Testosterone supplementation is commonly used for its effects on sexual function, bone health and body composition, yet its effects on disease outcomes are unknown. To better understand this, we ...identified genetic determinants of testosterone levels and related sex hormone traits in 425,097 UK Biobank study participants. Using 2,571 genome-wide significant associations, we demonstrate that the genetic determinants of testosterone levels are substantially different between sexes and that genetically higher testosterone is harmful for metabolic diseases in women but beneficial in men. For example, a genetically determined 1 s.d. higher testosterone increases the risks of type 2 diabetes (odds ratio (OR) = 1.37 (95% confidence interval (95% CI): 1.22-1.53)) and polycystic ovary syndrome (OR = 1.51 (95% CI: 1.33-1.72)) in women, but reduces type 2 diabetes risk in men (OR = 0.86 (95% CI: 0.76-0.98)). We also show adverse effects of higher testosterone on breast and endometrial cancers in women and prostate cancer in men. Our findings provide insights into the disease impacts of testosterone and highlight the importance of sex-specific genetic analyses.
Investigation of activity budgets in relation to seasonal, intrinsic (age, sex) and extrinsic (time of day, spatial) covariates enables an understanding of how such covariates shape behavioural ...strategies. However, conducting such investigations in the wild is challenging, because of the required large sample size of individuals across the annual cycle, and difficulties in categorising behavioural states and analysing the resulting individual‐referenced and serially correlated data. In this study, from telemetry tags deployed on 63 grey seals Halichoerus grypus and 126 harbour seals Phoca vitulina we used behavioural data, and movement data within a Bayesian state–space model (SSM), to define population‐level activity budgets around Britain. Using generalised estimating equations (GEEs) we then examined how time spent in four states (resting on land (hauled out), resting at sea, foraging and travelling) was influenced by seasonal, intrinsic and extrinsic covariates. We present and discuss the following key findings. 1) We found no evidence that regional variation in foraging effort was linked to regional population trajectories in harbour seals. 2) Grey seals demonstrated sex‐specific seasonal differences in their activity budgets, independent from those related to reproductive costs. 3) In these sympatric species there was evidence of temporal separation in time hauled out, but not in time foraging. 4) In both species, time spent resting at sea was separated into inshore (associated with tidal haul out availability) and offshore areas. Time spent resting at sea and on land was interchangeable to some extent, suggesting a degree of overlap in their functionality. This may result in a relaxation of the constraints associated with a central place foraging strategy. More generally, we demonstrate how a large dataset, incorporating differing tag parameters, can be analysed to define activity budgets and subsequently address important ecological questions.
The successful development of high-performance, durable platinum group metal-free (PGM-free) electrocatalysts and electrodes for polymer electrolyte membrane fuel cells (PEMFCs) will ultimately ...improve the cost-competiveness of fuel cells in a wide range of applications. This is considered to be a critical development especially for automotive fuel cell applications in order to bring the system cost of an automotive fuel cell system down to the $30/kW cost target set by the U.S. Department of Energy (DOE). The platinum group metal (PGM) electrocatalysts are a major contributor to the system cost. Addressing the technical challenges to PGM-free electrocatalyst and electrode development, therefore, represents one of DOE's most pressing research and development (R&D) priorities. ElectroCat was formed by the DOE as part of the Energy Materials Network (EMN) in early 2016, and shares with other EMN consortia the goal of decreasing the time to market for advanced materials related to clean energy technologies, in the context of increasing U.S. fuel cell electric vehicle (FCEV) manufacturing competitiveness. To accomplish this, the consortium performs core research and development and provides universities and companies streamlined access to the unique, world-class set of tools and expertise relevant to early-stage applied PGM-free catalyst R&D of the member national laboratories. Moreover, ElectroCat fosters a systematic methodology by which prospective catalysts and electrodes are prepared and analyzed rapidly and comprehensively using high-throughput, combinatorial methods. Catalyst discovery is augmented by theory as well as foundational electrocatalysis and materials knowledge at the participating national laboratories. Furthermore, ElectroCat has developed a data sharing framework, requisite of all EMN consortia, for disseminating its findings to the public via a searchable database, to further expedite incorporation of PGM-free electrocatalysts into next-generation fuel cells by advancing the general understanding of the PGM-free electrocatalyst field.
•PGM-free catalysts essential to increase economic competitiveness of PEMFCs.•ElectroCat couples U.S. DOE national lab expertise with academic/industry partners for PGM-free catalyst and electrode R&D.•High-throughput, combinatorial methods expedite catalyst discovery and elucidate structure-function relationships.•Early experimental accomplishments include first direct observation of single-atom Fe sites in PGM-free catalyst.•Early computational accomplishments include an automated active site durability descriptor calculation.
Mendelian randomization is the use of genetic variants as instrumental variables to estimate causal effects of risk factors on outcomes. The total causal effect of a risk factor is the change in the ...outcome resulting from intervening on the risk factor. This total causal effect may potentially encompass multiple mediating mechanisms. For a proposed mediator, the direct effect of the risk factor is the change in the outcome resulting from a change in the risk factor, keeping the mediator constant. A difference between the total effect and the direct effect indicates that the causal pathway from the risk factor to the outcome acts at least in part via the mediator (an indirect effect). Here, we show that Mendelian randomization estimates of total and direct effects can be obtained using summarized data on genetic associations with the risk factor, mediator, and outcome, potentially from different data sources. We perform simulations to test the validity of this approach when there is unmeasured confounding and/or bidirectional effects between the risk factor and mediator. We illustrate this method using the relationship between age at menarche and risk of breast cancer, with body mass index (BMI) as a potential mediator. We show an inverse direct causal effect of age at menarche on risk of breast cancer (independent of BMI), and a positive indirect effect via BMI. In conclusion, multivariable Mendelian randomization using summarized genetic data provides a rapid and accessible analytic strategy that can be undertaken using publicly available data to better understand causal mechanisms.
Mosaic loss of chromosome Y (LOY) in circulating white blood cells is the most common form of clonal mosaicism
, yet our knowledge of the causes and consequences of this is limited. Here, using a ...computational approach, we estimate that 20% of the male population represented in the UK Biobank study (n = 205,011) has detectable LOY. We identify 156 autosomal genetic determinants of LOY, which we replicate in 757,114 men of European and Japanese ancestry. These loci highlight genes that are involved in cell-cycle regulation and cancer susceptibility, as well as somatic drivers of tumour growth and targets of cancer therapy. We demonstrate that genetic susceptibility to LOY is associated with non-haematological effects on health in both men and women, which supports the hypothesis that clonal haematopoiesis is a biomarker of genomic instability in other tissues. Single-cell RNA sequencing identifies dysregulated expression of autosomal genes in leukocytes with LOY and provides insights into why clonal expansion of these cells may occur. Collectively, these data highlight the value of studying clonal mosaicism to uncover fundamental mechanisms that underlie cancer and other ageing-related diseases.
Both estrous cycle and sex affect the numbers and types of neuronal and glial profiles containing the classical estrogen receptors α and β, and synaptic levels in the rodent dorsal hippocampus. Here, ...we examined whether the membrane estrogen receptor, G-protein-coupled estrogen receptor 1 (GPER1), is anatomically positioned in the dorsal hippocampus of mice to regulate synaptic plasticity. By light microscopy, GPER1-immunoreactivity (IR) was most noticeable in the pyramidal cell layer and interspersed interneurons, especially those in the hilus of the dentate gyrus. Diffuse GPER1-IR was found in all lamina but was most dense in stratum lucidum of CA3. Ultrastructural analysis revealed discrete extranuclear GPER1-IR affiliated with the plasma membrane and endoplasmic reticulum of neuronal perikarya and dendritic shafts, synaptic specializations in dendritic spines, and clusters of vesicles in axon terminals. Moreover, GPER1-IR was found in unmyelinated axons and glial profiles. Overall, the types and amounts of GPER1-labeled profiles were similar between males and females; however, in females elevated estrogen levels generally increased axonal labeling. Some estradiol-induced changes observed in previous studies were replicated by the GPER agonist G1: G1 increased PSD95-IR in strata oriens, lucidum, and radiatum of CA3 in ovariectomized mice 6 h after administration. In contrast, estradiol but not G1 increased Akt phosphorylation levels. Instead, GPER1 actions in the synapse may be due to interactions with synaptic scaffolding proteins, such as SAP97. These results suggest that although estrogen's actions via GPER1 may converge on the same synaptic elements, different pathways are used to achieve these actions.
Insulinemia and type 2 diabetes (T2D) have been associated with endometrial cancer risk in numerous observational studies. However, the causality of these associations is uncertain. Here we use a ...Mendelian randomization (MR) approach to assess whether insulinemia and T2D are causally associated with endometrial cancer.
We used single nucleotide polymorphisms (SNPs) associated with T2D (49 variants), fasting glucose (36 variants), fasting insulin (18 variants), early insulin secretion (17 variants), and body mass index (BMI) (32 variants) as instrumental variables in MR analyses. We calculated MR estimates for each risk factor with endometrial cancer using an inverse-variance weighted method with SNP-endometrial cancer associations from 1287 case patients and 8273 control participants.
Genetically predicted higher fasting insulin levels were associated with greater risk of endometrial cancer (odds ratio OR per standard deviation = 2.34, 95% confidence internal CI = 1.06 to 5.14, P = .03). Consistently, genetically predicted higher 30-minute postchallenge insulin levels were also associated with endometrial cancer risk (OR = 1.40, 95% CI = 1.12 to 1.76, P = .003). We observed no associations between genetic risk of type 2 diabetes (OR = 0.91, 95% CI = 0.79 to 1.04, P = .16) or higher fasting glucose (OR = 1.00, 95% CI = 0.67 to 1.50, P = .99) and endometrial cancer. In contrast, endometrial cancer risk was higher in individuals with genetically predicted higher BMI (OR = 3.86, 95% CI = 2.24 to 6.64, P = 1.2x10(-6)).
This study provides evidence to support a causal association of higher insulin levels, independently of BMI, with endometrial cancer risk.
Despite recognition of the importance of stakeholder input into research, there is a lack of validated measures to assess how well constituencies are engaged and their input integrated into research ...design. Measurement theory suggests that a community engagement measure should use clear and simple language and capture important components of underlying constructs, resulting in a valid measure that is accessible to a broad audience.
The primary objective of this study was to evaluate how community members understood and responded to a measure of community engagement developed to be reliable, valid, easily administered, and broadly usable.
Cognitive response interviews were completed, during which participants described their reactions to items and how they processed them. Participants were asked to interpret item meaning, paraphrase items, and identify difficult or problematic terms and phrases, as well as provide any concerns with response options while responding to 16 of 32 survey items.
The results of the cognitive response interviews of participants (N = 16) suggest concerns about plain language and literacy, clarity of question focus, and the lack of context clues to facilitate processing in response to items querying research experience. Minimal concerns were related to response options. Participants suggested changes in words and terms, as well as item structure.
Qualitative research can improve the validity and accessibility of measures that assess stakeholder experience of community-engaged research. The findings suggest wording and sentence structure changes that improve ability to assess implementation of community engagement and its impact on research outcomes.
Genome-wide association studies (GWAS) have successfully identified common genetic variants that contribute to breast cancer risk. Discovering additional variants has become difficult, as power to ...detect variants of weaker effect with present sample sizes is limited. An alternative approach is to look for variants associated with quantitative traits that in turn affect disease risk. As exposure to high circulating estradiol and testosterone, and low sex hormone-binding globulin (SHBG) levels is implicated in breast cancer etiology, we conducted GWAS analyses of plasma estradiol, testosterone, and SHBG to identify new susceptibility alleles. Cancer Genetic Markers of Susceptibility (CGEMS) data from the Nurses' Health Study (NHS), and Sisters in Breast Cancer Screening data were used to carry out primary meta-analyses among ~1600 postmenopausal women who were not taking postmenopausal hormones at blood draw. We observed a genome-wide significant association between SHBG levels and rs727428 (joint β = -0.126; joint P = 2.09 × 10(-16)), downstream of the SHBG gene. No genome-wide significant associations were observed with estradiol or testosterone levels. Among variants that were suggestively associated with estradiol (P<10(-5)), several were located at the CYP19A1 gene locus. Overall results were similar in secondary meta-analyses that included ~900 NHS current postmenopausal hormone users. No variant associated with estradiol, testosterone, or SHBG at P<10(-5) was associated with postmenopausal breast cancer risk among CGEMS participants. Our results suggest that the small magnitude of difference in hormone levels associated with common genetic variants is likely insufficient to detectably contribute to breast cancer risk.
To analyse the association between survival from critical illness and suicide or self-harm after hospital discharge.
Population based cohort study using linked and validated provincial databases.
...Ontario, Canada between January 2009 and December 2017 (inclusive).
Consecutive adult intensive care unit (ICU) survivors (≥18 years) were included. Linked administrative databases were used to compare ICU hospital survivors with hospital survivors who never required ICU admission (non-ICU hospital survivors). Patients were categorised based on their index hospital admission (ICU or non-ICU) during the study period.
The primary outcome was the composite of death by suicide (as noted in provincial death records) and deliberate self-harm events after discharge. Each outcome was also assessed independently. Incidence of suicide was evaluated while accounting for competing risk of death from other causes. Analyses were conducted by using overlap propensity score weighted, cause specific Cox proportional hazard models.
423 060 consecutive ICU survivors (mean age 61.7 years, 39% women) were identified. During the study period, the crude incidence (per 100 000 person years) of suicide, self-harm, and the composite of suicide or self-harm among ICU survivors was 41.4, 327.9, and 361.0, respectively, compared with 16.8, 177.3, and 191.6 in non-ICU hospital survivors. Analysis using weighted models showed that ICU survivors (
non-ICU hospital survivors) had a higher risk of suicide (adjusted hazards ratio 1.22, 95% confidence interval 1.11 to 1.33) and self-harm (1.15, 1.12 to 1.19). Among ICU survivors, several factors were associated with suicide or self-harm: previous depression or anxiety (5.69, 5.38 to 6.02), previous post-traumatic stress disorder (1.87, 1.64 to 2.13), invasive mechanical ventilation (1.45, 1.38 to 1.54), and renal replacement therapy (1.35, 1.17 to 1.56).
Survivors of critical illness have increased risk of suicide and self-harm, and these outcomes were associated with pre-existing psychiatric illness and receipt of invasive life support. Knowledge of these prognostic factors might allow for earlier intervention to potentially reduce this important public health problem.
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