combining various ideas we will demonstrate the strength of the so-called probabilistic method, a powerful tool in combinatoricsSIGLEAvailable from TIB Hannover: RN 4052(93800) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekDEGerman

eLearning Among Medical Undergraduates: How Students Use Educational Materials

Background: With advances in technology and increasing access to a wide variety of learning resources online, how medical undergraduates study has changed considerably. How to make most effective use of these resources remains largely unanswered. Summary of Work: A 25-item survey was developed and distributed by email eliciting information on students’ use of educational resources. Fisher’s exact and Mann-Whitney U test were used. P<0.05 was taken as significant. Summary of Results: Students continue to find textbooks most beneficial (84%), followed by search engines (52%), podcasts (28%), Wikipedia (28%) and Pubmed or journals (19%). Use of electronic resources differed by stage of training, sex and previous degree. 42% of students usually evaluate the quality of evidence but 31% rarely do. Students who used pubmed/journals were more likely to evaluate the quality of evidence (p=0.008) and students who used Wikipaedia were less likely to (p=0.003). 73% of students base their study on the current topic that week, 68% according to forthcoming exams, and 28% based on patients seen and this differed by stage of training (p<0.001). Discussion and Conclusions: Use of electronic learning resources are popular amongst medical undergraduates although textbooks remain the most frequently used and popular resource. Use of resources changes by stage in training suggesting that students are acquiring study skills throughout their degrees. Take-home messages: Medical students require guidance throughout their course as to effective use and critical appraisal of learning resources and this is something that should be included by course designers

Clustering of IRE1alpha depends on sensing ER stress but not on its RNase activity

The sensors of the unfolded protein response react to endoplasmic reticulum (ER) stress by transient activation of their enzymatic activities, which initiate various signaling cascades. In addition, the sensor IRE1α exhibits stress-induced clustering in a transient time frame similar to activation of its endoRNase activity. Previous work had suggested that the clustering response and RNase activity of IRE1α are functionally linked, but here we show that they are independent of each other and have different behaviors and modes of activation. Although both clustering and the RNase activity are responsive to luminal stress conditions and to depletion of the ER chaperone binding protein, RNase-inactive IRE1α still clusters and, conversely, full RNase activity can be accomplished without clustering. The clusters formed by RNase-inactive IRE1α are much larger and persist longer than those induced by ER stress. Clustering requires autophosphorylation, and an IRE1α mutant whose RNase domain is responsive to ligands that bind the kinase domain forms yet a third type of stress-independent cluster, with distinct physical properties and half-lives. These data suggest that IRE1α clustering can follow distinct pathways upon activation of the sensor.-Ricci, D., Marrocco, I., Blumenthal, D., Dibos, M., Eletto, D., Vargas, J., Boyle, S., Iwamoto, Y., Chomistek, S., Paton, J. C., Paton, A. W., Argon, Y. Clustering of IRE1α depends on sensing ER stress but not on its RNase activity.Daniela Ricci, Ilaria Marrocco, Daniel Blumenthal, Miriam Dibos, Daniela Eletto, Jade Vargas, Sarah Boyle, Yuichiro Iwamoto, Steven Chomistek, James C. Paton, Adrienne W. Paton, and Yair Argo

Serum lactate and base deficit as predictors of mortality after ruptured abdominal aortic aneurysm repair.

OBJECTIVE Whole body hypoperfusion and lower torso ischaemia-reperfusion contribute to post-operative organ dysfunction in patients undergoing repair of ruptured abdominal aortic aneurysm (AAA). Serum lactate and base deficit are markers of tissue ischaemia and are used to assess the adequacy of resuscitation. This study examines the prognostic value of immediate post-operative levels of serum lactate and base deficit in ruptured AAA. METHODS Thirty patients (24 men and 6 women of median age 74, range 51-85, years) who survived to at least 12h after ruptured AAA repair were studied retrospectively. The relationship between immediate post-operative lactate, base deficit and mortality was determined. RESULTS Fifteen patients (50%) died, all from organ failure. An elevated lactate (>2.1 mmol/l) and base deficit ( or =4.0 mmol/l was 13 of 15 (87%) and 12 of 15 (80%), respectively, and base deficit or =4.0 mmol/l and base deficit or =-7 mmol/l were associated with a 4% probability of death. CONCLUSION These data demonstrate that an immediate post-operative serum lactate > or =4.0 mmol/l and base deficit < or =-7 mmol/l are good predictors of outcome after ruptured AAA repair. The prognostic value of these simple and inexpensive tests require corroboration in a larger prospective study

The Impact of Extension Services on Farm?level Income: An Instrumental Variable Approach to Combat Endogeneity Concerns

Agricultural extension is an important policy instrument utilized to diffuse knowledge and increase profitability among farmers. However, analyses on impact are subject to endogeneity concerns, causing multiple biases. Failure to combat endogeneity can lead to false inferences on impact. This article addresses this issue by applying an instrumental variable approach with distance to local advisory office and a policy change chosen as instruments for extension participation. The results show that participation significantly increased farm income and that OLS estimates underestimated the impact. Therefore, a superior estimate of impact is achieved which can be leveraged to better support accurate policy making