Showing papers by "University of Colorado Denver published in 2015"
TL;DR: Because of the increased complexity of analysis and interpretation of clinical genetic testing described in this report, the ACMG strongly recommends thatclinical molecular genetic testing should be performed in a Clinical Laboratory Improvement Amendments–approved laboratory, with results interpreted by a board-certified clinical molecular geneticist or molecular genetic pathologist or the equivalent.
17,834 citations
The Royal Marsden NHS Foundation Trust1, European Institute of Oncology2, University of Colorado Denver3, Aix-Marseille University4, Baylor University5, University of Michigan6, University of Zurich7, Cross Cancer Institute8, Peter MacCallum Cancer Centre9, Netherlands Cancer Institute10, Hospital General Universitario Gregorio Marañón11, Memorial Sloan Kettering Cancer Center12, Huntsman Cancer Institute13, Yale University14, University of Melbourne15, University of Sydney16, Cornell University17, Ludwig Institute for Cancer Research18, University of Utah19, Yale Cancer Center20, Odense University Hospital21, Bristol-Myers Squibb22, Harvard University23
TL;DR: Among previously untreated patients with metastatic melanoma, nivolumab alone or combined with ipilimumab resulted in significantly longer progression-free survival than ipILimumab alone, and in patients with PD-L1-negative tumors, the combination of PD-1 and CTLA-4 blockade was more effective than either agent alone.
Abstract: The median progression-free survival was 11.5 months (95% confidence interval [CI], 8.9 to 16.7) with nivolumab plus ipilimumab, as compared with 2.9 months (95% CI, 2.8 to 3.4) with ipilimumab (hazard ratio for death or disease progression, 0.42; 99.5% CI, 0.31 to 0.57; P<0.001), and 6.9 months (95% CI, 4.3 to 9.5) with nivolumab (hazard ratio for the comparison with ipilimumab, 0.57; 99.5% CI, 0.43 to 0.76; P<0.001). In patients with tumors positive for the PD-1 ligand (PD-L1), the median progression-free survival was 14.0 months in the nivolumab-plus-ipilimumab group and in the nivolumab group, but in patients with PD-L1–negative tumors, progression-free survival was longer with the combination therapy than with nivolumab alone (11.2 months [95% CI, 8.0 to not reached] vs. 5.3 months [95% CI, 2.8 to 7.1]). Treatment-related adverse events of grade 3 or 4 occurred in 16.3% of the patients in the nivolumab group, 55.0% of those in the nivolumab-plus-ipilimumab group, and 27.3% of those in the ipilimumab group. CONCLUSIONS Among previously untreated patients with metastatic melanoma, nivolumab alone or combined with ipilimumab resulted in significantly longer progression-free survival than ipilimumab alone. In patients with PD-L1–negative tumors, the combination of PD-1 and CTLA-4 blockade was more effective than either agent alone. (Funded by Bristol-Myers Squibb; CheckMate 067 ClinicalTrials.gov number, NCT01844505.)
6,318 citations
Mohammad H. Forouzanfar1, Lily Alexander, H. Ross Anderson, Victoria F Bachman1 +733 more•Institutions (289)
TL;DR: The Global Burden of Disease, Injuries, and Risk Factor study 2013 (GBD 2013) as discussed by the authors provides a timely opportunity to update the comparative risk assessment with new data for exposure, relative risks, and evidence on the appropriate counterfactual risk distribution.
5,668 citations
University Hospital Bonn1, University of California, Riverside2, Harvard University3, Case Western Reserve University4, University of Illinois at Chicago5, European Institute6, VA Palo Alto Healthcare System7, Stanford University8, Spanish National Research Council9, Cleveland Clinic Lerner Research Institute10, Hong Kong University of Science and Technology11, University of California, Los Angeles12, University of Southern Denmark13, University of Cambridge14, University of the Basque Country15, Ikerbasque16, University of Manchester17, RIKEN Brain Science Institute18, University of Eastern Finland19, University of Massachusetts Medical School20, University of Bonn21, Center of Advanced European Studies and Research22, University of Southern California23, University of South Florida24, Duke University25, Southampton General Hospital26, Moorgreen Hospital27, University of Southampton28, Louisiana State University29, Imperial College London30, Centre national de la recherche scientifique31, Karolinska Institutet32, Max Planck Society33, University of Tübingen34, University of Groningen35, University of Colorado Denver36, Douglas Mental Health University Institute37
TL;DR: Genome-wide analysis suggests that several genes that increase the risk for sporadic Alzheimer's disease encode factors that regulate glial clearance of misfolded proteins and the inflammatory reaction.
Abstract: Increasing evidence suggests that Alzheimer's disease pathogenesis is not restricted to the neuronal compartment, but includes strong interactions with immunological mechanisms in the brain. Misfolded and aggregated proteins bind to pattern recognition receptors on microglia and astroglia, and trigger an innate immune response characterised by release of inflammatory mediators, which contribute to disease progression and severity. Genome-wide analysis suggests that several genes that increase the risk for sporadic Alzheimer's disease encode factors that regulate glial clearance of misfolded proteins and the inflammatory reaction. External factors, including systemic inflammation and obesity, are likely to interfere with immunological processes of the brain and further promote disease progression. Modulation of risk factors and targeting of these immune mechanisms could lead to future therapeutic or preventive strategies for Alzheimer's disease.
3,947 citations
University of Helsinki1, Semmelweis University2, Hungarian Academy of Sciences3, University of Szeged4, University of Palermo5, University of Porto6, Institute of Molecular Pathology and Immunology of the University of Porto7, Autonomous University of Barcelona8, Instituto de Biologia Molecular e Celular9, Ikerbasque10, Harvard University11, University of Duisburg-Essen12, Paracelsus Private Medical University of Salzburg13, Salk Institute for Biological Studies14, University of Colorado Denver15, Bilkent University16, Middle East Technical University17, University of Southern Denmark18, Statens Serum Institut19, Ghent University Hospital20, Oslo University Hospital21, University of Belgrade22, University of Ljubljana23, University of Mainz24, Finnish Red Cross25, University of Gothenburg26, Latvian Biomedical Research and Study centre27, University of Applied Sciences and Arts Northwestern Switzerland FHNW28, University of Valencia29, Centro Nacional de Investigaciones Cardiovasculares30, University of Freiburg31, Utrecht University32, Trinity College, Dublin33, Catalan Institution for Research and Advanced Studies34, University of Barcelona35, International University Of Catalonia36, Aarhus University Hospital37
TL;DR: A comprehensive overview of the current understanding of the physiological roles of EVs is provided, drawing on the unique EV expertise of academia-based scientists, clinicians and industry based in 27 European countries, the United States and Australia.
Abstract: In the past decade, extracellular vesicles (EVs) have been recognized as potent vehicles of intercellular communication, both in prokaryotes and eukaryotes. This is due to their capacity to transfer proteins, lipids and nucleic acids, thereby influencing various physiological and pathological functions of both recipient and parent cells. While intensive investigation has targeted the role of EVs in different pathological processes, for example, in cancer and autoimmune diseases, the EV-mediated maintenance of homeostasis and the regulation of physiological functions have remained less explored. Here, we provide a comprehensive overview of the current understanding of the physiological roles of EVs, which has been written by crowd-sourcing, drawing on the unique EV expertise of academia-based scientists, clinicians and industry based in 27 European countries, the United States and Australia. This review is intended to be of relevance to both researchers already working on EV biology and to newcomers who will encounter this universal cell biological system. Therefore, here we address the molecular contents and functions of EVs in various tissues and body fluids from cell systems to organs. We also review the physiological mechanisms of EVs in bacteria, lower eukaryotes and plants to highlight the functional uniformity of this emerging communication system.
3,690 citations
University of Washington1, Institute for Health Metrics and Evaluation2, Iran University of Medical Sciences3, King's College London4, Arabian Gulf University5, University of North Texas6, Auckland University of Technology7, Alaska Native Tribal Health Consortium8, Columbia University9, Wuhan University10, Imperial College London11, University of Alabama at Birmingham12, University at Albany, SUNY13, City University of New York14, University of California, San Francisco15, Griffith University16, Environment Agency17, New York University18, Southern University College19, Emory University20, University of Ottawa21, Kosin University22, University of Toronto23, University of British Columbia24, United Arab Emirates University25, Albert Einstein College of Medicine26, University of São Paulo27, Nova Southeastern University28, University of Sydney29, Heidelberg University30, Case Western Reserve University31, Cancer Treatment Centers of America32, University of Oxford33, George Mason University34, James Cook University35, University of Trieste36, University of Calgary37, Wageningen University and Research Centre38, University of the Witwatersrand39, University of Gothenburg40, Harvard University41, Jackson State University42, University of Arizona43, University of Hong Kong44, Tehran University of Medical Sciences45, University of Western Australia46, Aintree University Hospitals NHS Foundation Trust47, University of Colorado Denver48, Veterans Health Administration49, Royal Children's Hospital50, University of Melbourne51, Australian National University52, University of Marburg53, Charité54, Health Canada55, College of Health Sciences, Bahrain56, Karolinska Institutet57, Northumbria University58, University of Edinburgh59, National Research University – Higher School of Economics60, Queen Mary University of London61, Addis Ababa University62, Northwestern University63, Northeastern University64, Mario Negri Institute for Pharmacological Research65, Arak University of Medical Sciences66, University of Nottingham67, University of Tokyo68, Public Health Foundation of India69, University of Groningen70, University of the Philippines Manila71, University of Bologna72, Kyung Hee University73, Brighton and Sussex Medical School74, University of Bergen75, Stavanger University Hospital76, University of Queensland77, National Centre for Disease Control78, University of Sheffield79, Universidad Autónoma Metropolitana80, University College London81, Genentech82, Universiti Tunku Abdul Rahman83, Norwegian Institute of Public Health84
TL;DR: To estimate mortality, incidence, years lived with disability, years of life lost, and disability-adjusted life-years for 28 cancers in 188 countries by sex from 1990 to 2013, the general methodology of the Global Burden of Disease 2013 study was used.
Abstract: Importance Cancer is among the leading causes of death worldwide. Current estimates of cancer burden in individual countries and regions are necessary to inform local cancer control strategies. Objective To estimate mortality, incidence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs) for 28 cancers in 188 countries by sex from 1990 to 2013. Evidence Review The general methodology of the Global Burden of Disease (GBD) 2013 study was used. Cancer registries were the source for cancer incidence data as well as mortality incidence (MI) ratios. Sources for cause of death data include vital registration system data, verbal autopsy studies, and other sources. The MI ratios were used to transform incidence data to mortality estimates and cause of death estimates to incidence estimates. Cancer prevalence was estimated using MI ratios as surrogates for survival data; YLDs were calculated by multiplying prevalence estimates with disability weights, which were derived from population-based surveys; YLLs were computed by multiplying the number of estimated cancer deaths at each age with a reference life expectancy; and DALYs were calculated as the sum of YLDs and YLLs. Findings In 2013 there were 14.9 million incident cancer cases, 8.2 million deaths, and 196.3 million DALYs. Prostate cancer was the leading cause for cancer incidence (1.4 million) for men and breast cancer for women (1.8 million). Tracheal, bronchus, and lung (TBL) cancer was the leading cause for cancer death in men and women, with 1.6 million deaths. For men, TBL cancer was the leading cause of DALYs (24.9 million). For women, breast cancer was the leading cause of DALYs (13.1 million). Age-standardized incidence rates (ASIRs) per 100 000 and age-standardized death rates (ASDRs) per 100 000 for both sexes in 2013 were higher in developing vs developed countries for stomach cancer (ASIR, 17 vs 14; ASDR, 15 vs 11), liver cancer (ASIR, 15 vs 7; ASDR, 16 vs 7), esophageal cancer (ASIR, 9 vs 4; ASDR, 9 vs 4), cervical cancer (ASIR, 8 vs 5; ASDR, 4 vs 2), lip and oral cavity cancer (ASIR, 7 vs 6; ASDR, 2 vs 2), and nasopharyngeal cancer (ASIR, 1.5 vs 0.4; ASDR, 1.2 vs 0.3). Between 1990 and 2013, ASIRs for all cancers combined (except nonmelanoma skin cancer and Kaposi sarcoma) increased by more than 10% in 113 countries and decreased by more than 10% in 12 of 188 countries. Conclusions and Relevance Cancer poses a major threat to public health worldwide, and incidence rates have increased in most countries since 1990. The trend is a particular threat to developing nations with health systems that are ill-equipped to deal with complex and expensive cancer treatments. The annual update on the Global Burden of Cancer will provide all stakeholders with timely estimates to guide policy efforts in cancer prevention, screening, treatment, and palliation.
2,375 citations
Mohammad H. Forouzanfar1, Lily Alexander1, H. Ross Anderson2, Victoria F Bachman1 +718 more•Institutions (295)
TL;DR: The Global Burden of Disease, Injuries, and Risk Factor study 2013 (GBD 2013) as mentioned in this paper provides a timely opportunity to update the comparative risk assessment with new data for exposure, relative risks, and evidence on the appropriate counterfactual risk distribution.
1,656 citations
University of California, Los Angeles1, Vanderbilt University2, University of Zurich3, University of Duisburg-Essen4, University of Paris-Sud5, Harvard University6, Sheba Medical Center7, New York University8, University of Colorado Denver9, University of Arizona10, Netherlands Cancer Institute11, Durham University12, Seattle Cancer Care Alliance13, University of Tübingen14, University of Pennsylvania15, Temple University16, University of North Carolina at Chapel Hill17, University of Pittsburgh18, Memorial Sloan Kettering Cancer Center19, Merck & Co.20, University of California, San Francisco21
TL;DR: In this article, the efficacy and safety of two pembrolizumab doses versus investigator-choice chemotherapy in patients with ipilimumab-refractory melanoma were compared.
Abstract: Summary Background Patients with melanoma that progresses on ipilimumab and, if BRAF V600 mutant-positive, a BRAF or MEK inhibitor or both, have few treatment options. We assessed the efficacy and safety of two pembrolizumab doses versus investigator-choice chemotherapy in patients with ipilimumab-refractory melanoma. Methods We carried out a randomised phase 2 trial of patients aged 18 years or older from 73 hospitals, clinics, and academic medical centres in 12 countries who had confirmed progressive disease within 24 weeks after two or more ipilimumab doses and, if BRAF V600 mutant-positive, previous treatment with a BRAF or MEK inhibitor or both. Patients had to have resolution of all ipilimumab-related adverse events to grade 0–1 and prednisone 10 mg/day or less for at least 2 weeks, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and at least one measurable lesion to be eligible. Using a centralised interactive voice response system, we randomly assigned (1:1:1) patients in a block size of six to receive intravenous pembrolizumab 2 mg/kg or 10 mg/kg every 3 weeks or investigator-choice chemotherapy (paclitaxel plus carboplatin, paclitaxel, carboplatin, dacarbazine, or oral temozolomide). Randomisation was stratified by ECOG performance status, lactate dehydrogenase concentration, and BRAF V600 mutation status. Individual treatment assignment between pembrolizumab and chemotherapy was open label, but investigators and patients were masked to assignment of the dose of pembrolizumab. We present the primary endpoint at the prespecified second interim analysis of progression-free survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01704287. The study is closed to enrolment but continues to follow up and treat patients. Findings Between Nov 30, 2012, and Nov 13, 2013, we enrolled 540 patients: 180 patients were randomly assigned to receive pembrolizumab 2 mg/kg, 181 to receive pembrolizumab 10 mg/kg, and 179 to receive chemotherapy. Based on 410 progression-free survival events, progression-free survival was improved in patients assigned to pembrolizumab 2 mg/kg (HR 0·57, 95% CI 0·45–0·73; p Interpretation These findings establish pembrolizumab as a new standard of care for the treatment of ipilimumab-refractory melanoma. Funding Merck Sharp & Dohme.
1,333 citations
Stanford University1, University of Zurich2, Freeman Hospital3, Duke University4, University of Toronto5, Columbia University6, University of Washington7, Washington University in St. Louis8, Alfred Hospital9, Katholieke Universiteit Leuven10, University of Colorado Denver11, St. Vincent's Health System12
TL;DR: Recommendations include discussions not present in previous ISHLT guidelines, including lung allocation scores, bridging to transplant with mechanical circulatory and ventilator support, and expanded indications for lung transplantation.
Abstract: The appropriate selection of lung transplant recipients is an important determinant of outcomes. This consensus document is an update of the recipient selection guidelines published in 2006. The Pulmonary Council of the International Society for Heart and Lung Transplantation (ISHLT) organized a Writing Committee of international experts to provide consensus opinion regarding the appropriate timing of referral and listing of candidates for lung transplantation. A comprehensive search of the medical literature was conducted with the assistance of a medical librarian. Writing Committee members were assigned specific topics to research and discuss. The Chairs of the Writing Committee were responsible for evaluating the completeness of the literature search, providing editorial support for the manuscript, and organizing group discussions regarding its content. The consensus document makes specific recommendations regarding the timing of referral and of listing for lung transplantation. These recommendations include discussions not present in previous ISHLT guidelines, including lung allocation scores, bridging to transplant with mechanical circulatory and ventilator support, and expanded indications for lung transplantation. In the absence of high-grade evidence to support decision making, these consensus guidelines remain part of a continuum of expert opinion based on available studies and personal experience. Some positions are immutable. Although transplant is rightly a treatment of last resort for end-stage lung disease, early referral allows proper evaluation and thorough patient education. Subsequent waiting list activation implies a tacit agreement that transplant offers a significant individual survival advantage. It is both the challenge and the responsibility of the transplant community globally to ensure organ allocation maximizes the potential benefits of a scarce resource, thereby achieving that advantage.
1,063 citations
University of California, San Francisco1, Harvard University2, University of Paris-Sud3, Université de Montréal4, Radboud University Nijmegen5, Charité6, University of Texas MD Anderson Cancer Center7, Hebron University8, University of Colorado Denver9, Fred Hutchinson Cancer Research Center10, University of Western Sydney11, Institute of Cancer Research12, Janssen Pharmaceutica13, Memorial Sloan Kettering Cancer Center14
TL;DR: Treatment with abiraterone acetate prolonged overall survival compared with prednisone alone by a margin that was both clinically and statistically significant, and further support the favourable safety profile of abiraton acetate in patients with chemotherapy-naive metastatic castration-resistant prostate cancer.
Abstract: Summary Background Abiraterone acetate plus prednisone significantly improved radiographic progression-free survival compared with placebo plus prednisone in men with chemotherapy-naive castration-resistant prostate cancer at the interim analyses of the COU-AA-302 trial. Here, we present the prespecified final analysis of the trial, assessing the effect of abiraterone acetate plus prednisone on overall survival, time to opiate use, and use of other subsequent therapies. Methods In this placebo-controlled, double-blind, randomised phase 3 study, 1088 asymptomatic or mildly symptomatic patients with chemotherapy-naive prostate cancer stratified by Eastern Cooperative Oncology performance status (0 vs 1) were randomly assigned with a permuted block allocation scheme via a web response system in a 1:1 ratio to receive either abiraterone acetate (1000 mg once daily) plus prednisone (5 mg twice daily; abiraterone acetate group) or placebo plus prednisone (placebo group). Coprimary endpoints were radiographic progression-free survival and overall survival analysed in the intention-to-treat population. The study is registered with ClinicalTrials.gov, number NCT00887198. Findings At a median follow-up of 49·2 months (IQR 47·0–51·8), 741 (96%) of the prespecified 773 death events for the final analysis had been observed: 354 (65%) of 546 patients in the abiraterone acetate group and 387 (71%) of 542 in the placebo group. 238 (44%) patients initially receiving prednisone alone subsequently received abiraterone acetate plus prednisone as crossover per protocol (93 patients) or as subsequent therapy (145 patients). Overall, 365 (67%) patients in the abiraterone acetate group and 435 (80%) in the placebo group received subsequent treatment with one or more approved agents. Median overall survival was significantly longer in the abiraterone acetate group than in the placebo group (34·7 months [95% CI 32·7–36·8] vs 30·3 months [28·7–33·3]; hazard ratio 0·81 [95% CI 0·70–0·93]; p=0·0033). The most common grade 3–4 adverse events of special interest were cardiac disorders (41 [8%] of 542 patients in the abiraterone acetate group vs 20 [4%] of 540 patients in the placebo group), increased alanine aminotransferase (32 [6%] vs four [ vs 17 [3%]). Interpretation In this randomised phase 3 trial with a median follow-up of more than 4 years, treatment with abiraterone acetate prolonged overall survival compared with prednisone alone by a margin that was both clinically and statistically significant. These results further support the favourable safety profile of abiraterone acetate in patients with chemotherapy-naive metastatic castration-resistant prostate cancer. Funding Janssen Research & Development.
1,041 citations
TL;DR: In extensively phenotyped cohorts, insights from sequencing whole genomes or exomes of nearly 10,000 individuals from population-based and disease collections are described and population structure and functional annotation of rare and low-frequency variants are described.
Abstract: The contribution of rare and low-frequency variants to human traits is largely unexplored. Here we describe insights from sequencing whole genomes (low read depth, 7×) or exomes (high read depth, 80×) of nearly 10,000 individuals from population-based and disease collections. In extensively phenotyped cohorts we characterize over 24 million novel sequence variants, generate a highly accurate imputation reference panel and identify novel alleles associated with levels of triglycerides (APOB), adiponectin (ADIPOQ) and low-density lipoprotein cholesterol (LDLR and RGAG1) from single-marker and rare variant aggregation tests. We describe population structure and functional annotation of rare and low-frequency variants, use the data to estimate the benefits of sequencing for association studies, and summarize lessons from disease-specific collections. Finally, we make available an extensive resource, including individual-level genetic and phenotypic data and web-based tools to facilitate the exploration of association results.
Institut Gustave Roussy1, French Institute of Health and Medical Research2, University of Pennsylvania3, University of Massachusetts Medical School4, University of Rome Tor Vergata5, University of California, San Francisco6, Virginia Commonwealth University7, Merck & Co.8, Harvard University9, University of South Australia10, University of Texas Southwestern Medical Center11, Trinity College, Dublin12, Austrian Academy of Sciences13, University of Cambridge14, University of Bern15, University of Oslo16, University of Colorado Denver17, Complutense University of Madrid18
TL;DR: The differential impact of autophagy on distinct phases of tumorigenesis is discussed and the implications of this concept for the use of Autophagy modulators in cancer therapy are discussed.
Abstract: Autophagy plays a key role in the maintenance of cellular homeostasis. In healthy cells, such a homeostatic activity constitutes a robust barrier against malignant transformation. Accordingly, many oncoproteins inhibit, and several oncosuppressor proteins promote, autophagy. Moreover, autophagy is required for optimal anticancer immunosurveillance. In neoplastic cells, however, autophagic responses constitute a means to cope with intracellular and environmental stress, thus favoring tumor progression. This implies that at least in some cases, oncogenesis proceeds along with a temporary inhibition of autophagy or a gain of molecular functions that antagonize its oncosuppressive activity. Here, we discuss the differential impact of autophagy on distinct phases of tumorigenesis and the implications of this concept for the use of autophagy modulators in cancer therapy.
German Cancer Research Center1, Boston Children's Hospital2, University of Texas MD Anderson Cancer Center3, St. Jude Children's Research Hospital4, University of Toronto5, Max Planck Society6, Heidelberg University7, University of Utah8, Tel Aviv University9, University of Colorado Denver10, University of Bern11, Masaryk University12, University of Texas Health Science Center at San Antonio13, University of California, San Francisco14, New York University15, University of Cambridge16, University of Hamburg17, University of Bonn18
TL;DR: The molecular classification proposed herein outperforms the current histopathological classification and thus might serve as a basis for the next World Health Organization classification of CNS tumors.
TL;DR: A sound platform has been provided from which to launch the requisite future research investigations of a more uniform cohort, and nomenclature and classification criteria for patients with IIP and autoimmune features are provided.
Abstract: Many patients with an idiopathic interstitial pneumonia (IIP) have clinical features that suggest an underlying autoimmune process but do not meet established criteria for a connective tissue disease (CTD). Researchers have proposed differing criteria and terms to describe these patients, and lack of consensus over nomenclature and classification limits the ability to conduct prospective studies of a uniform cohort.
The “European Respiratory Society/American Thoracic Society Task Force on Undifferentiated Forms of Connective Tissue Disease-associated Interstitial Lung Disease” was formed to create consensus regarding the nomenclature and classification criteria for patients with IIP and features of autoimmunity.
The task force proposes the term “interstitial pneumonia with autoimmune features” (IPAF) and offers classification criteria organised around the presence of a combination of features from three domains: a clinical domain consisting of specific extra-thoracic features, a serologic domain consisting of specific autoantibodies, and a morphologic domain consisting of specific chest imaging, histopathologic or pulmonary physiologic features.
A designation of IPAF should be used to identify individuals with IIP and features suggestive of, but not definitive for, a CTD. With IPAF, a sound platform has been provided from which to launch the requisite future research investigations of a more uniform cohort.
ERS/ATS task force provides nomenclature and classification criteria for patients with IIP and autoimmune features
TL;DR: The relationship between diabetes and CVD is summarized, possible mechanisms of disease progression are examined, current treatment recommendations are discussed, and future research directions are outlined.
Abstract: The incidence of diabetes mellitus (DM) continues to rise and has quickly become one of the most prevalent and costly chronic diseases worldwide. A close link exists between DM and cardiovascular disease (CVD), which is the most prevalent cause of morbidity and mortality in diabetic patients. Cardiovascular (CV) risk factors such as obesity, hypertension and dyslipidemia are common in patients with DM, placing them at increased risk for cardiac events. In addition, many studies have found biological mechanisms associated with DM that independently increase the risk of CVD in diabetic patients. Therefore, targeting CV risk factors in patients with DM is critical to minimize the long-term CV complications of the disease. This paper summarizes the relationship between diabetes and CVD, examines possible mechanisms of disease progression, discusses current treatment recommendations, and outlines future research directions.
University of Southern Denmark1, Brigham and Women's Hospital2, University of Barcelona3, Autonomous University of Madrid4, University of Arizona5, University of Colorado Denver6, Manchester Academic Health Science Centre7, Autonomous University of Chile8, Harvard University9, Lovelace Respiratory Research Institute10, University of New Mexico11
TL;DR: It is suggested that low FEV1 in early adulthood is important in the genesis of COPD and that accelerated decline inFEV1 is not an obligate feature of COPd.
Abstract: BackgroundChronic obstructive pulmonary disease (COPD) is thought to result from an accelerated decline in forced expiratory volume in 1 second (FEV1) over time. Yet it is possible that a normal decline in FEV1 could also lead to COPD in persons whose maximally attained FEV1 is less than population norms. MethodsWe stratified participants in three independent cohorts (the Framingham Offspring Cohort, the Copenhagen City Heart Study, and the Lovelace Smokers Cohort) according to lung function (FEV1 ≥80% or <80% of the predicted value) at cohort inception (mean age of patients, approximately 40 years) and the presence or absence of COPD at the last study visit. We then determined the rate of decline in FEV1 over time among the participants according to their FEV1 at cohort inception and COPD status at study end. ResultsAmong 657 persons who had an FEV1 of less than 80% of the predicted value before 40 years of age, 174 (26%) had COPD after 22 years of observation, whereas among 2207 persons who had a baseli...
Emory University1, DePaul University2, University of Miami3, Baylor College of Medicine4, Pennsylvania State University5, University of California, Irvine6, Duke University7, University of Colorado Denver8, Medical University of South Carolina9, University of Oklahoma10, University of Texas Southwestern Medical Center11, University of Illinois at Chicago12, Tulane University13, University of California, San Francisco14, Icahn School of Medicine at Mount Sinai15, Harvard University16, Virginia Commonwealth University17, University of Pennsylvania18, Rush University Medical Center19, Oregon Health & Science University20
TL;DR: This document represents a continuation of the National Lipid Association recommendations developed by a diverse panel of experts who examined the evidence base and provided recommendations regarding the following topics: lifestyle therapies and strategies to improve patient outcomes by increasing adherence and using team-based collaborative care.
University of Tennessee Health Science Center1, University of Colorado Denver2, University of Kiel3, University of Milan4, University of Manchester5, Harvard University6, University of Copenhagen7, University of Hamburg8, Ghent University9, National University of Singapore10, Mackay Memorial Hospital11
TL;DR: The information gained from collaborative studies has helped decipher the heterogeneity of ALL to help improve personalized treatment, which will further advance the current high cure rate and the quality of life for children and adolescents with ALL.
Abstract: Purpose To review the impact of collaborative studies on advances in the biology and treatment of acute lymphoblastic leukemia (ALL) in children and adolescents. Methods A review of English literature on childhood ALL focusing on collaborative studies was performed. The resulting article was reviewed and revised by the committee chairs of the major ALL study groups. Results With long-term survival rates for ALL approaching 90% and the advent of high-resolution genome-wide analyses, several international study groups or consortia were established to conduct collaborative research to further improve outcome. As a result, treatment strategies have been improved for several subtypes of ALL, such as infant, MLL-rearranged, Philadelphia chromosome–positive, and Philadelphia chromosome–like ALL. Many recurrent genetic abnormalities that respond to tyrosine kinase inhibitors and multiple genetic determinants of drug resistance and toxicities have been identified to help develop targeted therapy. Several genetic p...
Primary Children's Hospital1, University of Colorado Denver2, Northwestern University3, Georgetown University4, University of Washington5, Columbia University6, University of North Carolina at Chapel Hill7, University of California, San Francisco8, Baylor University Medical Center9, Mayo Clinic10, University of California, San Diego11, University of Miami12, Johns Hopkins University13, University of Kansas14, Henry Ford Health System15, Indiana University16, Washington University in St. Louis17, Duke University18, New York University19, University of Michigan20, University of Pennsylvania21, Harvard University22
TL;DR: The combination of ledipasvir, sofosbuvir, and ribavirin for 12 weeks produced high rates of SVR12 in patients with advanced liver disease, including those with decompensated cirrhosis before and after liver transplantation.
Abstract: Background & Aims There are no effective and safe treatments for chronic hepatitis C virus (HCV) infection of patients who have advanced liver disease. Methods In this phase 2, open-label study, we assessed treatment with the NS5A inhibitor ledipasvir, the nucleotide polymerase inhibitor sofosbuvir, and ribavirin in patients infected with HCV genotypes 1 or 4. Cohort A enrolled patients with cirrhosis and moderate or severe hepatic impairment who had not undergone liver transplantation. Cohort B enrolled patients who had undergone liver transplantation: those without cirrhosis; those with cirrhosis and mild, moderate, or severe hepatic impairment; and those with fibrosing cholestatic hepatitis. Patients were assigned randomly (1:1) to receive 12 or 24 weeks of a fixed-dose combination tablet containing ledipasvir and sofosbuvir, once daily, plus ribavirin. The primary end point was sustained virologic response at 12 weeks after the end of treatment (SVR12). Results We enrolled 337 patients, 332 (99%) with HCV genotype 1 infection and 5 (1%) with HCV genotype 4 infection. In cohort A (nontransplant), SVR12 was achieved by 86%–89% of patients. In cohort B (transplant recipients), SVR12 was achieved by 96%–98% of patients without cirrhosis or with compensated cirrhosis, by 85%−88% of patients with moderate hepatic impairment, by 60%–75% of patients with severe hepatic impairment, and by all 6 patients with fibrosing cholestatic hepatitis. Response rates in the 12- and 24-week groups were similar. Thirteen patients (4%) discontinued the ledipasvir and sofosbuvir combination prematurely because of adverse events; 10 patients died, mainly from complications related to hepatic decompensation. Conclusion The combination of ledipasvir, sofosbuvir, and ribavirin for 12 weeks produced high rates of SVR12 in patients with advanced liver disease, including those with decompensated cirrhosis before and after liver transplantation. ClinTrials.gov: NCT01938430.
Primary Children's Hospital1, University of Colorado Denver2, Northwestern University3, Georgetown University4, University of Washington5, Columbia University6, University of North Carolina at Chapel Hill7, University of California, San Francisco8, Baylor University Medical Center9, Mayo Clinic10, University of California, San Diego11, University of Miami12, Johns Hopkins University13, University of Kansas14, Henry Ford Health System15, Indiana University16, Washington University in St. Louis17, Duke University18, New York University19, University of Michigan20, University of Pennsylvania21, Harvard University22
TL;DR: In this article, the NS5A inhibitor ledipasvir, the nucleotide polymerase inhibitor sofosbuvir, and ribavirin were used to treat chronic hepatitis C virus (HCV) infection in patients with advanced liver disease.
Harvard University1, Niigata University2, University of California, San Francisco3, Duke University4, University of Bonn5, Heidelberg University6, University of Texas MD Anderson Cancer Center7, University of Colorado Denver8, Queen's University9, University of Groningen10, Henry Ford Health System11, University of California, Irvine12, University of Western Ontario13, Stanford University14, University of Maryland, Baltimore15, University of Virginia16, University of Turin17, Cleveland Clinic18, Erasmus University Rotterdam19
TL;DR: Recommendations for standard response and progression criteria for the assessment of brain metastases in clinical trials are presented and hopefully facilitate the development of novel approaches to this difficult problem by providing more uniformity.
Abstract: CNS metastases are the most common cause of malignant brain tumours in adults. Historically, patients with brain metastases have been excluded from most clinical trials, but their inclusion is now becoming more common. The medical literature is difficult to interpret because of substantial variation in the response and progression criteria used across clinical trials. The Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) working group is an international, multidisciplinary effort to develop standard response and progression criteria for use in clinical trials of treatment for brain metastases. Previous efforts have focused on aspects of trial design, such as patient population, variations in existing response and progression criteria, and challenges when incorporating neurological, neuro-cognitive, and quality-of-life endpoints into trials of patients with brain metastases. Here, we present our recommendations for standard response and progression criteria for the assessment of brain metastases in clinical trials. The proposed criteria will hopefully facilitate the development of novel approaches to this difficult problem by providing more uniformity in the assessment of CNS metastases across trials.
TL;DR: It is indicated that risk variants for psychiatric disorders aggregate in particular biological pathways and that these pathways are frequently shared between disorders.
Abstract: Genome-wide association studies (GWAS) of psychiatric disorders have identified multiple genetic associations with such disorders, but better methods are needed to derive the underlying biological mechanisms that these signals indicate. We sought to identify biological pathways in GWAS data from over 60,000 participants from the Psychiatric Genomics Consortium. We developed an analysis framework to rank pathways that requires only summary statistics. We combined this score across disorders to find common pathways across three adult psychiatric disorders: schizophrenia, major depression and bipolar disorder. Histone methylation processes showed the strongest association, and we also found statistically significant evidence for associations with multiple immune and neuronal signaling pathways and with the postsynaptic density. Our study indicates that risk variants for psychiatric disorders aggregate in particular biological pathways and that these pathways are frequently shared between disorders. Our results confirm known mechanisms and suggest several novel insights into the etiology of psychiatric disorders.
TL;DR: The purpose of this paper is to discuss the ways that the goal of the study, the research objective, and the research purpose shape the formation of research questions, and to provide a framework for linking research questions to mixed methods data analysis techniques.
Abstract: The purpose of this paper is to discuss the development of research questions in mixed methods studies. First, we discuss the ways that the goal of the study, the research objective(s), and the research purpose shape the formation of research questions. Second, we compare and contrast quantitative research questions and qualitative research questions. Third, we describe how to write mixed methods research questions, which we define as questions that embed quantitative and qualitative research questions. Finally, we provide a framework for linking research questions to mixed methods data analysis techniques. A major goal of our framework is to illustrate that the development of research questions and data analysis procedures in mixed method studies should occur logically and sequentially. Key Words: Mixed Methods, Quantitative Research Questions, Qualitative Research Questions, and Mixed Methods Data Analysis Setting the Scene Conducting mixed methods research involves collecting, analyzing, and interpreting quantitative and qualitative data in a single study or in a series of studies that investigate the same underlying phenomenon. As noted by Johnson and Onwuegbuzie (2004, p. 17), "its logic of inquiry includes the use of induction (or discovery of patterns), deduction (testing of theories and hypotheses), and abduction (uncovering and relying on the best of a set of explanations for understanding one's results)." Because of its logical and intuitive appeal, providing a bridge between the qualitative and quantitative paradigms, an increasing number of researchers are utilizing mixed methods research to undertake their studies. As conceptualized by Collins, Onwuegbuzie, and Sutton (2006), mixed methods research can be conceptualized as comprising the following 13 distinct steps: 1. determining the goal of the study 2. formulating the research objective(s), 3. determining the research/mixing rationale, 4. determining the research/mixing purpose, 5. determining the research question(s), 6. selecting the sampling design 7. selecting the mixed methods research design, 8. collecting the data, 9. analyzing the data, 10. validating/legitimating the data, 11. interpreting the data, 12. writing the mixed methods research report, and 13. reformulating the research question(s). This process is illustrated in Figure 1. [FIGURE 1 OMITTED] The Importance of Questions Determining the research question(s) is an extremely important step in both the quantitative research process and the qualitative research process because these questions narrow the research objective and research purpose to specific questions that researchers attempt to address in their studies (Creswell, 2005; Johnson & Christensen, 2004). However, research questions are even more important in mixed methods research because mixed methods researchers make use of the pragmatic method and system of philosophy. As such, in mixed methods studies, research questions drive the methods used (Newman & Benz, 1998; Tashakkori & Teddlie, 1998). Moreover, research questions in mixed methods studies are vitally important because they, in large part, dictate the type of research design used, the sample size and sampling scheme employed, and the type of instruments administered as well as the data analysis techniques (i.e., statistical or qualitative) used. Unfortunately, forming research questions is much more difficult in mixed methods studies than in monomethod (i.e., quantitative or qualitative) investigations because it involves the formation of both quantitative and qualitative research questions within the same inquiry. Thus, it is surprising that an extensive review of the literature revealed no guidance as to how to write research questions specifically in mixed methods studies. …
Icahn School of Medicine at Mount Sinai1, University of Connecticut2, Baylor University Medical Center3, Northwestern University4, Autonomous University of Barcelona5, University of Colorado Denver6, Medical University of Vienna7, Harvard University8, University of Paris9, Kaiser Permanente10, Dalhousie University11, Paul Sabatier University12, Centre Hospitalier Universitaire de Nice13, University of Texas Health Science Center at Houston14, University of Rome Tor Vergata15, University of Utah16, University of California, San Francisco17, Amgen18
TL;DR: Bdalumab treatment resulted in significant clinical improvements in patients with moderate-to-severe psoriasis, and was found to be superior to placebo at week 12 with respect to a 100% reduction in PASI score (PASI 100).
Abstract: BackgroundEarly clinical studies suggested that the anti–interleukin-17 receptor A monoclonal antibody brodalumab has efficacy in the treatment of psoriasis. MethodsIn two phase 3 studies (AMAGINE-2 and AMAGINE-3), patients with moderate-to-severe psoriasis were randomly assigned to receive brodalumab (210 mg or 140 mg every 2 weeks), ustekinumab (45 mg for patients with a body weight ≤100 kg and 90 mg for patients >100 kg), or placebo. At week 12, patients receiving brodalumab were randomly assigned again to receive a brodalumab maintenance dose of 210 mg every 2 weeks or 140 mg every 2 weeks, every 4 weeks, or every 8 weeks; patients receiving ustekinumab continued to receive ustekinumab every 12 weeks, and patients receiving placebo received 210 mg of brodalumab every 2 weeks. The primary aims were to evaluate the superiority of brodalumab over placebo at week 12 with respect to at least a 75% reduction in the psoriasis area-and-severity index score (PASI 75) and a static physician’s global assessment ...
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TL;DR: Two recent studies published in JAMA involved the analysis of observational data to estimate the effect of a treatment on patient outcomes, and the technique of propensity score stratification was used.
Abstract: Two recent studies published in JAMA involved the analysis of observational data to estimate the effect of a treatment on patient outcomes. In the study by Roze et al,1 a large observational data set was analyzed to estimate the relationship between early echocardiography screening for patent ductus arteriosus and mortality among preterm infants. The authors compared mortality rates of 847 infants who were screened for patent ductus arteriosus and 666 who were not. The 2 infant groups were dissimilar; infants who were screened were younger, more likely female, and less likely to have received corticosteroids. The authors used propensity score matching to create 605 matched infant pairs from the original cohort to adjust for these differences. In the study by Huybrechts et al,2 the Medicaid Analytic eXtract data set was analyzed to estimate the association between antidepressant use during pregnancy and persistent pulmonary hypertension of the newborn. The authors included 3 789 330 women, of which 128 950 had used antidepressants. Women who used antidepressants were different from those who had not, with differences in age, race/ethnicity, chronic illnesses, obesity, tobacco use, and health care use. The authors adjusted for these differences using, in part, the technique of propensity score stratification.
TL;DR: Molecular immigration from the oral cavity appears to be the significant source of the lung microbiome during health, but unlike the stomach, the lungs exhibit evidence of selective elimination of Prevotella bacteria derived from the upper airways.
Abstract: No studies have examined the relationships between bacterial communities along sites of the upper aerodigestive tract of an individual subject. Our objective was to perform an intrasubject and intersite analysis to determine the contributions of two upper mucosal sites (mouth and nose) as source communities for the bacterial microbiome of lower sites (lungs and stom- ach). Oral wash, bronchoalveolar lavage (BAL)fluid, nasal swab, and gastric aspirate samples were collected from 28 healthy subjects. Extensive analysis of controls and serial intrasubject BALfluid samples demonstrated that sampling of the lungs by bronchoscopy was not confounded by oral microbiome contamination. By quantitative PCR, the oral cavity and stomach con- tained the highest bacterial signal levels and the nasal cavity and lungs contained much lower levels. Pyrosequencing of 16S rRNA gene amplicon libraries generated from these samples showed that the oral and gastric compartments had the greatest species richness, which was significantly greater in both than the richness measured in the lungs and nasal cavity. The bacterial communities of the lungs were significantly different from those of the mouth, nose, and stomach, while the greatest similarity was between the oral and gastric communities. However, the bacterial communities of healthy lungs shared significant member- ship with the mouth, but not the nose, and marked subject-subject variation was noted. In summary, microbial immigration from the oral cavity appears to be the significant source of the lung microbiome during health, but unlike the stomach, the lungs exhibit evidence of selective elimination of Prevotellabacteria derived from the upper airways. IMPORTANCE We have demonstrated that the bacterial communities of the healthy lung overlapped those found in the mouth but were found at lower concentrations, with lower membership and a different community composition. The nasal microbiome, which was distinct from the oral microbiome, appeared to contribute little to the composition of the lung microbiome in healthy subjects. Our studies of the nasal, oral, lung, and stomach microbiomes within an individual illustrate the microbiological conti- nuity of the aerodigestive tract in healthy adults and provide culture-independent microbiological support for the concept that microaspiration is common in healthy individuals.
TL;DR: Crizotinib was associated with systemic and intracranial disease control in patients with ALK-rearranged NSCLC who were ALK inhibitor naive and had brain metastases, however, progression of preexisting or development of new intrac Cranial lesions while receiving therapy was a common manifestation of acquired resistance to crizotin ib.
Abstract: Purpose Crizotinib is an oral kinase inhibitor approved for the treatment of ALK-rearranged non–small-cell lung cancer (NSCLC). The clinical benefits of crizotinib in patients with brain metastases have not been previously studied. Patients and Methods Patients with advanced ALK-rearranged NSCLC enrolled onto clinical trial PROFILE 1005 or 1007 (randomly assigned to crizotinib) were included in this retrospective analysis. Patients with asymptomatic brain metastases (nontarget or target lesions) were allowed to enroll. Tumor assessments were evaluated every 6 weeks using RECIST (version 1.1). Results At baseline, 31% of patients (275 of 888) had asymptomatic brain metastases; 109 had received no prior and 166 had received prior brain radiotherapy as treatment. Among patients with previously untreated asymptomatic brain metastases, the systemic disease control rate (DCR) at 12 weeks was 63% (95% CI, 54% to 72%), the intracranial DCR was 56% (95% CI, 46% to 66%), and the median intracranial time to progress...
University of Alabama at Birmingham1, University of Texas Southwestern Medical Center2, Carolinas Medical Center3, Johns Hopkins University4, University of Pittsburgh5, University of California, Irvine6, University of Washington7, University of South Alabama8, University of Arkansas for Medical Sciences9, University of Colorado Denver10, University of Rochester11, Medical University of South Carolina12, University of South Florida13, Washington University in St. Louis14, George Washington University15, University of Minnesota16, University of Mississippi17, State University of New York Upstate Medical University18, Louisiana State University19, Brown University20, Bristol Royal Hospital for Children21, University College London22, Stanford University23, Vanderbilt University24, University of Southern California25, Emory University26, St George’s University Hospitals NHS Foundation Trust27, University of Nebraska Medical Center28, University of Louisville29
TL;DR: Treating symptomatic congenital CMV disease with valganciclovir for 6 months, as compared with 6 weeks, did not improve hearing in the short term but appeared to improve hearing and developmental outcomes modestly in the longer term.
Abstract: BackgroundThe treatment of symptomatic congenital cytomegalovirus (CMV) disease with intravenous ganciclovir for 6 weeks has been shown to improve audiologic outcomes at 6 months, but the benefits wane over time. MethodsWe conducted a randomized, placebo-controlled trial of valganciclovir therapy in neonates with symptomatic congenital CMV disease, comparing 6 months of therapy with 6 weeks of therapy. The primary end point was the change in hearing in the better ear (“best-ear” hearing) from baseline to 6 months. Secondary end points included the change in hearing from baseline to follow-up at 12 and 24 months and neurodevelopmental outcomes, with each end point adjusted for central nervous system involvement at baseline. ResultsA total of 96 neonates underwent randomization, of whom 86 had follow-up data at 6 months that could be evaluated. Best-ear hearing at 6 months was similar in the 6-month group and the 6-week group (2 and 3 participants, respectively, had improvement; 36 and 37 had no change; and...
TL;DR: Renal regulation of these ions occurs through glomerular filtration and tubular re absorption and/or secretion and is therefore an important determinant of plasma ion concentration.
Abstract: Calcium, phosphate, and magnesium are multivalent cations that are important for many biologic and cellular functions. The kidneys play a central role in the homeostasis of these ions. Gastrointestinal absorption is balanced by renal excretion. When body stores of these ions decline significantly, gastrointestinal absorption, bone resorption, and renal tubular reabsorption increase to normalize their levels. Renal regulation of these ions occurs through glomerular filtration and tubular reabsorption and/or secretion and is therefore an important determinant of plasma ion concentration. Under physiologic conditions, the whole body balance of calcium, phosphate, and magnesium is maintained by fine adjustments of urinary excretion to equal the net intake. This review discusses how calcium, phosphate, and magnesium are handled by the kidneys.
TL;DR: The reasons the HRRP was implemented, the penalties levied, the impact it has had on transitional care and readmissions, the pros and cons of the policy, and its future are described.
Abstract: Hospital readmission measures have been touted not only as a quality measure but also as a means to bend the healthcare cost curve. The Affordable Care Act (ACA) established the Hospital Readmission Reduction Program (HRRP) in 2012. Under this program, hospitals are financially penalized if they have higher-than-expected risk-standardized 30-day readmission rates for acute myocardial infarction, heart failure, and pneumonia. The HRRP has garnered significant attention from the medical community, both positive and negative. Here, we describe the reasons the HRRP was implemented, the penalties levied, the impact it has had on transitional care and readmissions, the pros and cons of the policy, and its future.
Hospital readmissions are associated with unfavorable patient outcomes and high financial costs.1,2 Causes of readmissions are multifactorial, and rates vary substantially by institution.3,4 Historically, nearly 20% of all Medicare discharges had a readmission within 30 days.1 The Medicare Payment Advisory Commission has estimated that 12% of readmissions are potentially avoidable. Preventing even 10% of these readmissions could save Medicare $1 billion.5 Therefore, reducing hospital readmissions has been made a national priority. In 2008, the Medicare Payment Advisory Commission recommended to Congress that the Centers for Medicare & Medicaid Services (CMS) begin confidentially reporting readmission rates and resource use to hospitals and physicians.6 In 2009, CMS began publicly reporting hospital-level readmission rates, which were added to the Hospital Compare Web site.7
Before 2012, hospitals had little direct financial incentive to reduce readmissions. For Medicare beneficiaries with inpatient stays, hospitals receive payment with the inpatient prospective payment system (IPPS). This payment, based on a diagnosis-related group (DRG), covers the inpatient stay and any outpatient diagnostic and admission-related outpatient nondiagnostic services provided by the institution on the date of the patient’s admission or within 3 days immediately …