Measures of outcome for stimulant trials: ACTTION recommendations and research agenda

BACKGROUND: The development and approval of an efficacious pharmacotherapy for stimulant use disorders has been limited by the lack of a meaningful indicator of treatment success, other than sustained abstinence. METHODS: In March, 2015, a meeting sponsored by Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) was convened to discuss the current state of the evidence regarding meaningful outcome measures in clinical trials for stimulant use disorders. Attendees included members of academia, funding and regulatory agencies, pharmaceutical companies, and healthcare organizations. The goal was to establish a research agenda for the development of a meaningful outcome measure that may be used as an endpoint in clinical trials for stimulant use disorders. RESULTS AND CONCLUSIONS: Based on guidelines for the selection of clinical trial endpoints, the lessons learned from prior addiction clinical trials, and the process that led to identification of a meaningful indicator of treatment success for alcohol use disorders, several recommendations for future research were generated. These include a focus on the validation of patient reported outcome measures of functioning, the exploration of patterns of stimulant abstinence that may be associated with physical and/or psychosocial benefits, the role of urine testing for validating self-reported measures of stimulant abstinence, and the operational definitions for reduction-based measures in terms of frequency rather than quantity of stimulant use. These recommendations may be useful for secondary analyses of clinical trial data, and in the design of future clinical trials that may help establish a meaningful indicator of treatment success

Shallow waters: social science research in South Africa's marine environment

This paper provides an overview of social science research in the marine environment of South Africa for the period 1994–2012. A bibliography based on a review of relevant literature and social science projects funded under the SEAChange programme of the South African Network for Coastal and Oceanic Research (SANCOR) was used to identify nine main themes that capture the knowledge generated in the marine social science field. Within these themes, a wide diversity of topics has been explored, covering a wide geographic area. The review suggests that there has been a steady increase in social science research activities and outputs over the past 18 years, with a marked increase in postgraduate dissertations in this field. The SEAChange programme has contributed to enhancing understanding of certain issues and social interactions in the marine environment but this work is limited. Furthermore, there has been limited dissemination of these research results amongst the broader marine science community and incorporation of this information into policy and management decisions has also been limited. However, marine scientists are increasingly recognising the importance of taking a more holistic and integrated approach to management, and are encouraging further social science research, as well as interdisciplinary research across the natural and social sciences. Possible reasons for the lack of communication and coordination amongst natural and social scientists, as well as the limited uptake of research results in policy and management decisions, are discussed and recommendations are proposed.Web of Scienc

Algorithms for enhancing public health utility of national causes-of-death data

<p>Abstract</p> <p>Background</p> <p>Coverage and quality of cause-of-death (CoD) data varies across countries and time. Valid, reliable, and comparable assessments of trends in causes of death from even the best systems are limited by three problems: a) changes in the <it>International Statistical Classification of Diseases and Related Health Problems </it>(ICD) over time; b) the use of tabulation lists where substantial detail on causes of death is lost; and c) many deaths assigned to causes that cannot or should not be considered underlying causes of death, often called garbage codes (GCs). The Global Burden of Disease Study and the World Health Organization have developed various methods to enhance comparability of CoD data. In this study, we attempt to build on these approaches to enhance the utility of national cause-of-death data for public health analysis.</p> <p>Methods</p> <p>Based on careful consideration of 4,434 country-years of CoD data from 145 countries from 1901 to 2008, encompassing 743 million deaths in ICD versions 1 to 10 as well as country-specific cause lists, we have developed a public health-oriented cause-of-death list. These 56 causes are organized hierarchically and encompass all deaths. Each cause has been mapped from ICD-6 to ICD-10 and, where possible, they have also been mapped to the <it>International List of Causes of Death </it>1-5. We developed a typology of different classes of GCs. In each ICD revision, GCs have been identified. Target causes to which these GCs should be redistributed have been identified based on certification practice and/or pathophysiology. Proportionate redistribution, statistical models, and expert algorithms have been developed to redistribute GCs to target codes for each age-sex group.</p> <p>Results</p> <p>The fraction of all deaths assigned to GCs varies tremendously across countries and revisions of the ICD. In general, across all country-years of data available, GCs have declined from more than 43% in ICD-7 to 24% in ICD-10. In some regions, such as Australasia, GCs in 2005 are as low as 11%, while in some developing countries, such as Thailand, they are greater than 50%. Across different age groups, the composition of GCs varies tremendously - three classes of GCs steadily increase with age, but ambiguous codes within a particular disease chapter are also common for injuries at younger ages. The impact of redistribution is to change the number of deaths assigned to particular causes for a given age-sex group. These changes alter ranks across countries for any given year by a number of different causes, change time trends, and alter the rank order of causes within a country.</p> <p>Conclusions</p> <p>By mapping CoD through different ICD versions and redistributing GCs, we believe the public health utility of CoD data can be substantially enhanced, leading to an increased demand for higher quality CoD data from health sector decision-makers.</p

Modeling causes of death: an integrated approach using CODEm

Background: Data on causes of death by age and sex are a critical input into health decision-making. Priority setting in public health should be informed not only by the current magnitude of health problems but by trends in them. However, cause of death data are often not available or are subject to substantial problems of comparability. We propose five general principles for cause of death model development, validation, and reporting.Methods: We detail a specific implementation of these principles that is embodied in an analytical tool - the Cause of Death Ensemble model (CODEm) - which explores a large variety of possible models to estimate trends in causes of death. Possible models are identified using a covariate selection algorithm that yields many plausible combinations of covariates, which are then run through four model classes. The model classes include mixed effects linear models and spatial-temporal Gaussian Process Regression models for cause fractions and death rates. All models for each cause of death are then assessed using out-of-sample predictive validity and combined into an ensemble with optimal out-of-sample predictive performance.Results: Ensemble models for cause of death estimation outperform any single component model in tests of root mean square error, frequency of predicting correct temporal trends, and achieving 95% coverage of the prediction interval. We present detailed results for CODEm applied to maternal mortality and summary results for several other causes of death, including cardiovascular disease and several cancers.Conclusions: CODEm produces better estimates of cause of death trends than previous methods and is less susceptible to bias in model specification. We demonstrate the utility of CODEm for the estimation of several major causes of death

SUMO Pathway Dependent Recruitment of Cellular Repressors to Herpes Simplex Virus Type 1 Genomes

Components of promyelocytic leukaemia (PML) nuclear bodies (ND10) are recruited to sites associated with herpes simplex virus type 1 (HSV-1) genomes soon after they enter the nucleus. This cellular response is linked to intrinsic antiviral resistance and is counteracted by viral regulatory protein ICP0. We report that the SUMO interaction motifs of PML, Sp100 and hDaxx are required for recruitment of these repressive proteins to HSV-1 induced foci, which also contain SUMO conjugates and PIAS2β, a SUMO E3 ligase. SUMO modification of PML and elements of its tripartite motif (TRIM) are also required for recruitment in cells lacking endogenous PML. Mutants of PML isoform I and hDaxx that are not recruited to virus induced foci are unable to reproduce the repression of ICP0 null mutant HSV-1 infection mediated by their wild type counterparts. We conclude that recruitment of ND10 components to sites associated with HSV-1 genomes reflects a cellular defence against invading pathogen DNA that is regulated through the SUMO modification pathway

Agricultural Management and Climatic Change Are the Major Drivers of Biodiversity Change in the UK

Action to reduce anthropogenic impact on the environment and species within it will be most effective when targeted towards activities that have the greatest impact on biodiversity. To do this effectively we need to better understand the relative importance of different activities and how they drive changes in species’ populations. Here, we present a novel, flexible framework that reviews evidence for the relative importance of these drivers of change and uses it to explain recent alterations in species’ populations. We review drivers of change across four hundred species sampled from a broad range of taxonomic groups in the UK. We found that species’ population change (~1970–2012) has been most strongly impacted by intensive management of agricultural land and by climatic change. The impact of the former was primarily deleterious, whereas the impact of climatic change to date has been more mixed. Findings were similar across the three major taxonomic groups assessed (insects, vascular plants and vertebrates). In general, the way a habitat was managed had a greater impact than changes in its extent, which accords with the relatively small changes in the areas occupied by different habitats during our study period, compared to substantial changes in habitat management. Of the drivers classified as conservation measures, low-intensity management of agricultural land and habitat creation had the greatest impact. Our framework could be used to assess the relative importance of drivers at a range of scales to better inform our policy and management decisions. Furthermore, by scoring the quality of evidence, this framework helps us identify research gaps and needs

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Adipocyte Phenotype Flexibility and Lipid Dysregulation

The prevalence of obesity and associated cardiometabolic diseases continues to rise, despite efforts to improve global health. The adipose tissue is now regarded as an endocrine organ since its multitude of secretions, lipids chief among them, regulate systemic functions. The loss of normal adipose tissue phenotypic flexibility, especially related to lipid homeostasis, appears to trigger cardiometabolic pathogenesis. The goal of this manuscript is to review lipid balance maintenance by the lean adipose tissue&rsquo;s propensity for phenotype switching, obese adipose tissue&rsquo;s narrower range of phenotype flexibility, and what initial factors account for the waning lipid regulatory capacity. Metabolic, hypoxic, and inflammatory factors contribute to the adipose tissue phenotype being made rigid. A better grasp of normal adipose tissue function provides the necessary context for recognizing the extent of obese adipose tissue dysfunction and gaining insight into how pathogenesis evolves

Adipocyte Phenotype Flexibility and Lipid Dysregulation

The prevalence of obesity and associated cardiometabolic diseases continues to rise, despite efforts to improve global health. The adipose tissue is now regarded as an endocrine organ since its multitude of secretions, lipids chief among them, regulate systemic functions. The loss of normal adipose tissue phenotypic flexibility, especially related to lipid homeostasis, appears to trigger cardiometabolic pathogenesis. The goal of this manuscript is to review lipid balance maintenance by the lean adipose tissue’s propensity for phenotype switching, obese adipose tissue’s narrower range of phenotype flexibility, and what initial factors account for the waning lipid regulatory capacity. Metabolic, hypoxic, and inflammatory factors contribute to the adipose tissue phenotype being made rigid. A better grasp of normal adipose tissue function provides the necessary context for recognizing the extent of obese adipose tissue dysfunction and gaining insight into how pathogenesis evolves