Showing papers by "Wake Forest University published in 2014"
National Institutes of Health1, University of Pittsburgh2, McMaster University3, University of Washington4, University of Cape Town5, Wake Forest University6, University of Leicester7, Karolinska Institutet8, University of Southampton9, Boston Children's Hospital10, John Hunter Hospital11, McGill University12, University of Wisconsin-Madison13, University of Virginia14
TL;DR: Recommendations and guidelines on the evaluation and treatment of severe asthma in children and adults and coordinated research efforts for improved phenotyping will provide safe and effective biomarker-driven approaches to severe asthma therapy are provided.
Abstract: Severe or therapy-resistant asthma is increasingly recognised as a major unmet need. A Task Force, supported by the European Respiratory Society and American Thoracic Society, reviewed the definition and provided recommendations and guidelines on the evaluation and treatment of severe asthma in children and adults. A literature review was performed, followed by discussion by an expert committee according to the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach for development of specific clinical recommendations. When the diagnosis of asthma is confirmed and comorbidities addressed, severe asthma is defined as asthma that requires treatment with high dose inhaled corticosteroids plus a second controller and/or systemic corticosteroids to prevent it from becoming “uncontrolled” or that remains “uncontrolled” despite this therapy. Severe asthma is a heterogeneous condition consisting of phenotypes such as eosinophilic asthma. Specific recommendations on the use of sputum eosinophil count and exhaled nitric oxide to guide therapy, as well as treatment with anti-IgE antibody, methotrexate, macrolide antibiotics, antifungal agents and bronchial thermoplasty are provided. Coordinated research efforts for improved phenotyping will provide safe and effective biomarker-driven approaches to severe asthma therapy.
2,795 citations
TL;DR: This article identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height, and all common variants together captured 60% of heritability.
Abstract: Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ∼2,000, ∼3,700 and ∼9,500 SNPs explained ∼21%, ∼24% and ∼29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/β-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.
1,872 citations
University of Pittsburgh1, California Pacific Medical Center2, University of Maryland, Baltimore3, Beth Israel Deaconess Medical Center4, National Institutes of Health5, University of Central Florida6, University of Connecticut Health Center7, Wake Forest University8, Columbia University9, Foundation for the National Institutes of Health10
TL;DR: Based on the analyses presented in this series, the final recommended cutpoints for weakness are grip strength <26kg for men and <16kg for women, and for low lean mass, appendicular lean mass adjusted for body mass index <0.789 forMen and women.
Abstract: Background.
Low muscle mass and weakness are common and potentially disabling in older adults, but in order to become recognized as a clinical condition, criteria for diagnosis should be based on clinically relevant thresholds and independently validated. The Foundation for the National Institutes of Health Biomarkers Consortium Sarcopenia Project used an evidence-based approach to develop these criteria. Initial findings were presented at a conference in May 2012, which generated recommendations that guided additional analyses to determine final recommended criteria. Details of the Project and its findings are presented in four accompanying manuscripts.
1,542 citations
Colorado School of Public Health1, University of North Carolina at Chapel Hill2, Centers for Disease Control and Prevention3, National Institutes of Health4, Wake Forest University5, Boston Children's Hospital6, University of South Carolina7, Kaiser Permanente8, Cincinnati Children's Hospital Medical Center9, University of Washington10
TL;DR: Significant increases occurred between 2001 and 2009 in both sexes, all age-groups, and in white, Hispanic, and black youth, with no significant changes for Asian Pacific Islanders and American Indians.
Abstract: RESULTS In 2001, 4958 of 3.3 million youth were diagnosed with type 1 diabetes for a prevalence of 1.48 per 1000 (95% CI, 1.44-1.52). In 2009, 6666 of 3.4 million youth were diagnosed with type 1 diabetes for a prevalence of 1.93 per 1000 (95% CI, 1.88-1.97). In 2009, the highest prevalence of type 1 diabetes was 2.55 per 1000 among white youth (95% CI, 2.48-2.62) and the lowest was 0.35 per 1000 in American Indian youth (95% CI, 0.26-0.47) and type 1 diabetes increased between 2001 and 2009 in all sex, age, and race/ethnic subgroups except for those with the lowest prevalence (age 0-4 years and American Indians). Adjusted for completeness of ascertainment, there was a 21.1% (95% CI, 15.6%-27.0%) increase in type 1 diabetes over 8 years. In 2001, 588 of 1.7 million youth were diagnosed with type 2 diabetes for a prevalence of 0.34 per 1000 (95% CI, 0.31-0.37). In 2009, 819 of 1.8 million were diagnosed with type 2 diabetes for a prevalence of 0.46 per 1000 (95% CI, 0.43-0.49). In 2009, the prevalence of type 2 diabetes was 1.20 per 1000 among American Indian youth (95% CI, 0.96-1.51); 1.06 per 1000 among black youth (95% CI, 0.93-1.22); 0.79 per 1000 among Hispanic youth (95% CI, 0.70-0.88); and 0.17 per 1000 among white youth (95% CI, 0.15-0.20). Significant increases occurred between 2001 and 2009 in both sexes, all age-groups, and in white, Hispanic, and black youth, with no significant changes for Asian Pacific Islanders and American Indians. Adjusted for completeness of ascertainment, there was a 30.5% (95% CI, 17.3%-45.1%) overall increase in type 2 diabetes. CONCLUSIONS AND RELEVANCE Between 2001 and 2009 in 5 areas of the United States, the prevalence of both type 1 and type 2 diabetes among children and adolescents increased. Further studies are required to determine the causes of these increases.
1,227 citations
University of Florida1, University of Maryland, Baltimore2, Wake Forest University3, University of South Carolina4, Pennington Biomedical Research Center5, United States Department of Agriculture6, Yale University7, University of California, San Diego8, Veterans Health Administration9, Stanford University10, Northwestern University11, University of Pittsburgh12
TL;DR: The findings suggest mobility benefit from a structured, moderate-intensity physical activity program compared with a health education program reduced major mobility disability over 2.6 years among older adults at risk for disability.
Abstract: Importance In older adults reduced mobility is common and is an independent risk factor for morbidity, hospitalization, disability, and mortality. Limited evidence suggests that physical activity may help prevent mobility disability; however, there are no definitive clinical trials examining whether physical activity prevents or delays mobility disability. Objective To test the hypothesis that a long-term structured physical activity program is more effective than a health education program (also referred to as a successful aging program) in reducing the risk of major mobility disability. Design, Setting, and Participants The Lifestyle Interventions and Independence for Elders (LIFE) study was a multicenter, randomized trial that enrolled participants between February 2010 and December 2011, who participated for an average of 2.6 years. Follow-up ended in December 2013. Outcome assessors were blinded to the intervention assignment. Participants were recruited from urban, suburban, and rural communities at 8 centers throughout the United States. We randomized a volunteer sample of 1635 sedentary men and women aged 70 to 89 years who had physical limitations, defined as a score on the Short Physical Performance Battery of 9 or below, but were able to walk 400 m. Interventions Participants were randomized to a structured, moderate-intensity physical activity program (n = 818) conducted in a center (twice/wk) and at home (3-4 times/wk) that included aerobic, resistance, and flexibility training activities or to a health education program (n = 817) consisting of workshops on topics relevant to older adults and upper extremity stretching exercises. Main Outcomes and Measures The primary outcome was major mobility disability objectively defined by loss of ability to walk 400 m. Results Incident major mobility disability occurred in 30.1% (246 participants) of the physical activity group and 35.5% (290 participants) of the health education group (hazard ratio [HR], 0.82 [95% CI, 0.69-0.98], P = .03). Persistent mobility disability was experienced by 120 participants (14.7%) in the physical activity group and 162 participants (19.8%) in the health education group (HR, 0.72 [95% CI, 0.57-0.91]; P = .006). Serious adverse events were reported by 404 participants (49.4%) in the physical activity group and 373 participants (45.7%) in the health education group (risk ratio, 1.08 [95% CI, 0.98-1.20]). Conclusions and Relevance A structured, moderate-intensity physical activity program compared with a health education program reduced major mobility disability over 2.6 years among older adults at risk for disability. These findings suggest mobility benefit from such a program in vulnerable older adults. Trial Registration clinicaltrials.gov Identifier:NCT01072500
1,089 citations
TL;DR: In this paper, the authors aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry.
Abstract: To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry.
954 citations
TL;DR: A method to infer relationships among quartets of taxa under the coalescent model using techniques from algebraic statistics is developed, and uncertainty in the estimated relationships is quantified using the nonparametric bootstrap.
Abstract: Motivation: Increasing attention has been devoted to estimation of species-level phylogenetic relationships under the coalescent model. However, existing methods either use summary statistics (gene trees) to carry out estimation, ignoring an important source of variability in the estimates, or involve computationally intensive Bayesian Markov chain Monte Carlo algorithms that do not scale well to whole-genome datasets.
Results: We develop a method to infer relationships among quartets of taxa under the coalescent model using techniques from algebraic statistics. Uncertainty in the estimated relationships is quantified using the nonparametric bootstrap. The performance of our method is assessed with simulated data. We then describe how our method could be used for species tree inference in larger taxon samples, and demonstrate its utility using datasets for Sistrurus rattlesnakes and for soybeans.
Availability and implementation: The method to infer the phylogenetic relationship among quartets is implemented in the software SVDquartets, available at www.stat.osu.edu/∼lkubatko/software/SVDquartets.
Contact: ude.uso.tats@oktabukl
Supplementary information: Supplementary data are available at Bioinformatics online.
908 citations
University of California, San Diego1, Boston Children's Hospital2, University of California, San Francisco3, Oregon Health & Science University4, Northwestern University5, University of Tennessee Health Science Center6, University of British Columbia7, Children's Memorial Hospital8, New York University9, Case Western Reserve University10, Mayo Clinic11, Wake Forest University12, University of Pennsylvania13, University of Nottingham14, University of Alabama at Birmingham15, Rafael Advanced Defense Systems16, American Academy of Dermatology17, Seattle Children's18
TL;DR: Treatment of atopic dermatitis with nonpharmacologic interventions and pharmacologic topical therapies are reviewed and suggestions on dosing and monitoring are given based on available evidence.
Abstract: Atopic dermatitis is a common and chronic, pruritic inflammatory skin condition that can affect all age groups. This evidence-based guideline addresses important clinical questions that arise in its management. In this second of 4 sections, treatment of atopic dermatitis with nonpharmacologic interventions and pharmacologic topical therapies are reviewed. Where possible, suggestions on dosing and monitoring are given based on available evidence.
889 citations
Boston Children's Hospital1, Children's Memorial Hospital2, Wake Forest University3, Oregon Health & Science University4, University of California, San Francisco5, University of British Columbia6, New York University7, Case Western Reserve University8, Mayo Clinic9, University of Pennsylvania10, Northwestern University11, Nottingham University Hospitals NHS Trust12, University of Alabama at Birmingham13, Rafael Advanced Defense Systems14, American Academy of Dermatology15, Seattle Children's16
TL;DR: This guideline addresses important clinical questions that arise in the management and care of AD, providing updated and expanded recommendations based on the available evidence.
Abstract: Atopic dermatitis (AD) is a chronic, pruritic, inflammatory dermatosis that affects up to 25% of children and 2% to 3% of adults. This guideline addresses important clinical questions that arise in the management and care of AD, providing updated and expanded recommendations based on the available evidence. In this first of 4 sections, methods for the diagnosis and monitoring of disease, outcomes measures for assessment, and common clinical associations that affect patients with AD are discussed. Known risk factors for the development of disease are also reviewed.
874 citations
TL;DR: The complete SEQC data sets, comprising >100 billion reads, provide unique resources for evaluating RNA-seq analyses for clinical and regulatory settings, and measurement performance depends on the platform and data analysis pipeline, and variation is large for transcript-level profiling.
Abstract: We present primary results from the Sequencing Quality Control (SEQC) project, coordinated by the US Food and Drug Administration. Examining Illumina HiSeq, Life Technologies SOLiD and Roche 454 platforms at multiple laboratory sites using reference RNA samples with built-in controls, we assess RNA sequencing (RNA-seq) performance for junction discovery and differential expression profiling and compare it to microarray and quantitative PCR (qPCR) data using complementary metrics. At all sequencing depths, we discover unannotated exon-exon junctions, with >80% validated by qPCR. We find that measurements of relative expression are accurate and reproducible across sites and platforms if specific filters are used. In contrast, RNA-seq and microarrays do not provide accurate absolute measurements, and gene-specific biases are observed for all examined platforms, including qPCR. Measurement performance depends on the platform and data analysis pipeline, and variation is large for transcript-level profiling. The complete SEQC data sets, comprising >100 billion reads (10Tb), provide unique resources for evaluating RNA-seq analyses for clinical and regulatory settings.
853 citations
TL;DR: Nationally representative data do not show any significant changes in obesity prevalence in the most recently available years, although the prevalence of obesity may be stabilizing, and there is an upward trend of more severe forms of obesity.
Abstract: Importance Childhood obesity is the focus of public health efforts and accurate estimates of the prevalence and severity of obesity are needed for policy decisions and directions for future research. Objective To examine the prevalence of obesity and severe obesity over time for 14 years of the continuous National Health and Nutrition Examination Survey, 1999 to 2012, and to examine differences in the trends by age, race/ethnicity, and sex. Design, Setting, and Participants Representative sample (N = 26 690) of children in the United States, ages 2 to 19 years, in repeated cross-sections of the National Health and Nutrition Examination Survey, 1999 to 2012. Main Outcomes and Measures Prevalence of overweight (body mass index [BMI] ≥ 85th percentile), obesity (BMI ≥ 95th percentile for age and sex), class 2 obesity (BMI ≥ 120% of the 95th percentile or BMI ≥ 35), and class 3 obesity (BMI ≥ 140% of the 95th percentile or BMI ≥ 40). Results From 2011 to 2012, 17.3% (95% CI, 15.3-19.3) of children in the United States aged 2 to 19 years were obese. Additionally, 5.9% (95% CI, 4.4-7.4) of children met criteria for class 2 obesity and 2.1% (95% CI, 1.6-2.7) met criteria for class 3 obesity. Although these rates were not significantly different from 2009 to 2010, all classes of obesity have increased over the last 14 years. Conclusions and Relevance Nationally representative data do not show any significant changes in obesity prevalence in the most recently available years, although the prevalence of obesity may be stabilizing. Continuing research is needed to determine which, if any, public health interventions can be credited with this stability. Unfortunately, there is an upward trend of more severe forms of obesity and further investigations into the causes of and solutions to this problem are needed.
TL;DR: More than 18% of all lung cancers detected by LDCT in the NLST seem to be indolent, and overdiagnosis should be considered when describing the risks of LDCT screening for lung cancer.
Abstract: Importance Screening for lung cancer has the potential to reduce mortality, but in addition to detecting aggressive tumors, screening will also detect indolent tumors that otherwise may not cause clinical symptoms. These overdiagnosis cases represent an important potential harm of screening because they incur additional cost, anxiety, and morbidity associated with cancer treatment. Objective To estimate overdiagnosis in the National Lung Screening Trial (NLST). Design, Setting, and Participants We used data from the NLST, a randomized trial comparing screening using low-dose computed tomography (LDCT) vs chest radiography (CXR) among 53 452 persons at high risk for lung cancer observed for 6.4 years, to estimate the excess number of lung cancers in the LDCT arm of the NLST compared with the CXR arm. Main Outcomes and Measures We calculated 2 measures of overdiagnosis: the probability that a lung cancer detected by screening with LDCT is an overdiagnosis ( PS ), defined as the excess lung cancers detected by LDCT divided by all lung cancers detected by screening in the LDCT arm; and the number of cases that were considered overdiagnosis relative to the number of persons needed to screen to prevent 1 death from lung cancer. Results During follow-up, 1089 lung cancers were reported in the LDCT arm and 969 in the CXR arm of the NLST. The probability is 18.5% (95% CI, 5.4%-30.6%) that any lung cancer detected by screening with LDCT was an overdiagnosis, 22.5% (95% CI, 9.7%-34.3%) that a non–small cell lung cancer detected by LDCT was an overdiagnosis, and 78.9% (95% CI, 62.2%-93.5%) that a bronchioalveolar lung cancer detected by LDCT was an overdiagnosis. The number of cases of overdiagnosis found among the 320 participants who would need to be screened in the NLST to prevent 1 death from lung cancer was 1.38. Conclusions and Relevance More than 18% of all lung cancers detected by LDCT in the NLST seem to be indolent, and overdiagnosis should be considered when describing the risks of LDCT screening for lung cancer.
University of Minnesota1, University of Maryland, College Park2, Iowa State University3, University of Oldenburg4, Utah State University5, Spanish National Research Council6, Wake Forest University7, University of Washington8, United States Department of Agriculture9, Colorado State University10, Michigan State University11, Trinity College, Dublin12, University of Queensland13, University of Toronto14, Lanzhou University15, University of California, San Diego16, Imperial College London17, University of Wisconsin-Madison18, University of Colorado Boulder19, United States Geological Survey20, Queensland University of Technology21, University of North Carolina at Chapel Hill22, University of Oxford23, University of Nebraska–Lincoln24, University of California, Berkeley25, University of Illinois at Urbana–Champaign26, University of Guelph27, University of Kentucky28, University of Melbourne29, Oregon State University30, Commonwealth Scientific and Industrial Research Organisation31, Swiss Federal Institute for Forest, Snow and Landscape Research32, Lancaster University33, Duke University34, University of California, Davis35
TL;DR: Testing the hypothesis that herbaceous plant species losses caused by eutrophication may be offset by increased light availability due to herbivory demonstrates that nutrients and herbivores can serve as counteracting forces to control local plant diversity through light limitation, independent of site productivity, soil nitrogen, herbivore type and climate.
Abstract: Human alterations to nutrient cycles and herbivore communities are affecting global biodiversity dramatically. Ecological theory predicts these changes should be strongly counteractive: nutrient addition drives plant species loss through intensified competition for light, whereas herbivores prevent competitive exclusion by increasing ground-level light, particularly in productive systems. Here we use experimental data spanning a globally relevant range of conditions to test the hypothesis that herbaceous plant species losses caused by eutrophication may be offset by increased light availability due to herbivory. This experiment, replicated in 40 grasslands on 6 continents, demonstrates that nutrients and herbivores can serve as counteracting forces to control local plant diversity through light limitation, independent of site productivity, soil nitrogen, herbivore type and climate. Nutrient addition consistently reduced local diversity through light limitation, and herbivory rescued diversity at sites where it alleviated light limitation. Thus, species loss from anthropogenic eutrophication can be ameliorated in grasslands where herbivory increases ground-level light.
Seattle Children's1, Mayo Clinic2, New York University3, University of California, San Francisco4, University of British Columbia5, Northwestern University6, Case Western Reserve University7, Wake Forest University8, Oregon Health & Science University9, University of Pennsylvania10, University of Tennessee Health Science Center11, University of San Diego12, Boston Children's Hospital13, University of Nottingham14, University of Alabama at Birmingham15, American Academy of Dermatology16
TL;DR: The treatment of atopic dermatitis with phototherapy and systemic immunomodulators, antimicrobials, and antihistamines is reviewed in this article, including indications for use and the risk-benefit profile of each treatment option.
Abstract: Atopic dermatitis is a chronic, pruritic inflammatory dermatosis that affects up to 25% of children and 2% to 3% of adults This guideline addresses important clinical questions that arise in atopic dermatitis management and care, providing recommendations based on the available evidence In this third of 4 sections, treatment of atopic dermatitis with phototherapy and systemic immunomodulators, antimicrobials, and antihistamines is reviewed, including indications for use and the risk-benefit profile of each treatment option
Colorado School of Public Health1, Wake Forest University2, Cincinnati Children's Hospital Medical Center3, Centers for Disease Control and Prevention4, Kaiser Permanente5, National Institutes of Health6, University of Washington7, University of North Carolina at Chapel Hill8, University of Hawaii at Manoa9, Monterrey Institute of Technology and Higher Education10
TL;DR: Markers of micro- and macrovascular complications are evident in youth with either type 1 and type 2 diabetes, highlighting the seriousness of diabetes in this contemporary cohort of youth.
Abstract: The SEARCH for Diabetes in Youth (SEARCH) study was initiated in 2000, with funding from the Centers for Disease Control and Prevention and support from the National Institute of Diabetes and Digestive and Kidney Diseases, to address major knowledge gaps in the understanding of childhood diabetes. SEARCH is being conducted at five sites across the U.S. and represents the largest, most diverse study of diabetes among U.S. youth. An active registry of youth diagnosed with diabetes at age <20 years allows the assessment of prevalence (in 2001 and 2009), annual incidence (since 2002), and trends by age, race/ethnicity, sex, and diabetes type. Prevalence increased significantly from 2001 to 2009 for both type 1 and type 2 diabetes in most age, sex, and race/ethnic groups. SEARCH has also established a longitudinal cohort to assess the natural history and risk factors for acute and chronic diabetes-related complications as well as the quality of care and quality of life of persons with diabetes from diagnosis into young adulthood. Many youth with diabetes, particularly those from low-resourced racial/ethnic minority populations, are not meeting recommended guidelines for diabetes care. Markers of micro- and macrovascular complications are evident in youth with either diabetes type, highlighting the seriousness of diabetes in this contemporary cohort. This review summarizes the study methods, describes key registry and cohort findings and their clinical and public health implications, and discusses future directions.
University of Southern California1, California Pacific Medical Center2, Comprehensive Epilepsy Center3, Cleveland Clinic4, Dartmouth College5, Henry Ford Health System6, Indiana University7, Harvard University8, Rush University Medical Center9, Thomas Jefferson University10, University of Texas Southwestern Medical Center11, Johns Hopkins University12, Georgia Regents University13, Boston Children's Hospital14, University of Wisconsin-Madison15, Mayo Clinic16, Oregon Health & Science University17, Baylor College of Medicine18, Medical University of South Carolina19, George Washington University20, University of Rochester21, University of Virginia22, Emory University23, University of Florida24, Yale University25, Columbia University26, Wake Forest University27, Stanford University28
TL;DR: To demonstrate the safety and effectiveness of responsive stimulation at the seizure focus as an adjunctive therapy to reduce the frequency of seizures in adults with medically intractable partial onset seizures arising from one or two seizure foci.
Abstract: SummaryObjective
To demonstrate the safety and effectiveness of responsive stimulation at the seizure focus as an adjunctive therapy to reduce the frequency of seizures in adults with medically intractable partial onset seizures arising from one or two seizure foci.
Methods
Randomized multicenter double-blinded controlled trial of responsive focal cortical stimulation (RNS System). Subjects with medically intractable partial onset seizures from one or two foci were implanted, and 1 month postimplant were randomized 1:1 to active or sham stimulation. After the fifth postimplant month, all subjects received responsive stimulation in an open label period (OLP) to complete 2 years of postimplant follow-up.
Results
All 191 subjects were randomized. The percent change in seizures at the end of the blinded period was −37.9% in the active and −17.3% in the sham stimulation group (p = 0.012, Generalized Estimating Equations). The median percent reduction in seizures in the OLP was 44% at 1 year and 53% at 2 years, which represents a progressive and significant improvement with time (p < 0.0001). The serious adverse event rate was not different between subjects receiving active and sham stimulation. Adverse events were consistent with the known risks of an implanted medical device, seizures, and of other epilepsy treatments. There were no adverse effects on neuropsychological function or mood.
Significance
Responsive stimulation to the seizure focus reduced the frequency of partial-onset seizures acutely, showed improving seizure reduction over time, was well tolerated, and was acceptably safe. The RNS System provides an additional treatment option for patients with medically intractable partial-onset seizures.
University of Edinburgh1, Macquarie University2, Wake Forest University3, National Centre for Biological Sciences4, University of Leeds5, Goethe University Frankfurt6, University of Otago7, Council for Scientific and Industrial Research8, University of the Witwatersrand9, North Carolina State University10, South Dakota State University11, Commonwealth Scientific and Industrial Research Organisation12, University of Queensland13, University of Brasília14, Charles Darwin University15, Venezuelan Institute for Scientific Research16, Simón Bolívar University17, University of Toulouse18, University of Tasmania19, University of Cape Town20
TL;DR: Using data from 2154 sites in savannas across Africa, Australia, and South America, it is found that increasing moisture availability drives increases in fire and tree basal area, whereas fire reduces tree basal Area.
Abstract: Ecologists have long sought to understand the factors controlling the structure of savanna vegetation. Using data from 2154 sites in savannas across Africa, Australia, and South America, we found that increasing moisture availability drives increases in fire and tree basal area, whereas fire reduces tree basal area. However, among continents, the magnitude of these effects varied substantially, so that a single model cannot adequately represent savanna woody biomass across these regions. Historical and environmental differences drive the regional variation in the functional relationships between woody vegetation, fire, and climate. These same differences will determine the regional responses of vegetation to future climates, with implications for global carbon stocks.
TL;DR: Chemical mechanisms for IR-induced modifications of biomolecules along with methods for their detection are described and the synergy of combined "omics" technologies such as genomics and epigenomics, proteomics, and metabolomics is highlighted.
Abstract: Significance: The detrimental effects of ionizing radiation (IR) involve a highly orchestrated series of events that are amplified by endogenous signaling and culminating in oxidative damage to DNA, lipids, proteins, and many metabolites. Despite the global impact of IR, the molecular mechanisms underlying tissue damage reveal that many biomolecules are chemoselectively modified by IR. Recent Advances: The development of high-throughput “omics” technologies for mapping DNA and protein modifications have revolutionized the study of IR effects on biological systems. Studies in cells, tissues, and biological fluids are used to identify molecular features or biomarkers of IR exposure and response and the molecular mechanisms that regulate their expression or synthesis. Critical Issues: In this review, chemical mechanisms are described for IR-induced modifications of biomolecules along with methods for their detection. Included with the detection methods are crucial experimental considerations and cav...
TL;DR: In this paper, a multivariate approach identified four asthma subphenotypes representing the severity spectrum from mild-to-moderate allergic asthma with minimal or eosinophil-predominant sputum inflammation to moderate to severe asthma with neutrophil-or mixed granulocytic inflammation.
Abstract: Background Clinical cluster analysis from the Severe Asthma Research Program (SARP) identified 5 asthma subphenotypes that represent the severity spectrum of early-onset allergic asthma, late-onset severe asthma, and severe asthma with chronic obstructive pulmonary disease characteristics. Analysis of induced sputum from a subset of SARP subjects showed 4 sputum inflammatory cellular patterns. Subjects with concurrent increases in eosinophil (≥2%) and neutrophil (≥40%) percentages had characteristics of very severe asthma. Objective To better understand interactions between inflammation and clinical subphenotypes, we integrated inflammatory cellular measures and clinical variables in a new cluster analysis. Methods Participants in SARP who underwent sputum induction at 3 clinical sites were included in this analysis (n = 423). Fifteen variables, including clinical characteristics and blood and sputum inflammatory cell assessments, were selected using factor analysis for unsupervised cluster analysis. Results Four phenotypic clusters were identified. Cluster A (n = 132) and B (n = 127) subjects had mild-to-moderate early-onset allergic asthma with paucigranulocytic or eosinophilic sputum inflammatory cell patterns. In contrast, these inflammatory patterns were present in only 7% of cluster C (n = 117) and D (n = 47) subjects who had moderate-to-severe asthma with frequent health care use despite treatment with high doses of inhaled or oral corticosteroids and, in cluster D, reduced lung function. The majority of these subjects (>83%) had sputum neutrophilia either alone or with concurrent sputum eosinophilia. Baseline lung function and sputum neutrophil percentages were the most important variables determining cluster assignment. Conclusion This multivariate approach identified 4 asthma subphenotypes representing the severity spectrum from mild-to-moderate allergic asthma with minimal or eosinophil-predominant sputum inflammation to moderate-to-severe asthma with neutrophil-predominant or mixed granulocytic inflammation.
Trinity University1, University of California, Davis2, California National Primate Research Center3, Wake Forest University4, Biomedical Primate Research Centre5, Yerkes National Primate Research Center6, Georgia State University7, University of Washington8, University of Texas Health Science Center at San Antonio9, Baylor College of Medicine10, University of Wisconsin-Madison11
TL;DR: Key areas in biomedicine where primate models have been, and continue to be, essential for advancing fundamental knowledge in biomedical and biological research are reviewed.
Abstract: Research involving nonhuman primates (NHPs) has played a vital role in many of the medical and scientific advances of the past century. NHPs are used because of their similarity to humans in physiology, neuroanatomy, reproduction, development, cognition, and social complexity-yet it is these very similarities that make the use of NHPs in biomedical research a considered decision. As primate researchers, we feel an obligation and responsibility to present the facts concerning why primates are used in various areas of biomedical research. Recent decisions in the United States, including the phasing out of chimpanzees in research by the National Institutes of Health and the pending closure of the New England Primate Research Center, illustrate to us the critical importance of conveying why continued research with primates is needed. Here, we review key areas in biomedicine where primate models have been, and continue to be, essential for advancing fundamental knowledge in biomedical and biological research.
TL;DR: The findings suggested that benralizumab 20 mg and 100 mg resided at the dose-response plateau, which was designed with a two-sided α of 0·2 and powered at 78% for the primary outcome in the eosinophilic population.
Harvard University1, Broad Institute2, Universidad Autónoma Metropolitana3, National Autonomous University of Mexico4, Universidad Autónoma de Nuevo León5, Massachusetts Institute of Technology6, University of Southern California7, Mexican Social Security Institute8, University of Hawaii at Manoa9, Max Planck Society10, University of Minnesota11, University of California, San Francisco12, National University of Singapore13, University of Oxford14, University of Michigan15, Yeshiva University16, Texas Biomedical Research Institute17, Wake Forest University18, National Health Service19, Imperial College London20, Hallym University21, Hebrew University of Jerusalem22, Wolfson Medical Center23, University of Texas Health Science Center at Houston24, University of Eastern Finland25, Agency for Science, Technology and Research26, University of Mississippi27, University of Texas Health Science Center at San Antonio28
TL;DR: Analysis in Mexican and Latin American individuals identified SLC16A11 as a novel candidate gene for type 2 diabetes with a possible role in triacylglycerol metabolism and an archaic genome sequence indicated that the risk haplotype introgressed into modern humans via admixture with Neanderthals.
Abstract: Performing genetic studies in multiple human populations can identify disease risk alleles that are common in one population but rare in others, with the potential to illuminate pathophysiology, health disparities, and the population genetic origins of disease alleles. Here we analysed 9.2 million single nucleotide polymorphisms (SNPs) in each of 8,214 Mexicans and other Latin Americans: 3,848 with type 2 diabetes and 4,366 non-diabetic controls. In addition to replicating previous findings, we identified a novel locus associated with type 2 diabetes at genome-wide significance spanning the solute carriers SLC16A11 and SLC16A13 (P = 3.9 × 10(-13); odds ratio (OR) = 1.29). The association was stronger in younger, leaner people with type 2 diabetes, and replicated in independent samples (P = 1.1 × 10(-4); OR = 1.20). The risk haplotype carries four amino acid substitutions, all in SLC16A11; it is present at ~50% frequency in Native American samples and ~10% in east Asian, but is rare in European and African samples. Analysis of an archaic genome sequence indicated that the risk haplotype introgressed into modern humans via admixture with Neanderthals. The SLC16A11 messenger RNA is expressed in liver, and V5-tagged SLC16A11 protein localizes to the endoplasmic reticulum. Expression of SLC16A11 in heterologous cells alters lipid metabolism, most notably causing an increase in intracellular triacylglycerol levels. Despite type 2 diabetes having been well studied by genome-wide association studies in other populations, analysis in Mexican and Latin American individuals identified SLC16A11 as a novel candidate gene for type 2 diabetes with a possible role in triacylglycerol metabolism.
TL;DR: The Systolic Blood Pressure Intervention Trial will provide important information on the risks and benefits of intensive blood pressure treatment targets in a diverse sample of high-risk participants, including those with prior cardiovascular disease, chronic kidney disease, and those aged ≥75 years.
Abstract: Background:High blood pressure is an important public health concern because it is highly prevalent and a risk factor for adverse health outcomes, including coronary heart disease, stroke, decompensated heart failure, chronic kidney disease, and decline in cognitive function. Observational studies show a progressive increase in risk associated with blood pressure above 115/75 mm Hg. Prior research has shown that reducing elevated systolic blood pressure lowers the risk of subsequent clinical complications from cardiovascular disease. However, the optimal systolic blood pressure to reduce blood pressure–related adverse outcomes is unclear, and the benefit of treating to a level of systolic blood pressure well below 140 mm Hg has not been proven in a large, definitive clinical trial.Purpose:To describe the design considerations of the Systolic Blood Pressure Intervention Trial (SPRINT) and the baseline characteristics of trial participants.Methods:The Systolic Blood Pressure Intervention Trial is a multicen...
Vanderbilt University1, Washington University in St. Louis2, Wayne State University3, George Washington University4, University of Alabama at Birmingham5, University of Mississippi6, St Thomas' Hospital7, Barts Health NHS Trust8, University of Toronto9, University of Texas Southwestern Medical Center10, Baylor College of Medicine11, University of Missouri–Kansas City12, Case Western Reserve University13, Medical College of Wisconsin14, East Carolina University15, University of Pennsylvania16, Ohio State University17, Northwestern University18, Indiana University19, University of North Carolina at Chapel Hill20, University College London21, Wake Forest University22, Georgetown University23, Cincinnati Children's Hospital Medical Center24, Johns Hopkins University25, National Institutes of Health26
TL;DR: Regular blood-transfusion therapy significantly reduced the incidence of the recurrence of cerebral infarct in children with sickle cell anemia.
Abstract: Background Silent cerebral infarcts are the most common neurologic injury in children with sickle cell anemia and are associated with the recurrence of an infarct (stroke or silent cerebral infarct). We tested the hypothesis that the incidence of the recurrence of an infarct would be lower among children who underwent regular blood-transfusion therapy than among those who received standard care. Methods In this randomized, single-blind clinical trial, we randomly assigned children with sickle cell anemia to receive regular blood transfusions (transfusion group) or standard care (observation group). Participants were between 5 and 15 years of age, with no history of stroke and with one or more silent cerebral infarcts on magnetic resonance imaging and a neurologic examination showing no abnormalities corresponding to these lesions. The primary end point was the recurrence of an infarct, defined as a stroke or a new or enlarged silent cerebral infarct. Results A total of 196 children (mean age, 10 years) we...
TL;DR: The foundation of β-cell failure in type 2 diabetes (T2D) is examined and areas for future research on the underlying mechanisms that may lead to improved prevention and treatment are suggested.
Abstract: OBJECTIVE This article examines the foundation of β-cell failure in type 2 diabetes (T2D) and suggests areas for future research on the underlying mechanisms that may lead to improved prevention and treatment. RESEARCH DESIGN AND METHODS A group of experts participated in a conference on 14–16 October 2013 cosponsored by the Endocrine Society and the American Diabetes Association. A writing group prepared this summary and recommendations. RESULTS The writing group based this article on conference presentations, discussion, and debate. Topics covered include genetic predisposition, foundations of β-cell failure, natural history of β-cell failure, and impact of therapeutic interventions. CONCLUSIONS β-Cell failure is central to the development and progression of T2D. It antedates and predicts diabetes onset and progression, is in part genetically determined, and often can be identified with accuracy even though current tests are cumbersome and not well standardized. Multiple pathways underlie decreased β-cell function and mass, some of which may be shared and may also be a consequence of processes that initially caused dysfunction. Goals for future research include to 1 ) impact the natural history of β-cell failure; 2 ) identify and characterize genetic loci for T2D; 3 ) target β-cell signaling, metabolic, and genetic pathways to improve function/mass; 4 ) develop alternative sources of β-cells for cell-based therapy; 5 ) focus on metabolic environment to provide indirect benefit to β-cells; 6 ) improve understanding of the physiology of responses to bypass surgery; and 7 ) identify circulating factors and neuronal circuits underlying the axis of communication between the brain and β-cells.
Ali Amin Al Olama1, Zsofia Kote-Jarai, Sonja I. Berndt2, David V. Conti3 +176 more•Institutions (53)
TL;DR: These findings provide new regions for investigation into the pathogenesis of prostate cancer and demonstrate the usefulness of combining ancestrally diverse populations to discover risk loci for disease.
Abstract: Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry. To identify additional susceptibility loci for this common cancer, we conducted a meta-analysis of > 10 million SNPs in 43,303 prostate cancer cases and 43,737 controls from studies in populations of European, African, Japanese and Latino ancestry. Twenty-three new susceptibility loci were identified at association P < 5 × 10(-8); 15 variants were identified among men of European ancestry, 7 were identified in multi-ancestry analyses and 1 was associated with early-onset prostate cancer. These 23 variants, in combination with known prostate cancer risk variants, explain 33% of the familial risk for this disease in European-ancestry populations. These findings provide new regions for investigation into the pathogenesis of prostate cancer and demonstrate the usefulness of combining ancestrally diverse populations to discover risk loci for disease.
Broad Institute1, Harvard University2, deCODE genetics3, University of Oxford4, University of Copenhagen5, University of Michigan6, Yeshiva University7, Texas Biomedical Research Institute8, Wake Forest University9, University of Southern Denmark10, Pfizer11, Ealing Hospital12, Imperial College London13, National Health Service14, Hallym University15, Lund University16, University of Helsinki17, University of Texas Health Science Center at Houston18, Norwegian University of Science and Technology19, Uppsala University20, University of Bergen21, Aalborg University22, Novo Nordisk23, University of Eastern Finland24, Technische Universität München25, University of North Carolina at Chapel Hill26, University of Liverpool27, National Institute for Health and Welfare28, National University of Singapore29, Agency for Science, Technology and Research30, University of Iceland31, King Abdulaziz University32, Danube University Krems33, University of Pennsylvania34, University of Mississippi35, Churchill Hospital36, Massachusetts Institute of Technology37
TL;DR: In this article, the authors identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8) and harbors a common variant (p.Trp325Arg) associated with T2D risk and glucose and proinsulin levels.
Abstract: Loss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets, but none have yet been described for type 2 diabetes (T2D). Through sequencing or genotyping of ~150,000 individuals across 5 ancestry groups, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8) and harbors a common variant (p.Trp325Arg) associated with T2D risk and glucose and proinsulin levels. Collectively, carriers of protein-truncating variants had 65% reduced T2D risk (P = 1.7 × 10(-6)), and non-diabetic Icelandic carriers of a frameshift variant (p.Lys34Serfs*50) demonstrated reduced glucose levels (-0.17 s.d., P = 4.6 × 10(-4)). The two most common protein-truncating variants (p.Arg138* and p.Lys34Serfs*50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested that reduced zinc transport increases T2D risk, and phenotypic heterogeneity was observed in mouse Slc30a8 knockouts. In contrast, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, suggesting ZnT8 inhibition as a therapeutic strategy in T2D prevention.
TL;DR: Cutpoints for weakness derived from this large, diverse sample of older adults may be useful to identify populations who may benefit from interventions to improve muscle strength and function.
Abstract: Muscle weakness is related to poor physical performance and incident mobility limitations among older adults (1–6). Weakness is considered a key element of frailty (7) and, increasingly, of sarcopenia (8,9). Although the association between weakness and functional limitations is strong, there is no consensus regarding a cutpoint for identification of risk for functional problems. In order to identify population subgroups in whom weakness is a potential contributor to functional limitations, it is necessary to determine what constitutes a clinically relevant degree of weakness.
This is the second in a series of reports from the Foundation for the National Institutes of Health (FNIH) Sarcopenia Project, which pooled data from multiple studies to develop and evaluate clinically relevant criteria for weakness and low muscle mass (10). The purpose of the analysis presented here was to identify cutpoints that distinguish weakness (measured by grip strength) associated with mobility impairment (measured by gait speed) using cross-sectional data (ie, to maximize concurrent validity). This analysis builds on previous research on the association between strength and walking speed using a data-driven approach across multiple populations and an analytic technique (Classification and Regression Tree [CART] analysis) designed to optimize concurrent validity in the context of complex interactions. Findings were used to address subsequent Project goals reported separately (11–13).
McGill University1, McGill University Health Centre2, Children's Hospital of Eastern Ontario3, University of Kentucky4, National and Kapodistrian University of Athens5, Wake Forest University6, Princess Margaret Cancer Centre7, Indiana University8, Duke University9, University of Cambridge10, University of Kiel11, University of Western Australia12, Belfast City Hospital13, University Health Network14, University of Münster15
TL;DR: Findings identify alterations in SMARCA4 as the major cause of SCCOHT, which could lead to improvements in genetic counseling and new treatment approaches, and at least one germline or somatic deleterious SMarCA4 mutation in 30 of 32 cases.
Abstract: Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is the most common undifferentiated ovarian malignancy in women under 40 years of age. We sequenced the exomes of six individuals from three families with SCCOHT. After discovering segregating deleterious germline mutations in SMARCA4 in all three families, we tested DNA from a fourth affected family, which also carried a segregating SMARCA4 germline mutation. All the familial tumors sequenced harbored either a somatic mutation or loss of the wild-type allele. Immunohistochemical analysis of these cases and additional familial and non-familial cases showed loss of SMARCA4 (BRG1) protein in 38 of 40 tumors overall. Sequencing of cases with available DNA identified at least one germline or somatic deleterious SMARCA4 mutation in 30 of 32 cases. Additionally, the SCCOHT cell line BIN-67 had biallelic deleterious mutations in SMARCA4. Our findings identify alterations in SMARCA4 as the major cause of SCCOHT, which could lead to improvements in genetic counseling and new treatment approaches.
TL;DR: A systematic review of the literature found that as a result of anti-immigration policies, undocumented immigrants were impacted by mental health outcomes, including depression, anxiety, and post-traumatic stress disorder.
Abstract: Over the past two decades, new anti-immigration policies and laws have emerged to address the migration of undocumented immigrants. A systematic review of the literature was conducted to assess and understand how these immigration policies and laws may affect both access to health services and health outcomes among undocumented immigrants. Eight databases were used to conduct this review, which returned 325 papers that were assessed for validity based on specified inclusion criteria. Forty critically appraised articles were selected for analysis; thirty articles related to access to health services, and ten related to health outcomes. The articles showed a direct relationship between anti-immigration policies and their effects on access to health services. In addition, as a result of these policies, undocumented immigrants were impacted by mental health outcomes, including depression, anxiety, and post-traumatic stress disorder. Action items were presented, including the promotion of cultural diversity training and the development of innovative strategies to support safety-net health care facilities serving vulnerable populations.