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

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Training General Practitioners to Detect Probable Mental Disorders in Young People During Health Risk Screening.

The purpose of the study is to investigate whether a training intervention increases general practitioners' (GPs) detection sensitivity for probable mental disorders in young people. Forty general practices were randomized to an intervention (29 GPs) or comparison arm (49 GPs). Intervention GPs participated in 9 hours of interactive training on youth-friendly care, psychosocial health risk screening, and responding to risk-taking behavior with motivational interviewing approaches, followed by practice visits assisting with integration of screening processes and tools. Youth aged 14-24 years attending GPs underwent a computer-assisted telephone interview about their consultation and psychosocial health risks. Having a "probable mental disorder" was defined as either scoring high on Kessler's scale of psychological distress (K10) or self-perceived mental illness. Other definitions tested were high K10; self-perceived mental illness; and high K10 and self-perceived mental illness. Psychosocial health risk screening rates, detection sensitivity, and other accuracy parameters (specificity, positive predictive value, and negative predictive value) were estimated. GPs' detection sensitivity improved after the intervention if having probable mental disorder was defined as high K10 score and self-perceived mental illness (odds ratio: 2.81; 95% confidence interval: 1.23-6.42). There was no significant difference in sensitivity of GPs' detection for our preferred definition, high K10 or self-perceived mental illness (.37 in both; odds ratio: .93; 95% confidence interval: .47-1.83), and detection accuracy was comparable (specificity: .84 vs. .87, positive predictive values: .54 vs. .60, and negative predictive values: .72 vs. .72). Improving recognition of mental disorder among young people attending primary care is likely to require a multifaceted approach targeting young people and GPs

The relationship between the angle of the trochlear groove and patella cartilage and bone morphology – a cross-sectional study of healthy adults

SummaryObjectivesAlthough the geometry of the trochlear groove is considered important in the pathogenesis of patellofemoral joint pathology it is unclear how the shape of the trochlear groove relates to patella morphology. This cross-sectional study investigated the relationship between the shape of the trochlear groove and patella cartilage and bone morphology in healthy adults.MethodsTwo hundred and ninety-seven healthy adults aged between 50 and 79 years with no clinical history of knee pain or pathology were examined using magnetic resonance imaging (MRI). From the magnetic resonance (MR) images, the bony angles formed at the distal and proximal trochlear groove were measured, together with patella cartilage and bone volumes and patella cartilage defects.ResultsAfter adjustment for potential confounders, there was an 8.70mm3 (95% confidence interval (CI) 2.15, 15.26) increase in patella cartilage volume (P=0.009), with no increased prevalence of cartilage defects (odds ratio=0.99 (95% CI 0.96, 1.02), P=0.35), for every 1° increase (i.e., as the angle became more flatter) at the distal trochlear groove. Moreover, there was a 53.86mm3 (95% CI −90.26, −17.46) reduction in patella bone volume for every 1° that the angle at the distal trochlear groove became more flattened (P=0.004). No significant association between the proximal trochlear groove angle and the patella cartilage or bone properties was observed.ConclusionA more flattened bony angle at the distal trochlear groove was associated with increased patella cartilage volume and reduced patella bone volume, but no increased prevalence of patella cartilage defects in adults with no history of knee pain or clinical disease. These cross-sectional findings suggest that a flattened distal trochlear groove may protect against degenerative patellofemoral conditions, such as osteoarthritis, but this will need to be confirmed in a longitudinal study

Iron-Overload–Related Disease in HFE Hereditary hemochromatosis

Background: Most persons who are homozygous for C282Y, the HFE allele most commonly asssociated with hereditary hemochromatosis, have elevated levels of serum ferritin and transferrin saturation. Diseases related to iron overload develop in some C282Y homozygotes, but the extent of the risk is controversial. Methods: We assessed HFE mutations in 31,192 persons of northern European descent between the ages of 40 and 69 years who participated in the Melbourne Collaborative Cohort Study and were followed for an average of 12 years. In a random sample of 1438 subjects stratified according to HFE genotype, including all 203 C282Y homozygotes (of whom 108 were women and 95 were men), we obtained clinical and biochemical data, including two sets of iron measurements performed 12 years apart. Disease related to iron overload was defined as documented iron overload and one or more of the following conditions: cirrhosis, liver fibrosis, hepatocellular carcinoma, elevated aminotransferase levels, physician-diagnosed symptomatic hemochromatosis, and arthropathy of the second and third metacarpophalangeal joints. Results: The proportion of C282Y homozygotes with documented iron-overload–related disease was 28.4% (95% confidence interval [CI], 18.8 to 40.2) for men and 1.2% (95% CI, 0.03 to 6.5) for women. Only one non-C282Y homozygote (a compound heterozygote) had documented iron-overload–related disease. Male C282Y homozygotes with a serum ferritin level of 1000 μg per liter or more were more likely to report fatigue, use of arthritis medicine, and a history of liver disease than were men who had the wild-type gene. Conclusions: In persons who are homozygous for the C282Y mutation, iron-overload–related disease developed in a substantial proportion of men but in a small proportion of women

A novel association between a SNP in CYBRD1 and serum ferritin levels in a cohort study of HFE hereditary haemochromatosis

There is emerging evidence that there are genetic modifiers of iron indices for HFE gene mutation carriers at risk of hereditary hemochromatosis. A random sample, stratified by HFE genotype, of 863 from a cohort of 31 192 people of northern European descent provided blood samples for genotyping of 476 single nucleotide polymorphisms (SNPs) in 44 genes involved in iron metabolism. Single SNP association testing, using linear regression models adjusted for sex, menopause and HFE genotype, was conducted for four continuously distributed outcomes: serum ferritin (log transformed), transferrin saturation, serum transferrin, and serum iron. The SNP rs884409 in CYBRD1 is a novel modifier specific to HFE C282Y homozygotes. Median unadjusted serum ferritin concentration decreased from 1194 microg/l (N = 27) to 387 microg/l (N = 16) for male C282Y homozygotes and from 357 microg/l (N = 42) to 69 microg/l (N = 12) for females, comparing those with no copies to those with one copy of rs884409. Functional testing of this CYBRD1 promoter polymorphism using a heterologous expression assay resulted in a 30% decrease in basal promoter activity relative to the common genotype (P = 0.004). This putative genetic modifier of iron overload expression accounts for 11% (95% CI 0.4%, 22.6%) of the variance in serum ferritin levels of C282Y homozygotes