Harvard University

limma powers differential expression analyses for RNA-sequencing and microarray studies

limma is an R/Bioconductor software package that provides an integrated solution for analysing data from gene expression experiments. It contains rich features for handling complex experimental designs and for information borrowing to overcome the problem of small sample sizes. Over the past decade, limma has been a popular choice for gene discovery through differential expression analyses of microarray and high-throughput PCR data. The package contains particularly strong facilities for reading, normalizing and exploring such data. Recently, the capabilities of limma have been significantly expanded in two important directions. First, the package can now perform both differential expression and differential splicing analyses of RNA sequencing (RNA-seq) data. All the downstream analysis tools previously restricted to microarray data are now available for RNA-seq as well. These capabilities allow users to analyse both RNA-seq and microarray data with very similar pipelines. Second, the package is now able to go past the traditional gene-wise expression analyses in a variety of ways, analysing expression profiles in terms of co-regulated sets of genes or in terms of higher-order expression signatures. This provides enhanced possibilities for biological interpretation of gene expression differences. This article reviews the philosophy and design of the limma package, summarizing both new and historical features, with an emphasis on recent enhancements and features that have not been previously described.

Meta-analysis in clinical trials

Dynamic capabilities and strategic management

The dynamic capabilities framework analyzes the sources and methods of wealth creation and capture by private enterprise firms operating in environments of rapid technological change. The competitive advantage of firms is seen as resting on distinctive processes (ways of coordinating and combining), shaped by the firm’s (specific) asset positions (such as the firm’s portfolio of difficult-to-trade knowledge assets and complementary assets), and the evolution path(s) it has adopted or inherited. The importance of path dependencies is amplified where conditions of increasing returns exist. Whether and how a firm’s competitive advantage is eroded depends on the stability of market demand, and the ease of replicability (expanding internally) and imitatability (replication by competitors). If correct, the framework suggests that private wealth creation in regimes of rapid technological change depends in large measure on honing internal technological, organizational, and managerial processes inside the firm. In short, identifying new opportunities and organizing effectively and efficiently to embrace them are generally more fundamental to private wealth creation than is strategizing, if by strategizing one means engaging in business conduct that keeps competitors off balance, raises rival’s costs, and excludes new entrants. © 1997 by John Wiley & Sons, Ltd.

Principles and Practice of Structural Equation Modeling

THE USE OF LEAD CITRATE AT HIGH pH AS AN ELECTRON-OPAQUE STAIN IN ELECTRON MICROSCOPY

Aqueous solutions of lead salts (1, 2) and saturated

The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary

Multiplex Genome Engineering Using CRISPR/Cas Systems

Functional elucidation of causal genetic variants and elements requires precise genome editing technologies. The type II prokaryotic CRISPR (clustered regularly interspaced short palindromic repeats)/Cas adaptive immune system has been shown to facilitate RNA-guided site-specific DNA cleavage. We engineered two different type II CRISPR/Cas systems and demonstrate that Cas9 nucleases can be directed by short RNAs to induce precise cleavage at endogenous genomic loci in human and mouse cells. Cas9 can also be converted into a nicking enzyme to facilitate homology-directed repair with minimal mutagenic activity. Lastly, multiple guide sequences can be encoded into a single CRISPR array to enable simultaneous editing of several sites within the mammalian genome, demonstrating easy programmability and wide applicability of the RNA-guided nuclease technology.

A Proportional Hazards Model for the Subdistribution of a Competing Risk

With explanatory covariates, the standard analysis for competing risks data involves modeling the cause-specific hazard functions via a proportional hazards assumption. Unfortunately, the cause-specific hazard function does not have a direct interpretation in terms of survival probabilities for the particular failure type. In recent years many clinicians have begun using the cumulative incidence function, the marginal failure probabilities for a particular cause, which is intuitively appealing and more easily explained to the nonstatistician. The cumulative incidence is especially relevant in cost-effectiveness analyses in which the survival probabilities are needed to determine treatment utility. Previously, authors have considered methods for combining estimates of the cause-specific hazard functions under the proportional hazards formulation. However, these methods do not allow the analyst to directly assess the effect of a covariate on the marginal probability function. In this article we propose a novel semiparametric proportional hazards model for the subdistribution. Using the partial likelihood principle and weighting techniques, we derive estimation and inference procedures for the finite-dimensional regression parameter under a variety of censoring scenarios. We give a uniformly consistent estimator for the predicted cumulative incidence for an individual with certain covariates; confidence intervals and bands can be obtained analytically or with an easy-to-implement simulation technique. To contrast the two approaches, we analyze a dataset from a breast cancer clinical trial under both models.

Bioconductor: open software development for computational biology and bioinformatics

The Bioconductor project is an initiative for the collaborative creation of extensible software for computational biology and bioinformatics. The goals of the project include: fostering collaborative development and widespread use of innovative software, reducing barriers to entry into interdisciplinary scientific research, and promoting the achievement of remote reproducibility of research results. We describe details of our aims and methods, identify current challenges, compare Bioconductor to other open bioinformatics projects, and provide working examples.

A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010

Genome engineering using the CRISPR-Cas9 system

Global Burden of Cardiovascular Diseases and Risk Factors, 1990–2019

Cardiovascular diseases (CVDs), principally ischemic heart disease (IHD) and stroke, are the leading cause of global mortality and a major contributor to disability. This paper reviews the magnitude of total CVD burden, including 13 underlying causes of cardiovascular death and 9 related risk factors, using estimates from the Global Burden of Disease (GBD) Study 2019. GBD, an ongoing multinational collaboration to provide comparable and consistent estimates of population health over time, used all available population-level data sources on incidence, prevalence, case fatality, mortality, and health risks to produce estimates for 204 countries and territories from 1990 to 2019. Prevalent cases of total CVD nearly doubled from 271 million (95% uncertainty interval [UI]: 257 to 285 million) in 1990 to 523 million (95% UI: 497 to 550 million) in 2019, and the number of CVD deaths steadily increased from 12.1 million (95% UI:11.4 to 12.6 million) in 1990, reaching 18.6 million (95% UI: 17.1 to 19.7 million) in 2019. The global trends for disability-adjusted life years (DALYs) and years of life lost also increased significantly, and years lived with disability doubled from 17.7 million (95% UI: 12.9 to 22.5 million) to 34.4 million (95% UI:24.9 to 43.6 million) over that period. The total number of DALYs due to IHD has risen steadily since 1990, reaching 182 million (95% UI: 170 to 194 million) DALYs, 9.14 million (95% UI: 8.40 to 9.74 million) deaths in the year 2019, and 197 million (95% UI: 178 to 220 million) prevalent cases of IHD in 2019. The total number of DALYs due to stroke has risen steadily since 1990, reaching 143 million (95% UI: 133 to 153 million) DALYs, 6.55 million (95% UI: 6.00 to 7.02 million) deaths in the year 2019, and 101 million (95% UI: 93.2 to 111 million) prevalent cases of stroke in 2019. Cardiovascular diseases remain the leading cause of disease burden in the world. CVD burden continues its decades-long rise for almost all countries outside high-income countries, and alarmingly, the age-standardized rate of CVD has begun to rise in some locations where it was previously declining in high-income countries. There is an urgent need to focus on implementing existing cost-effective policies and interventions if the world is to meet the targets for Sustainable Development Goal 3 and achieve a 30% reduction in premature mortality due to noncommunicable diseases.

A Short Physical Performance Battery Assessing Lower Extremity Function: Association With Self-Reported Disability and Prediction of Mortality and Nursing Home Admission

BACKGROUND: A short battery of physical performance tests was used to assess lower extremity function in more than 5,000 persons age 71 years and older in three communities. METHODS: Balance, gait, strength, and endurance were evaluated by examining ability to stand with the feet together in the side-by-side, semi-tandem, and tandem positions, time to walk 8 feet, and time to rise from a chair and return to the seated position 5 times. RESULTS: A wide distribution of performance was observed for each test. Each test and a summary performance scale, created by summing categorical rankings of performance on each test, were strongly associated with self-report of disability. Both self-report items and performance tests were independent predictors of short-term mortality and nursing home admission in multivariate analyses. However, evidence is presented that the performance tests provide information not available from self-report items. Of particular importance is the finding that in those at the high end of the functional spectrum, who reported almost no disability, the performance test scores distinguished a gradient of risk for mortality and nursing home admission. Additionally, within subgroups with identical self-report profiles, there were systematic differences in physical performance related to age and sex. CONCLUSION: This study provides evidence that performance measures can validly characterize older persons across a broad spectrum of lower extremity function. Performance and self-report measures may complement each other in providing useful information about functional status.

RNA-Guided Human Genome Engineering via Cas9

Bacteria and archaea have evolved adaptive immune defenses, termed clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) systems, that use short RNA to direct degradation of foreign nucleic acids. Here, we engineer the type II bacterial CRISPR system to function with custom guide RNA (gRNA) in human cells. For the endogenous AAVS1 locus, we obtained targeting rates of 10 to 25% in 293T cells, 13 to 8% in K562 cells, and 2 to 4% in induced pluripotent stem cells. We show that this process relies on CRISPR components; is sequence-specific; and, upon simultaneous introduction of multiple gRNAs, can effect multiplex editing of target loci. We also compute a genome-wide resource of ~190 K unique gRNAs targeting ~40.5% of human exons. Our results establish an RNA-guided editing tool for facile, robust, and multiplexable human genome engineering.

Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010

The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity

Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010

Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-years for 32 Cancer Groups, 1990 to 2015

IMPORTANCE: Cancer is the second leading cause of death worldwide. Current estimates on the burden of cancer are needed for cancer control planning. OBJECTIVE: To estimate mortality, incidence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs) for 32 cancers in 195 countries and territories from 1990 to 2015. EVIDENCE REVIEW: Cancer mortality was estimated using vital registration system data, cancer registry incidence data (transformed to mortality estimates using separately estimated mortality to incidence [MI] ratios), and verbal autopsy data. Cancer incidence was calculated by dividing mortality estimates through the modeled MI ratios. To calculate cancer prevalence, MI ratios were used to model survival. To calculate YLDs, prevalence estimates were multiplied by disability weights. The YLLs were estimated by multiplying age-specific cancer deaths by the reference life expectancy. DALYs were estimated as the sum of YLDs and YLLs. A sociodemographic index (SDI) was created for each location based on income per capita, educational attainment, and fertility. Countries were categorized by SDI quintiles to summarize results. FINDINGS: In 2015, there were 17.5 million cancer cases worldwide and 8.7 million deaths. Between 2005 and 2015, cancer cases increased by 33%, with population aging contributing 16%, population growth 13%, and changes in age-specific rates contributing 4%. For men, the most common cancer globally was prostate cancer (1.6 million cases). Tracheal, bronchus, and lung cancer was the leading cause of cancer deaths and DALYs in men (1.2 million deaths and 25.9 million DALYs). For women, the most common cancer was breast cancer (2.4 million cases). Breast cancer was also the leading cause of cancer deaths and DALYs for women (523 000 deaths and 15.1 million DALYs). Overall, cancer caused 208.3 million DALYs worldwide in 2015 for both sexes combined. Between 2005 and 2015, age-standardized incidence rates for all cancers combined increased in 174 of 195 countries or territories. Age-standardized death rates (ASDRs) for all cancers combined decreased within that timeframe in 140 of 195 countries or territories. Countries with an increase in the ASDR due to all cancers were largely located on the African continent. Of all cancers, deaths between 2005 and 2015 decreased significantly for Hodgkin lymphoma (-6.1% [95% uncertainty interval (UI), -10.6% to -1.3%]). The number of deaths also decreased for esophageal cancer, stomach cancer, and chronic myeloid leukemia, although these results were not statistically significant. CONCLUSION AND RELEVANCE: As part of the epidemiological transition, cancer incidence is expected to increase in the future, further straining limited health care resources. Appropriate allocation of resources for cancer prevention, early diagnosis, and curative and palliative care requires detailed knowledge of the local burden of cancer. The GBD 2015 study results demonstrate that progress is possible in the war against cancer. However, the major findings also highlight an unmet need for cancer prevention efforts, including tobacco control, vaccination, and the promotion of physical activity and a healthy diet.

The Structure of Haplotype Blocks in the Human Genome

Haplotype-based methods offer a powerful approach to disease gene mapping, based on the association between causal mutations and the ancestral haplotypes on which they arose. As part of The SNP Consortium Allele Frequency Projects, we characterized haplotype patterns across 51 autosomal regions (spanning 13 megabases of the human genome) in samples from Africa, Europe, and Asia. We show that the human genome can be parsed objectively into haplotype blocks: sizable regions over which there is little evidence for historical recombination and within which only a few common haplotypes are observed. The boundaries of blocks and specific haplotypes they contain are highly correlated across populations. We demonstrate that such haplotype frameworks provide substantial statistical power in association studies of common genetic variation across each region. Our results provide a foundation for the construction of a haplotype map of the human genome, facilitating comprehensive genetic association studies of human disease.

Marginal Structural Models and Causal Inference in Epidemiology

In observational studies with exposures or treatments that vary over time, standard approaches for adjustment of confounding are biased when there exist time-dependent confounders that are also affected by previous treatment. This paper introduces marginal structural models, a new class of causal models that allow for improved adjustment of confounding in those situations. The parameters of a marginal structural model can be consistently estimated using a new class of estimators, the inverse-probability-of-treatment weighted estimators.

Genetic studies of body mass index yield new insights for obesity biology

High-quality health systems in the Sustainable Development Goals era: time for a revolution

and respecting all workers to deliver the best care possible. Fourth, governments and civil society should ignite demand for quality in the population to empower people to hold systems accountable and actively seek high-quality care. Additional targeted actions in areas such as health financing, management, district-level learning, and others can complement these efforts. What works in one setting might not work elsewhere, and improvement efforts should be adapted for local context and monitored. Funders should align their support with system-wide strategies rather than contribute to the proliferation of micro-level efforts.

Global, Regional, and National Burden of Cardiovascular Diseases for 10 Causes, 1990 to 2015

BACKGROUND: The burden of cardiovascular diseases (CVDs) remains unclear in many regions of the world. OBJECTIVES: The GBD (Global Burden of Disease) 2015 study integrated data on disease incidence, prevalence, and mortality to produce consistent, up-to-date estimates for cardiovascular burden. METHODS: CVD mortality was estimated from vital registration and verbal autopsy data. CVD prevalence was estimated using modeling software and data from health surveys, prospective cohorts, health system administrative data, and registries. Years lived with disability (YLD) were estimated by multiplying prevalence by disability weights. Years of life lost (YLL) were estimated by multiplying age-specific CVD deaths by a reference life expectancy. A sociodemographic index (SDI) was created for each location based on income per capita, educational attainment, and fertility. RESULTS: In 2015, there were an estimated 422.7 million cases of CVD (95% uncertainty interval: 415.53 to 427.87 million cases) and 17.92 million CVD deaths (95% uncertainty interval: 17.59 to 18.28 million CVD deaths). Declines in the age-standardized CVD death rate occurred between 1990 and 2015 in all high-income and some middle-income countries. Ischemic heart disease was the leading cause of CVD health lost globally, as well as in each world region, followed by stroke. As SDI increased beyond 0.25, the highest CVD mortality shifted from women to men. CVD mortality decreased sharply for both sexes in countries with an SDI >0.75. CONCLUSIONS: CVDs remain a major cause of health loss for all regions of the world. Sociodemographic change over the past 25 years has been associated with dramatic declines in CVD in regions with very high SDI, but only a gradual decrease or no change in most regions. Future updates of the GBD study can be used to guide policymakers who are focused on reducing the overall burden of noncommunicable disease and achieving specific global health targets for CVD.

Global Surgery 2030: evidence and solutions for achieving health, welfare, and economic development

Artificial intelligence in radiology

The Lancet Commission on global mental health and sustainable development

Chemistry and Physics in One Dimension:  Synthesis and Properties of Nanowires and Nanotubes

Dimensionality plays a critical role in determining the properties of materials due to, for example, the different ways that electrons interact in three-dimensional, two-dimensional (2D), and one-dimensional (1D) structures.1-5

Estimating the global incidence of traumatic brain injury

OBJECTIVE: Traumatic brain injury (TBI)-the "silent epidemic"-contributes to worldwide death and disability more than any other traumatic insult. Yet, TBI incidence and distribution across regions and socioeconomic divides remain unknown. In an effort to promote advocacy, understanding, and targeted intervention, the authors sought to quantify the case burden of TBI across World Health Organization (WHO) regions and World Bank (WB) income groups. METHODS: Open-source epidemiological data on road traffic injuries (RTIs) were used to model the incidence of TBI using literature-derived ratios. First, a systematic review on the proportion of RTIs resulting in TBI was conducted, and a meta-analysis of study-derived proportions was performed. Next, a separate systematic review identified primary source studies describing mechanisms of injury contributing to TBI, and an additional meta-analysis yielded a proportion of TBI that is secondary to the mechanism of RTI. Then, the incidence of RTI as published by the Global Burden of Disease Study 2015 was applied to these two ratios to generate the incidence and estimated case volume of TBI for each WHO region and WB income group. RESULTS: Relevant articles and registries were identified via systematic review; study quality was higher in the high-income countries (HICs) than in the low- and middle-income countries (LMICs). Sixty-nine million (95% CI 64-74 million) individuals worldwide are estimated to sustain a TBI each year. The proportion of TBIs resulting from road traffic collisions was greatest in Africa and Southeast Asia (both 56%) and lowest in North America (25%). The incidence of RTI was similar in Southeast Asia (1.5% of the population per year) and Europe (1.2%). The overall incidence of TBI per 100,000 people was greatest in North America (1299 cases, 95% CI 650-1947) and Europe (1012 cases, 95% CI 911-1113) and least in Africa (801 cases, 95% CI 732-871) and the Eastern Mediterranean (897 cases, 95% CI 771-1023). The LMICs experience nearly 3 times more cases of TBI proportionally than HICs. CONCLUSIONS: Sixty-nine million (95% CI 64-74 million) individuals are estimated to suffer TBI from all causes each year, with the Southeast Asian and Western Pacific regions experiencing the greatest overall burden of disease. Head injury following road traffic collision is more common in LMICs, and the proportion of TBIs secondary to road traffic collision is likewise greatest in these countries. Meanwhile, the estimated incidence of TBI is highest in regions with higher-quality data, specifically in North America and Europe.

A communal catalogue reveals Earth’s multiscale microbial diversity

Our growing awareness of the microbial world's importance and diversity contrasts starkly with our limited understanding of its fundamental structure. Despite recent advances in DNA sequencing, a lack of standardized protocols and common analytical frameworks impedes comparisons among studies, hindering the development of global inferences about microbial life on Earth. Here we present a meta-analysis of microbial community samples collected by hundreds of researchers for the Earth Microbiome Project. Coordinated protocols and new analytical methods, particularly the use of exact sequences instead of clustered operational taxonomic units, enable bacterial and archaeal ribosomal RNA gene sequences to be followed across multiple studies and allow us to explore patterns of diversity at an unprecedented scale. The result is both a reference database giving global context to DNA sequence data and a framework for incorporating data from future studies, fostering increasingly complete characterization of Earth's microbial diversity.

Mapping genomic loci implicates genes and synaptic biology in schizophrenia

Schizophrenia has a heritability of 60–80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies. A genome-wide association study including over 76,000 individuals with schizophrenia and over 243,000 control individuals identifies common variant associations at 287 genomic loci, and further fine-mapping analyses highlight the importance of genes involved in synaptic processes.

Artificial intelligence in healthcare

Cross-national prevalence and risk factors for suicidal ideation, plans and attempts

BACKGROUND: Suicide is a leading cause of death worldwide; however, the prevalence and risk factors for the immediate precursors to suicide - suicidal ideation, plans and attempts - are not wellknown, especially in low- and middle-income countries. AIMS: To report on the prevalence and risk factors for suicidal behaviours across 17 countries. METHOD: A total of 84 850 adults were interviewed regarding suicidal behaviours and socio-demographic and psychiatric risk factors. RESULTS: The cross-national lifetime prevalence of suicidal ideation, plans, and attempts is 9.2% (s.e.=0.1), 3.1% (s.e.=0.1), and 2.7% (s.e.=0.1). Across all countries, 60% of transitions from ideation to plan and attempt occur within the first year after ideation onset. Consistent cross-national risk factors included being female, younger, less educated, unmarried and having a mental disorder. Interestingly, the strongest diagnostic risk factors were mood disorders in high-income countries but impulse control disorders in low- and middle-income countries. CONCLUSION: There is cross-national variability in the prevalence of suicidal behaviours, but strong consistency in the characteristics and risk factors for these behaviours. These findings have significant implications for the prediction and prevention of suicidal behaviours.

Structural and Functional Aspects of Metal Sites in Biology

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTStructural and Functional Aspects of Metal Sites in BiologyRichard H. Holm, Pierre Kennepohl, and Edward I. SolomonView Author Information Departments of Chemistry, Harvard University, Cambridge, Massachusetts 02138, and Stanford University, Stanford, California 94305 Cite this: Chem. Rev. 1996, 96, 7, 2239–2314Publication Date (Web):November 7, 1996Publication History Received10 June 1996Revised3 September 1996Published online7 November 1996Published inissue 1 January 1996https://pubs.acs.org/doi/10.1021/cr9500390https://doi.org/10.1021/cr9500390research-articleACS PublicationsCopyright © 1996 American Chemical SocietyRequest reuse permissionsArticle Views16245Altmetric-Citations2150LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Copper,Iron,Ligands,Metals,Peptides and proteins Get e-Alerts

Childhood adversities and adult psychopathology in the WHO World Mental Health Surveys

BACKGROUND: Although significant associations of childhood adversities with adult mental disorders are widely documented, most studies focus on single childhood adversities predicting single disorders. AIMS: To examine joint associations of 12 childhood adversities with first onset of 20 DSM-IV disorders in World Mental Health (WMH) Surveys in 21 countries. METHOD: Nationally or regionally representative surveys of 51 945 adults assessed childhood adversities and lifetime DSM-IV disorders with the WHO Composite International Diagnostic Interview (CIDI). RESULTS: Childhood adversities were highly prevalent and interrelated. Childhood adversities associated with maladaptive family functioning (e.g. parental mental illness, child abuse, neglect) were the strongest predictors of disorders. Co-occurring childhood adversities associated with maladaptive family functioning had significant subadditive predictive associations and little specificity across disorders. Childhood adversities account for 29.8% of all disorders across countries. CONCLUSIONS: Childhood adversities have strong associations with all classes of disorders at all life-course stages in all groups of WMH countries. Long-term associations imply the existence of as-yet undetermined mediators.

Child and adolescent mental health worldwide: evidence for action

Malignant astrocytic glioma: genetics, biology, and paths to treatment

Malignant astrocytic gliomas such as glioblastoma are the most common and lethal intracranial tumors. These cancers exhibit a relentless malignant progression characterized by widespread invasion throughout the brain, resistance to traditional and newer targeted therapeutic approaches, destruction of normal brain tissue, and certain death. The recent confluence of advances in stem cell biology, cell signaling, genome and computational science and genetic model systems have revolutionized our understanding of the mechanisms underlying the genetics, biology and clinical behavior of glioblastoma. This progress is fueling new opportunities for understanding the fundamental basis for development of this devastating disease and also novel therapies that, for the first time, portend meaningful clinical responses.

Opportunities and obstacles for deep learning in biology and medicine

Deep learning describes a class of machine learning algorithms that are capable of combining raw inputs into layers of intermediate features. These algorithms have recently shown impressive results across a variety of domains. Biology and medicine are data-rich disciplines, but the data are complex and often ill-understood. Hence, deep learning techniques may be particularly well suited to solve problems of these fields. We examine applications of deep learning to a variety of biomedical problems-patient classification, fundamental biological processes and treatment of patients-and discuss whether deep learning will be able to transform these tasks or if the biomedical sphere poses unique challenges. Following from an extensive literature review, we find that deep learning has yet to revolutionize biomedicine or definitively resolve any of the most pressing challenges in the field, but promising advances have been made on the prior state of the art. Even though improvements over previous baselines have been modest in general, the recent progress indicates that deep learning methods will provide valuable means for speeding up or aiding human investigation. Though progress has been made linking a specific neural network's prediction to input features, understanding how users should interpret these models to make testable hypotheses about the system under study remains an open challenge. Furthermore, the limited amount of labelled data for training presents problems in some domains, as do legal and privacy constraints on work with sensitive health records. Nonetheless, we foresee deep learning enabling changes at both bench and bedside with the potential to transform several areas of biology and medicine.

Grand challenges in global mental health

Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk

Fat and Beyond: The Diverse Biology of PPARγ

The nuclear receptor PPARgamma is a ligand-activated transcription factor that plays an important role in the control of gene expression linked to a variety of physiological processes. PPARgamma was initially characterized as the master regulator for the development of adipose cells. Ligands for PPARgamma include naturally occurring fatty acids and the thiazolidinedione (TZD) class of antidiabetic drugs. Activation of PPARgamma improves insulin sensitivity in rodents and humans through a combination of metabolic actions, including partitioning of lipid stores and the regulation of metabolic and inflammatory mediators termed adipokines. PPARgamma signaling has also been implicated in the control of cell proliferation, atherosclerosis, macrophage function, and immunity. Here, we review recent advances in our understanding of the diverse biological actions of PPARgamma with an eye toward the expanding therapeutic potential of PPARgamma agonist drugs.

Cause and Effect in Biology

Copper Active Sites in Biology

ADVERTISEMENT RETURN TO ISSUEPREVReviewNEXTCopper Active Sites in BiologyEdward I. Solomon*, David E. Heppner, Esther M. Johnston, Jake W. Ginsbach, Jordi Cirera, Munzarin Qayyum, Matthew T. Kieber-Emmons, Christian H. Kjaergaard, Ryan G. Hadt, and Li TianView Author Information Department of Chemistry, Stanford University, Stanford, California 94305, United States*E-mail: [email protected]Cite this: Chem. Rev. 2014, 114, 7, 3659–3853Publication Date (Web):March 3, 2014Publication History Received17 June 2013Published online3 March 2014Published inissue 9 April 2014https://pubs.acs.org/doi/10.1021/cr400327thttps://doi.org/10.1021/cr400327treview-articleACS PublicationsCopyright © 2014 American Chemical SocietyRequest reuse permissionsArticle Views32519Altmetric-Citations1308LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Copper,Crystal structure,Ligands,Peptides and proteins,Redox reactions Get e-Alerts

Use of mental health services for anxiety, mood, and substance disorders in 17 countries in the WHO world mental health surveys

Global, regional, and national levels and causes of maternal mortality during 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013

Lectures on holographic methods for condensed matter physics

These notes are loosely based on lectures given at the CERN Winter School on Supergravity, Strings and Gauge theories, February 2009, and at the IPM String School in Tehran, April 2009. I have focused on a few concrete topics and also on addressing questions that have arisen repeatedly. Background condensed matter physics material is included as motivation and easy reference for the high energy physics community. The discussion of holographic techniques progresses from equilibrium, to transport and to superconductivity.

Trauma and PTSD in the WHO World Mental Health Surveys

Background: Although post-traumatic stress disorder (PTSD) onset-persistence is thought to vary significantly by trauma type, most epidemiological surveys are incapable of assessing this because they evaluate lifetime PTSD only for traumas nominated by respondents as their ‘worst.’Objective: To review research on associations of trauma type with PTSD in the WHO World Mental Health (WMH) surveys, a series of epidemiological surveys that obtained representative data on trauma-specific PTSD.Method: WMH Surveys in 24 countries (n = 68,894) assessed 29 lifetime traumas and evaluated PTSD twice for each respondent: once for the ‘worst’ lifetime trauma and separately for a randomly-selected trauma with weighting to adjust for individual differences in trauma exposures. PTSD onset-persistence was evaluated with the WHO Composite International Diagnostic Interview.Results: In total, 70.4% of respondents experienced lifetime traumas, with exposure averaging 3.2 traumas per capita. Substantial between-trauma differences were found in PTSD onset but less in persistence. Traumas involving interpersonal violence had highest risk. Burden of PTSD, determined by multiplying trauma prevalence by trauma-specific PTSD risk and persistence, was 77.7 person-years/100 respondents. The trauma types with highest proportions of this burden were rape (13.1%), other sexual assault (15.1%), being stalked (9.8%), and unexpected death of a loved one (11.6%). The first three of these four represent relatively uncommon traumas with high PTSD risk and the last a very common trauma with low PTSD risk. The broad category of intimate partner sexual violence accounted for nearly 42.7% of all person-years with PTSD. Prior trauma history predicted both future trauma exposure and future PTSD risk.Conclusions: Trauma exposure is common throughout the world, unequally distributed, and differential across trauma types with respect to PTSD risk. Although a substantial minority of PTSD cases remits within months after onset, mean symptom duration is considerably longer than previously recognized.

Mental disorders among college students in the World Health Organization World Mental Health Surveys

BACKGROUND: Although mental disorders are significant predictors of educational attainment throughout the entire educational career, most research on mental disorders among students has focused on the primary and secondary school years. METHOD: The World Health Organization World Mental Health Surveys were used to examine the associations of mental disorders with college entry and attrition by comparing college students (n = 1572) and non-students in the same age range (18-22 years; n = 4178), including non-students who recently left college without graduating (n = 702) based on surveys in 21 countries (four low/lower-middle income, five upper-middle-income, one lower-middle or upper-middle at the times of two different surveys, and 11 high income). Lifetime and 12-month prevalence and age-of-onset of DSM-IV anxiety, mood, behavioral and substance disorders were assessed with the Composite International Diagnostic Interview (CIDI). RESULTS: One-fifth (20.3%) of college students had 12-month DSM-IV/CIDI disorders; 83.1% of these cases had pre-matriculation onsets. Disorders with pre-matriculation onsets were more important than those with post-matriculation onsets in predicting subsequent college attrition, with substance disorders and, among women, major depression the most important such disorders. Only 16.4% of students with 12-month disorders received any 12-month healthcare treatment for their mental disorders. CONCLUSIONS: Mental disorders are common among college students, have onsets that mostly occur prior to college entry, in the case of pre-matriculation disorders are associated with college attrition, and are typically untreated. Detection and effective treatment of these disorders early in the college career might reduce attrition and improve educational and psychosocial functioning.

Integrated genomic and molecular characterization of cervical cancer

Cervical cancer remains one of the leading causes of cancer-related deaths worldwide. Here we report the extensive molecular characterization of 228 primary cervical cancers, one of the largest comprehensive genomic studies of cervical cancer to date. We observed notable APOBEC mutagenesis patterns and identified SHKBP1, ERBB3, CASP8, HLA-A and TGFBR2 as novel significantly mutated genes in cervical cancer. We also discovered amplifications in immune targets CD274 (also known as PD-L1) and PDCD1LG2 (also known as PD-L2), and the BCAR4 long non-coding RNA, which has been associated with response to lapatinib. Integration of human papilloma virus (HPV) was observed in all HPV18-related samples and 76% of HPV16-related samples, and was associated with structural aberrations and increased target-gene expression. We identified a unique set of endometrial-like cervical cancers, comprised predominantly of HPV-negative tumours with relatively high frequencies of KRAS, ARID1A and PTEN mutations. Integrative clustering of 178 samples identified keratin-low squamous, keratin-high squamous and adenocarcinoma-rich subgroups. These molecular analyses reveal new potential therapeutic targets for cervical cancers. This paper describes molecular subtypes of cervical cancers, including squamous cell carcinoma and adenocarcinoma clusters defined by HPV status and molecular features, and distinct molecular pathways that are activated in cervical carcinomas caused by different somatic alterations and HPV types. Cervical cancer is one of the main causes of cancer-related deaths worldwide, and 95% of cases result from human papilloma virus (HPV) infection. The Cancer Genome Atlas Research Network now reports the genomic and molecular characterization of 228 primary cervical cancers. The authors identify significantly mutated genes and pathways that differ by cervical cancer subtype, and find that keratin-low squamous, keratin-high squamous and adenocarcinoma-rich clusters are marked by different HPV types and molecular features.

Global Burden of Cardiovascular Diseases and Risks, 1990-2022

The World Federation of ADHD International Consensus Statement: 208 Evidence-based conclusions about the disorder

BACKGROUND: Misconceptions about ADHD stigmatize affected people, reduce credibility of providers, and prevent/delay treatment. To challenge misconceptions, we curated findings with strong evidence base. METHODS: We reviewed studies with more than 2000 participants or meta-analyses from five or more studies or 2000 or more participants. We excluded meta-analyses that did not assess publication bias, except for meta-analyses of prevalence. For network meta-analyses we required comparison adjusted funnel plots. We excluded treatment studies with waiting-list or treatment as usual controls. From this literature, we extracted evidence-based assertions about the disorder. RESULTS: We generated 208 empirically supported statements about ADHD. The status of the included statements as empirically supported is approved by 80 authors from 27 countries and 6 continents. The contents of the manuscript are endorsed by 366 people who have read this document and agree with its contents. CONCLUSIONS: Many findings in ADHD are supported by meta-analysis. These allow for firm statements about the nature, course, outcome causes, and treatments for disorders that are useful for reducing misconceptions and stigma.

Screening for serious mental illness in the general population with the K6 screening scale: results from the WHO World Mental Health (WMH) survey initiative

Data are reported on the background and performance of the K6 screening scale for serious mental illness (SMI) in the World Health Organization (WHO) World Mental Health (WMH) surveys. The K6 is a six-item scale developed to provide a brief valid screen for Diagnostic and Statistical Manual of Mental Disorders 4th edition (DSM-IV) SMI based on the criteria in the US ADAMHA Reorganization Act. Although methodological studies have documented good K6 validity in a number of countries, optimal scoring rules have never been proposed. Such rules are presented here based on analysis of K6 data in nationally or regionally representative WMH surveys in 14 countries (combined N = 41,770 respondents). Twelve-month prevalence of DSM-IV SMI was assessed with the fully-structured WHO Composite International Diagnostic Interview. Nested logistic regression analysis was used to generate estimates of the predicted probability of SMI for each respondent from K6 scores, taking into consideration the possibility of variable concordance as a function of respondent age, gender, education, and country. Concordance, assessed by calculating the area under the receiver operating characteristic curve, was generally substantial (median 0.83; range 0.76-0.89; inter-quartile range 0.81-0.85). Based on this result, optimal scaling rules are presented for use by investigators working with the K6 scale in the countries studied.

The epidemiology of traumatic event exposure worldwide: results from the World Mental Health Survey Consortium

BACKGROUND: Considerable research has documented that exposure to traumatic events has negative effects on physical and mental health. Much less research has examined the predictors of traumatic event exposure. Increased understanding of risk factors for exposure to traumatic events could be of considerable value in targeting preventive interventions and anticipating service needs. METHOD: General population surveys in 24 countries with a combined sample of 68 894 adult respondents across six continents assessed exposure to 29 traumatic event types. Differences in prevalence were examined with cross-tabulations. Exploratory factor analysis was conducted to determine whether traumatic event types clustered into interpretable factors. Survival analysis was carried out to examine associations of sociodemographic characteristics and prior traumatic events with subsequent exposure. RESULTS: Over 70% of respondents reported a traumatic event; 30.5% were exposed to four or more. Five types - witnessing death or serious injury, the unexpected death of a loved one, being mugged, being in a life-threatening automobile accident, and experiencing a life-threatening illness or injury - accounted for over half of all exposures. Exposure varied by country, sociodemographics and history of prior traumatic events. Being married was the most consistent protective factor. Exposure to interpersonal violence had the strongest associations with subsequent traumatic events. CONCLUSIONS: Given the near ubiquity of exposure, limited resources may best be dedicated to those that are more likely to be further exposed such as victims of interpersonal violence. Identifying mechanisms that account for the associations of prior interpersonal violence with subsequent trauma is critical to develop interventions to prevent revictimization.

Posttraumatic stress disorder in the World Mental Health Surveys

BACKGROUND: Traumatic events are common globally; however, comprehensive population-based cross-national data on the epidemiology of posttraumatic stress disorder (PTSD), the paradigmatic trauma-related mental disorder, are lacking. METHODS: Data were analyzed from 26 population surveys in the World Health Organization World Mental Health Surveys. A total of 71 083 respondents ages 18+ participated. The Composite International Diagnostic Interview assessed exposure to traumatic events as well as 30-day, 12-month, and lifetime PTSD. Respondents were also assessed for treatment in the 12 months preceding the survey. Age of onset distributions were examined by country income level. Associations of PTSD were examined with country income, world region, and respondent demographics. RESULTS: The cross-national lifetime prevalence of PTSD was 3.9% in the total sample and 5.6% among the trauma exposed. Half of respondents with PTSD reported persistent symptoms. Treatment seeking in high-income countries (53.5%) was roughly double that in low-lower middle income (22.8%) and upper-middle income (28.7%) countries. Social disadvantage, including younger age, female sex, being unmarried, being less educated, having lower household income, and being unemployed, was associated with increased risk of lifetime PTSD among the trauma exposed. CONCLUSIONS: PTSD is prevalent cross-nationally, with half of all global cases being persistent. Only half of those with severe PTSD report receiving any treatment and only a minority receive specialty mental health care. Striking disparities in PTSD treatment exist by country income level. Increasing access to effective treatment, especially in low- and middle-income countries, remains critical for reducing the population burden of PTSD.

Barriers to mental health treatment: results from the WHO World Mental Health surveys

BACKGROUND: To examine barriers to initiation and continuation of mental health treatment among individuals with common mental disorders. METHOD: Data were from the World Health Organization (WHO) World Mental Health (WMH) surveys. Representative household samples were interviewed face to face in 24 countries. Reasons to initiate and continue treatment were examined in a subsample (n = 63,678) and analyzed at different levels of clinical severity. RESULTS: Among those with a DSM-IV disorder in the past 12 months, low perceived need was the most common reason for not initiating treatment and more common among moderate and mild than severe cases. Women and younger people with disorders were more likely to recognize a need for treatment. A desire to handle the problem on one's own was the most common barrier among respondents with a disorder who perceived a need for treatment (63.8%). Attitudinal barriers were much more important than structural barriers to both initiating and continuing treatment. However, attitudinal barriers dominated for mild-moderate cases and structural barriers for severe cases. Perceived ineffectiveness of treatment was the most commonly reported reason for treatment drop-out (39.3%), followed by negative experiences with treatment providers (26.9% of respondents with severe disorders). CONCLUSIONS: Low perceived need and attitudinal barriers are the major barriers to seeking and staying in treatment among individuals with common mental disorders worldwide. Apart from targeting structural barriers, mainly in countries with poor resources, increasing population mental health literacy is an important endeavor worldwide.

Genomic surveillance elucidates Ebola virus origin and transmission during the 2014 outbreak

In its largest outbreak, Ebola virus disease is spreading through Guinea, Liberia, Sierra Leone, and Nigeria. We sequenced 99 Ebola virus genomes from 78 patients in Sierra Leone to ~2000× coverage. We observed a rapid accumulation of interhost and intrahost genetic variation, allowing us to characterize patterns of viral transmission over the initial weeks of the epidemic. This West African variant likely diverged from central African lineages around 2004, crossed from Guinea to Sierra Leone in May 2014, and has exhibited sustained human-to-human transmission subsequently, with no evidence of additional zoonotic sources. Because many of the mutations alter protein sequences and other biologically meaningful targets, they should be monitored for impact on diagnostics, vaccines, and therapies critical to outbreak response.