The Asp298 allele of endothelial nitric oxide synthase is a risk factor for myocardial infarction among patients with type 2 diabetes mellitus

Background: Endothelial dysfunction plays a central role in atherosclerotic progression and cardiovascular complications of type 2 diabetes mellitus (T2DM). Given the role of nitric oxide in the vascular system, we aimed to test hypotheses of synergy between the common endothelial nitric oxide synthase (eNOS) Asp(298) allele and T2DM in predisposing to acute myocardial infarction (AMI). Methods: In a population-based patient survey with 403 persons with T2DM and 799 healthy subjects from the population without diabetes or hypertension, we analysed the relation between T2DM, sex and the eNOS Asp(298) allele versus the risk for AMI. Results: In an overall analysis, T2DM was a significant independent risk factor for AMI. In patients with T2DM, homozygosity for the eNOS Asp(298) allele was a significant risk factor (HR 3.12 [1.49-6.56], p = 0.003), but not in subjects without diabetes or hypertension. Compared to wild-type non-diabetic subjects, all patients with T2DM had a significantly increased risk of AMI regardless of genotype. This risk was however markedly higher in patients with T2DM homozygous for the Asp(298) allele (HR 7.20 [3.01-17.20], p < 0.001), independent of sex, BMI, systolic blood pressure, serum triglycerides, HDL -cholesterol, current smoking, and leisure time physical activity. The pattern seemed stronger in women than in men. Conclusion: We show here a strong independent association between eNOS genotype and AMI in patients with T2DM. This suggests a synergistic effect of the eNOS Asp(298) allele and diabetes, and confirms the role of eNOS as an important pathological bottleneck for cardiovascular disease in patients with T2DM

Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney

Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA. Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation

Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk

Elevated blood pressure is the leading heritable risk factor for cardiovascular disease worldwide. We report genetic association of blood pressure (systolic, diastolic, pulse pressure) among UK Biobank participants of European ancestry with independent replication in other cohorts, and robust validation of 107 independent loci. We also identify new independent variants at 11 previously reported blood pressure loci. In combination with results from a range of in silico functional analyses and wet bench experiments, our findings highlight new biological pathways for blood pressure regulation enriched for genes expressed in vascular tissues and identify potential therapeutic targets for hypertension. Results from genetic risk score models raise the possibility of a precision medicine approach through early lifestyle intervention to offset the impact of blood pressure-raising genetic variants on future cardiovascular disease risk

Dominance of biologically produced nitrate in upland waters of Great Britain indicated by stable isotopes

Atmospheric deposition of nitrogen (N) compounds is the major source of anthropogenic N to most upland ecosystems, where leaching of nitrate (NO3−) into surface waters contributes to eutrophication and acidification as well as indicating an excess of N in the terrestrial catchment ecosystems. Natural abundance stable isotopes ratios, 15N/14N and 18O/16O (the “dual isotope” technique) have previously been used in biogeochemical studies of alpine and forested ecosystems to demonstrate that most of the NO3− in upland surface waters has been microbially produced. Here we present an application of the technique to four moorland catchments in the British uplands including a comparison of lakes and their stream inflows at two sites. The NO3− concentrations of bulk deposition and surface waters at three sites are very similar. While noting the constraints imposed by uncertainty in the precise δ18O value for microbial NO3−, however, we estimate that 79–98% of the annual mean NO3− has been microbially produced. Direct leaching of atmospheric NO3− is a minor component of catchment NO3− export, although greater than in many similar studies in forested watersheds. A greater proportion of atmospheric NO3− is seen in the two lake sites relative to their inflow streams, demonstrating the importance of direct NO3− deposition to lake surfaces in catchments where terrestrial ecosystems intercept a large proportion of deposited N. The dominance of microbial sources of NO3− in upland waters suggests that reduced and oxidised N deposition may have similar implications in terms of contributing to NO3− leaching

Burnout in the disaster response workforce: The impact of work roles and the COVID-19 pandemic

The coronavirus-2019 (COVID-19) pandemic cor­responded with a record-breaking year for billion-dollar disasters. While the pandemic swept across the United States, the country also experienced a record-setting hurricane season on the East Coast and an unprecedented wildfire season on the West Coast. These co-occurring threats have placed unprecedented strain on our disaster response workforce with poten­tial long-term implications for turnover and disaster response efficacy. In this paper, we draw from the Job Demands-Resources model to address the influence of workers’ role stressors and community infection rates during the COVID-19 pandemic and job burnout and turnover in the disaster response workforce. </jats:p

Engaged, overextended, or burned out: What is the state of the disaster response workforce?

The prolonged coronavirus-2019 (COVID-19) pandemic and co-occurring disasters during 2020 took a toll on everyone, taxing public health and disaster management personnel particularly. This initial study evaluated levels of exhaustion, cynicism, and professional efficacy among a broad array of the disaster workforce responding to these events through an online survey. Responses were compared to normative standards from an international dataset using a one-sample t-test and described using k-means cluster analysis. Results from 111 emergency management and disaster services, public health, healthcare, first responders, and other professionals and volunteers indicated high levels of emotional exhaustion and cynicism, along with high levels of personal efficacy compared to normative samples. Perceptions of the heightened risk of contracting COVID-19 were significantly associated with increased emotional exhaustion and cynicism. Cluster analysis results indicated three different patterns of burnout: half of the respondents were overextended (high levels of emotional exhaustion, cynicism, and efficacy) or burned out (high emotional exhaustion and cynicism, low efficacy), while 50 percent were engaged (low emotional exhaustion, low cynicism, and high personal efficacy). This suggests that despite the COVID-19 pandemic, a substantial proportion of the disaster response workforce is still thriving. However, a large proportion is burned out or at high risk (overextended). Limitations of this study include a lack of diversity in the sample, which, although similar to the demographic characteristics of the emergency manager population, may limit the generalizability of the study results. System-level planners can use this information to develop comprehensive workforce approaches, policies, and procedures to prevent burnout for these essential personnel working behind the scenes.</jats:p