Showing papers by "Medical University of South Carolina published in 2017"
TL;DR: Gene signature-based tumor microenvironment inference revealed a decrease in invading monocytes and a subtype-dependent increase in macrophages/microglia cells upon disease recurrence within weeks of diagnosis and at recurrence.
1,182 citations
Children's Hospital of Philadelphia1, Duke University2, Washington University in St. Louis3, Baylor University4, Brigham and Women's Hospital5, University of Pittsburgh6, University of Texas MD Anderson Cancer Center7, Vanderbilt University Medical Center8, Medical University of South Carolina9, Memorial Sloan Kettering Cancer Center10
TL;DR: A four-tiered system to categorize somatic sequence variations based on their clinical significances is proposed, with variants with strong clinical significance and variants with potential clinical significance in tier I; tier III, variants of unknown clinical significance; and tier IV, variants deemed benign or likely benign.
1,113 citations
26 Jun 2017
TL;DR: In this article, a general theory of stress termed conservation of resources (COR) is proposed to understand the nature of stress as a human phenomenon that is tied to people's experience regardless of the setting or context, be it work, home, hunt, or vacation.
Abstract: This chapter outlines a general theory of stress termed conservation of resources (COR). It provides an overarching framework to understand the nature of stress as a human phenomenon that is tied to people's experience regardless of the setting or context, be it work, home, hunt, or vacation. COR theory is a basic motivational theory and it is postulated that when this basic motivation is threatened or denied, stress ensues. It may be applied as a theoretical model that explains the etiology of burnout and the processes that are likely to accompany chronic, relatively low-level, work-related stress. COR theory proposes that loss is primary, but let us consider some of the other leading approaches. It suggests that intervention should be based on enhancing resources and eliminating vulnerability to resource loss. A cognitive approach to stress management might act to enhance people's sense of personality hardiness.
762 citations
TL;DR: Three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease are observed, providing additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's Disease.
Abstract: We identified rare coding variants associated with Alzheimer's disease in a three-stage case–control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10−4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10−8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10−10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10−10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10−14, OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein–protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.
730 citations
University of Göttingen1, City College of New York2, University of São Paulo3, University of Toronto4, University of Erlangen-Nuremberg5, Aalborg University6, Greifswald University Hospital7, Spaulding Rehabilitation Hospital8, Medical University of South Carolina9, University of Pennsylvania10, Technische Universität Ilmenau11, University of Oldenburg12, École Polytechnique Fédérale de Lausanne13, Paris 12 Val de Marne University14, University of New South Wales15, University of Aberdeen16, University of Trento17, University of Lisbon18, University of Kiel19, Technical University of Dortmund20, Ruhr University Bochum21, Ludwig Maximilian University of Munich22, Beth Israel Deaconess Medical Center23, Mannheim University of Applied Sciences24, University of Siena25, The Catholic University of America26, University College London27, University of Copenhagen28, Fukushima Medical University29, Massachusetts Institute of Technology30, University of Tübingen31
TL;DR: Structured interviews are provided and recommend their use in future controlled studies, in particular when trying to extend the parameters applied, to discuss recent regulatory issues, reporting practices and ethical issues.
699 citations
Roswell Park Cancer Institute1, Food and Drug Administration2, United States Department of Health and Human Services3, Westat4, University of Waterloo5, Medical University of South Carolina6, Johns Hopkins University7, University of California, San Diego8, Dartmouth College9, Ontario Institute for Cancer Research10
TL;DR: The cumulative, population-based data generated over time by the PATH Study will contribute to the evidence base to inform FDA's regulatory mission under the Family Smoking Prevention and Tobacco Control Act and efforts to reduce the Nation's burden of tobacco-related death and disease.
Abstract: Background This paper describes the methods and conceptual framework for Wave 1 of the Population Assessment of Tobacco and Health (PATH) Study data collection. The National Institutes of Health, through the National Institute on Drug Abuse, is partnering with the Food and Drug Administration9s (FDA) Center for Tobacco Products to conduct the PATH Study under a contract with Westat. Methods The PATH Study is a nationally representative, longitudinal cohort study of 45 971 adults and youth in the USA, aged 12 years and older. Wave 1 was conducted from 12 September 2013 to 15 December 2014 using Audio Computer-Assisted Self-Interviewing to collect information on tobacco-use patterns, risk perceptions and attitudes towards current and newly emerging tobacco products, tobacco initiation, cessation, relapse behaviours and health outcomes. The PATH Study9s design allows for the longitudinal assessment of patterns of use of a spectrum of tobacco products, including initiation, cessation, relapse and transitions between products, as well as factors associated with use patterns. Additionally, the PATH Study collects biospecimens from consenting adults aged 18 years and older and measures biomarkers of exposure and potential harm related to tobacco use. Conclusions The cumulative, population-based data generated over time by the PATH Study will contribute to the evidence base to inform FDA9s regulatory mission under the Family Smoking Prevention and Tobacco Control Act and efforts to reduce the Nation9s burden of tobacco-related death and disease.
581 citations
TL;DR: This study showed long‐term durability of weight loss and effective remission and prevention of type 2 diabetes, hypertension, and dyslipidemia after Roux‐en‐Y gastric bypass.
Abstract: BackgroundFew long-term or controlled studies of bariatric surgery have been conducted to date. We report the 12-year follow-up results of an observational, prospective study of Roux-en-Y gastric bypass that was conducted in the United States. MethodsA total of 1156 patients with severe obesity comprised three groups: 418 patients who sought and underwent Roux-en-Y gastric bypass (surgery group), 417 patients who sought but did not undergo surgery (primarily for insurance reasons) (nonsurgery group 1), and 321 patients who did not seek surgery (nonsurgery group 2). We performed clinical examinations at baseline and at 2 years, 6 years, and 12 years to ascertain the presence of type 2 diabetes, hypertension, and dyslipidemia. ResultsThe follow-up rate exceeded 90% at 12 years. The adjusted mean change from baseline in body weight in the surgery group was −45.0 kg (95% confidence interval [CI], −47.2 to −42.9; mean percent change, −35.0) at 2 years, −36.3 kg (95% CI, −39.0 to −33.5; mean percent change, −28...
572 citations
University of Toronto1, Tulane University2, Ohio State University3, Hannover Medical School4, University of Texas Southwestern Medical Center5, Washington University in St. Louis6, University of California, San Francisco7, Laval University8, Boston Children's Hospital9, University of Hamburg10, University of Pennsylvania11, Sheba Medical Center12, University of Padua13, University of Pittsburgh14, Oregon Health & Science University15, Medical College of Wisconsin16, University of New South Wales17, Medical University of South Carolina18, University of Manitoba19, Tel Aviv University20, Tel Aviv Sourasky Medical Center21, Saint George Hospital22, University of Wisconsin-Madison23
TL;DR: An extensive assessment of mutation burden through sequencing analysis of >81,000 tumors from pediatric and adult patients, including tumors with hypermutation caused by chemotherapy, carcinogens, or germline alterations, uncovered new driver mutations in the replication-repair-associated DNA polymerases and a distinct impact of microsatellite instability and replication repair deficiency on the scale of mutation load.
567 citations
University of North Florida1, Georgia Regents University2, Medical University of South Carolina3, East Carolina University4, Universidade Federal do Rio Grande do Sul5, Baptist Health6, University of the West Indies7, University of Miami8, University of Illinois at Chicago9, University of São Paulo10, State University of Campinas11, Virginia Commonwealth University12
TL;DR: In patients with Sickle cell disease, crizanlizumab therapy resulted in a significantly lower rate of sickle cell–related pain crises than placebo and was associated with a low incidence of adverse events.
Abstract: BackgroundThe up-regulation of P-selectin in endothelial cells and platelets contributes to the cell–cell interactions that are involved in the pathogenesis of vaso-occlusion and sickle cell–related pain crises. The safety and efficacy of crizanlizumab, an antibody against the adhesion molecule P-selectin, were evaluated in patients with sickle cell disease. MethodsIn this double-blind, randomized, placebo-controlled, phase 2 trial, we assigned patients to receive low-dose crizanlizumab (2.5 mg per kilogram of body weight), high-dose crizanlizumab (5.0 mg per kilogram), or placebo, administered intravenously 14 times over a period of 52 weeks. Patients who were receiving concomitant hydroxyurea as well as those not receiving hydroxyurea were included in the study. The primary end point was the annual rate of sickle cell–related pain crises with high-dose crizanlizumab versus placebo. The annual rate of days hospitalized, the times to first and second crises, annual rates of uncomplicated crises (defined a...
544 citations
TL;DR: Prevalence estimates for 12 types of tobacco products are presented, using data from 45,971 adult and youth participants from Wave 1 of the Population Assessment of Tobacco and Health (PATH) Study, a large, nationally representative, longitudinal study of tobacco use and health in the United States.
Abstract: BackgroundNoncigarette tobacco products are evolving rapidly, with increasing popularity in the United States. MethodsWe present prevalence estimates for 12 types of tobacco products, using data from 45,971 adult and youth participants (≥12 years of age) from Wave 1 (September 2013 through December 2014) of the Population Assessment of Tobacco and Health (PATH) Study, a large, nationally representative, longitudinal study of tobacco use and health in the United States. Participants were asked about their use of cigarettes, e-cigarettes, traditional cigars, cigarillos, filtered cigars, pipe tobacco, hookah, snus pouches, other smokeless tobacco, dissolvable tobacco, bidis, and kreteks. Estimates of the prevalence of use for each product were determined according to use category (e.g., current use or use in the previous 30 days) and demographic subgroup, and the prevalence of multiple-product use was explored. ResultsMore than a quarter (27.6%) of adults were current users of at least one type of tobacco pr...
497 citations
TL;DR: In this article, the Structured Days Hypothesis (SDH) was used to compare weekend day versus weekday (structured) obesogenic behaviors in U.S. elementary school-aged children.
Abstract: Although the scientific community has acknowledged modest improvements can be made to weight status and obesogenic behaviors (i.e., physical activity, sedentary/screen time, diet, and sleep) during the school year, studies suggests improvements are erased as elementary-age children are released to summer vacation. Emerging evidence shows children return to school after summer vacation displaying accelerated weight gain compared to the weight gained occurring during the school year. Understanding how summer days differ from when children are in school is, therefore, essential. There is limited evidence on the etiology of accelerated weight gain during summer, with few studies comparing obesogenic behaviors on the same children during school and summer. For many children, summer days may be analogous to weekend days throughout the school year. Weekend days are often limited in consistent and formal structure, and thus differ from school days where segmented, pre-planned, restrictive, and compulsory components exist that shape obesogenic behaviors. The authors hypothesize that obesogenic behaviors are beneficially regulated when children are exposed to a structured day (i.e., school weekday) compared to what commonly occurs during summer. This is referred to as the ‘Structured Days Hypothesis’ (SDH). To illustrate how the SDH operates, this study examines empirical data that compares weekend day (less-structured) versus weekday (structured) obesogenic behaviors in U.S. elementary school-aged children. From 190 studies, 155 (~80%) demonstrate elementary-aged children’s obesogenic behaviors are more unfavorable during weekend days compared to weekdays. In light of the SDH, consistent evidence demonstrates the structured environment of weekdays may help to protect children by regulating obesogenic behaviors, most likely through compulsory physical activity opportunities, restricting caloric intake, reducing screen time occasions, and regulating sleep schedules. Summer is emerging as the critical period where childhood obesity prevention efforts need to be focused. The SDH can help researchers understand the drivers of obesogenic behaviors during summer and lead to innovative intervention development.
TL;DR: Recommendations for how to incorporate VR into psychiatric care are presented and future directions for VR-based treatment and clinical research are discussed.
Abstract: After participating in this activity, learners should be better able to:• Evaluate the literature regarding the effectiveness of incorporating virtual reality (VR) in the treatment of psychiatric disorders• Assess the use of exposure-based intervention for anxiety disorders ABSTRACT: Virtual reality (VR) allows users to experience a sense of presence in a computer-generated, three-dimensional environment. Sensory information is delivered through a head-mounted display and specialized interface devices. These devices track head movements so that the movements and images change in a natural way with head motion, allowing for a sense of immersion. VR, which allows for controlled delivery of sensory stimulation via the therapist, is a convenient and cost-effective treatment. This review focuses on the available literature regarding the effectiveness of incorporating VR within the treatment of various psychiatric disorders, with particular attention to exposure-based intervention for anxiety disorders. A systematic literature search was conducted in order to identify studies implementing VR-based treatment for anxiety or other psychiatric disorders. This article reviews the history of the development of VR-based technology and its use within psychiatric treatment, the empirical evidence for VR-based treatment, and the benefits for using VR for psychiatric research and treatment. It also presents recommendations for how to incorporate VR into psychiatric care and discusses future directions for VR-based treatment and clinical research.
TL;DR: SCAF duration >24 h was associated with a significant increased risk of subsequent stroke or systemic embolism, and patients with SCAF between 6 min and 24’h was not significantly different from patients without SCAF.
Abstract: Background ASSERT demonstrated that subclinical atrial fibrillation (SCAF) is common in pacemaker patients without prior AF and is associated with increased risk of ischemic stroke or systemic embolism. SCAF episodes vary in duration and little is known about the incidence of different durations of SCAF, or their prognosis. Methods and results ASSERT followed 2580 patients receiving a pacemaker or ICD, aged >65 years with hypertension, without prior AF. The effect of SCAF duration on subsequent risk of ischemic stroke or embolism was evaluated with time-dependent covariate Cox models. Patients in whom the longest SCAF was ≤6 min were excluded from the analysis (n=125). Among 2455 patients during mean follow-up of 2.5 years, the longest single episode of SCAF lasted >6 min to 6 h in 462 patients (18.8%), >6-24 h in 169 (6.9%), and >24 h in 262 (10.7%). SCAF duration >24 h was associated with a significant increased risk of subsequent stroke or systemic embolism (adjusted hazard ratio [HR] 3.24, 95% confidence interval [CI] 1.51-6.95, P=0.003). The risk of ischemic stroke or systemic embolism in patients with SCAF between 6 min and 24 h was not significantly different from patients without SCAF. Conclusions SCAF >24 h is associated with an increased risk of ischemic stroke or systemic embolism.
University of Pennsylvania1, Northwestern University2, University of Texas MD Anderson Cancer Center3, University of California, San Francisco4, Mayo Clinic5, University of Maryland, College Park6, Pennsylvania State University7, University of Alabama at Birmingham8, Center for Global Development9, Rutgers University10, Columbia University11, University of Chicago12, Cornell University13, University of California, Los Angeles14, Vanderbilt University15, University of Würzburg16, University of Minnesota17, Roswell Park Cancer Institute18, Medical University of South Carolina19, Dresden University of Technology20, University of Bologna21, Johns Hopkins University22
TL;DR: Gilteritinib was well tolerated in this heavily pretreated population; Grade 3 diarrhea and hepatic transaminase elevation limited dosing above 300 mg/d; response rate was improved in FLT3mut+ patients at doses ≥80mg/d.
Abstract: Summary Background Internal tandem duplication mutations in FLT3 are common in acute myeloid leukaemia and are associated with rapid relapse and short overall survival. The clinical benefit of FLT3 inhibitors in patients with acute myeloid leukaemia has been limited by rapid generation of resistance mutations, particularly in codon Asp835 (D835). We aimed to assess the highly selective oral FLT3 inhibitor gilteritinib in patients with relapsed or refractory acute myeloid leukaemia. Methods In this phase 1–2 trial, we enrolled patients aged 18 years or older with acute myeloid leukaemia who either were refractory to induction therapy or had relapsed after achieving remission with previous treatment. Patients were enrolled into one of seven dose-escalation or dose-expansion cohorts assigned to receive once-daily doses of oral gilteritinib (20 mg, 40 mg, 80 mg, 120 mg, 200 mg, 300 mg, or 450 mg). Cohort expansion was based on safety and tolerability, FLT3 inhibition in correlative assays, and antileukaemic activity. Although the presence of an FLT3 mutation was not an inclusion criterion, we required ten or more patients with locally confirmed FLT3 mutations ( FLT3 mut+ ) to be enrolled in expansion cohorts at each dose level. On the basis of emerging findings, we further expanded the 120 mg and 200 mg dose cohorts to include FLT3 mut+ patients only. The primary endpoints were the safety, tolerability, and pharmacokinetics of gilteritinib. Safety and tolerability were assessed in the safety analysis set (all patients who received at least one dose of gilteritinib). Responses were assessed in the full analysis set (all patients who received at least one dose of study drug and who had at least one datapoint post-treatment). Pharmacokinetics were assessed in a subset of the safety analysis set for which sufficient data for concentrations of gilteritinib in plasma were available to enable derivation of one or more pharmacokinetic variables. This study is registered with ClinicalTrials.gov, number NCT02014558, and is ongoing. Findings Between Oct 15, 2013, and Aug 27, 2015, 252 adults with relapsed or refractory acute myeloid leukaemia received oral gilteritinib once daily in one of seven dose-escalation (n=23) or dose-expansion (n=229) cohorts. Gilteritinib was well tolerated; the maximum tolerated dose was established as 300 mg/day when two of three patients enrolled in the 450 mg dose-escalation cohort had two dose-limiting toxicities (grade 3 diarrhoea and grade 3 elevated aspartate aminotransferase). The most common grade 3–4 adverse events irrespective of relation to treatment were febrile neutropenia (97 [39%] of 252), anaemia (61 [24%]), thrombocytopenia (33 [13%]), sepsis (28 [11%]), and pneumonia (27 [11%]). Commonly reported treatment-related adverse events were diarrhoea (41 [16%] of 252]), fatigue (37 [15%]), elevated aspartate aminotransferase (33 [13%]), and elevated alanine aminotransferase (24 [10%]). Serious adverse events occurring in 5% or more of patients were febrile neutropenia (78 [31%] of 252; five related to treatment), progressive disease (43 [17%]), sepsis (36 [14%]; two related to treatment), pneumonia (27 [11%]), acute renal failure (25 [10%]; five related to treatment), pyrexia (21 [8%]; three related to treatment), bacteraemia (14 [6%]; one related to treatment), and respiratory failure (14 [6%]). 95 people died in the safety analysis set, of which seven deaths were judged possibly or probably related to treatment (pulmonary embolism [200 mg/day], respiratory failure [120 mg/day], haemoptysis [80 mg/day], intracranial haemorrhage [20 mg/day], ventricular fibrillation [120 mg/day], septic shock [80 mg/day], and neutropenia [120 mg/day]). An exposure-related increase in inhibition of FLT3 phosphorylation was noted with increasing concentrations in plasma of gilteritinib. In-vivo inhibition of FLT3 phosphorylation occurred at all dose levels. At least 90% of FLT3 phosphorylation inhibition was seen by day 8 in most patients receiving a daily dose of 80 mg or higher. 100 (40%) of 249 patients in the full analysis set achieved a response, with 19 (8%) achieving complete remission, ten (4%) complete remission with incomplete platelet recovery, 46 (18%) complete remission with incomplete haematological recovery, and 25 (10%) partial remission. Interpretation Gilteritinib had a favourable safety profile and showed consistent FLT3 inhibition in patients with relapsed or refractory acute myeloid leukaemia. These findings confirm that FLT3 is a high-value target for treatment of relapsed or refractory acute myeloid leukaemia; based on activity data, gilteritinib at 120 mg/day is being tested in phase 3 trials. Funding Astellas Pharma, National Cancer Institute (Leukemia Specialized Program of Research Excellence grant), Associazione Italiana Ricerca sul Cancro.
TL;DR: A common pattern of disruption across major psychiatric disorders that parallels the "multiple-demand network" observed in intact cognition is demonstrated, demonstrated to be transdiagnostically vulnerable to gray matter reduction.
Abstract: Objective:Cognitive deficits are a common feature of psychiatric disorders. The authors investigated the nature of disruptions in neural circuitry underlying cognitive control capacities across psychiatric disorders through a transdiagnostic neuroimaging meta-analysis.Method:A PubMed search was conducted for whole-brain functional neuroimaging articles published through June 2015 that compared activation in patients with axis I disorders and matched healthy control participants during cognitive control tasks. Tasks that probed performance or conflict monitoring, response inhibition or selection, set shifting, verbal fluency, and recognition or working memory were included. Activation likelihood estimation meta-analyses were conducted on peak voxel coordinates.Results:The 283 experiments submitted to meta-analysis included 5,728 control participants and 5,493 patients with various disorders (schizophrenia, bipolar or unipolar depression, anxiety disorders, and substance use disorders). Transdiagnostically ...
TL;DR: The 7-level, modified Rankin Scale (mRS) has several major strengths: it covers the entire range of functional outcomes from no symptoms to death, its categories are intuitive and easily grasped by both clinicians and patients, its concurrent validity is demonstrated by strong correlation with measures of stroke pathology and agreement with other stroke scales, and its use has demarcated effective and ineffective acute stroke therapies in trials with appropriately powered sample sizes.
Abstract: Who would have guessed that a scale introduced by Dr John Rankin in 1957 would become the primary outcome scale for almost all acute stroke trials?1 The Rankin Scale was modified to its current form by Charles Warlow and others as part of the UK-TIA (United Kingdom Transient Ischaemic Attack) trial in the 1980s,2 and its reproducibility was first examined by van Swieten et al, in 1988 (Table 1).3
View this table:
Table 1.
The Modified Rankin Scale (mRS)
There is no perfect stroke outcome scale. Regardless, the 7-level, modified Rankin Scale (mRS) has several major strengths: it covers the entire range of functional outcomes from no symptoms to death, its categories are intuitive and easily grasped by both clinicians and patients, its concurrent validity is demonstrated by strong correlation with measures of stroke pathology (eg, infarct volumes) and agreement with other stroke scales,4 and its use has demarcated effective and ineffective acute stroke therapies in trials with appropriately powered sample sizes. With a limited number of levels, the mRS may be less responsive to change than some other stroke scales; however, a single-point change on the mRS is clinically relevant.4
A limitation of the mRS has been the subjective determination between categories and the reproducibility of the score by examiners and patients.4 A systematic review and meta-analysis of studies describing interobserver variability of the mRS reports pooled reliability across 10 published studies (n=587 patients) of a κ=0.46 and a weighted κ of 0.90.5 Multimedia training and certification of examiners in the use of the mRS (http://rankinscale.org/), structured interviews and questionnaires,6–10 and centralized review of videotape assessments11 have sought to address these issues, but reproducibility remains a concern.
But the challenge for a trialist designing a new acute stroke trial is not whether …
Emory University1, Centers for Disease Control and Prevention2, Duke University3, Washington University in St. Louis4, University of British Columbia5, University of Maryland, Baltimore6, Dalhousie University7, Tufts University8, University of Virginia9, Monash University10, Medical University of South Carolina11
TL;DR: These guidelines are intended for use by healthcare professionals who care for children and adults with suspected or confirmed infectious diarrhea and are not intended to replace physician judgement regarding specific patients or clinical or public health situations.
Abstract: These guidelines are intended for use by healthcare professionals who care for children and adults with suspected or confirmed infectious diarrhea. They are not intended to replace physician judgement regarding specific patients or clinical or public health situations. This document does not provide detailed recommendations on infection prevention and control aspects related to infectious diarrhea.
TL;DR: In this article, the authors examined the association between objectively measured sedentary behavior (its total volume and accrual in prolonged, uninterrupted bouts) and all-cause mortality and found that greater total sedentary time (HR, 1.22 [95% CI, 0.80 to 1.85]; and HR,1.96 [CI, 131 to 2.63] were both associated with a higher risk for all cause mortality.
Abstract: Background Excessive sedentary time is ubiquitous in Western societies. Previous studies have relied on self-reporting to evaluate the total volume of sedentary time as a prognostic risk factor for mortality and have not examined whether the manner in which sedentary time is accrued (in short or long bouts) carries prognostic relevance. Objective To examine the association between objectively measured sedentary behavior (its total volume and accrual in prolonged, uninterrupted bouts) and all-cause mortality. Design Prospective cohort study. Setting Contiguous United States. Participants 7985 black and white adults aged 45 years or older. Measurements Sedentary time was measured using a hip-mounted accelerometer. Prolonged, uninterrupted sedentariness was expressed as mean sedentary bout length. Hazard ratios (HRs) were calculated comparing quartiles 2 through 4 to quartile 1 for each exposure (quartile cut points: 689.7, 746.5, and 799.4 min/d for total sedentary time; 7.7, 9.6, and 12.4 min/bout for sedentary bout duration) in models that included moderate to vigorous physical activity. Results Over a median follow-up of 4.0 years, 340 participants died. In multivariable-adjusted models, greater total sedentary time (HR, 1.22 [95% CI, 0.74 to 2.02]; HR, 1.61 [CI, 0.99 to 2.63]; and HR, 2.63 [CI, 1.60 to 4.30]; P for trend < 0.001) and longer sedentary bout duration (HR, 1.03 [CI, 0.67 to 1.60]; HR, 1.22 [CI, 0.80 to 1.85]; and HR, 1.96 [CI, 1.31 to 2.93]; P for trend < 0.001) were both associated with a higher risk for all-cause mortality. Evaluation of their joint association showed that participants classified as high for both sedentary characteristics (high sedentary time [≥12.5 h/d] and high bout duration [≥10 min/bout]) had the greatest risk for death. Limitation Participants may not be representative of the general U.S. population. Conclusion Both the total volume of sedentary time and its accrual in prolonged, uninterrupted bouts are associated with all-cause mortality, suggesting that physical activity guidelines should target reducing and interrupting sedentary time to reduce risk for death. Primary Funding Source National Institutes of Health.
University of Texas Southwestern Medical Center1, Duke University2, Johns Hopkins University3, Brown University4, Emory University5, Cornell University6, University of Michigan7, University of California, Los Angeles8, Rowan University9, University of California, San Francisco10, Mayo Clinic11, Harvard University12, University of Minnesota13, Medical University of South Carolina14, United States Department of Veterans Affairs15
TL;DR: In this article, the authors provided expert recommendations for the safe and effective application of repetitive transcranial magnetic stimulation (rTMS) in the treatment of major depressive disorder (MDD).
Abstract: Objective To provide expert recommendations for the safe and effective application of repetitive transcranial magnetic stimulation (rTMS) in the treatment of major depressive disorder (MDD). Participants Participants included a group of 17 expert clinicians and researchers with expertise in the clinical application of rTMS, representing both the National Network of Depression Centers (NNDC) rTMS Task Group and the American Psychiatric Association Council on Research (APA CoR) Task Force on Novel Biomarkers and Treatments. Evidence The consensus statement is based on a review of extensive literature from 2 databases (OvidSP MEDLINE and PsycINFO) searched from 1990 through 2016. The search terms included variants of major depressive disorder and transcranial magnetic stimulation. The results were limited to articles written in English that focused on adult populations. Of the approximately 1,500 retrieved studies, a total of 118 publications were included in the consensus statement and were supplemented with expert opinion to achieve consensus recommendations on key issues surrounding the administration of rTMS for MDD in clinical practice settings. Consensus process In cases in which the research evidence was equivocal or unclear, a consensus decision on how rTMS should be administered was reached by the authors of this article and is denoted in the article as "expert opinion." Conclusions Multiple randomized controlled trials and published literature have supported the safety and efficacy of rTMS antidepressant therapy. These consensus recommendations, developed by the NNDC rTMS Task Group and APA CoR Task Force on Novel Biomarkers and Treatments, provide comprehensive information for the safe and effective clinical application of rTMS in the treatment of MDD.
University of California, Irvine1, University at Buffalo2, Harvard University3, University of Texas MD Anderson Cancer Center4, University of Oklahoma5, Hebron University6, University of Cincinnati Academic Health Center7, Kettering University8, Memorial Sloan Kettering Cancer Center9, Indiana University10, Ohio State University11, Medical University of South Carolina12, University of Pennsylvania13, University of Mississippi Medical Center14, Case Western Reserve University15, Genentech16, University of Washington17, University of Arizona18
TL;DR: In this article, the authors report the prespecified final analysis of the primary objectives, OS and adverse events, assessed at the second interim and final analysis by the masked Data and Safety Monitoring Board.
University of Glasgow1, Golden Jubilee National Hospital2, Harvard University3, Mario Negri Institute for Pharmacological Research4, Imperial College London5, Glasgow Royal Infirmary6, Duke University7, University of Oslo8, University of Copenhagen9, University of Michigan10, University of Gothenburg11, University of Lorraine12, Medical University of South Carolina13
TL;DR: Rates of sudden death declined substantially over time among ambulatory patients with heart failure with reduced ejection fraction who were enrolled in clinical trials, a finding that is consistent with a cumulative benefit of evidence‐based medications on this cause of death.
Abstract: BackgroundThe risk of sudden death has changed over time among patients with symptomatic heart failure and reduced ejection fraction with the sequential introduction of medications including angiotensin-converting–enzyme inhibitors, angiotensin-receptor blockers, beta-blockers, and mineralocorticoid-receptor antagonists. We sought to examine this trend in detail. MethodsWe analyzed data from 40,195 patients who had heart failure with reduced ejection fraction and were enrolled in any of 12 clinical trials spanning the period from 1995 through 2014. Patients who had an implantable cardioverter–defibrillator at the time of trial enrollment were excluded. Weighted multivariable regression was used to examine trends in rates of sudden death over time. Adjusted hazard ratios for sudden death in each trial group were calculated with the use of Cox regression models. The cumulative incidence rates of sudden death were assessed at different time points after randomization and according to the length of time betwe...
TL;DR: The structure–function relationships that enable arrestins to perform their diverse roles are examined, addressing arrestin structure at the molecular level, the relationship between arrestin conformation and function, and sites of interaction between arrestins, GPCRs, and nonreceptor-binding partners.
Abstract: The visual/β-arrestins, a small family of proteins originally described for their role in the desensitization and intracellular trafficking of G protein–coupled receptors (GPCRs), have emerged as key regulators of multiple signaling pathways. Evolutionarily related to a larger group of regulatory scaffolds that share a common arrestin fold, the visual/β-arrestins acquired the capacity to detect and bind activated GPCRs on the plasma membrane, which enables them to control GPCR desensitization, internalization, and intracellular trafficking. By acting as scaffolds that bind key pathway intermediates, visual/β-arrestins both influence the tonic level of pathway activity in cells and, in some cases, serve as ligand-regulated scaffolds for GPCR-mediated signaling. Growing evidence supports the physiologic and pathophysiologic roles of arrestins and underscores their potential as therapeutic targets. Circumventing arrestin-dependent GPCR desensitization may alleviate the problem of tachyphylaxis to drugs that target GPCRs, and find application in the management of chronic pain, asthma, and psychiatric illness. As signaling scaffolds, arrestins are also central regulators of pathways controlling cell growth, migration, and survival, suggesting that manipulating their scaffolding functions may be beneficial in inflammatory diseases, fibrosis, and cancer. In this review we examine the structure–function relationships that enable arrestins to perform their diverse roles, addressing arrestin structure at the molecular level, the relationship between arrestin conformation and function, and sites of interaction between arrestins, GPCRs, and nonreceptor-binding partners. We conclude with a discussion of arrestins as therapeutic targets and the settings in which manipulating arrestin function might be of clinical benefit.
Catherine M. Phelan, Karoline Kuchenbaecker1, Karoline Kuchenbaecker2, Jonathan Tyrer1 +440 more•Institutions (156)
TL;DR: Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.
Abstract: To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.
TL;DR: To maximize generalizability of results, trial enrollment criteria should strive for inclusiveness and Rationale for excluding patients should be clearly articulated and reflect expected toxicities associated with the therapy under investigation.
Abstract: Purpose The primary purposes of eligibility criteria are to protect the safety of trial participants and define the trial population. Excessive or overly restrictive eligibility criteria can slow trial accrual, jeopardize the generalizability of results, and limit understanding of the intervention's benefit-risk profile. Methods ASCO, Friends of Cancer Research, and the US Food and Drug Administration examined specific eligibility criteria (ie, brain metastases, minimum age, HIV infection, and organ dysfunction and prior and concurrent malignancies) to determine whether to modify definitions to extend trials to a broader population. Working groups developed consensus recommendations based on review of evidence, consideration of the patient population, and consultation with the research community. Results Patients with treated or clinically stable brain metastases should be routinely included in trials and only excluded if there is compelling rationale. In initial dose-finding trials, pediatric-specific cohorts should be included based on strong scientific rationale for benefit. Later phase trials in diseases that span adult and pediatric populations should include patients older than age 12 years. HIV-infected patients who are healthy and have low risk of AIDS-related outcomes should be included absent specific rationale for exclusion. Renal function criteria should enable liberal creatinine clearance, unless the investigational agent involves renal excretion. Patients with prior or concurrent malignancies should be included, especially when the risk of the malignancy interfering with either safety or efficacy endpoints is very low. Conclusion To maximize generalizability of results, trial enrollment criteria should strive for inclusiveness. Rationale for excluding patients should be clearly articulated and reflect expected toxicities associated with the therapy under investigation.
TL;DR: This multiancestry study recommends investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where G 6PD deficiency is common, and investigates the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance.
Abstract: Background: Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identif ...
University of Texas Southwestern Medical Center1, George Washington University2, Northwestern University3, University of Utah4, Wayne State University5, National Institutes of Health6, Columbia University7, University of North Carolina at Chapel Hill8, University of Texas Medical Branch9, University of Alabama at Birmingham10, Brown University11, University of Texas Health Science Center at Houston12, Ohio State University13, Case Western Reserve University14, Oregon Health & Science University15, University of Pittsburgh16, Medical University of South Carolina17
TL;DR: Treatment for subclinical hypothyroidism or hypothyroxinemia beginning between 8 and 20 weeks of gestation did not result in significantly better cognitive outcomes in children through 5 years of age than no treatment for those conditions.
Abstract: BackgroundSubclinical thyroid disease during pregnancy may be associated with adverse outcomes, including a lower-than-normal IQ in offspring. It is unknown whether levothyroxine treatment of women who are identified as having subclinical hypothyroidism or hypothyroxinemia during pregnancy improves cognitive function in their children. MethodsWe screened women with a singleton pregnancy before 20 weeks of gestation for subclinical hypothyroidism, defined as a thyrotropin level of 4.00 mU or more per liter and a normal free thyroxine (T4) level (0.86 to 1.90 ng per deciliter [11 to 24 pmol per liter]), and for hypothyroxinemia, defined as a normal thyrotropin level (0.08 to 3.99 mU per liter) and a low free T4 level (<0.86 ng per deciliter). In separate trials for the two conditions, women were randomly assigned to receive levothyroxine or placebo. Thyroid function was assessed monthly, and the levothyroxine dose was adjusted to attain a normal thyrotropin or free T4 level (depending on the trial), with sh...
Veterans Health Administration1, Case Western Reserve University2, Wake Forest University3, University of Utah4, National Institutes of Health5, University of Tennessee Health Science Center6, University of Alabama at Birmingham7, Tulane University8, Medical University of South Carolina9, Ohio State University10, Stanford University11, Anschutz Medical Campus12, Mayo Clinic13, University of California, San Diego14, University of Minnesota15, University of Illinois at Chicago16, New York University17, United States Department of Veterans Affairs18, Henry Ford Health System19
TL;DR: Among patients with CKD and hypertension without diabetes, targeting an SBP<120 mm Hg compared with <140mm Hg reduced rates of major cardiovascular events and all-cause death without evidence of effect modifications by CKD or deleterious effect on the main kidney outcome.
Abstract: The appropriate target for BP in patients with CKD and hypertension remains uncertain. We report prespecified subgroup analyses of outcomes in participants with baseline CKD in the Systolic Blood Pressure Intervention Trial. We randomly assigned participants to a systolic BP target of <120 mm Hg (intensive group; n=1330) or <140 mm Hg (standard group; n=1316). After a median follow-up of 3.3 years, the primary composite cardiovascular outcome occurred in 112 intensive group and 131 standard group CKD participants (hazard ratio [HR], 0.81; 95% confidence interval [95% CI], 0.63 to 1.05). The intensive group also had a lower rate of all-cause death (HR, 0.72; 95% CI, 0.53 to 0.99). Treatment effects did not differ between participants with and without CKD (P values for interactions ≥0.30). The prespecified main kidney outcome, defined as the composite of ≥50% decrease in eGFR from baseline or ESRD, occurred in 15 intensive group and 16 standard group participants (HR, 0.90; 95% CI, 0.44 to 1.83). After the initial 6 months, the intensive group had a slightly higher rate of change in eGFR (-0.47 versus -0.32 ml/min per 1.73 m2 per year; P<0.03). The overall rate of serious adverse events did not differ between treatment groups, although some specific adverse events occurred more often in the intensive group. Thus, among patients with CKD and hypertension without diabetes, targeting an SBP<120 mm Hg compared with <140 mm Hg reduced rates of major cardiovascular events and all-cause death without evidence of effect modifications by CKD or deleterious effect on the main kidney outcome.
National Institute of Standards and Technology1, University of Florida2, Roskamp Institute3, Steno Diabetes Center4, University of Nebraska Medical Center5, University of California, San Diego6, Beth Israel Deaconess Medical Center7, Harvard University8, Kyushu University9, Centers for Disease Control and Prevention10, Uppsala University11, Southampton General Hospital12, University of California, Davis13, National University of Singapore14, Karolinska Institutet15, Baker IDI Heart and Diabetes Institute16, Brigham and Women's Hospital17, Columbia University Medical Center18, King Abdulaziz University19, New York Medical College20, University of Victoria21, Thermo Fisher Scientific22, Örebro University23, University of Michigan24, Biocrates Life Sciences AG25, Medical University of Graz26, Albert Einstein College of Medicine27, Wayne State University28, Concordia University29, Duke University30, Åbo Akademi University31, Medical University of South Carolina32, Kansas State University33, Max Planck Society34
TL;DR: The central theme of the interlaboratory study was to provide values to help harmonize lipids, lipid mediators, and precursor measurements across the community, and it was also initiated to stimulate a discussion regarding areas in need of improvement.
University of East Anglia1, Joint Genome Institute2, Norwich Research Park3, Stazione Zoologica Anton Dohrn4, Scripps Institution of Oceanography5, J. Craig Venter Institute6, Alfred Wegener Institute for Polar and Marine Research7, Université Paris-Saclay8, École Normale Supérieure9, University of Paris10, Leibniz Association11, University of Cologne12, University of Konstanz13, Medical University of South Carolina14, University of Duisburg-Essen15, Leibniz Institute for Neurobiology16, University of Washington17, University of Nevada, Las Vegas18, Monterey Bay Aquarium Research Institute19, University of British Columbia20, University of California, Berkeley21
TL;DR: In this article, the genome evolution of a cold-adapted diatom from the Southern Ocean, Fragilariopsis cylindrus, based on a comparison with temperate diatoms was studied.
Abstract: The Southern Ocean houses a diverse and productive community of organisms. Unicellular eukaryotic diatoms are the main primary producers in this environment, where photosynthesis is limited by low concentrations of dissolved iron and large seasonal fluctuations in light, temperature and the extent of sea ice. How diatoms have adapted to this extreme environment is largely unknown. Here we present insights into the genome evolution of a cold-adapted diatom from the Southern Ocean, Fragilariopsis cylindrus, based on a comparison with temperate diatoms. We find that approximately 24.7 per cent of the diploid F. cylindrus genome consists of genetic loci with alleles that are highly divergent (15.1 megabases of the total genome size of 61.1 megabases). These divergent alleles were differentially expressed across environmental conditions, including darkness, low iron, freezing, elevated temperature and increased CO2. Alleles with the largest ratio of non-synonymous to synonymous nucleotide substitutions also show the most pronounced condition-dependent expression, suggesting a correlation between diversifying selection and allelic differentiation. Divergent alleles may be involved in adaptation to environmental fluctuations in the Southern Ocean.
Dartmouth College1, University of Cambridge2, St. Jude Children's Research Hospital3, Case Western Reserve University4, Cedars-Sinai Medical Center5, University of Southern California6, Harvard University7, Johns Hopkins University8, QIMR Berghofer Medical Research Institute9, Van Andel Institute10, University of Copenhagen11, McGill University12, Princess Margaret Cancer Centre13, Huntsman Cancer Institute14, Mayo Clinic15, University of Tasmania16, Cancer Council Victoria17, University of Göttingen18, German Cancer Research Center19, University of Salzburg20, Laval University21, Institute of Cancer Research22, University of Washington23, International Agency for Research on Cancer24, Medical University of South Carolina25, Duke University26, Nanjing Medical University27, Shanghai Jiao Tong University28, University of South Florida29, Research Triangle Park30, University of Liverpool31, Seoul National University32, Cornell University33, Memorial Hospital of South Bend34, Memorial Sloan Kettering Cancer Center35, University of Southern Denmark36, Sapienza University of Rome37, University of Toronto38, University of Oxford39, Fred Hutchinson Cancer Research Center40, University of California, Davis41
TL;DR: Results from these analyses will enable researchers to identify new susceptibility loci, perform fine-mapping of new or known loci associated with either single or multiple cancers, assess the degree of overlap in cancer causation and pleiotropic effects of loci that have been identified for disease-specific risk, and jointly model genetic, environmental, and lifestyle-related exposures.
Abstract: BACKGROUND: Common cancers develop through a multistep process often including inherited susceptibility. Collaboration among multiple institutions, and funding from multiple sources, has allowed the development of an inexpensive genotyping microarray, the OncoArray. The array includes a genome-wide backbone, comprising 230,000 SNPs tagging most common genetic variants, together with dense mapping of known susceptibility regions, rare variants from sequencing experiments, pharmacogenetic markers, and cancer-related traits. METHODS: The OncoArray can be genotyped using a novel technology developed by Illumina to facilitate efficient genotyping. The consortium developed standard approaches for selecting SNPs for study, for quality control of markers, and for ancestry analysis. The array was genotyped at selected sites and with prespecified replicate samples to permit evaluation of genotyping accuracy among centers and by ethnic background. RESULTS: The OncoArray consortium genotyped 447,705 samples. A total of 494,763 SNPs passed quality control steps with a sample success rate of 97% of the samples. Participating sites performed ancestry analysis using a common set of markers and a scoring algorithm based on principal components analysis. CONCLUSIONS: Results from these analyses will enable researchers to identify new susceptibility loci, perform fine-mapping of new or known loci associated with either single or multiple cancers, assess the degree of overlap in cancer causation and pleiotropic effects of loci that have been identified for disease-specific risk, and jointly model genetic, environmental, and lifestyle-related exposures. IMPACT: Ongoing analyses will shed light on etiology and risk assessment for many types of cancer. Cancer Epidemiol Biomarkers Prev; 26(1); 126-35. ©2016 AACR.