Showing papers by "Research Triangle Park published in 2018"
TL;DR: Triple therapy with fluticasone furoate, umeclidinium, and vilanterol resulted in a lower rate of moderate or severe COPD exacerbations than flutic asonefuroate–vilanterol or u meclid inium–vilAnterol in this population.
Abstract: Background The benefits of triple therapy for chronic obstructive pulmonary disease (COPD) with an inhaled glucocorticoid, a long-acting muscarinic antagonist (LAMA), and a long-acting β2-agonist (LABA), as compared with dual therapy (either inhaled glucocorticoid–LABA or LAMA–LABA), are uncertain. Methods In this randomized trial involving 10,355 patients with COPD, we compared 52 weeks of a once-daily combination of fluticasone furoate (an inhaled glucocorticoid) at a dose of 100 μg, umeclidinium (a LAMA) at a dose of 62.5 μg, and vilanterol (a LABA) at a dose of 25 μg (triple therapy) with fluticasone furoate–vilanterol (at doses of 100 μg and 25 μg, respectively) and umeclidinium–vilanterol (at doses of 62.5 μg and 25 μg, respectively). Each regimen was administered in a single Ellipta inhaler. The primary outcome was the annual rate of moderate or severe COPD exacerbations during treatment. Results The rate of moderate or severe exacerbations in the triple-therapy group was 0.91 per year, as...
760 citations
Case Western Reserve University1, Newcastle University2, Research Triangle Park3, Seattle Children's4, Boston Children's Hospital5, Duke University6, University of Pittsburgh7, Children's Hospital of Eastern Ontario8, University of Rochester9, Centers for Disease Control and Prevention10, Children's Hospital of Philadelphia11, Johns Hopkins University12, University of Rochester Medical Center13
TL;DR: Care considerations for diagnosis of DMD and neuromuscular, rehabilitation, endocrine (growth, puberty, and adrenal insufficiency), and gastrointestinal (including nutrition and dysphagia) management are presented.
Abstract: Since the publication of the Duchenne muscular dystrophy (DMD) care considerations in 2010, multidisciplinary care of this severe, progressive neuromuscular disease has evolved. In conjunction with improved patient survival, a shift to more anticipatory diagnostic and therapeutic strategies has occurred, with a renewed focus on patient quality of life. In 2014, a steering committee of experts from a wide range of disciplines was established to update the 2010 DMD care considerations, with the goal of improving patient care. The new care considerations aim to address the needs of patients with prolonged survival, to provide guidance on advances in assessments and interventions, and to consider the implications of emerging genetic and molecular therapies for DMD. The committee identified 11 topics to be included in the update, eight of which were addressed in the original care considerations. The three new topics are primary care and emergency management, endocrine management, and transitions of care across the lifespan. In part 1 of this three-part update, we present care considerations for diagnosis of DMD and neuromuscular, rehabilitation, endocrine (growth, puberty, and adrenal insufficiency), and gastrointestinal (including nutrition and dysphagia) management.
667 citations
Case Western Reserve University1, Newcastle University2, Research Triangle Park3, Duke University4, Seattle Children's5, Nationwide Children's Hospital6, Children's Hospital of Eastern Ontario7, State University of New York System8, Centers for Disease Control and Prevention9, University of Rochester Medical Center10
TL;DR: The new care considerations acknowledge the effects of long-term glucocorticoid use on the natural history of DMD, and the need for care guidance across the lifespan as patients live longer.
Abstract: A coordinated, multidisciplinary approach to care is essential for optimum management of the primary manifestations and secondary complications of Duchenne muscular dystrophy (DMD). Contemporary care has been shaped by the availability of more sensitive diagnostic techniques and the earlier use of therapeutic interventions, which have the potential to improve patients' duration and quality of life. In part 2 of this update of the DMD care considerations, we present the latest recommendations for respiratory, cardiac, bone health and osteoporosis, and orthopaedic and surgical management for boys and men with DMD. Additionally, we provide guidance on cardiac management for female carriers of a disease-causing mutation. The new care considerations acknowledge the effects of long-term glucocorticoid use on the natural history of DMD, and the need for care guidance across the lifespan as patients live longer. The management of DMD looks set to change substantially as new genetic and molecular therapies become available.
608 citations
TL;DR: Add-on cannabidiol is efficacious for the treatment of patients with drop seizures associated with Lennox-Gastaut syndrome and is generally well tolerated.
593 citations
Raymond K. Walters1, Raymond K. Walters2, Renato Polimanti3, Emma C. Johnson4 +168 more•Institutions (48)
TL;DR: The largest genome-wide association study to date of DSM-IV-diagnosed AD found loci associated with AD and characterized the relationship between AD and other psychiatric and behavioral outcomes, underscoring the genetic distinction between pathological and nonpathological drinking behaviors.
Abstract: Liability to alcohol dependence (AD) is heritable, but little is known about its complex polygenic architecture or its genetic relationship with other disorders. To discover loci associated with AD and characterize the relationship between AD and other psychiatric and behavioral outcomes, we carried out the largest genome-wide association study to date of DSM-IV-diagnosed AD. Genome-wide data on 14,904 individuals with AD and 37,944 controls from 28 case-control and family-based studies were meta-analyzed, stratified by genetic ancestry (European, n = 46,568; African, n = 6,280). Independent, genome-wide significant effects of different ADH1B variants were identified in European (rs1229984; P = 9.8 × 10-13) and African ancestries (rs2066702; P = 2.2 × 10-9). Significant genetic correlations were observed with 17 phenotypes, including schizophrenia, attention deficit-hyperactivity disorder, depression, and use of cigarettes and cannabis. The genetic underpinnings of AD only partially overlap with those for alcohol consumption, underscoring the genetic distinction between pathological and nonpathological drinking behaviors.
434 citations
Joint Genome Institute1, University of North Carolina at Chapel Hill2, Howard Hughes Medical Institute3, ETH Zurich4, Stanford University5, Gansu Agricultural University6, Virginia Tech7, International Centre for Genetic Engineering and Biotechnology8, Oak Ridge National Laboratory9, University of Tennessee10, Cornell University11, Research Triangle Park12, University of Washington13, Max Planck Society14, University of California, Merced15
TL;DR: This work sequenced 484 genomes of bacterial isolates from roots of Brassicaceae, poplar, and maize and validated candidates from two sets of plant-associated genes, including one involved in plant colonization and the other serving in microbe–microbe competition between plant and microbe.
Abstract: Plants intimately associate with diverse bacteria. Plant-associated bacteria have ostensibly evolved genes that enable them to adapt to plant environments. However, the identities of such genes are mostly unknown, and their functions are poorly characterized. We sequenced 484 genomes of bacterial isolates from roots of Brassicaceae, poplar, and maize. We then compared 3,837 bacterial genomes to identify thousands of plant-associated gene clusters. Genomes of plant-associated bacteria encode more carbohydrate metabolism functions and fewer mobile elements than related non-plant-associated genomes do. We experimentally validated candidates from two sets of plant-associated genes: one involved in plant colonization, and the other serving in microbe-microbe competition between plant-associated bacteria. We also identified 64 plant-associated protein domains that potentially mimic plant domains; some are shared with plant-associated fungi and oomycetes. This work expands the genome-based understanding of plant-microbe interactions and provides potential leads for efficient and sustainable agriculture through microbiome engineering.
378 citations
Stanford University1, Columbia University2, University of North Carolina at Chapel Hill3, Emory University4, Virginia Commonwealth University5, Duke University6, Veterans Health Administration7, Washington University in St. Louis8, Cardiff University9, Harvard University10, University of Cape Town11, Boston University12, Yale University13, Research Triangle Park14, University of Michigan15, Groote Schuur Hospital16, University of Pennsylvania17, VA Boston Healthcare System18, University of California, San Diego19, Broad Institute20, Rhode Island Hospital21, Charité22, Columbia University Medical Center23, University of Illinois at Urbana–Champaign24, Uniformed Services University of the Health Sciences25, Icahn School of Medicine at Mount Sinai26, McLean Hospital27
TL;DR: The results demonstrate genetic influences on the development of PTSD, identify shared genetic risk between PTSD and other psychiatric disorders and highlight the importance of multiethnic/racial samples.
Abstract: The Psychiatric Genomics Consortium-Posttraumatic Stress Disorder group (PGC-PTSD) combined genome-wide case–control molecular genetic data across 11 multiethnic studies to quantify PTSD heritability, to examine potential shared genetic risk with schizophrenia, bipolar disorder, and major depressive disorder and to identify risk loci for PTSD. Examining 20 730 individuals, we report a molecular genetics-based heritability estimate (h2SNP) for European-American females of 29% that is similar to h2SNP for schizophrenia and is substantially higher than h2SNP in European-American males (estimate not distinguishable from zero). We found strong evidence of overlapping genetic risk between PTSD and schizophrenia along with more modest evidence of overlap with bipolar and major depressive disorder. No single-nucleotide polymorphisms (SNPs) exceeded genome-wide significance in the transethnic (overall) meta-analysis and we do not replicate previously reported associations. Still, SNP-level summary statistics made available here afford the best-available molecular genetic index of PTSD—for both European- and African-American individuals—and can be used in polygenic risk prediction and genetic correlation studies of diverse phenotypes. Publication of summary statistics for ∼10 000 African Americans contributes to the broader goal of increased ancestral diversity in genomic data resources. In sum, the results demonstrate genetic influences on the development of PTSD, identify shared genetic risk between PTSD and other psychiatric disorders and highlight the importance of multiethnic/racial samples. As has been the case with schizophrenia and other complex genetic disorders, larger sample sizes are needed to identify specific risk loci.
363 citations
TL;DR: A crystal structure of human KOP in complex with the potent epoxymorphinan opioid agonist MP1104 and an active-state-stabilizing nanobody is provided and key residues that propagate larger-scale structural rearrangements and transducer binding are illuminated that elucidate the structural determinants of KOP pharmacology, function, and biased signaling.
277 citations
TL;DR: Dolutegravir-rilpivirine was non-inferior to CAR over 48 weeks in participants with HIV suppression and showed a safety profile consistent with its components, which supports the use of this two-drug regimen to maintain HIV suppression.
275 citations
TL;DR: This study aims to develop robust QSAR/QSPR models for chemical properties of environmental interest that can be used for regulatory purposes and uses data from the publicly available PHYSPROP database, a set of 13 common physicochemical and environmental fate properties.
Abstract: The collection of chemical structure information and associated experimental data for quantitative structure–activity/property relationship (QSAR/QSPR) modeling is facilitated by an increasing number of public databases containing large amounts of useful data. However, the performance of QSAR models highly depends on the quality of the data and modeling methodology used. This study aims to develop robust QSAR/QSPR models for chemical properties of environmental interest that can be used for regulatory purposes. This study primarily uses data from the publicly available PHYSPROP database consisting of a set of 13 common physicochemical and environmental fate properties. These datasets have undergone extensive curation using an automated workflow to select only high-quality data, and the chemical structures were standardized prior to calculation of the molecular descriptors. The modeling procedure was developed based on the five Organization for Economic Cooperation and Development (OECD) principles for QSAR models. A weighted k-nearest neighbor approach was adopted using a minimum number of required descriptors calculated using PaDEL, an open-source software. The genetic algorithms selected only the most pertinent and mechanistically interpretable descriptors (2–15, with an average of 11 descriptors). The sizes of the modeled datasets varied from 150 chemicals for biodegradability half-life to 14,050 chemicals for logP, with an average of 3222 chemicals across all endpoints. The optimal models were built on randomly selected training sets (75%) and validated using fivefold cross-validation (CV) and test sets (25%). The CV Q2 of the models varied from 0.72 to 0.95, with an average of 0.86 and an R2 test value from 0.71 to 0.96, with an average of 0.82. Modeling and performance details are described in QSAR model reporting format and were validated by the European Commission’s Joint Research Center to be OECD compliant. All models are freely available as an open-source, command-line application called OPEn structure–activity/property Relationship App (OPERA). OPERA models were applied to more than 750,000 chemicals to produce freely available predicted data on the U.S. Environmental Protection Agency’s CompTox Chemistry Dashboard.
271 citations
Washington University in St. Louis1, Australian National University2, Heidelberg University3, University of Michigan4, Flinders University5, Paris Diderot University6, King's College London7, Office of Population Research8, University of Montpellier9, French Institute of Health and Medical Research10, University of Otago11, Hungarian Academy of Sciences12, University of Sussex13, University of Bologna14, VU University Amsterdam15, University of Adelaide16, University of London17, University of Oxford18, University of Queensland19, University of New England (Australia)20, University of Pennsylvania21, Georgetown University22, National and Kapodistrian University of Athens23, Roy J. and Lucille A. Carver College of Medicine24, University of Basel25, Greifswald University Hospital26, University Medical Center Groningen27, Semmelweis University28, VU University Medical Center29, Michigan State University30, University of Cambridge31, Icahn School of Medicine at Mount Sinai32, University of Manchester33, University of Münster34, Uppsala University35, Research Triangle Park36, QIMR Berghofer Medical Research Institute37, University of Bristol38, Deakin University39, Charité40, University of Melbourne41, University of Molise42, University of California, San Francisco43, Indiana University44
TL;DR: If an interaction exists in which the S allele of 5-HTTLPR increases risk of depression only in stressed individuals, then it is not broadly generalisable, but must be of modest effect size and only observable in limited situations.
Abstract: The hypothesis that the S allele of the 5-HTTLPR serotonin transporter promoter region is associated with increased risk of depression, but only in individuals exposed to stressful situations, has generated much interest, research and controversy since first proposed in 2003. Multiple meta-analyses combining results from heterogeneous analyses have not settled the issue. To determine the magnitude of the interaction and the conditions under which it might be observed, we performed new analyses on 31 data sets containing 38 802 European ancestry subjects genotyped for 5-HTTLPR and assessed for depression and childhood maltreatment or other stressful life events, and meta-analysed the results. Analyses targeted two stressors (narrow, broad) and two depression outcomes (current, lifetime). All groups that published on this topic prior to the initiation of our study and met the assessment and sample size criteria were invited to participate. Additional groups, identified by consortium members or self-identified in response to our protocol (published prior to the start of analysis) with qualifying unpublished data, were also invited to participate. A uniform data analysis script implementing the protocol was executed by each of the consortium members. Our findings do not support the interaction hypothesis. We found no subgroups or variable definitions for which an interaction between stress and 5-HTTLPR genotype was statistically significant. In contrast, our findings for the main effects of life stressors (strong risk factor) and 5-HTTLPR genotype (no impact on risk) are strikingly consistent across our contributing studies, the original study reporting the interaction and subsequent meta-analyses. Our conclusion is that if an interaction exists in which the S allele of 5-HTTLPR increases risk of depression only in stressed individuals, then it is not broadly generalisable, but must be of modest effect size and only observable in limited situations.
National Health and Medical Research Council1, University of Otago2, University of California, San Diego3, University of Pennsylvania4, McMaster University5, Royal Women's Hospital6, University of Alabama at Birmingham7, University of Oxford8, University of Birmingham9, RTI International10, Research Triangle Park11, Dalhousie University12, University of Tübingen13, University of Toronto14, Auckland City Hospital15, Queen's University Belfast16, University College London17, James Cook University18, University of Cambridge19
TL;DR: There was no significant difference between a lower SpO2 target range compared with a higher SpO 2 target range on the primary composite outcome of death or major disability at a corrected age of 18 to 24 months.
Abstract: Importance There are potential benefits and harms of hyperoxemia and hypoxemia for extremely preterm infants receiving more vs less supplemental oxygen. Objective To compare the effects of different target ranges for oxygen saturation as measured by pulse oximetry (Spo 2 ) on death or major morbidity. Design, Setting, and Participants Prospectively planned meta-analysis of individual participant data from 5 randomized clinical trials (conducted from 2005-2014) enrolling infants born before 28 weeks’ gestation. Exposures Spo 2 target range that was lower (85%-89%) vs higher (91%-95%). Main Outcomes and Measures The primary outcome was a composite of death or major disability (bilateral blindness, deafness, cerebral palsy diagnosed as ≥2 level on the Gross Motor Function Classification System, or Bayley-III cognitive or language score Results A total of 4965 infants were randomized (2480 to the lower Spo 2 target range and 2485 to the higher Spo 2 range) and had a median gestational age of 26 weeks (interquartile range, 25-27 weeks) and a mean birth weight of 832 g (SD, 190 g). The primary outcome occurred in 1191 of 2228 infants (53.5%) in the lower Spo 2 target group and 1150 of 2229 infants (51.6%) in the higher Spo 2 target group (risk difference, 1.7% [95% CI, −1.3% to 4.6%]; relative risk [RR], 1.04 [95% CI, 0.98 to 1.09], P = .21). Of the 16 secondary outcomes, 11 were null, 2 significantly favored the lower Spo 2 target group, and 3 significantly favored the higher Spo 2 target group. Death occurred in 484 of 2433 infants (19.9%) in the lower Spo 2 target group and 418 of 2440 infants (17.1%) in the higher Spo 2 target group (risk difference, 2.8% [95% CI, 0.6% to 5.0%]; RR, 1.17 [95% CI, 1.04 to 1.31], P = .01). Treatment for retinopathy of prematurity was administered to 220 of 2020 infants (10.9%) in the lower Spo 2 target group and 308 of 2065 infants (14.9%) in the higher Spo 2 target group (risk difference, −4.0% [95% CI, −6.1% to −2.0%]; RR, 0.74 [95% CI, 0.63 to 0.86], P 2 target group and 170 of 2465 infants (6.9%) in the higher Spo 2 target group (risk difference, 2.3% [95% CI, 0.8% to 3.8%]; RR, 1.33 [95% CI, 1.10 to 1.61], P = .003). Conclusions and Relevance In this prospectively planned meta-analysis of individual participant data from extremely preterm infants, there was no significant difference between a lower Spo 2 target range compared with a higher Spo 2 target range on the primary composite outcome of death or major disability at a corrected age of 18 to 24 months. The lower Spo 2 target range was associated with a higher risk of death and necrotizing enterocolitis, but a lower risk of retinopathy of prematurity treatment.
Case Western Reserve University1, Newcastle University2, Research Triangle Park3, Seattle Children's4, Harvard University5, Nationwide Children's Hospital6, Oak Ridge Institute for Science and Education7, Centers for Disease Control and Prevention8, University of California, San Francisco9, Baylor College of Medicine10, University of Iowa11, University of Rochester Medical Center12, Children's Hospital of Eastern Ontario13
TL;DR: Assessments and interventions that are designed to improve mental health and independence, functionality, and quality of life in critical domains of living, including health care, education, employment, interpersonal relationships, and intimacy are discussed.
Abstract: Summary Improvements in the function, quality of life, and longevity of patients with Duchenne muscular dystrophy (DMD) have been achieved through a multidisciplinary approach to management across a range of health-care specialties. In part 3 of this update of the DMD care considerations, we focus on primary care, emergency management, psychosocial care, and transitions of care across the lifespan. Many primary care and emergency medicine clinicians are inexperienced at managing the complications of DMD. We provide a guide to the acute and chronic medical conditions that these first-line providers are likely to encounter. With prolonged survival, individuals with DMD face a unique set of challenges related to psychosocial issues and transitions of care. We discuss assessments and interventions that are designed to improve mental health and independence, functionality, and quality of life in critical domains of living, including health care, education, employment, interpersonal relationships, and intimacy.
Stockholm Environment Institute1, Alion Science and Technology2, Research Triangle Park3, University of North Carolina at Chapel Hill4, Geophysical Fluid Dynamics Laboratory5, Forschungszentrum Jülich6, National Research Council7, Hong Kong Polytechnic University8, Appalachian State University9, United States Forest Service10, University of British Columbia11, Chinese Academy of Sciences12, University of Tokyo13, Norwegian Institute for Air Research14, Catholic University of the Sacred Heart15
TL;DR: The scientific underpinnings necessary to better understand the implications of and rationale for selecting a specific TOAR metric for assessing spatial and temporal variation in ozone for a particular impact are provided.
Abstract: Assessment of spatial and temporal variation in the impacts of ozone on human health, vegetation, and climate requires appropriate metrics. A key component of the Tropospheric Ozone Assessment Report (TOAR) is the consistent calculation of these metrics at thousands of monitoring sites globally. Investigating temporal trends in these metrics required that the same statistical methods be applied across these ozone monitoring sites. The nonparametric Mann-Kendall test (for significant trends) and the Theil-Sen estimator (for estimating the magnitude of trend) were selected to provide robust methods across all sites. This paper provides the scientific underpinnings necessary to better understand the implications of and rationale for selecting a specific TOAR metric for assessing spatial and temporal variation in ozone for a particular impact. The rationale and underlying research evidence that influence the derivation of specific metrics are given. The form of 25 metrics (4 for model-measurement comparison, 5 for characterization of ozone in the free troposphere, 11 for human health impacts, and 5 for vegetation impacts) are described. Finally, this study categorizes health and vegetation exposure metrics based on the extent to which they are determined only by the highest hourly ozone levels, or by a wider range of values. The magnitude of the metrics is influenced by both the distribution of hourly average ozone concentrations at a site location, and the extent to which a particular metric is determined by relatively low, moderate, and high hourly ozone levels. Hence, for the same ozone time series, changes in the distribution of ozone concentrations can result in different changes in the magnitude and direction of trends for different metrics. Thus, dissimilar conclusions about the effect of changes in the drivers of ozone variability (e.g., precursor emissions) on health and vegetation exposure can result from the selection of different metrics.
George Washington University1, University of Colorado Boulder2, Boston University3, Research Triangle Park4, Stockholm Environment Institute5, Goddard Space Flight Center6, Dalhousie University7, Smithsonian Astrophysical Observatory8, University of British Columbia9, Institute for Health Metrics and Evaluation10, University of Edinburgh11, Norwegian Meteorological Institute12, Japan Agency for Marine-Earth Science and Technology13, Nagoya University14
TL;DR: In this article, Ambient air pollution exacerbates asthma among populations around the world and is the most prevalent chronic respiratory disease worldwide, affecting 358 million people in 2015, according to the World Health Organization.
Abstract: Background: Asthma is the most prevalent chronic respiratory disease worldwide, affecting 358 million people in 2015. Ambient air pollution exacerbates asthma among populations around the world and...
University of California, Berkeley1, University of California, Riverside2, University of Washington3, United States Environmental Protection Agency4, Research Triangle Park5, University of Colorado Boulder6, Georgia Institute of Technology7, National Oceanic and Atmospheric Administration8, Pennsylvania State University9
TL;DR: The results suggest that secondary OA from monoterpene oxidation accounts for approximately half of summertime fine OA in Centreville, AL, a forested area in the southeastern United States influenced by anthropogenic pollution.
Abstract: The chemical complexity of atmospheric organic aerosol (OA) has caused substantial uncertainties in understanding its origins and environmental impacts. Here, we provide constraints on OA origins through compositional characterization with molecular-level details. Our results suggest that secondary OA (SOA) from monoterpene oxidation accounts for approximately half of summertime fine OA in Centreville, AL, a forested area in the southeastern United States influenced by anthropogenic pollution. We find that different chemical processes involving nitrogen oxides, during days and nights, play a central role in determining the mass of monoterpene SOA produced. These findings elucidate the strong anthropogenic-biogenic interaction affecting ambient aerosol in the southeastern United States and point out the importance of reducing anthropogenic emissions, especially under a changing climate, where biogenic emissions will likely keep increasing.
TL;DR: Self-reported sleep duration overestimated objectively measured sleep across all races, and compared with PSG, overestimation is significantly greater in whites compared with blacks.
Abstract: Study Objectives
To identify systematic biases across groups in objectively and subjectively measured sleep duration.
TL;DR: This first human observation linking the gut microbiome to arterial stiffness suggests that targeting the microbiome may be a way to treat arterial ageing, and Gut microbiome diversity is inversely associated with arterials stiffness in women.
Abstract: Aims The gut microbiome influences metabolic syndrome (MetS) and inflammation and is therapeutically modifiable. Arterial stiffness is poorly correlated with most traditional risk factors. Our aim was to examine whether gut microbial composition is associated with arterial stiffness. Methods and results We assessed the correlation between carotid-femoral pulse wave velocity (PWV), a measure of arterial stiffness, and gut microbiome composition in 617 middle-aged women from the TwinsUK cohort with concurrent serum metabolomics data. Pulse wave velocity was negatively correlated with gut microbiome alpha diversity (Shannon index, Beta(SE)= -0.25(0.07), P = 1 × 10-4) after adjustment for covariates. We identified seven operational taxonomic units associated with PWV after adjusting for covariates and multiple testing-two belonging to the Ruminococcaceae family. Associations between microbe abundances, microbe diversity, and PWV remained significant after adjustment for levels of gut-derived metabolites (indolepropionate, trimethylamine oxide, and phenylacetylglutamine). We linearly combined the PWV-associated gut microbiome-derived variables and found that microbiome factors explained 8.3% (95% confidence interval 4.3-12.4%) of the variance in PWV. A formal mediation analysis revealed that only a small proportion (5.51%) of the total effect of the gut microbiome on PWV was mediated by insulin resistance and visceral fat, c-reactive protein, and cardiovascular risk factors after adjusting for age, body mass index, and mean arterial pressure. Conclusions Gut microbiome diversity is inversely associated with arterial stiffness in women. The effect of gut microbiome composition on PWV is only minimally mediated by MetS. This first human observation linking the gut microbiome to arterial stiffness suggests that targeting the microbiome may be a way to treat arterial ageing.
TL;DR: In patients with COPD with CVD or risk factors for CVD, exacerbations confer an increased risk of subsequent CVD events, especially in hospitalized patients and within the first 30 days after exacerbation.
Abstract: Rationale: Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are common, associated with acute inflammation, and may increase subsequent cardiovascular disease (CVD) risk.Object...
TL;DR: To develop a haploid inducer in rice, an allelic series was generated in the putative ZmMATL orthologue, OsMATL, and it was found that knockout mutations led to a reduced seed set and a 2–6% haploid induction rate.
Abstract: Intraspecific haploid induction in maize (Zea mays) is triggered by a native frameshift mutation in MATRILINEAL (MATL), which encodes a pollen-specific phospholipase. To develop a haploid inducer in rice (Oryza sativa), we generated an allelic series in the putative ZmMATL orthologue, OsMATL, and found that knockout mutations led to a reduced seed set and a 2–6% haploid induction rate. This demonstrates MATL functional conservation and represents a major advance for rice breeding.
TL;DR: Among women who had undergone vaginal surgery for apical pelvic organ vaginal prolapse, there was no significant difference between ULS and SSLF in rates of surgical failure and nosignificant difference between perioperative behavioral muscle training and usual care on rates of anatomic success and symptom scores at 5 years.
Abstract: Importance Uterosacral ligament suspension (ULS) and sacrospinous ligament fixation (SSLF) are commonly performed pelvic organ prolapse procedures despite a lack of long-term efficacy data. Objective To compare outcomes in women randomized to (1) ULS or SSLF and (2) usual care or perioperative behavioral therapy and pelvic floor muscle training (BPMT) for vaginal apical prolapse. Design, Setting, and Participants This 2 × 2 factorial randomized clinical trial was conducted at 9 US medical centers. Eligible participants who completed the Operations and Pelvic Muscle Training in the Management of Apical Support Loss Trial enrolled between January 2008 and March 2011 and were followed up 5 years after their index surgery from April 2011 through June 2016. Interventions Two randomizations: (1) BPMT (n = 186) or usual care (n = 188) and (2) surgical intervention (ULS: n = 188 or SSLF: n = 186). Main Outcomes and Measures The primary surgical outcome was time to surgical failure. Surgical failure was defined as (1) apical descent greater than one-third of total vaginal length or anterior or posterior vaginal wall beyond the hymen or retreatment for prolapse (anatomic failure), or (2) bothersome bulge symptoms. The primary behavioral outcomes were time to anatomic failure and Pelvic Organ Prolapse Distress Inventory scores (range, 0-300). Results The original study randomized 374 patients, of whom 309 were eligible for this extended trial. For this study, 285 enrolled (mean age, 57.2 years), of whom 244 (86%) completed the extended trial. By year 5, the estimated surgical failure rate was 61.5% in the ULS group and 70.3% in the SSLF group (adjusted difference, −8.8% [95% CI, −24.2 to 6.6]). The estimated anatomic failure rate was 45.6% in the BPMT group and 47.2% in the usual care group (adjusted difference, −1.6% [95% CI, −21.2 to 17.9]). Improvements in Pelvic Organ Prolapse Distress Inventory scores were −59.4 in the BPMT group and −61.8 in the usual care group (adjusted mean difference, 2.4 [95% CI, −13.7 to 18.4]). Conclusions and Relevance Among women who had undergone vaginal surgery for apical pelvic organ vaginal prolapse, there was no significant difference between ULS and SSLF in rates of surgical failure and no significant difference between perioperative behavioral muscle training and usual care on rates of anatomic success and symptom scores at 5 years. Compared with outcomes at 2 years, rates of surgical failure increased during the follow-up period, although prolapse symptom scores remained improved. Trial Registration clinicaltrials.gov Identifier:NCT01166373
TL;DR: It is shown that ALL cells in the circulation are unable to breach the blood–brain barrier in mice; instead, they migrate into the CNS along vessels that pass directly between vertebral or calvarial bone marrow and the subarachnoid space.
Abstract: Acute lymphoblastic leukaemia (ALL) has a marked propensity to metastasize to the central nervous system (CNS). In contrast to brain metastases from solid tumours, metastases of ALL seldom involve the parenchyma but are isolated to the leptomeninges, which is an infrequent site for carcinomatous invasion. Although metastasis to the CNS occurs across all subtypes of ALL, a unifying mechanism for invasion has not yet been determined. Here we show that ALL cells in the circulation are unable to breach the blood–brain barrier in mice; instead, they migrate into the CNS along vessels that pass directly between vertebral or calvarial bone marrow and the subarachnoid space. The basement membrane of these bridging vessels is enriched in laminin, which is known to coordinate pathfinding of neuronal progenitor cells in the CNS. The laminin receptor α6 integrin is expressed in most cases of ALL. We found that α6 integrin–laminin interactions mediated the migration of ALL cells towards the cerebrospinal fluid in vitro. Mice with ALL xenografts were treated with either a PI3Kδ inhibitor, which decreased α6 integrin expression on ALL cells, or specific α6 integrin-neutralizing antibodies and showed significant reductions in ALL transit along bridging vessels, blast counts in the cerebrospinal fluid and CNS disease symptoms despite minimally decreased bone marrow disease burden. Our data suggest that α6 integrin expression, which is common in ALL, allows cells to use neural migratory pathways to invade the CNS.
TL;DR: E-cigarettes are an evolving product class, and retail sales data available at more frequent intervals (eg, weekly) can complement annual surveys and identify emerging trends.
Abstract: Electronic Cigarette Sales in the United States, 2013-2017 Electronic cigarettes (e-cigarettes) deliver an inhaled aerosol to the user that typically contains nicotine, flavorings, and other additives.1 e-Cigarettes come in many shapes and sizes but generally contain a battery, a heating element, and an e-liquid reservoir.1 e-Cigarettes could help adult smokers if used as a complete substitute for conventional cigarettes.1,2 However, research on the effectiveness of e-cigarettes for smoking cessation is inconclusive,2 and e-cigarettes are not currently approved by the US Food and Drug Administration as a cessation aid.1,2 Moreover, e-cigarette aerosol can contain harmful constituents,1,2 and use of these products among young people is a public health concern.1 Most e-cigarettes deliver nicotine, which is addictive and can harm the developing adolescent brain.1 National self-reported surveys traditionally provide annual estimates of tobacco product use. In 2016, 3.2% of US adults and 11.3% of US high school students were current users of e-cigarettes.3 However, e-cigarettes are an evolving product class, and retail sales data available at more frequent intervals (eg, weekly) can complement annual surveys and identify emerging trends.1 This study assessed e-cigarette sales in the United States during 2013-2017.
TL;DR: In this paper, the authors present a review of the literature to understand how academic entrepreneurship is conceptualized and the extent to which it adopts an ecosystem approach, finding that scholars have largely focused on individual ecosystem elements and characteristics, eschewing strategic and systemic conceptualizations of entrepreneurship ecosystems.
Abstract: Policy-related discussions increasingly view universities as so-called “engines of economic growth”. Recognizing that the economic impact of universities is dependent, at least in part, on the success of university-affiliated entrepreneurial ventures, this paper reviews the extant literature to understand how academic entrepreneurship is conceptualized and the extent to which it adopts an ecosystem approach. We find that scholars have largely focused on individual ecosystem elements and characteristics, eschewing strategic and systemic conceptualizations of entrepreneurship ecosystems. As a result, we argue that the ecosystem perspective has not been fully leveraged to influence policy decisions. We conclude by offering several concrete recommendations on future research directions that, if pursued, would further enhance our understanding of the economic impact of universities.
02 Nov 2018
TL;DR: Significant, sometimes adverse, drug effects can occur at relatively low THC doses in infrequent cannabis users, and accordingly these data should be considered with regard to regulation of retail cannabis products and education for individuals initiating cannabis use.
Abstract: Importance Vaporization is an increasingly popular method for cannabis administration, and policy changes have increased adult access to cannabis drastically. Controlled examinations of cannabis vaporization among adults with infrequent current cannabis use patterns (>30 days since last use) are needed. Objective To evaluate the acute dose effects of smoked and vaporized cannabis using controlled administration methods. Design, Setting, and Participants This within-participant, double-blind, crossover study was conducted from June 2016 to January 2017 at the Behavioral Pharmacology Research Unit, Johns Hopkins University School of Medicine, and included 17 healthy adults. Six smoked and vaporized outpatient experimental sessions (1-week washout between sessions) were completed in clusters (order counterbalanced across participants); dose order was randomized within each cluster. Interventions Cannabis containing Δ9-tetrahydrocannabinol (THC) doses of 0 mg, 10 mg, and 25 mg was vaporized and smoked by each participant. Main Outcomes and Measures Change from baseline scores for subjective drug effects, cognitive and psychomotor performance, vital signs, and blood THC concentration. Results The sample included 17 healthy adults (mean [SD] age, 27.3 [5.7] years; 9 men and 8 women) with no cannabis use in the prior month (mean [SD] days since last cannabis use, 398 [437] days). Inhalation of cannabis containing 10 mg of THC produced discriminative drug effects (mean [SD] ratings on a 100-point visual analog scale, smoked: 46 [26]; vaporized: 69 [26]) and modest impairment of cognitive functioning. The 25-mg dose produced significant drug effects (mean [SD] ratings, smoked: 66 [29]; vaporized: 78 [24]), increased incidence of adverse effects, and pronounced impairment of cognitive and psychomotor ability (eg, significant decreased task performance compared with placebo in vaporized conditions). Vaporized cannabis resulted in qualitatively stronger drug effects for most pharmacodynamic outcomes and higher peak concentrations of THC in blood, compared with equal doses of smoked cannabis (25-mg dose: smoked, 10.2 ng/mL; vaporized, 14.4 ng/mL). Blood THC concentrations and heart rate peaked within 30 minutes after cannabis administration and returned to baseline within 3 to 4 hours. Several subjective drug effects and observed cognitive and psychomotor impairments persisted for up to 6 hours on average. Conclusions and Relevance Vaporized and smoked cannabis produced dose-orderly drug effects, which were stronger when vaporized. These data can inform regulatory and clinical decisions surrounding the use of cannabis among adults with little or no prior cannabis exposure. Trial Registration ClinicalTrials.gov Identifier: NCT03676166.
Emory University1, University of Texas Southwestern Medical Center2, Children's Hospital of Philadelphia3, University of Texas Health Science Center at Houston4, Lucile Packard Children's Hospital5, Wayne State University6, Brown University7, Research Triangle Park8, RTI International9, National Institutes of Health10
TL;DR: The rate of moderate to severe NDI did not differ, but the rates of severe CP decreased, and mild CP increased over time, suggesting Extremely preterm children are at risk for NDI.
Abstract: OBJECTIVES: Evaluate the spectrum of neurodevelopmental outcome in a contemporary cohort of extremely preterm infants. We hypothesize that the rate of severe neurodevelopmental impairment (NDI) decreases over time. METHODS: Retrospective analysis of neurodevelopmental outcome of preterm infants ≤27 weeks’ gestational age (GA) from a Neonatal Research Network center that completed neurodevelopmental follow-up assessments between April 1, 2011, and January 1, 2015. The Bayley Scales of Infant Development-III (BSID III) and a standardized neurosensory examination were performed between 18 and 26 months’ adjusted age. Outcome measures were neurologic examination diagnoses, BSID III cognitive and motor scores, sensory impairment, and the composite outcome of NDI, based on the BSID III cognitive score (analyzed by using a cutoff of RESULTS: Two thousand one hundred and thirteen infants with a mean GA of 25.0 ± 1.0 weeks and mean birth weight of 760 ± 154 g were evaluated. The 11% lost to follow-up were less likely to have private insurance, late-onset sepsis, or severe intraventricular hemorrhage. Neurologic examination results were normal in 59%, suspect abnormal in 19%, and definitely abnormal in 22%. Severe CP decreased 43% whereas mild CP increased 13% during the study. The rate of moderate to severe NDI decreased from 21% to 16% when using the BSID III cognitive cutoff of CONCLUSIONS: Extremely preterm children are at risk for NDI. Over time, the rate of moderate to severe NDI did not differ, but the rates of severe CP decreased, and mild CP increased.
TL;DR: Incidence rates of isolated ACL reconstruction and rates of concomitant meniscal surgery have increased, particularly among children and adolescents, and a renewed focus on adoption of injury prevention programs is needed to mitigate these trends.
Abstract: Background:Few population-based descriptive studies on the incidence of anterior cruciate ligament (ACL) reconstruction and concomitant pathology exist.Hypothesis:Incidence of ACL reconstruction ha...
TL;DR: Vitamin D supplementation alone or with calcium was not associated with reduced fracture incidence among community-dwelling adults without known vitamin D deficiency, osteoporosis, or prior fracture and was associated with an increase in the incidence of kidney stones.
Abstract: Importance Osteoporotic fractures result in significant morbidity and mortality. Objective To update the evidence for benefits and harms of vitamin D, calcium, or combined supplementation for the primary prevention of fractures in community-dwelling adults to inform the US Preventive Services Task Force. Data Sources PubMed, EMBASE, Cochrane Library, and trial registries through March 21, 2017; references; and experts. Surveillance continued through February 28, 2018. Study Selection English-language randomized clinical trials (RCTs) or observational studies of supplementation with vitamin D, calcium, or both among adult populations; studies of populations that were institutionalized or had known vitamin D deficiency, osteoporosis, or prior fracture were excluded. Data Extraction and Synthesis Dual, independent review of titles/abstracts and full-text articles and study quality rating using predefined criteria. Random-effects meta-analysis used when at least 3 similar studies were available. Main Outcomes and Measures Incident fracture, mortality, kidney stones, cardiovascular events, and cancer. Results Eleven RCTs (N = 51 419) in adults 50 years and older conducted over 2 to 7 years were included. Compared with placebo, supplementation with vitamin D decreased total fracture incidence (1 RCT [n = 2686]; absolute risk difference [ARD], −2.26% [95% CI, −4.53% to 0.00%]) but had no significant association with hip fracture (3 RCTs [n = 5496]; pooled ARD, −0.01% [95% CI, −0.80% to 0.78%]). Supplementation using vitamin D with calcium had no effect on total fracture incidence (1 RCT [n = 36 282]; ARD, −0.35% [95% CI, −1.02% to 0.31%]) or hip fracture incidence (2 RCTs [n = 36 727]; ARD from the larger trial, −0.14% [95% CI, −0.34% to 0.07%]). The evidence for calcium alone was limited, with only 2 studies (n = 339 total) and very imprecise results. Supplementation with vitamin D alone or with calcium had no significant effect on all-cause mortality or incident cardiovascular disease; ARDs ranged from −1.93% to 1.79%, with CIs consistent with no significant differences. Supplementation using vitamin D with calcium was associated with an increased incidence of kidney stones (3 RCTs [n = 39 213]; pooled ARD, 0.33% [95% CI, 0.06% to 0.60%]), but supplementation with calcium alone was not associated with an increased risk (3 RCTs [n = 1259]; pooled ARD, 0.00% [95% CI, −0.87% to 0.87%]). Supplementation with vitamin D and calcium was not associated with an increase in cancer incidence (3 RCTs [n = 39 213]; pooled ARD, −1.48% [95% CI, −3.32% to 0.35%]). Conclusions and Relevance Vitamin D supplementation alone or with calcium was not associated with reduced fracture incidence among community-dwelling adults without known vitamin D deficiency, osteoporosis, or prior fracture. Vitamin D with calcium was associated with an increase in the incidence of kidney stones.
Research Triangle Park1, United States Environmental Protection Agency2, Dow Chemical Company3, University of North Carolina at Chapel Hill4, National Institutes of Health5, Simulations Plus, Inc.6, Simcyp7, Food and Drug Administration8, Oak Ridge Institute for Science and Education9, Procter & Gamble10
TL;DR: The U.S. Environmental Protection Agency Office of Research and Development and the National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods co-organized a workshop and webinar series to explore the capabilities and limitations of IVIVE within this context.
TL;DR: A novel selective oxazole-based inverse agonist of REV-ERB, which protects REV -ERB&agr; protein from degradation, is developed, and used to reveal how proinflammatory cytokines trigger rapid degradation of REB&bgr; in the elaboration of an inflammatory response.
Abstract: Recent studies reveal that airway epithelial cells are critical pulmonary circadian pacemaker cells, mediating rhythmic inflammatory responses. Using mouse models, we now identify the rhythmic circadian repressor REV-ERBα as essential to the mechanism coupling the pulmonary clock to innate immunity, involving both myeloid and bronchial epithelial cells in temporal gating and determining amplitude of response to inhaled endotoxin. Dual mutation of REV-ERBα and its paralog REV-ERBβ in bronchial epithelia further augmented inflammatory responses and chemokine activation, but also initiated a basal inflammatory state, revealing a critical homeostatic role for REV-ERB proteins in the suppression of the endogenous proinflammatory mechanism in unchallenged cells. However, REV-ERBα plays the dominant role, as deletion of REV-ERBβ alone had no impact on inflammatory responses. In turn, inflammatory challenges cause striking changes in stability and degradation of REV-ERBα protein, driven by SUMOylation and ubiquitination. We developed a novel selective oxazole-based inverse agonist of REV-ERB, which protects REV-ERBα protein from degradation, and used this to reveal how proinflammatory cytokines trigger rapid degradation of REV-ERBα in the elaboration of an inflammatory response. Thus, dynamic changes in stability of REV-ERBα protein couple the core clock to innate immunity.