Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer

Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 × 10−8) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER- negative loci combined account for ~11% of familial relative risk for ER- negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction

Integrative Taxonomy, a New Tool for Fisheries Conservation

Species delimitation is becoming increasingly objective and integrative. Sequence capture approaches allow collection of 1000s of loci for 100s of individuals. New approaches address the computational challenges of large datasets and offer potential for genome-wide sampling of variation at different evolutionary scales. These new approaches also allow integration of genetic and non-genetic data in a unified framework. Despite these advances, few studies have attempted to combine genetic and morphological data for delimiting species. Hakes (Merluccius spp.) are an ideal group for an empirical test of the power and applicability of these new methods because they are morphologically conserved and have distributional patterns ideal for studying a broad range of evolutionary questions. They also are of economic and conservation concern so the results of this phylogenetic study can be directly applied to fisheries management. Hakes are demersal fishes that inhabit the continental shelf and slope of the Atlantic, Pacific, and around New Zealand and there are 16 putative species. Hakes can be difficult to identify due to their conservative external morphology and high level of intraspecific variation, resulting in serious identification problems. Many species of hakes are sympatric and there is moderate ecological overlap. Unresolved alpha taxonomy and the lack of diagnostic characters have led to mixed-species in landings data, making management and conservation difficult. This study uses a broad taxonomic and geographic sampling combined with new morphological and genetic characters to clarify the taxonomy, systematics and the global biogeography and diversification of hake species

Understanding the potential of Sentinel-2 for monitoring methane point emissions

The use of satellite instruments to detect and quantify methane emissions from fossil fuel production activities is highly beneficial to support climate change mitigation. Different hyperspectral and multispectral satellite sensors have recently shown potential to detect and quantify point-source emissions from space. The Sentinel-2 (S2) mission, despite its limited spectral design, supports the detection of large emissions with global coverage and high revisit frequency thanks to coarse spectral coverage of methane absorption lines in the shortwave infrared. Validation of S2 methane retrieval algorithms is instrumental in accelerating the development of a systematic and global monitoring system for methane point sources. Here we develop a benchmarking framework for such validation. We first develop a methodology to generate simulated S2 datasets including methane point-source plumes. These benchmark datasets have been created for scenes in three oil and gas basins (Hassi Messaoud, Algeria; Korpeje, Turkmenistan; Permian Basin, USA) under different scene heterogeneity conditions and for simulated methane plumes with different spatial distributions. We use the simulated methane plumes to validate the retrieval for different flux rate levels and define a minimum detection threshold for each case study. The results suggest that for homogeneous surfaces, the detection limit of the proposed S2 methane retrieval ranges from 1000 kg h&minus;1 to 2000 kg h&minus;1, whereas for areas with large surface heterogeneity, the retrieval can only detect plumes in excess of 5000 kg h&minus;1. The different sources of uncertainty in the flux rate estimates have also been examined. Dominant quantification errors are either wind-related or plume mask-related, depending on the surface type. Uncertainty in wind speed, both in the 10-m wind (U10) and in mapping U10 to the effective wind (Ueff ) driving plume transport, is the dominant source of error for quantifying individual plumes in homogeneous scenes. For heterogeneous scenes, the surface structure underlying the methane plume affects the plume masking and can become a dominant source of uncertainty.</p

Quantification of Linear and Nonlinear Cardiorespiratory Interactions under Autonomic Nervous System Blockade

This paper proposes a methodology to extract both linear and nonlinear respiratory influences from the heart rate variability (HRV), by decomposing the HRV into a respiratory and a residual component. This methodology is based on least-squares support vector machines (LS-SVM) formulated for nonlinear function estimation. From this decomposition, a better estimation of the respiratory sinus arrhythmia (RSA) and the sympathovagal balance (SB) can be achieved. These estimates are first analyzed during autonomic blockade and an orthostatic maneuver, and then compared against the classical HRV and a model that considers only linear interactions. Results are evaluated using surrogate data analysis and they indicate that the classical HRV and the linear model underestimate the cardiorespiratory interactions. Moreover, the linear and nonlinear interactions appear to be mediated by different control mechanisms. These findings will allow to better assess the ANS and to improve the understanding of the interactions within the cardiorespiratory system

Effect of the Heart Rate Variability Representations on the Quantification of the Cardiorespiratory Interactions during Autonomic Nervous System Blockade

The Heart Rate Variability (HRV) is a noninvasive tool to evaluate the activity of the autonomic nervous system. To study the HRV, different mathematical representations can be used. The selection of a representation might have an effect on the evaluation of the mechanisms that modulate the Heart Rate (HR). One of these mechanisms is the Respiratory Sinus Arrhythmia (RSA), i.e. an increased HR during inhalation and a decreased HR during exhalation. Different methods exist to quantify the RSA. A common approach is to calculate the power in the High Frequency (HF, 0.15 - 0.4 Hz) band of the spectrum of the HRV representation. More recently proposed methods use the respiratory signals to estimate the strength of the RSA.This paper studies the effect of the HRV representations on the quantification of the RSA. To this end, an experiment is used in which the sympathetic and parasympathetic branches of the autonomic nervous system are selectively blocked. Three different HRV representations are considered. Afterwards, the strength of the RSA is estimated using three approaches, namely the spectral content in the HF band of the HRV representations, orthogonal subspace projections and a time-frequency representation.The results suggest that the selection of an HRV representation does not have a significant impact on the RSA estimates in a healthy population

Prevalence, underlying causes, and preventability of sepsis-associated mortality in US acute care hospitals

Importance: Sepsis is present in many hospitalizations that culminate in death. The contribution of sepsis to these deaths, and the extent to which they are preventable, is unknown. Objective: To estimate the prevalence, underlying causes, and preventability of sepsis-associated mortality in acute care hospitals. Design, Setting, and Participants: Cohort study in which a retrospective medical record review was conducted of 568 randomly selected adults admitted to 6 US academic and community hospitals from January 1, 2014, to December 31, 2015, who died in the hospital or were discharged to hospice and not readmitted. Medical records were reviewed from January 1, 2017, to March 31, 2018. Main Outcomes and Measures: Clinicians reviewed cases for sepsis during hospitalization using Sepsis-3 criteria, hospice-qualifying criteria on admission, immediate and underlying causes of death, and suboptimal sepsis-related care such as inappropriate or delayed antibiotics, inadequate source control, or other medical errors. The preventability of each sepsis-associated death was rated on a 6-point Likert scale. Results: The study cohort included 568 patients (289 [50.9%] men; mean [SD] age, 70.5 [16.1] years) who died in the hospital or were discharged to hospice. Sepsis was present in 300 hospitalizations (52.8%; 95% CI, 48.6%-57.0%) and was the immediate cause of death in 198 cases (34.9%; 95% CI, 30.9%-38.9%). The next most common immediate causes of death were progressive cancer (92 [16.2%]) and heart failure (39 [6.9%]). The most common underlying causes of death in patients with sepsis were solid cancer (63 of 300 [21.0%]), chronic heart disease (46 of 300 [15.3%]), hematologic cancer (31 of 300 [10.3%]), dementia (29 of 300 [9.7%]), and chronic lung disease (27 of 300 [9.0%]). Hospice-qualifying conditions were present on admission in 121 of 300 sepsis-associated deaths (40.3%; 95% CI 34.7%-46.1%), most commonly end-stage cancer. Suboptimal care, most commonly delays in antibiotics, was identified in 68 of 300 sepsis-associated deaths (22.7%). However, only 11 sepsis-associated deaths (3.7%) were judged definitely or moderately likely preventable; another 25 sepsis-associated deaths (8.3%) were considered possibly preventable. Conclusions and Relevance: In this cohort from 6 US hospitals, sepsis was the most common immediate cause of death. However, most underlying causes of death were related to severe chronic comorbidities and most sepsis-associated deaths were unlikely to be preventable through better hospital-based care. Further innovations in the prevention and care of underlying conditions may be necessary before a major reduction in sepsis-associated deaths can be achieved

Detecting and quantifying methane emissions from oil and gas production: algorithm development with ground-truth calibration based on Sentinel-2 satellite imagery

Sentinel-2 satellite imagery has been shown by studies to be capable of detecting and quantifying methane emissions from oil and gas production. However, current methods lack performance calibration with ground-truth testing. This study developed a multi-band–multi-pass–multi-comparison-date methane retrieval algorithm that enhances Sentinel-2 sensitivity to methane plumes. The method was calibrated using data from a large-scale controlled-release test in Ehrenberg, Arizona, in fall 2021, with three algorithm parameters tuned based on the true emission rates. Tuned parameters are the pixel-level concentration upper-bound threshold during extreme value removal, the number of comparison dates, and the pixel-level methane concentration percentage threshold when determining the spatial extent of a plume. We found that a low value of the upper-bound threshold during extreme value removal can result in false negatives. A high number of comparison dates helps enhance the algorithm sensitivity to the plumes in the target date, but values in excess of 12 d are neither necessary nor computationally efficient. A high percentage threshold when determining the spatial extent of a plume helps enhance the quantification accuracy, but it may harm the yes/no detection accuracy. We found that there is a trade-off between quantification accuracy and detection accuracy. In a scenario with the highest quantification accuracy, we achieved the lowest quantification error and had zero false-positive detections; however, the algorithm missed three true plumes, which reduced the yes/no detection accuracy. In contrast, all of the true plumes were detected in the highest detection accuracy scenario, but the emission rate quantification had higher errors. We illustrated a two-step method that updates the emission rate estimates in an interim step, which improves quantification accuracy while keeping high yes/no detection accuracy. We also validated the algorithm's ability to detect true positives and true negatives in two application studies.</p