Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial

Background: Tranexamic acid reduces surgical bleeding and reduces death due to bleeding in patients with trauma. Meta-analyses of small trials show that tranexamic acid might decrease deaths from gastrointestinal bleeding. We aimed to assess the effects of tranexamic acid in patients with gastrointestinal bleeding. Methods: We did an international, multicentre, randomised, placebo-controlled trial in 164 hospitals in 15 countries. Patients were enrolled if the responsible clinician was uncertain whether to use tranexamic acid, were aged above the minimum age considered an adult in their country (either aged 16 years and older or aged 18 years and older), and had significant (defined as at risk of bleeding to death) upper or lower gastrointestinal bleeding. Patients were randomly assigned by selection of a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients received either a loading dose of 1 g tranexamic acid, which was added to 100 mL infusion bag of 0·9% sodium chloride and infused by slow intravenous injection over 10 min, followed by a maintenance dose of 3 g tranexamic acid added to 1 L of any isotonic intravenous solution and infused at 125 mg/h for 24 h, or placebo (sodium chloride 0·9%). Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcome was death due to bleeding within 5 days of randomisation; analysis excluded patients who received neither dose of the allocated treatment and those for whom outcome data on death were unavailable. This trial was registered with Current Controlled Trials, ISRCTN11225767, and ClinicalTrials.gov, NCT01658124. Findings: Between July 4, 2013, and June 21, 2019, we randomly allocated 12 009 patients to receive tranexamic acid (5994, 49·9%) or matching placebo (6015, 50·1%), of whom 11 952 (99·5%) received the first dose of the allocated treatment. Death due to bleeding within 5 days of randomisation occurred in 222 (4%) of 5956 patients in the tranexamic acid group and in 226 (4%) of 5981 patients in the placebo group (risk ratio [RR] 0·99, 95% CI 0·82–1·18). Arterial thromboembolic events (myocardial infarction or stroke) were similar in the tranexamic acid group and placebo group (42 [0·7%] of 5952 vs 46 [0·8%] of 5977; 0·92; 0·60 to 1·39). Venous thromboembolic events (deep vein thrombosis or pulmonary embolism) were higher in tranexamic acid group than in the placebo group (48 [0·8%] of 5952 vs 26 [0·4%] of 5977; RR 1·85; 95% CI 1·15 to 2·98). Interpretation: We found that tranexamic acid did not reduce death from gastrointestinal bleeding. On the basis of our results, tranexamic acid should not be used for the treatment of gastrointestinal bleeding outside the context of a randomised trial

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

THE IMPLICATIONS OF ATMOSPHERIC POLLEN RAIN FOR FOSSIL POLLEN PROFILES IN THE ARID SOUTHWEST (AEROBIOLOGY, PALAEOBOTANY, TAPHONOMY, PRESERVATION).

I compared atmospheric and soil pollen values to determine taphonomic influences on pollen in Southwestern soils. Burkard traps sampled atmospheric pollen for six years from multiple sites in Tucson, Arizona. Tauber and soil samples were collected for two years at Tumamoc Hill (Tucson). Morus, Ambrosia, Gramineae, and Chenopodiaceae-Amaranthus characterize Tucson's airborne pollen. Artemisia, Garrya and summer Pinus pollen are transported from the mountains. Annual pollen capture is similar between Burkard and Tauber samplers. Atmospheric pollen is seasonally variable; annual variability is low. Spatial variability among sites is low. Pollen concentrations vary widely among sites, but taxonomic composition remains constant. Reentrained soil pollen comprises 11% of the airborne pollen. Gramineae and Chenopodiaceae-Amaranthus pollen comprise 90% of the reentrained pollen. Pollen reentrainment varies seasonally. High maximum and minimum temperatures, low dew point and moderate wind speeds are associated with maximum atmospheric pollen concentrations. Winds preceding summer storms cause increased pollen concentrations. Deterioration characterizes pollen from soils. Chenopodiaceae-Amaranthus, Ambrosia, Other Compositae and Graminear are commonly found; Morus is rarely found. Pinus, Sphaeralcea, Boerhaavia and Kallstroemia are present in low numbers. These taxa have thick pollen walls, and they resist destruction. Seasonally collected soil samples have similar pollen spectra. Seasonal airborne pollen variability does not affect the soil pollen spectra. Inoculated soil pollen is well preserved, but pollen is lost rapidly. After one year, pollen concentrations approached background levels for seven of the eight pollen taxa tested. Solidago remained an order of magnitude higher. Pollen morphology may play a role in differential pollen loss. Pollen from the inoculated plots is lost through post-mortem transport. Pollen in soils is time-averaged and exhibits little temporal variability. The average airborne pollen spectra differs from the pollen in the soil. Soil pollen was degraded; inoculated plot pollen was well preserved. I conclude airborne pollen contributes little to the soil pollen of Tumamoc Hill. The soil pollen spectra is affected by selective- or non-deposition of airborne pollen (e.g. Morus), differential pollen destruction, and differential post mortem transport

An absolute pollen chronology of Seneca Lake, New York

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Imputation methods for addressing missing data in short-term monitoring of air pollutants

Monitoring of environmental contaminants is a critical part of exposure sciences research and public health practice. Missing data are often encountered when performing short-term monitoring (<24 h) of air pollutants with real-time monitors, especially in resource-limited areas. Approaches for handling consecutive periods of missing and incomplete data in this context remain unclear. Our aim is to evaluate existing imputation methods for handling missing data for real-time monitors operating for short durations. In a current field-study, realtime PM2.5 monitors were placed outside of 20 households and ran for 24-hours. Missing data was simulated in these households at four consecutive periods of missingness (20%, 40%, 60%, 80%). Univariate (Mean, Median, Last Observation Carried Forward, Kalman Filter, Random, Markov) and multivariate time-series (Predictive Mean Matching, Row Mean Method) methods were used to impute missing concentrations, and performance was evaluated using five error metrics (Absolute Bias, Percent Absolute Error in Means, R2 Coefficient of Determination, Root Mean Square Error, Mean Absolute Error). Univariate methods of Markov, random, and mean imputations were the best performingmethods that yielded 24-hour mean concentrations with the lowest error and highest R2 values across all levels of missingness. When evaluating error metrics minute-by-minute, Kalman filters, median, and Markov methods performed well at low levels of missingness (20-40%). However, at higher levels of missingness (60-80%), Markov, random, median, and mean imputation performed best on average. Multivariate methods were the worst performing imputation methods across all levels of missingness. Imputation using univariate methods may provide a reasonable solution to addressing missing data for short-term monitoring of air pollutants, especially in resource-limited areas. Further efforts are needed to evaluate imputation methods that are generalizable across a diverse range of study environments. (C) 2020 Elsevier B.V. All rights reserved.24 month embargo; published online: 3 May 2020This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Relation of dietary inorganic arsenic to serum matrix metalloproteinase-9 (MMP-9) at different threshold concentrations of tap water arsenic.

Arsenic (As) exposure is associated with cancer, lung and cardiovascular disease, yet the mechanisms involved are not clearly understood. Elevated matrix metalloproteinase-9 (MMP-9) levels are also associated with these diseases, as well as with exposure to water As. Our objective was to evaluate the effects of dietary components of inorganic As (iAs) intake on serum MMP-9 concentration at differing levels of tap water As. In a cross-sectional study of 214 adults, dietary iAs intake was estimated from 24-h dietary recall interviews using published iAs residue data; drinking and cooking water As intake from water samples and consumption data. Aggregate iAs intake (food plus water) was associated with elevated serum MMP-9 in mixed model regression, with and without adjustment for covariates. In models stratified by tap water As, aggregate intake was a significant positive predictor of serum MMP-9 in subjects exposed to water As≤10 μg/l. Inorganic As from food alone was associated with serum MMP-9 in subjects exposed to tap water As≤3 μg/l. Exposure to iAs from food and water combined, in areas where tap water As concentration is ≤10 μg/l, may contribute to As-induced changes in a biomarker associated with toxicity.U.S. EPA Star Grant # R83399201-0; University of Arizona Specialized Program of Research Excellence (SPORE) (NIH/NCI Grant # CA95060); Southwest Environmental Health Sciences Center (NIEHS Grant # ES06694)Published online 21 January 2015; 6 month embargo.This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]