Genome-wide association study identifies loci associated with liability to alcohol and drug dependence that is associated with variability in reward-related ventral striatum activity in African- and European-Americans.

Genetic influences on alcohol and drug dependence partially overlap, however, specific loci underlying this overlap remain unclear. We conducted a genome-wide association study (GWAS) of a phenotype representing alcohol or illicit drug dependence (ANYDEP) among 7291 European-Americans (EA; 2927 cases) and 3132 African-Americans (AA: 1315 cases) participating in the family-based Collaborative Study on the Genetics of Alcoholism. ANYDEP was heritable (h 2 in EA = 0.60, AA = 0.37). The AA GWAS identified three regions with genome-wide significant (GWS; P < 5E-08) single nucleotide polymorphisms (SNPs) on chromosomes 3 (rs34066662, rs58801820) and 13 (rs75168521, rs78886294), and an insertion-deletion on chromosome 5 (chr5:141988181). No polymorphisms reached GWS in the EA. One GWS region (chromosome 1: rs1890881) emerged from a trans-ancestral meta-analysis (EA + AA) of ANYDEP, and was attributable to alcohol dependence in both samples. Four genes (AA: CRKL, DZIP3, SBK3; EA: P2RX6) and four sets of genes were significantly enriched within biological pathways for hemostasis and signal transduction. GWS signals did not replicate in two independent samples but there was weak evidence for association between rs1890881 and alcohol intake in the UK Biobank. Among 118 AA and 481 EA individuals from the Duke Neurogenetics Study, rs75168521 and rs1890881 genotypes were associated with variability in reward-related ventral striatum activation. This study identified novel loci for substance dependence and provides preliminary evidence that these variants are also associated with individual differences in neural reward reactivity. Gene discovery efforts in non-European samples with distinct patterns of substance use may lead to the identification of novel ancestry-specific genetic markers of risk

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015

SummaryBackground The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors—the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6–58·8) of global deaths and 41·2% (39·8–42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding Bill & Melinda Gates Foundation

Cigarette smoking, nicotine dependence and anxiety disorders : a systematic review of population-based, epidemiological studies

Background Multiple studies have demonstrated that rates of smoking and nicotine dependence are increased in individuals with anxiety disorders. However, significant variability exists in the epidemiological literature exploring this relationship, including study design (cross-sectional versus prospective), the population assessed (random sample versus clinical population) and diagnostic instrument utilized.Methods We undertook a systematic review of population-based observational studies that utilized recognized structured clinical diagnostic criteria (Diagnostic and Statistical Manual of Mental Disorders (DSM) or International Classification of Diseases (ICD)) for anxiety disorder diagnosis to investigate the relationship between cigarette smoking, nicotine dependence and anxiety disorders.Results In total, 47 studies met the predefined inclusion criteria, with 12 studies providing prospective information and 5 studies providing quasiprospective information. The available evidence suggests that some baseline anxiety disorders are a risk factor for initiation of smoking and nicotine dependence, although the evidence is heterogeneous and many studies did not control for the effect of comorbid substance use disorders. The identified evidence however appeared to more consistently support cigarette smoking and nicotine dependence as being a risk factor for development of some anxiety disorders (for example, panic disorder, generalized anxiety disorder), although these findings were not replicated in all studies. A number of inconsistencies in the literature were identified.Conclusions Although many studies have demonstrated increased rates of smoking and nicotine dependence in individuals with anxiety disorders, there is a limited and heterogeneous literature that has prospectively examined this relationship in population studies using validated diagnostic criteria. The most consistent evidence supports smoking and nicotine dependence as increasing the risk of panic disorder and generalized anxiety disorder. The literature assessing anxiety disorders increasing smoking and nicotine dependence is inconsistent. Potential issues with the current literature are discussed and directions for future research are suggested

Ginkgo biloba Responds to Herbivory by Activating Early Signaling and Direct Defenses

Background: Ginkgo biloba (Ginkgoaceae) is one of the most ancient living seed plants and is regarded as a living fossil. G. biloba has a broad spectrum of resistance or tolerance to many pathogens and herbivores because of the presence of toxic leaf compounds. Little is known about early and late events occurring in G. biloba upon herbivory. The aim of this study was to assess whether herbivory by the generalist Spodoptera littoralis was able to induce early signaling and direct defense in G. biloba by evaluating early and late responses. Methodology/Principal Findings: Early and late responses in mechanically wounded leaves and in leaves damaged by S. littoralis included plasma transmembrane potential (Vm) variations, time-course changes in both cytosolic calcium concentration ([Ca 2+]cyt) and H2O2 production, the regulation of genes correlated to terpenoid and flavonoid biosynthesis, the induction of direct defense compounds, and the release of volatile organic compounds (VOCs). The results show that G. biloba responded to hebivory with a significant Vm depolarization which was associated to significant increases in both [Ca 2+] cyt and H 2O 2. Several defense genes were regulated by herbivory, including those coding for ROS scavenging enzymes and the synthesis of terpenoids and flavonoids. Metabolomic analyses revealed the herbivore-induced production of several flavonoids and VOCs. Surprisingly, no significant induction by herbivory was found for two of the most characteristic G. biloba classes of bioactive compounds; ginkgolides and bilobalides

Review of methods used by chiropractors to determine the site for applying manipulation

Background: With the development of increasing evidence for the use of manipulation in the management of musculoskeletal conditions, there is growing interest in identifying the appropriate indications for care. Recently, attempts have been made to develop clinical prediction rules, however the validity of these clinical prediction rules remains unclear and their impact on care delivery has yet to be established. The current study was designed to evaluate the literature on the validity and reliability of the more common methods used by doctors of chiropractic to inform the choice of the site at which to apply spinal manipulation. Methods: Structured searches were conducted in Medline, PubMed, CINAHL and ICL, supported by hand searches of archives, to identify studies of the diagnostic reliability and validity of common methods used to identify the site of treatment application. To be included, studies were to present original data from studies of human subjects and be designed to address the region or location of care delivery. Only English language manuscripts from peer-reviewed journals were included. The quality of evidence was ranked using QUADAS for validity and QAREL for reliability, as appropriate. Data were extracted and synthesized, and were evaluated in terms of strength of evidence and the degree to which the evidence was favourable for clinical use of the method under investigation. Results: A total of 2594 titles were screened from which 201 articles met all inclusion criteria. The spectrum of manuscript quality was quite broad, as was the degree to which the evidence favoured clinical application of the diagnostic methods reviewed. The most convincing favourable evidence was for methods which confirmed or provoked pain at a specific spinal segmental level or region. There was also high quality evidence supporting the use, with limitations, of static and motion palpation, and measures of leg length inequality. Evidence of mixed quality supported the use, with limitations, of postural evaluation. The evidence was unclear on the applicability of measures of stiffness and the use of spinal x-rays. The evidence was of mixed quality, but unfavourable for the use of manual muscle testing, skin conductance, surface electromyography and skin temperature measurement. Conclusions: A considerable range of methods is in use for determining where in the spine to administer spinal manipulation. The currently published evidence falls across a spectrum ranging from strongly favourable to strongly unfavourable in regard to using these methods. In general, the stronger and more favourable evidence is for those procedures which take a direct measure of the presumptive site of care– methods involving pain provocation upon palpation or localized tissue examination. Procedures which involve some indirect assessment for identifying the manipulable lesion of the spine–such as skin conductance or thermography–tend not to be supported by the available evidence.https://doi.org/10.1186/2045-709X-21-3

Global, regional, and national incidence, prevalence, and mortality of HIV, 1980–2017, and forecasts to 2030, for 195 countries and territories: a systematic analysis for the Global Burden of Diseases, Injuries, and Risk Factors Study 2017

Background Understanding the patterns of HIV/AIDS epidemics is crucial to tracking and monitoring the progress of prevention and control efforts in countries. We provide a comprehensive assessment of the levels and trends of HIV/AIDS incidence, prevalence, mortality, and coverage of antiretroviral therapy (ART) for 1980–2017 and forecast these estimates to 2030 for 195 countries and territories. Methods We determined a modelling strategy for each country on the basis of the availability and quality of data. For countries and territories with data from population-based seroprevalence surveys or antenatal care clinics, we estimated prevalence and incidence using an open-source version of the Estimation and Projection Package—a natural history model originally developed by the UNAIDS Reference Group on Estimates, Modelling, and Projections. For countries with cause-specific vital registration data, we corrected data for garbage coding (ie, deaths coded to an intermediate, immediate, or poorly defined cause) and HIV misclassification. We developed a process of cohort incidence bias adjustment to use information on survival and deaths recorded in vital registration to back-calculate HIV incidence. For countries without any representative data on HIV, we produced incidence estimates by pulling information from observed bias in the geographical region. We used a re-coded version of the Spectrum model (a cohort component model that uses rates of disease progression and HIV mortality on and off ART) to produce age-sex-specific incidence, prevalence, and mortality, and treatment coverage results for all countries, and forecast these measures to 2030 using Spectrum with inputs that were extended on the basis of past trends in treatment scale-up and new infections. Findings Global HIV mortality peaked in 2006 with 1·95 million deaths (95% uncertainty interval 1·87–2·04) and has since decreased to 0·95 million deaths (0·91–1·01) in 2017. New cases of HIV globally peaked in 1999 (3·16 million, 2·79–3·67) and since then have gradually decreased to 1·94 million (1·63–2·29) in 2017. These trends, along with ART scale-up, have globally resulted in increased prevalence, with 36·8 million (34·8–39·2) people living with HIV in 2017. Prevalence of HIV was highest in southern sub-Saharan Africa in 2017, and countries in the region had ART coverage ranging from 65·7% in Lesotho to 85·7% in eSwatini. Our forecasts showed that 54 countries will meet the UNAIDS target of 81% ART coverage by 2020 and 12 countries are on track to meet 90% ART coverage by 2030. Forecasted results estimate that few countries will meet the UNAIDS 2020 and 2030 mortality and incidence targets. Interpretation Despite progress in reducing HIV-related mortality over the past decade, slow decreases in incidence, combined with the current context of stagnated funding for related interventions, mean that many countries are not on track to reach the 2020 and 2030 global targets for reduction in incidence and mortality. With a growing population of people living with HIV, it will continue to be a major threat to public health for years to come. The pace of progress needs to be hastened by continuing to expand access to ART and increasing investments in proven HIV prevention initiatives that can be scaled up to have population-level impact

Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015:a systematic analysis for the Global Burden of Disease Study 2015

Background Non-fatal outcomes of disease and injury increasingly detract from the ability of the world's population to live in full health, a trend largely attributable to an epidemiological transition in many countries from causes affecting children, to non-communicable diseases (NCDs) more common in adults. For the Global Burden of Diseases, Injuries, and Risk Factors Study 2015 (GBD 2015), we estimated the incidence, prevalence, and years lived with disability for diseases and injuries at the global, regional, and national scale over the period of 1990 to 2015.Methods We estimated incidence and prevalence by age, sex, cause, year, and geography with a wide range of updated and standardised analytical procedures. Improvements from GBD 2013 included the addition of new data sources, updates to literature reviews for 85 causes, and the identification and inclusion of additional studies published up to November, 2015, to expand the database used for estimation of non-fatal outcomes to 60 900 unique data sources. Prevalence and incidence by cause and sequelae were determined with DisMod-MR 2.1, an improved version of the DisMod-MR Bayesian meta-regression tool first developed for GBD 2010 and GBD 2013. For some causes, we used alternative modelling strategies where the complexity of the disease was not suited to DisMod-MR 2.1 or where incidence and prevalence needed to be determined from other data. For GBD 2015 we created a summary indicator that combines measures of income per capita, educational attainment, and fertility (the Socio-demographic Index [SDI]) and used it to compare observed patterns of health loss to the expected pattern for countries or locations with similar SDI scores.Findings We generated 9.3 billion estimates from the various combinations of prevalence, incidence, and YLDs for causes, sequelae, and impairments by age, sex, geography, and year. In 2015, two causes had acute incidences in excess of 1 billion: upper respiratory infections (17.2 billion, 95% uncertainty interval [UI] 15.4-19.2 billion) and diarrhoeal diseases (2.39 billion, 2.30-2.50 billion). Eight causes of chronic disease and injury each affected more than 10% of the world's population in 2015: permanent caries, tension-type headache, iron-deficiency anaemia, age-related and other hearing loss, migraine, genital herpes, refraction and accommodation disorders, and ascariasis. The impairment that affected the greatest number of people in 2015 was anaemia, with 2.36 billion (2.35-2.37 billion) individuals affected. The second and third leading impairments by number of individuals affected were hearing loss and vision loss, respectively. Between 2005 and 2015, there was little change in the leading causes of years lived with disability (YLDs) on a global basis. NCDs accounted for 18 of the leading 20 causes of age-standardised YLDs on a global scale. Where rates were decreasing, the rate of decrease for YLDs was slower than that of years of life lost (YLLs) for nearly every cause included in our analysis. For low SDI geographies, Group 1 causes typically accounted for 20-30% of total disability, largely attributable to nutritional deficiencies, malaria, neglected tropical diseases, HIV/AIDS, and tuberculosis. Lower back and neck pain was the leading global cause of disability in 2015 in most countries. The leading cause was sense organ disorders in 22 countries in Asia and Africa and one in central Latin America; diabetes in four countries in Oceania; HIV/AIDS in three southern sub-Saharan African countries; collective violence and legal intervention in two north African and Middle Eastern countries; iron-deficiency anaemia in Somalia and Venezuela; depression in Uganda; onchoceriasis in Liberia; and other neglected tropical diseases in the Democratic Republic of the Congo.Interpretation Ageing of the world's population is increasing the number of people living with sequelae of diseases and injuries. Shifts in the epidemiological profile driven by socioeconomic change also contribute to the continued increase in years lived with disability (YLDs) as well as the rate of increase in YLDs. Despite limitations imposed by gaps in data availability and the variable quality of the data available, the standardised and comprehensive approach of the GBD study provides opportunities to examine broad trends, compare those trends between countries or subnational geographies, benchmark against locations at similar stages of development, and gauge the strength or weakness of the estimates available. Copyright (C) The Author(s). Published by Elsevier Ltd.</p

Five insights from the Global Burden of Disease Study 2019

The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 provides a rules-based synthesis of the available evidence on levels and trends in health outcomes, a diverse set of risk factors, and health system responses. GBD 2019 covered 204 countries and territories, as well as first administrative level disaggregations for 22 countries, from 1990 to 2019. Because GBD is highly standardised and comprehensive, spanning both fatal and non-fatal outcomes, and uses a mutually exclusive and collectively exhaustive list of hierarchical disease and injury causes, the study provides a powerful basis for detailed and broad insights on global health trends and emerging challenges. GBD 2019 incorporates data from 281 586 sources and provides more than 3.5 billion estimates of health outcome and health system measures of interest for global, national, and subnational policy dialogue. All GBD estimates are publicly available and adhere to the Guidelines on Accurate and Transparent Health Estimate Reporting. From this vast amount of information, five key insights that are important for health, social, and economic development strategies have been distilled. These insights are subject to the many limitations outlined in each of the component GBD capstone papers.Peer reviewe