Showing papers by "Virginia Commonwealth University published in 2015"
TL;DR: In the Global Burden of Disease Study 2013 (GBD 2013) as discussed by the authors, the authors used the GBD 2010 methods with some refinements to improve accuracy applied to an updated database of vital registration, survey, and census data.
5,792 citations
Mohammad H. Forouzanfar1, Lily Alexander, H. Ross Anderson, Victoria F Bachman1 +733 more•Institutions (289)
TL;DR: The Global Burden of Disease, Injuries, and Risk Factor study 2013 (GBD 2013) as discussed by the authors provides a timely opportunity to update the comparative risk assessment with new data for exposure, relative risks, and evidence on the appropriate counterfactual risk distribution.
5,668 citations
Alexander A. Aarts, Joanna E. Anderson1, Christopher J. Anderson2, Peter Raymond Attridge3 +287 more•Institutions (116)
TL;DR: A large-scale assessment suggests that experimental reproducibility in psychology leaves a lot to be desired, and correlational tests suggest that replication success was better predicted by the strength of original evidence than by characteristics of the original and replication teams.
Abstract: Reproducibility is a defining feature of science, but the extent to which it characterizes current research is unknown. We conducted replications of 100 experimental and correlational studies published in three psychology journals using high-powered designs and original materials when available. Replication effects were half the magnitude of original effects, representing a substantial decline. Ninety-seven percent of original studies had statistically significant results. Thirty-six percent of replications had statistically significant results; 47% of original effect sizes were in the 95% confidence interval of the replication effect size; 39% of effects were subjectively rated to have replicated the original result; and if no bias in original results is assumed, combining original and replication results left 68% with statistically significant effects. Correlational tests suggest that replication success was better predicted by the strength of original evidence than by characteristics of the original and replication teams.
5,532 citations
University of Washington1, University of Maryland, Baltimore2, Harvard University3, Broad Institute4, Mayo Clinic5, Yale University6, Washington University in St. Louis7, University of Michigan8, University of Texas Health Science Center at Houston9, Louisiana State University10, University of North Carolina at Charlotte11, Wellcome Trust12, University of Texas MD Anderson Cancer Center13, Boston College14, Yeshiva University15, Bilkent University16, University of California, San Diego17, National Institutes of Health18, Leiden University19, Baylor College of Medicine20, Cornell University21, University of Oxford22, Utrecht University23, Icahn School of Medicine at Mount Sinai24, Kyoto University25, Virginia Commonwealth University26, Heidelberg University27, Ewha Womans University28
TL;DR: In this paper, the authors describe an integrated set of eight structural variant classes comprising both balanced and unbalanced variants, which are constructed using short-read DNA sequencing data and statistically phased onto haplotype blocks in 26 human populations.
Abstract: Structural variants are implicated in numerous diseases and make up the majority of varying nucleotides among human genomes. Here we describe an integrated set of eight structural variant classes comprising both balanced and unbalanced variants, which we constructed using short-read DNA sequencing data and statistically phased onto haplotype blocks in 26 human populations. Analysing this set, we identify numerous gene-intersecting structural variants exhibiting population stratification and describe naturally occurring homozygous gene knockouts that suggest the dispensability of a variety of human genes. We demonstrate that structural variants are enriched on haplotypes identified by genome-wide association studies and exhibit enrichment for expression quantitative trait loci. Additionally, we uncover appreciable levels of structural variant complexity at different scales, including genic loci subject to clusters of repeated rearrangement and complex structural variants with multiple breakpoints likely to have formed through individual mutational events. Our catalogue will enhance future studies into structural variant demography, functional impact and disease association.
1,971 citations
Saint Louis University1, University of California, San Diego2, Virginia Commonwealth University3, Columbia University4, Johns Hopkins University5, Duke University6, Indiana University – Purdue University Indianapolis7, Case Western Reserve University8, University of California, San Francisco9, Virginia Mason Medical Center10, Cleveland Clinic11, Washington University in St. Louis12, National Institutes of Health13
TL;DR: Obeticholic acid improved the histological features of non-alcoholic steatohepatitis, but its long-term benefits and safety need further clarification.
1,798 citations
Mohammad H. Forouzanfar1, Lily Alexander1, H. Ross Anderson2, Victoria F Bachman1 +718 more•Institutions (295)
TL;DR: The Global Burden of Disease, Injuries, and Risk Factor study 2013 (GBD 2013) as mentioned in this paper provides a timely opportunity to update the comparative risk assessment with new data for exposure, relative risks, and evidence on the appropriate counterfactual risk distribution.
1,656 citations
TL;DR: Around 7 million Americans are living with a hip or knee replacement, and consequently, in most cases, are mobile, despite advanced arthritis, and these numbers underscore the substantial public health impact of total hip and knee arthroplasties.
Abstract: Background Descriptive epidemiology of total joint replacement procedures is limited to annual procedure volumes (incidence). The prevalence of the growing number of individuals living with a total hip or total knee replacement is currently unknown. Our objective was to estimate the prevalence of total hip and total knee replacement in the United States. Methods Prevalence was estimated using the counting method by combining historical incidence data from the National Hospital Discharge Survey and the Healthcare Cost and Utilization Project (HCUP) State Inpatient Databases from 1969 to 2010 with general population census and mortality counts. We accounted for relative differences in mortality rates between those who have had total hip or knee replacement and the general population. Results The 2010 prevalence of total hip and total knee replacement in the total U.S. population was 0.83% and 1.52%, respectively. Prevalence was higher among women than among men and increased with age, reaching 5.26% for total hip replacement and 10.38% for total knee replacement at eighty years. These estimates corresponded to 2.5 million individuals (1.4 million women and 1.1 million men) with total hip replacement and 4.7 million individuals (3.0 million women and 1.7 million men) with total knee replacement in 2010. Secular trends indicated a substantial rise in prevalence over time and a shift to younger ages. Conclusions Around 7 million Americans are living with a hip or knee replacement, and consequently, in most cases, are mobile, despite advanced arthritis. These numbers underscore the substantial public health impact of total hip and knee arthroplasties.
1,171 citations
TL;DR: It is shown that penta-graphene, composed of only carbon pentagons and resembling Cairo pentagonal tiling, is dynamically, thermally, and mechanically stable, and exhibits negative Poisson's ratio, a large band gap, and an ultrahigh mechanical strength.
Abstract: A 2D metastable carbon allotrope, penta-graphene, composed entirely of carbon pentagons and resembling the Cairo pentagonal tiling, is proposed. State-of-the-art theoretical calculations confirm that the new carbon polymorph is not only dynamically and mechanically stable, but also can withstand temperatures as high as 1000 K. Due to its unique atomic configuration, penta-graphene has an unusual negative Poisson’s ratio and ultrahigh ideal strength that can even outperform graphene. Furthermore, unlike graphene that needs to be functionalized for opening a band gap, penta-graphene possesses an intrinsic quasi-direct band gap as large as 3.25 eV, close to that of ZnO and GaN. Equally important, penta-graphene can be exfoliated from T12-carbon. When rolled up, it can form pentagon-based nanotubes which are semiconducting, regardless of their chirality. When stacked in different patterns, stable 3D twin structures of T12-carbon are generated with band gaps even larger than that of T12-carbon. The versatility of penta-graphene and its derivatives are expected to have broad applications in nanoelectronics and nanomechanics.
1,060 citations
Yeshiva University1, Harvard University2, Hamilton Health Sciences3, Sunnybrook Research Institute4, Loyola University Chicago5, University of Michigan6, Virginia Commonwealth University7, University of North Carolina at Chapel Hill8, Mayo Clinic9, University of Maryland, Baltimore10, Duke University11, Wake Forest University12, National Institutes of Health13, Indiana University14, Northwestern University15, Washington University in St. Louis16, Baylor College of Medicine17, Yonsei University18, Allegheny General Hospital19, Emory University20, University of Texas at San Antonio21, Vanderbilt University22, University of Pittsburgh23, Rutgers University24, Indiana University – Purdue University Indianapolis25, Stanford University26
TL;DR: In this article, a prospective trial involving women with hormone-receptor-positive, human epidermal growth factor receptor type 2 (HER2)-negative, axillary node-negative breast cancer with tumors of 1.1 to 5.0 cm in the greatest dimension (or 0.6 to 1.0cm in the intermediate or high tumor grade) who met established guidelines for the consideration of adjuvant chemotherapy on the basis of clinicopathologic features.
Abstract: BackgroundPrior studies with the use of a prospective–retrospective design including archival tumor samples have shown that gene-expression assays provide clinically useful prognostic information. However, a prospectively conducted study in a uniformly treated population provides the highest level of evidence supporting the clinical validity and usefulness of a biomarker. MethodsWe performed a prospective trial involving women with hormone-receptor–positive, human epidermal growth factor receptor type 2 (HER2)–negative, axillary node–negative breast cancer with tumors of 1.1 to 5.0 cm in the greatest dimension (or 0.6 to 1.0 cm in the greatest dimension and intermediate or high tumor grade) who met established guidelines for the consideration of adjuvant chemotherapy on the basis of clinicopathologic features. A reverse-transcriptase–polymerase-chain-reaction assay of 21 genes was performed on the paraffin-embedded tumor tissue, and the results were used to calculate a score indicating the risk of breast-...
1,059 citations
French Institute of Health and Medical Research1, Institut Gustave Roussy2, University of Pennsylvania3, University of Massachusetts Medical School4, University of Rome Tor Vergata5, University of California, San Francisco6, Virginia Commonwealth University7, Merck & Co.8, Harvard University9, University of South Australia10, University of Texas Southwestern Medical Center11, Trinity College, Dublin12, Austrian Academy of Sciences13, University of Cambridge14, University of Bern15, University of Oslo16, University of Colorado Denver17, Complutense University of Madrid18
TL;DR: The differential impact of autophagy on distinct phases of tumorigenesis is discussed and the implications of this concept for the use of Autophagy modulators in cancer therapy are discussed.
Abstract: Autophagy plays a key role in the maintenance of cellular homeostasis. In healthy cells, such a homeostatic activity constitutes a robust barrier against malignant transformation. Accordingly, many oncoproteins inhibit, and several oncosuppressor proteins promote, autophagy. Moreover, autophagy is required for optimal anticancer immunosurveillance. In neoplastic cells, however, autophagic responses constitute a means to cope with intracellular and environmental stress, thus favoring tumor progression. This implies that at least in some cases, oncogenesis proceeds along with a temporary inhibition of autophagy or a gain of molecular functions that antagonize its oncosuppressive activity. Here, we discuss the differential impact of autophagy on distinct phases of tumorigenesis and the implications of this concept for the use of autophagy modulators in cancer therapy.
945 citations
Virginia Commonwealth University1, University of Texas MD Anderson Cancer Center2, University of Pennsylvania3, University of Chicago4, University of Messina5, Federal University of São Paulo6, Yale University7, University of Toronto8, Mayo Clinic9, University of Marburg10, University of Washington11, Tel Aviv University12, Nagasaki University13
TL;DR: These inaugural guidelines provide recommendations for the evaluation and management of thyroid nodules in children and adolescents, including the role and interpretation of ultrasound, fine-needle aspiration cytology, and the management of benign nodules.
Abstract: Background: Previous guidelines for the management of thyroid nodules and cancers were geared toward adults. Compared with thyroid neoplasms in adults, however, those in the pediatric population ex...
TL;DR: SDM, when perceived by patients as occurring, tends to result in improved affective-cognitive outcomes, and evidence is lacking for the association between empirical measures of SDM and patient behavioral and health outcomes.
Abstract: Background. Despite widespread advocacy for shared decision making (SDM), the empirical evidence regarding its effectiveness to improve patient outcomes has not been systematically reviewed. The purpose of this study was to systematically review the empirical evidence linking patient outcomes and SDM, when the decision-making process has been explicitly measured, and to identify under what measurement perspectives SDM is associated with which types of patient outcomes (affective-cognitive, behavioral, and health). Data Sources. PubMed (through December 2012) and hand search of article bibliographies. Study Selection. Studies were included if they empirically 1) measured SDM in the context of a patient-clinician interaction and 2) evaluated the relationship between SDM and at least 1 patient outcome. Data Extraction. Study results were categorized by SDM measurement perspective (patient-reported, clinician-reported, or observer-rated) and outcome type (affective-cognitive, behavioral, or health). Data Synt...
University of Oxford1, Virginia Commonwealth University2, Capital Medical University3, Nanjing Medical University4, Hebei Medical University5, Harbin Medical University6, Shantou University7, Sichuan University8, Sun Yat-sen University9, Chongqing University10, Jinan University11, Xi'an Jiaotong University12, Shanxi Medical University13, Zhengzhou University14, Lanzhou University15, Central South University16, Jiangsu University17, Wuhan University18, Zhejiang Chinese Medical University19, China Medical University (PRC)20, Kanazawa Medical University21, Tianjin First Center Hospital22, Tongji University23, Fourth Military Medical University24, Max Planck Society25, Shanghai Jiao Tong University26, Fudan University27, Peking Union Medical College28, University of Copenhagen29, Macau University of Science and Technology30, King Abdulaziz University31, East China Normal University32
TL;DR: Using low-coverage whole-genome sequencing of 5,303 Chinese women with recurrent MDD selected to reduce phenotypic heterogeneity, and 5,337 controls screened to exclude MDD, two loci contributing to risk of MDD on chromosome 10 are identified: one near the SIRT1 gene and the other in an intron of the LHPP gene.
Abstract: Genomic analysis of 5,303 Chinese women with recurrent major depressive disorder (MDD) enables the identification and replication of two genome-wide significant loci contributing to risk of MDD on chromosome 10: one near the SIRT1 gene; the other in an intron of the LHPP gene.
TL;DR: This guideline update reflects changes in evidence since the previous guideline and recommends combination cytotoxic chemotherapy is recommended, guided by histology, with early concurrent palliative care.
Abstract: Purpose Provide evidence-based recommendations updating the 2015 ASCO guideline on systemic therapy for patients with stage IV non-small-cell lung cancer (NSCLC). Methods The ASCO NSCLC Expert Panel made recommendations based on a systematic review of randomized controlled trials from February 2014 to December 2016 plus the Cancer Care Ontario Program in Evidence-Based Care's update of a previous ASCO search. Results This guideline update reflects changes in evidence since the previous guideline update. Fourteen randomized controlled trials provide the evidence base; earlier phase trials also informed recommendation development. Recommendations New or revised recommendations include the following. Regarding first-line treatment for patients with non-squamous cell carcinoma or squamous cell carcinoma (without positive markers, eg, EGFR/ALK /ROS1), if the patient has high programmed death ligand 1 (PD-L1) expression, pembrolizumab should be used alone; if the patient has low PD-L1 expression, clinicians should offer standard chemotherapy. All other clinical scenarios follow 2015 recommendations. Regarding second-line treatment in patients who received first-line chemotherapy, without prior immune checkpoint therapy, if NSCLC tumor is positive for PD-L1 expression, clinicians should use single-agent nivolumab, pembrolizumab, or atezolizumab; if tumor has negative or unknown PD-L1 expression, clinicians should use nivolumab or atezolizumab. All immune checkpoint therapy is recommended alone plus in the absence of contraindications. For patients who received a prior first-line immune checkpoint inhibitor, clinicians should offer standard chemotherapy. For patients who cannot receive immune checkpoint inhibitor after chemotherapy, docetaxel is recommended; in patients with nonsquamous NSCLC, pemetrexed is recommended. In patients with a sensitizing EGFR mutation, disease progression after first-line epidermal growth factor receptor tyrosine kinase inhibitor therapy, and T790M mutation, osimertinib is recommended; if NSCLC lacks the T790M mutation, then chemotherapy is recommended. Patients with ROS1 gene rearrangement without prior crizotinib may be offered crizotinib, or if they previously received crizotinib, they may be offered chemotherapy.
Emory University1, DePaul University2, University of Miami3, Baylor College of Medicine4, Pennsylvania State University5, University of California, Irvine6, Duke University7, University of Colorado Denver8, Medical University of South Carolina9, University of Oklahoma10, University of Texas Southwestern Medical Center11, University of Illinois at Chicago12, Tulane University13, University of California, San Francisco14, Icahn School of Medicine at Mount Sinai15, Harvard University16, Virginia Commonwealth University17, University of Pennsylvania18, Rush University Medical Center19, Oregon Health & Science University20
TL;DR: This document represents a continuation of the National Lipid Association recommendations developed by a diverse panel of experts who examined the evidence base and provided recommendations regarding the following topics: lifestyle therapies and strategies to improve patient outcomes by increasing adherence and using team-based collaborative care.
TL;DR: Overall, it is concluded that fear appeals are effective at positively influencing attitude, intentions, and behaviors; there are very few circumstances under which they are not effective; and there are no identified circumstances underwhich they backfire and lead to undesirable outcomes.
Abstract: Fear appeals are a polarizing issue, with proponents confident in their efficacy and opponents confident that they backfire. We present the results of a comprehensive meta-analysis investigating fear appeals' effectiveness for influencing attitudes, intentions, and behaviors. We tested predictions from a large number of theories, the majority of which have never been tested meta-analytically until now. Studies were included if they contained a treatment group exposed to a fear appeal, a valid comparison group, a manipulation of depicted fear, a measure of attitudes, intentions, or behaviors concerning the targeted risk or recommended solution, and adequate statistics to calculate effect sizes. The meta-analysis included 127 articles (9% unpublished) yielding 248 independent samples (NTotal = 27,372) collected from diverse populations. Results showed a positive effect of fear appeals on attitudes, intentions, and behaviors, with the average effect on a composite index being random-effects d = 0.29. Moderation analyses based on prominent fear appeal theories showed that the effectiveness of fear appeals increased when the message included efficacy statements, depicted high susceptibility and severity, recommended one-time only (vs. repeated) behaviors, and targeted audiences that included a larger percentage of female message recipients. Overall, we conclude that (a) fear appeals are effective at positively influencing attitude, intentions, and behaviors; (b) there are very few circumstances under which they are not effective; and (c) there are no identified circumstances under which they backfire and lead to undesirable outcomes.
TL;DR: It is indicated that risk variants for psychiatric disorders aggregate in particular biological pathways and that these pathways are frequently shared between disorders.
Abstract: Genome-wide association studies (GWAS) of psychiatric disorders have identified multiple genetic associations with such disorders, but better methods are needed to derive the underlying biological mechanisms that these signals indicate. We sought to identify biological pathways in GWAS data from over 60,000 participants from the Psychiatric Genomics Consortium. We developed an analysis framework to rank pathways that requires only summary statistics. We combined this score across disorders to find common pathways across three adult psychiatric disorders: schizophrenia, major depression and bipolar disorder. Histone methylation processes showed the strongest association, and we also found statistically significant evidence for associations with multiple immune and neuronal signaling pathways and with the postsynaptic density. Our study indicates that risk variants for psychiatric disorders aggregate in particular biological pathways and that these pathways are frequently shared between disorders. Our results confirm known mechanisms and suggest several novel insights into the etiology of psychiatric disorders.
Montreal Heart Institute1, Pennsylvania State University2, Virginia Commonwealth University3, Children's Medical Research Institute4, University of Southern California5, University of Washington6, University of Michigan7, University of California, San Francisco8, Duke University9, University of Geneva10, University of Pennsylvania11, Harvard University12, University of Connecticut13, Centre national de la recherche scientifique14, University of Arizona15, Université de Sherbrooke16, University of Pittsburgh17, Johns Hopkins University18
TL;DR: The Pediatric Acute Lung Injury Consensus Conference developed pediatric-specific definitions for acute respiratory distress syndrome and recommendations regarding treatment and future research priorities intended to promote optimization and consistency of care for children with Pediatrics.
Abstract: Objective: To describe the final recommendations of the Pediatric Acute Lung Injury Consensus Conference. Design: Consensus conference of experts in pediatric acute lung injury. Setting: Not applicable. Subjects: PICU patients with evidence of acute lung injury or acute respiratory distress syndrome. Interventions: None. Methods: A panel of 27 experts met over the course of 2 years to develop a taxonomy to define pediatric acute respiratory distress syndrome and to make recommendations regarding treatment and research priorities. When published, data were lacking a modified Delphi approach emphasizing strong professional agreement was used. Measurements and Main Results: A panel of 27 experts met over the course of 2 years to develop a taxonomy to define pediatric acute respiratory distress syndrome and to make recommendations regarding treatment and research priorities. When published data were lacking a modified Delphi approach emphasizing strong professional agreement was used. The Pediatric Acute Lung Injury Consensus Conference experts developed and voted on a total of 151 recommendations addressing the following topics related to pediatric acute respiratory distress syndrome: 1) Definition, prevalence, and epidemiology; 2) Pathophysiology, comorbidities, and severity; 3) Ventilatory support; 4) Pulmonary-specific ancillary treatment; 5) Nonpulmonary treatment; 6) Monitoring; 7) Noninvasive support and ventilation; 8) Extracorporeal support; and 9) Morbidity and long-term outcomes. There were 132 recommendations with strong agreement and 19 recommendations with weak agreement. Once restated, the final iteration of the recommendations had none with equipoise or disagreement. Conclusions: The Consensus Conference developed pediatric-specific definitions for acute respiratory distress syndrome and recommendations regarding treatment and future research priorities. These are intended to promote optimization and consistency of care for children with pediatric acute respiratory distress syndrome and identify areas of uncertainty requiring further investigation.
TL;DR: This document provides support for a consensus set of recommendations for patient-centered management of dyslipidemia in clinical medicine and an elevated level of cholesterol carried by circulating apolipoprotein B-containing lipoproteins is a root cause of atherosclerosis.
TL;DR: It is imperative to know how this dual action of ROS works during NLRP3 inflammation activation on different stimuli and what relevance such spatiotemporal redox regulation ofNLRP3 inflammasomes has in cell or organ functions and possible human diseases.
Abstract: Significance: Inflammasomes are multiprotein complexes localized within the cytoplasm of the cell that are responsible for the maturation of proinflammatory cytokines such as interleukin-1β (IL-1β) and IL-18, and the activation of a highly inflammatory form of cell death, pyroptosis. In response to infection or cellular stress, inflammasomes are assembled, activated, and involved in host defense and pathophysiology of diseases. Clarification of the molecular mechanisms leading to the activation of this intracellular inflammatory machinery may provide new insights into the concept of inflammation as the root of and route to human diseases. Recent Advances: The activation of inflammasomes, specifically the most fully characterized inflammasome—the nucleotide-binding oligomerization domain (NOD)-like receptor containing pyrin domain 3 (NLRP3) inflammasome, is now emerging as a critical molecular mechanism for many degenerative diseases. Several models have been developed to describe how NLRP3 inflam...
TL;DR: Salinization, a widespread threat to the structure and ecological functioning of inland and coastal wetlands, is currently occurring at an unprecedented rate and geographic scale as discussed by the authors, and the causes of salinization are diverse and include alterations to freshwater flows, land-clearance, irrigation, disposal of wastewater effluent, sea level rise, storm surges, and applications of de-icing salts.
Abstract: Salinization, a widespread threat to the structure and ecological functioning of inland and coastal wetlands, is currently occurring at an unprecedented rate and geographic scale. The causes of salinization are diverse and include alterations to freshwater flows, land-clearance, irrigation, disposal of wastewater effluent, sea level rise, storm surges, and applications of de-icing salts. Climate change and anthropogenic modifications to the hydrologic cycle are expected to further increase the extent and severity of wetland salinization. Salinization alters the fundamental physicochemical nature of the soil-water environment, increasing ionic concentrations and altering chemical equilibria and mineral solubility. Increased concentrations of solutes, especially sulfate, alter the biogeochemical cycling of major elements including carbon, nitrogen, phosphorus, sulfur, iron, and silica. The effects of salinization on wetland biogeochemistry typically include decreased inorganic nitrogen removal (with implica...
University of Melbourne1, University of Newcastle2, Harvard University3, University of Chicago4, European Organisation for Research and Treatment of Cancer5, University of Bordeaux6, University of Pittsburgh7, Virginia Commonwealth University8, Alberta Health Services9, University of Regensburg10, Mayo Clinic11, University of Bern12, European Institute of Oncology13, University of Milan14, University of Sydney15
TL;DR: Adding ovarian suppression to tamoxifen did not provide a significant benefit in the overall study population, but for women who were at sufficient risk for recurrence to warrant adjuvant chemotherapy and who remained premenopausal, the addition of ovarian suppression improved disease outcomes.
Abstract: We randomly assigned 3066 premenopausal women, stratified according to prior receipt or nonreceipt of chemotherapy, to receive 5 years of tamoxifen, tamoxifen plus ovarian suppression, or exemestane plus ovarian suppression. The primary analysis tested the hypothesis that tamoxifen plus ovarian suppression would improve disease-free survival, as compared with tamoxifen alone. In the primary analysis, 46.7% of the patients had not received chemotherapy previously, and 53.3% had received chemotherapy and remained premenopausal. RESULTS After a median follow-up of 67 months, the estimated disease-free survival rate at 5 years was 86.6% in the tamoxifen–ovarian suppression group and 84.7% in the tamoxifen group (hazard ratio for disease recurrence, second invasive cancer, or death, 0.83; 95% confidence interval [CI], 0.66 to 1.04; P = 0.10). Multivariable allowance for prognostic factors suggested a greater treatment effect with tamoxifen plus ovarian suppression than with tamoxifen alone (hazard ratio, 0.78; 95% CI, 0.62 to 0.98). Most recurrences occurred in patients who had received prior chemotherapy, among whom the rate of freedom from breast cancer at 5 years was 82.5% in the tamoxifen–ovarian suppression group and 78.0% in the tamoxifen group (hazard ratio for recurrence, 0.78; 95% CI, 0.60 to 1.02). At 5 years, the rate of freedom from breast cancer was 85.7% in the exemestane–ovarian suppression group (hazard ratio for recurrence vs. tamoxifen, 0.65; 95% CI, 0.49 to 0.87). CONCLUSIONS Adding ovarian suppression to tamoxifen did not provide a significant benefit in the overall study population. However, for women who were at sufficient risk for recurrence to warrant adjuvant chemotherapy and who remained premenopausal, the addition of ovarian suppression improved disease outcomes. Further improvement was seen with the use of exemestane plus ovarian suppression. (Funded by Pfizer and others; SOFT ClinicalTrials.gov number, NCT00066690.)
TL;DR: Expected future directions in the field of landscape genomics are summarized, such as the extension of statistical approaches, environmental association analysis for ecological gene annotation, and the need for replication and post hoc validation studies.
Abstract: Landscape genomics is an emerging research field that aims to identify the environmental factors that shape adaptive genetic variation and the gene variants that drive local adaptation. Its development has been facilitated by next-generation sequencing, which allows for screening thousands to millions of single nucleotide polymorphisms in many individuals and populations at reasonable costs. In parallel, data sets describing environmental factors have greatly improved and increasingly become publicly accessible. Accordingly, numerous analytical methods for environmental association studies have been developed. Environmental association analysis identifies genetic variants associated with particular environmental factors and has the potential to uncover adaptive patterns that are not discovered by traditional tests for the detection of outlier loci based on population genetic differentiation. We review methods for conducting environmental association analysis including categorical tests, logistic regressions, matrix correlations, general linear models and mixed effects models. We discuss the advantages and disadvantages of different approaches, provide a list of dedicated software packages and their specific properties, and stress the importance of incorporating neutral genetic structure in the analysis. We also touch on additional important aspects such as sampling design, environmental data preparation, pooled and reduced-representation sequencing, candidate-gene approaches, linearity of allele-environment associations and the combination of environmental association analyses with traditional outlier detection tests. We conclude by summarizing expected future directions in the field, such as the extension of statistical approaches, environmental association analysis for ecological gene annotation, and the need for replication and post hoc validation studies.
TL;DR: The state of the art of critical eCB functions in peripheral organs is reviewed to establish consensus views on the relevance of the peripheral ECS for human health and disease pathogenesis, as well as highlighting emerging challenges and therapeutic hopes.
TL;DR: This study extracted 147,328 correlations and developed a hierarchical taxonomy of variables reported in Journal of Applied Psychology and Personnel Psychology from 1980 to 2010 to produce empirical effect size benchmarks at the omnibus level, for 20 common research domains, and for an even finer grained level of generality.
Abstract: Effect size information is essential for the scientific enterprise and plays an increasingly central role in the scientific process. We extracted 147,328 correlations and developed a hierarchical taxonomy of variables reported in Journal of Applied Psychology and Personnel Psychology from 1980 to 2010 to produce empirical effect size benchmarks at the omnibus level, for 20 common research domains, and for an even finer grained level of generality. Results indicate that the usual interpretation and classification of effect sizes as small, medium, and large bear almost no resemblance to findings in the field, because distributions of effect sizes exhibit tertile partitions at values approximately one-half to one-third those intuited by Cohen (1988). Our results offer information that can be used for research planning and design purposes, such as producing better informed non-nil hypotheses and estimating statistical power and planning sample size accordingly. We also offer information useful for understanding the relative importance of the effect sizes found in a particular study in relationship to others and which research domains have advanced more or less, given that larger effect sizes indicate a better understanding of a phenomenon. Also, our study offers information about research domains for which the investigation of moderating effects may be more fruitful and provide information that is likely to facilitate the implementation of Bayesian analysis. Finally, our study offers information that practitioners can use to evaluate the relative effectiveness of various types of interventions.
TL;DR: A weighted quantile sum (WQS) approach to estimating a body burden index, which identifies “bad actors” in a set of highly correlated environmental chemicals, and demonstrates the improvement in accuracy this method provides over traditional ordinary regression and shrinkage methods.
Abstract: In risk evaluation, the effect of mixtures of environmental chemicals on a common adverse outcome is of interest. However, due to the high dimensionality and inherent correlations among chemicals that occur together, the traditional methods (e.g. ordinary or logistic regression) suffer from collinearity and variance inflation, and shrinkage methods have limitations in selecting among correlated components. We propose a weighted quantile sum (WQS) approach to estimating a body burden index, which identifies “bad actors” in a set of highly correlated environmental chemicals. We evaluate and characterize the accuracy of WQS regression in variable selection through extensive simulation studies through sensitivity and specificity (i.e., ability of the WQS method to select the bad actors correctly and not incorrect ones). We demonstrate the improvement in accuracy this method provides over traditional ordinary regression and shrinkage methods (lasso, adaptive lasso, and elastic net). Results from simulations demonstrate that WQS regression is accurate under some environmentally relevant conditions, but its accuracy decreases for a fixed correlation pattern as the association with a response variable diminishes. Nonzero weights (i.e., weights exceeding a selection threshold parameter) may be used to identify bad actors; however, components within a cluster of highly correlated active components tend to have lower weights, with the sum of their weights representative of the set.
University of Virginia1, Case Western Reserve University2, University of Toronto3, Virginia Commonwealth University4, University of Washington5, Harvard University6, Washington University in St. Louis7, Veterans Health Administration8, University of Michigan9, University of Miami10, Wake Forest University11, University of South Carolina12, University of California, San Diego13, University of Texas Health Science Center at San Antonio14, University of Medicine and Dentistry of New Jersey15, University of California, Davis16, University of California, San Francisco17, University of Minnesota18, University of Louisville19, Johns Hopkins University20
TL;DR: In patients with intraabdominal infections who had undergone an adequate source-control procedure, the outcomes after fixed-duration antibiotic therapy were similar to those after a longer course of antibiotics that extended until after the resolution of physiological abnormalities.
Abstract: Surgical-site infection, recurrent intraabdominal infection, or death occurred in 56 of 257 patients in the experimental group (21.8%), as compared with 58 of 260 patients in the control group (22.3%) (absolute difference, −0.5 percentage point; 95% confidence interval [CI], −7.0 to 8.0; P = 0.92). The median duration of antibiotic therapy was 4.0 days (interquartile range, 4.0 to 5.0) in the experimental group, as compared with 8.0 days (interquartile range, 5.0 to 10.0) in the control group (absolute difference, −4.0 days; 95% CI, −4.7 to −3.3; P<0.001). No signifi cant between-group differences were found in the individual rates of the components of the primary outcome or in other secondary outcomes. CONCLUSIONS In patients with intraabdominal infections who had undergone an adequate sourcecontrol procedure, the outcomes after fixed-duration antibiotic therapy (approximately 4 days) were similar to those after a longer course of antibiotics (approximately 8 days) that extended until after the resolution of physiological abnormalities. (Funded by the National Institutes of Health; STOP-IT ClinicalTrials .gov number, NCT00657566.)
TL;DR: A meta-analysis of twin and adoption studies of AUD found evidence for modest shared environmental effects suggesting that environmental factors also contribute to the familial aggregation of AUDs.
Abstract: Background. To clarify the role of genetic and environmental risk factors in alcohol use disorders (AUDs), we performed a meta-analysis of twin and adoption studies and explored the impact of sex, assessment method (interview v. hospital/population records), and study design (twin v. adoption study) on heritability estimates. Method. The literature was searched for all unique twin and adoption studies of AUD and identified 12 twin and five adoption studies. The data were then reconstructed and analyzed using ordinal data full information maximum likelihood in the OpenMx program. Heterogeneity was tested with likelihood ratio tests by equating the parameters across studies. Results. There was no evidence for heterogeneity by study design, sex or assessment method. The best-fit estimate of the heritability of AUD was 0.49 [95% confidence interval (CI) 0.43–0.53], and the proportion of shared environmental variance was 0.10 (95% CI 0.03–0.16). Estimates of unique environmental proportions of variance differed significantly across studies. Conclusions. AUD is approximately 50% heritable. The multiple genetically informative studies of this syndrome have produced consistent results that support the validity of this heritability estimate, especially given the different potential methodological weaknesses of twin and adoption designs, and of assessments of AUD based on personal interviews v. official records. We also found evidence for modest shared environmental effects suggesting that environmental factors also contribute to the familial aggregation of AUDs.
University of Birmingham1, University of Alberta2, Virginia Commonwealth University3, Veterans Health Administration4, Mayo Clinic5, Arizona State University6, Ford Motor Company7, University of Texas Southwestern Medical Center8, Virginia Mason Medical Center9, Icahn School of Medicine at Mount Sinai10, Beth Israel Medical Center11, University of Barcelona12, Medical University of Vienna13, University of Gothenburg14, Intercept Pharmaceuticals15
TL;DR: Daily doses of OCA significantly reduced levels of ALP, γ-glutamyl transpeptidase, and alanine aminotransferase, compared with placebo, in patients with primary biliary cirrhosis who had inadequate responses to ursodeoxycholic acid.
TL;DR: The current knowledge of the role of BCL2 family members in cancer development and response to therapy, focusing on targeted therapeutics, recent progress in the development of apoptotic biomarkers, and therapeutic strategies designed to overcome deficiencies in apoptosis are summarized.
Abstract: The ability of cancer cells to suppress apoptosis is critical for carcinogenesis. The BCL2 family proteins comprise the sentinel network that regulates the mitochondrial or intrinsic apoptotic response. Recent advances in our understanding of apoptotic signaling pathways have enabled methods to identify cancers that are “primed” to undergo apoptosis, and have revealed potential biomarkers that may predict which cancers will undergo apoptosis in response to specific therapies. Complementary efforts have focused on developing novel drugs that directly target antiapoptotic BCL2 family proteins. In this review, we summarize the current knowledge of the role of BCL2 family members in cancer development and response to therapy, focusing on targeted therapeutics, recent progress in the development of apoptotic biomarkers, and therapeutic strategies designed to overcome deficiencies in apoptosis.
Significance: Apoptosis, long known to be important for response to conventional cytotoxic chemotherapy, has more recently been shown to be essential for the efficacy of targeted therapies. Approaches that increase the likelihood of a cancer to undergo apoptosis following therapy may help improve targeted treatment strategies. Cancer Discov; 5(5); 475–87. ©2015 AACR .