Fine-Scale Mapping of the 4q24 Locus Identifies Two Independent Loci Associated with Breast Cancer Risk

Background: A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored. Methods: We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium. Results: Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P = 2.51 × 10−4; OR, 1.04; 95% confidence interval (CI), 1.02–1.07] and rs77928427 (P = 1.86 × 10−4; OR, 1.04; 95% CI, 1.02–1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r2 ≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor–binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue. Conclusion: Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2. Impact: Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk

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

An assessment of the polar HOx photochemical budget based on 2003 Summit Greenland field observations

An interpretative modeling analysis is conducted to simulate the diurnal variations in OH and HO2 + RO2 observed at Summit, Greenland in 2003. The main goal is to assess the HOx budget and to quantify the impact of snow emissions on ambient HOx as well as on CH2O and H2O2. This analysis is based on composite diurnal profiles of HOx precursors recorded during a 3-day period (July 7-9), which were generally compatible with values reported in earlier studies. The model simulations can reproduce the observed diurnal variation in HO2 + RO2 when they are constrained by observations of H2O2 and CH2O. By contrast, model predictions of OH were about factor of 2 higher than the observed values. Modeling analysis of H2O2 suggests that its distinct diurnal variation is likely controlled by snow emissions and loss by deposition and/or scavenging. Similarly, deposition and/or scavenging sinks are needed to reproduce the observed diel profile in CH2O. This study suggests that for the Summit 2003 period snow emissions contribute similar to 25% of the total CH2O production, while photochemical oxidation of hydrocarbon appears to be the dominant source. A budget assessment of HOx radicals shows that primary production from O(D-1) + H2O and photolysis of snow emitted precursors (i.e., H2O2 and CH2O)are the largest primary HOx sources at Summit, contributing 41% and 40%, respectively. The snow contribution to the HOx budget is mostly in the form of emissions of H2O2. The dominant HO, sink involves the HO2 + HO2 reaction forming H2O2, followed by its deposition to snow. These results differ from those previously reported for the South Pole (SP), in that primary production of HOx was shown to be largely driven by both the photolysis of CH2O and H2O2 emissions (46%) with smaller contributions coming from the oxidation of CH4 and the 0(D-1) + H2O reaction (i.e., 27% each). In sharp contrast to the findings at Summit in 2003, due to the much higher levels of NOx the SP HO, sinks are dominated by HOx-NOx reactions, leading to the formation and deposition of HNO3 and HO2NO2. Thus, a comparison between SP and Summit studies suggests that snow emissions appear to play a prominent role in controlling primary HOx production in both environments. However, as regards to maintaining highly elevated levels of OH, the two environments differ substantially. At Summit the elevated rate for primary production of HOx is most important; whereas, at SP it is the rapid recycling of the more prevalent HO2 radical, through reaction with NO, back to OH that is primarily responsible

The management of acute necrotizing encephalitis: a review of 369 cases

SCOPUS: ar.jinfo:eu-repo/semantics/publishe