High urinary tungsten concentration is associated with stroke in the National Health and Nutrition Examination Survey 1999-2010.

Published onlineClinical TrialMulticenter StudyResearch Support, Non-U.S. Gov'tBACKGROUND: In recent years there has been an exponential increase in tungsten demand, potentially increasing human exposure to the metal. Currently, the toxicology of tungsten is poorly understood, but mounting evidence suggests that both the elemental metal and its alloys have cytotoxic effects. Here, we investigate the association between tungsten and cardiovascular disease (CVD) or stroke using six waves of the National Health and Nutrition Examination Survey (NHANES). METHODS: We investigated associations using crude and adjusted logistic regression models in a cohort of 8614 adults (18-74 years) with 193 reported stroke diagnoses and 428 reported diagnoses of CVD. We also stratified our data to characterize associations in a subset of younger individuals (18-50 years). RESULTS: Elevated tungsten concentrations were strongly associated with an increase in the prevalence of stroke, independent of typical risk factors (Odds Ratio (OR): 1.66, 95% Confidence Interval (95% CI): 1.17, 2.34). The association between tungsten and stroke in the young age category was still evident (OR: 2.17, 95% CI: 1.33, 3.53). CONCLUSION: This study represents the most comprehensive analysis of the human health effects of tungsten to date. Individuals with higher urinary tungsten concentrations have double the odds of reported stroke. We hypothesize that the pathological pathway resulting from tungsten exposure may involve oxidative stress.This work was supported by funding from University of Exeter Medical School. No funding organization or sponsor played any part in the design or conduct of the study, in the analysis or interpretation of the data, or preparation, review, or approval of the manuscript. The European Centre for the Environment and Human Health (part of the University of Exeter Medical School) is supported by investment from the ERDF (European Regional Development Fund) and ESF (European Social Fund) Convergence Programmed for Cornwall and the Isles of Scilly. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Culture matters: using a cultural contexts of health approach to enhance policy-making

This is the final version of the report. Freely available online from WHO via the link in this recordThis policy brief has been developed in response to the increasing awareness among policy-makers and the public health community of the important relationship between culture and health. By exploring the three key public health areas of nutrition, migration and environment, the policy brief demonstrates how cultural awareness is central to understanding health and well-being and to developing more effective and equitable health policies. Consequently, it argues that public health policy-making has much to gain from applying research from the health-related humanities and social sciencesWorld Health Organisatio

Islands of linkage in an ocean of pervasive recombination reveals two-speed evolution of human cytomegalovirus genomes

Human cytomegalovirus (HCMV) infects most of the population worldwide, persisting throughout the host's life in a latent state with periodic episodes of reactivation. While typically asymptomatic, HCMV can cause fatal disease among congenitally infected infants and immunocompromised patients. These clinical issues are compounded by the emergence of antiviral resistance and the absence of an effective vaccine, the development of which is likely complicated by the numerous immune evasins encoded by HCMV to counter the host's adaptive immune responses, a feature that facilitates frequent super-infections. Understanding the evolutionary dynamics of HCMV is essential for the development of effective new drugs and vaccines. By comparing viral genomes from uncultivated or low-passaged clinical samples of diverse origins, we observe evidence of frequent homologous recombination events, both recent and ancient, and no structure of HCMV genetic diversity at the whole-genome scale. Analysis of individual gene-scale loci reveals a striking dichotomy: while most of the genome is highly conserved, recombines essentially freely and has evolved under purifying selection, 21 genes display extreme diversity, structured into distinct genotypes that do not recombine with each other. Most of these hyper-variable genes encode glycoproteins involved in cell entry or escape of host immunity. Evidence that half of them have diverged through episodes of intense positive selection suggests that rapid evolution of hyper-variable loci is likely driven by interactions with host immunity. It appears that this process is enabled by recombination unlinking hyper-variable loci from strongly constrained neighboring sites. It is conceivable that viral mechanisms facilitating super-infection have evolved to promote recombination between diverged genotypes, allowing the virus to continuously diversify at key loci to escape immune detection, while maintaining a genome optimally adapted to its asymptomatic infectious lifecycle

Indicators of ocean health and human health: developing a research and monitoring framework

This is the final version of the article. Available from NIEHS via the DOI in this record.We need to critically assess the present quality of the marine ecosystem, especially the connection between ecosystem change and threats to human health. In this article we review the current state of indicators to link changes in marine organisms with eventual effects to human health, identify research opportunities in the use of indicators of ocean and human health, and discuss how to establish collaborations between national and international governmental and private sector groups. We present a synthesis of the present state of understanding of the connection between ocean health and human health, a discussion of areas where resources are required, and a discussion of critical research needs and a template for future work in this field. To understand fully the interactions between ocean health and human health, programs should be organized around a "models-based" approach focusing on critical themes and attributes of marine environmental and public health risks. Given the extent and complex nature of ocean and human health issues, a program networking across geographic and disciplinary boundaries is essential. The overall goal of this approach would be the early detection of potential marine-based contaminants, the protection of marine ecosystems, the prevention of associated human illness, and by implication, the development of products to enhance human well-being. The tight connection between research and monitoring is essential to develop such an indicator-based effort.This work was funded by the National Institute of Environmental Health Sciences, the Intergovernmental Oceanographic Commission (UNESCO), and the Bermuda Biological Station for Research, Inc. (contribution 1615)

Use of Whole-genome Sequencing of Adenovirus in Immunocompromised Paediatric Patients to Identify Nosocomial Transmission and Mixed-genotype Infection

Background: Adenoviruses are significant pathogens for the immunocompromised, arising from primary infection or reinfection. Serotyping is insufficient to support nosocomial transmission investigations. We investigate whether whole-genome sequencing (WGS) provides clinically relevant information on transmission among patients in a paediatric tertiary hospital. Methods: We developed a target-enriched adenovirus WGS technique for clinical samples and retrospectively sequenced 107 adenovirus-positive residual diagnostic samples, including viraemias (>5x104 copies/ml), from 37 patients collected January 2011 - March 2016. WGS was used to determine genotype and for phylogenetic analysis. Results: Adenovirus sequences were recovered from 105/107 samples. Full genome sequences were recovered from all 20 non-species C samples and from 36/85 species C viruses, with partial genome sequences recovered from the rest. Whole genome phylogenetic analysis suggested linkage of three genotype A31 cases and uncovered an unsuspected epidemiological link to an A31 infection first detected on the same ward four years earlier. In nine samples from one patient who died we identified a mixed genotype adenovirus infection. Conclusions: Adenovirus WGS from clinical samples is possible and useful for genotyping and molecular epidemiology. WGS identified likely nosocomial transmission with greater resolution than conventional genotyping, and distinguished between adenovirus disease due to single or multiple genotypes

Detection of Low Frequency Multi-Drug Resistance and Novel Putative Maribavir Resistance in Immunocompromised Pediatric Patients with Cytomegalovirus.

Human cytomegalovirus (HCMV) is a significant pathogen in immunocompromised individuals, with the potential to cause fatal pneumonitis and colitis, as well as increasing the risk of organ rejection in transplant patients. With the advent of new anti-HCMV drugs there is therefore considerable interest in using virus sequence data to monitor emerging resistance to antiviral drugs in HCMV viraemia and disease, including the identification of putative new mutations. We used target-enrichment to deep sequence HCMV DNA from 11 immunosuppressed pediatric patients receiving single or combination anti-HCMV treatment, serially sampled over 1-27 weeks. Changes in consensus sequence and resistance mutations were analyzed for three ORFs targeted by anti-HCMV drugs and the frequencies of drug resistance mutations monitored. Targeted-enriched sequencing of clinical material detected mutations occurring at frequencies of 2%. Seven patients showed no evidence of drug resistance mutations. Four patients developed drug resistance mutations a mean of 16 weeks after starting treatment. In two patients, multiple resistance mutations accumulated at frequencies of 20% or less, including putative maribavir and ganciclovir resistance mutations P522Q (UL54) and C480F (UL97). In one patient, resistance was detected 14 days earlier than by PCR. Phylogenetic analysis suggested recombination or superinfection in one patient. Deep sequencing of HCMV enriched from clinical samples excluded resistance in 7 of 11 subjects and identified resistance mutations earlier than conventional PCR-based resistance testing in 2 patients. Detection of multiple low level resistance mutations was associated with poor outcome

Non-state actors in hybrid global climate governance: justice, legitimacy, and effectiveness in a post-Paris era

In this article, we outline the multifaceted roles played by non-state actors within the United Nations Framework Convention on Climate Change and place this within the wider landscape of global climate governance. In doing so, we look at both the formation and aftermath of the 2015 Paris Agreement. We argue that the Paris Agreement cements an architecture of hybrid multilateralism that enables and constrains non-state actor participation in global climate governance. We flesh out the constitutive features of hybrid multilateralism, enumerate the multiple positions non-state actors may employ under these conditions, and contend that non-state actors will play an increasingly important role in the post-Paris era. To substantiate these claims, we assess these shifts and ask how non-state actors may affect the legitimacy, justice, and effectiveness of the Paris Agreement

Republication: Targeting PI3KC2β Impairs Proliferation and Survival in Acute Leukemia, Brain Tumours and Neuroendocrine Tumours

BACKGROUND Eight human catalytic phosphoinositide 3-kinase (PI3K) isoforms exist which are subdivided into three classes. While class I isoforms have been well-studied in cancer, little is known about the functions of class II PI3Ks. MATERIALS AND METHODS The expression pattern and functions of the class II PI3KC2β isoform were investigated in a panel of tumour samples and cell lines. RESULTS Overexpression of PI3KC2β was found in subsets of tumours and cell lines from acute myeloid leukemia (AML), glioblastoma multiforme (GBM), medulloblastoma (MB), neuroblastoma (NB), and small cell lung cancer (SCLC). Specific pharmacological inhibitors of PI3KC2β or RNA interference impaired proliferation of a panel of human cancer cell lines and primary cultures. Inhibition of PI3KC2β also induced apoptosis and sensitised the cancer cells to chemotherapeutic agents. CONCLUSION Together, these data show that PI3KC2β contributes to proliferation and survival in AML, brain tumours and neuroendocrine tumours, and may represent a novel target in these malignancies