Showing papers by "University of Pennsylvania published in 2012"
TL;DR: The Global Burden of Diseases, Injuries, and Risk Factors Study 2010 aimed to estimate annual deaths for the world and 21 regions between 1980 and 2010 for 235 causes, with uncertainty intervals (UIs), separately by age and sex, using the Cause of Death Ensemble model.
11,809 citations
TL;DR: In this article, a search for the Standard Model Higgs boson in proton-proton collisions with the ATLAS detector at the LHC is presented, which has a significance of 5.9 standard deviations, corresponding to a background fluctuation probability of 1.7×10−9.
9,282 citations
TL;DR: The Human Microbiome Project Consortium reported the first results of their analysis of microbial communities from distinct, clinically relevant body habitats in a human cohort; the insights into the microbial communities of a healthy population lay foundations for future exploration of the epidemiology, ecology and translational applications of the human microbiome as discussed by the authors.
Abstract: The Human Microbiome Project Consortium reports the first results of their analysis of microbial communities from distinct, clinically relevant body habitats in a human cohort; the insights into the microbial communities of a healthy population lay foundations for future exploration of the epidemiology, ecology and translational applications of the human microbiome.
8,410 citations
TL;DR: Prevalence and severity of health loss were weakly correlated and age-specific prevalence of YLDs increased with age in all regions and has decreased slightly from 1990 to 2010, but population growth and ageing have increased YLD numbers and crude rates over the past two decades.
7,021 citations
TL;DR: The results for 1990 and 2010 supersede all previously published Global Burden of Disease results and highlight the importance of understanding local burden of disease and setting goals and targets for the post-2015 agenda taking such patterns into account.
6,861 citations
TL;DR: The need to consider the microbiome when evaluating human development, nutritional needs, physiological variations and the impact of westernization is underscored, as distinctive features of the functional maturation of the gut microbiome are evident in early infancy as well as adulthood.
Abstract: Gut microbial communities represent one source of human genetic and metabolic diversity. To examine how gut microbiomes differ among human populations, here we characterize bacterial species in fecal samples from 531 individuals, plus the gene content of 110 of them. The cohort encompassed healthy children and adults from the Amazonas of Venezuela, rural Malawi and US metropolitan areas and included mono- and dizygotic twins. Shared features of the functional maturation of the gut microbiome were identified during the first three years of life in all three populations, including age-associated changes in the genes involved in vitamin biosynthesis and metabolism. Pronounced differences in bacterial assemblages and functional gene repertoires were noted between US residents and those in the other two countries. These distinctive features are evident in early infancy as well as adulthood. Our findings underscore the need to consider the microbiome when evaluating human development, nutritional needs, physiological variations and the impact of westernization.
6,047 citations
Tohoku University1, University of Zurich2, Lawrence Berkeley National Laboratory3, Stanford University4, College of William & Mary5, University of Genoa6, University of Urbino7, CERN8, Budker Institute of Nuclear Physics9, University of California, Irvine10, Cornell University11, Argonne National Laboratory12, ETH Zurich13, Tata Institute of Fundamental Research14, Hillsdale College15, Spanish National Research Council16, Ohio State University17, University of Notre Dame18, Kent State University19, University of California, San Diego20, University of California, Berkeley21, University of Minnesota22, University of Alabama23, University of Helsinki24, Los Alamos National Laboratory25, California Institute of Technology26, George Washington University27, Syracuse University28, Lawrence Livermore National Laboratory29, Oklahoma State University–Stillwater30, University of Washington31, Max Planck Society32, Boston University33, University of California, Los Angeles34, Royal Holloway, University of London35, Université Paris-Saclay36, Fermilab37, University of Pennsylvania38, University of Illinois at Urbana–Champaign39, University of Bristol40, University of Tokyo41, University of Delaware42, Carnegie Mellon University43, University of California, Santa Cruz44, Karlsruhe Institute of Technology45, Heidelberg University46, Florida State University47, Carleton University48, University of Mainz49, University of Edinburgh50, Brookhaven National Laboratory51, Durham University52, University of Lausanne53, Massachusetts Institute of Technology54, University of Southampton55, Nagoya University56, University of Oxford57, Northwestern University58, University of British Columbia59, Columbia University60, Lund University61, University of Sheffield62, University of California, Santa Barbara63, Iowa State University64, University of Alberta65, University of Cambridge66
TL;DR: The Particle Data Group's biennial review as mentioned in this paper summarizes much of particle physics, using data from previous editions, plus 2658 new measurements from 644 papers, and lists, evaluates, and average measured properties of gauge bosons, leptons, quarks, mesons, and baryons.
Abstract: This biennial Review summarizes much of particle physics. Using data from previous editions, plus 2658 new measurements from 644 papers, we list, evaluate, and average measured properties of gauge bosons, leptons, quarks, mesons, and baryons. We summarize searches for hypothetical particles such as Higgs bosons, heavy neutrinos, and supersymmetric particles. All the particle properties and search limits are listed in Summary Tables. We also give numerous tables, figures, formulae, and reviews of topics such as the Standard Model, particle detectors, probability, and statistics. Among the 112 reviews are many that are new or heavily revised including those on Heavy-Quark and Soft-Collinear Effective Theory, Neutrino Cross Section Measurements, Monte Carlo Event Generators, Lattice QCD, Heavy Quarkonium Spectroscopy, Top Quark, Dark Matter, V-cb & V-ub, Quantum Chromodynamics, High-Energy Collider Parameters, Astrophysical Constants, Cosmological Parameters, and Dark Matter. A booklet is available containing the Summary Tables and abbreviated versions of some of the other sections of this full Review. All tables, listings, and reviews (and errata) are also available on the Particle Data Group website: http://pdg.lbl.gov.
4,465 citations
Daniel J. Klionsky1, Fábio Camargo Abdalla2, Hagai Abeliovich3, Robert T. Abraham4 +1284 more•Institutions (463)
TL;DR: These guidelines are presented for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes.
Abstract: In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
4,316 citations
Wellcome Trust Sanger Institute1, Broad Institute2, University of Groningen3, University of Pittsburgh4, Cedars-Sinai Medical Center5, Yale University6, University of Cambridge7, University of Chicago8, Harvard University9, Katholieke Universiteit Leuven10, University of Liège11, King's College London12, Université de Montréal13, New Jersey Institute of Technology14, Cleveland Clinic15, Peninsula College of Medicine and Dentistry16, Université libre de Bruxelles17, Aarhus University18, University of Adelaide19, University of Kiel20, Flinders University21, McGill University22, Ludwig Maximilian University of Munich23, Charité24, Icahn School of Medicine at Mount Sinai25, University of Bonn26, Karolinska Institutet27, Torbay Hospital28, University of Auckland29, Christchurch Hospital30, Imperial College London31, Queen's University32, University of Oslo33, Lithuanian University of Health Sciences34, Emory University35, Casa Sollievo della Sofferenza36, Ghent University37, University of Western Australia38, University of Edinburgh39, Queensland Health40, Newcastle University41, University of Dundee42, University of Manchester43, University of Amsterdam44, University of Maribor45, Royal Hospital for Sick Children46, Guy's and St Thomas' NHS Foundation Trust47, QIMR Berghofer Medical Research Institute48, Norfolk and Norwich University Hospital49, Leiden University50, Technische Universität München51, University of Toronto52, University of Pennsylvania53, Johns Hopkins University54, University of Queensland55
TL;DR: A meta-analysis of Crohn’s disease and ulcerative colitis genome-wide association scans is undertaken, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls.
Abstract: Crohn's disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations. Genome-wide association studies and subsequent meta-analyses of these two diseases as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy, in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases. Here we expand on the knowledge of relevant pathways by undertaking a meta-analysis of Crohn's disease and ulcerative colitis genome-wide association scans, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci, that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional (consistently favouring one allele over the course of human history) and balancing (favouring the retention of both alleles within populations) selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe considerable overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.
4,094 citations
University of Florida1, Veterans Health Administration2, University of Chicago3, University of Minnesota4, University of Washington5, University of Pennsylvania6, Case Western Reserve University7, University of Arizona8, Harvard University9, University of Southern California10, American Academy of Sleep Medicine11
TL;DR: The task force made recommendations concerning recommended and alternative sensors for the detection of apnea and hypopnea to be used during diagnostic and positive airway pressure (PAP) titration polysomnography, and recommended scoring rules.
Abstract: The American Academy of Sleep Medicine (AASM) Sleep Apnea Definitions Task Force reviewed the current rules for scoring respiratory events in the 2007 AASM Manual for the Scoring and Sleep and Associated Events to determine if revision was indicated. The goals of the task force were (1) to clarify and simplify the current scoring rules, (2) to review evidence for new monitoring technologies relevant to the scoring rules, and (3) to strive for greater concordance between adult and pediatric rules. The task force reviewed the evidence cited by the AASM systematic review of the reliability and validity of scoring respiratory events published in 2007 and relevant studies that have appeared in the literature since that publication. Given the limitations of the published evidence, a consensus process was used to formulate the majority of the task force recommendations concerning revisions.The task force made recommendations concerning recommended and alternative sensors for the detection of apnea and hypopnea to be used during diagnostic and positive airway pressure (PAP) titration polysomnography. An alternative sensor is used if the recommended sensor fails or the signal is inaccurate. The PAP device flow signal is the recommended sensor for the detection of apnea, hypopnea, and respiratory effort related arousals (RERAs) during PAP titration studies. Appropriate filter settings for recording (display) of the nasal pressure signal to facilitate visualization of inspiratory flattening are also specified. The respiratory inductance plethysmography (RIP) signals to be used as alternative sensors for apnea and hypopnea detection are specified. The task force reached consensus on use of the same sensors for adult and pediatric patients except for the following: (1) the end-tidal PCO(2) signal can be used as an alternative sensor for apnea detection in children only, and (2) polyvinylidene fluoride (PVDF) belts can be used to monitor respiratory effort (thoracoabdominal belts) and as an alternative sensor for detection of apnea and hypopnea (PVDFsum) only in adults.The task force recommends the following changes to the 2007 respiratory scoring rules. Apnea in adults is scored when there is a drop in the peak signal excursion by ≥ 90% of pre-event baseline using an oronasal thermal sensor (diagnostic study), PAP device flow (titration study), or an alternative apnea sensor, for ≥ 10 seconds. Hypopnea in adults is scored when the peak signal excursions drop by ≥ 30% of pre-event baseline using nasal pressure (diagnostic study), PAP device flow (titration study), or an alternative sensor, for ≥ 10 seconds in association with either ≥ 3% arterial oxygen desaturation or an arousal. Scoring a hypopnea as either obstructive or central is now listed as optional, and the recommended scoring rules are presented. In children an apnea is scored when peak signal excursions drop by ≥ 90% of pre-event baseline using an oronasal thermal sensor (diagnostic study), PAP device flow (titration study), or an alternative sensor; and the event meets duration and respiratory effort criteria for an obstructive, mixed, or central apnea. A central apnea is scored in children when the event meets criteria for an apnea, there is an absence of inspiratory effort throughout the event, and at least one of the following is met: (1) the event is ≥ 20 seconds in duration, (2) the event is associated with an arousal or ≥ 3% oxygen desaturation, (3) (infants under 1 year of age only) the event is associated with a decrease in heart rate to less than 50 beats per minute for at least 5 seconds or less than 60 beats per minute for 15 seconds. A hypopnea is scored in children when the peak signal excursions drop is ≥ 30% of pre-event baseline using nasal pressure (diagnostic study), PAP device flow (titration study), or an alternative sensor, for ≥ the duration of 2 breaths in association with either ≥ 3% oxygen desaturation or an arousal. In children and adults, surrogates of the arterial PCO(2) are the end-tidal PCO(2) or transcutaneous PCO(2) (diagnostic study) or transcutaneous PCO(2) (titration study). For adults, sleep hypoventilation is scored when the arterial PCO(2) (or surrogate) is > 55 mm Hg for ≥ 10 minutes or there is an increase in the arterial PCO(2) (or surrogate) ≥ 10 mm Hg (in comparison to an awake supine value) to a value exceeding 50 mm Hg for ≥ 10 minutes. For pediatric patients hypoventilation is scored when the arterial PCO(2) (or surrogate) is > 50 mm Hg for > 25% of total sleep time. In adults Cheyne-Stokes breathing is scored when both of the following are met: (1) there are episodes of ≥ 3 consecutive central apneas and/or central hypopneas separated by a crescendo and decrescendo change in breathing amplitude with a cycle length of at least 40 seconds (typically 45 to 90 seconds), and (2) there are five or more central apneas and/or central hypopneas per hour associated with the crescendo/decrescendo breathing pattern recorded over a minimum of 2 hours of monitoring.
3,888 citations
Johns Hopkins University1, University of Alabama at Birmingham2, University of Birmingham3, Oklahoma Medical Research Foundation4, Laval University5, University of Manchester6, University College London7, University of California, Los Angeles8, Lund University9, Northwestern University10, Hanyang University11, Dalhousie University12, University of Toronto13, McGill University14, North Shore-LIJ Health System15, Allegheny General Hospital16, University of California, San Diego17, University of Pennsylvania18, Monklands Hospital19, University of the Basque Country20, St Thomas' Hospital21, University of Copenhagen22, New York University23, University of North Carolina at Chapel Hill24, Karolinska Institutet25, SUNY Downstate Medical Center26, University of Manitoba27, Wake Forest University28, University of Louisville29, Emory University30, Istanbul University31, Medical University of South Carolina32, University of Texas Health Science Center at San Antonio33, Cedars-Sinai Medical Center34, University of Maryland, Baltimore35
TL;DR: The Systemic Lupus International Collaborating Clinics (SLICC) group revised and validated the American College of Rheumatology (ACR) systemic lupus erythematosus (SLE) classification criteria in order to improve clinical relevance, meet stringent methodology requirements, and incorporate new knowledge regarding the immunology of SLE.
Abstract: Objective The Systemic Lupus International Collaborating Clinics (SLICC) group revised and validated the American College of Rheumatology (ACR) systemic lupus erythematosus (SLE) classification criteria in order to improve clinical relevance, meet stringent methodology requirements, and incorporate new knowledge regarding the immunology of SLE. Methods The classification criteria were derived from a set of 702 expert-rated patient scenarios. Recursive partitioning was used to derive an initial rule that was simplified and refined based on SLICC physician consensus. The SLICC group validated the classification criteria in a new validation sample of 690 new expert-rated patient scenarios. Results Seventeen criteria were identified. In the derivation set, the SLICC classification criteria resulted in fewer misclassifications compared with the current ACR classification criteria (49 versus 70; P = 0.0082) and had greater sensitivity (94% versus 86%; P < 0.0001) and equal specificity (92% versus 93%; P = 0.39). In the validation set, the SLICC classification criteria resulted in fewer misclassifications compared with the current ACR classification criteria (62 versus 74; P = 0.24) and had greater sensitivity (97% versus 83%; P < 0.0001) but lower specificity (84% versus 96%; P < 0.0001). Conclusion The new SLICC classification criteria performed well in a large set of patient scenarios rated by experts. According to the SLICC rule for the classification of SLE, the patient must satisfy at least 4 criteria, including at least one clinical criterion and one immunologic criterion OR the patient must have biopsy-proven lupus nephritis in the presence of antinuclear antibodies or antidouble-stranded DNA antibodies. (Less)
TL;DR: The combined creatinine-cystatin C equation performed better than equations based on either of these markers alone and may be useful as a confirmatory test for chronic kidney disease.
Abstract: A b s t r ac t Background Estimates of glomerular filtration rate (GFR) that are based on serum creatinine are routinely used; however, they are imprecise, potentially leading to the overdiagnosis of chronic kidney disease. Cystatin C is an alternative filtration marker for estimating GFR. Methods Using cross-sectional analyses, we developed estimating equations based on cystatin C alone and in combination with creatinine in diverse populations totaling 5352 participants from 13 studies. These equations were then validated in 1119 participants from 5 different studies in which GFR had been measured. Cystatin and creatinine assays were traceable to primary reference materials. Results Mean measured GFRs were 68 and 70 ml per minute per 1.73 m 2 of body-surface area in the development and validation data sets, respectively. In the validation data set, the creatinine–cystatin C equation performed better than equations that used creatinine or cystatin C alone. Bias was similar among the three equations, with a median difference between measured and estimated GFR of 3.9 ml per minute per 1.73 m 2 with the combined equation, as compared with 3.7 and 3.4 ml per minute per 1.73 m 2 with the creatinine equation and the cystatin C equation (P = 0.07 and P = 0.05), respectively. Precision was improved with the combined equation (interquartile range of the difference, 13.4 vs. 15.4 and 16.4 ml per minute per 1.73 m 2 , respectively [P = 0.001 and P 30% of measured GFR, 8.5 vs. 12.8 and 14.1, respectively [P<0.001 for both comparisons]). In participants whose estimated GFR based on creatinine was 45 to 74 ml per minute per 1.73 m 2 , the combined equation improved the classification of measured GFR as either less than 60 ml per minute per 1.73 m 2 or greater than or equal to 60 ml per minute per 1.73 m 2 (net reclassification index, 19.4% [P<0.001]) and correctly reclassified 16.9% of those with an estimated GFR of 45 to 59 ml per minute per 1.73 m 2 as having a GFR of 60 ml or higher per minute per 1.73 m 2 . Conclusions The combined creatinine–cystatin C equation performed better than equations based on either of these markers alone and may be useful as a confirmatory test for chronic kidney disease. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases.)
Johns Hopkins University1, University of Barcelona2, St George's, University of London3, Taipei Veterans General Hospital4, Maastricht University5, Washington University in St. Louis6, Imperial College London7, University of Virginia8, Virginia Commonwealth University9, Thomas Jefferson University10, Beaumont Hospital11, University of Bordeaux12, Leipzig University13, University of Oklahoma14, University of Michigan15, Royal Melbourne Hospital16, University College Dublin17, Korea University18, University of Birmingham19, University of Münster20, University of Western Ontario21, Cleveland Clinic22, Harvard University23, University of Pennsylvania24, Northwestern University25, Université de Montréal26, Mayo Clinic27, Icahn School of Medicine at Mount Sinai28, University of California, Los Angeles29, National Yang-Ming University30, Loyola University Chicago31
TL;DR: This 2012 Consensus Statement is to provide a state-of-the-art review of the field of catheter and surgical ablation of AF and to report the findings of a Task Force, convened by the Heart Rhythm Society, the European Heart Rhythm Association, and the European Cardiac Arrhythmia Society and charged with defining the indications, techniques, and outcomes of this procedure.
Abstract: During the past decade, catheter ablation of atrial fibrillation (AF) has evolved rapidly from an investigational procedure to its current status as a commonly performed ablation procedure in many major hospitals throughout the world. Surgical ablation of AF, using either standard or minimally invasive techniques, is also performed in many major hospitals throughout the world.
In 2007, an initial Consensus Statement on Catheter and Surgical AF Ablation was developed as a joint effort of the Heart Rhythm Society, the European Heart Rhythm Association, and the European Cardiac Arrhythmia Society.1 The 2007 document was also developed in collaboration with the Society of Thoracic Surgeons and the American College of Cardiology. Since the publication of the 2007 document, there has been much learned about AF ablation, and the indications for these procedures have changed. Therefore the purpose of this 2012 Consensus Statement is to provide a state-of-the-art review of the field of catheter and surgical ablation of AF and to report the findings of a Task Force, convened by the Heart Rhythm Society, the European Heart Rhythm Association, and the European Cardiac Arrhythmia Society and charged with defining the indications, techniques, and outcomes of this procedure. Included within this document are recommendations pertinent to the design of clinical trials in the field of AF ablation, including definitions relevant to this topic.
This statement summarizes the opinion of the Task Force members based on an extensive literature review as well as their own experience. It is directed to all health care professionals who are involved in the care of patients with AF, particularly those who are undergoing, or are being considered for, catheter or surgical ablation procedures for AF. This statement is not intended to recommend or promote catheter ablation of AF. Rather the ultimate judgment regarding care of a particular patient …
TL;DR: This paper used a generalized vector autoregressive framework to characterize daily volatility spillovers across US stock, bond, foreign exchange and commodities markets, from January 1999 to January 2010, and showed that despite significant volatility fluctuations in all four markets during the sample, cross-market volatility spillover were quite limited until the global financial crisis, which began in 2007.
TL;DR: The richness of the understanding of MYC is reviewed, highlighting new biological insights and opportunities for cancer therapies.
Harvard University1, Sarah Cannon Research Institute2, University of California, San Francisco3, University of Colorado Denver4, University of Sydney5, Vanderbilt University6, University of Pennsylvania7, University of Melbourne8, University of South Florida9, University of Texas MD Anderson Cancer Center10, GlaxoSmithKline11
TL;DR: Dabrafenib and trametinib were safely combined at full monotherapy doses, and the rate of pyrexia was increased with combination therapy, whereas the rates of proliferative skin lesions was nonsignificantly reduced.
Abstract: Dose-limiting toxic effects were infrequently observed in patients receiving combination therapy with 150 mg of da braf e nib and 2 mg of tra me ti nib (combination 150/2). Cutaneous squamous-cell carcinoma was seen in 7% of patients receiving combination 150/2 and in 19% receiving monotherapy (P = 0.09), whereas pyrexia was more common in the combination 150/2 group than in the monotherapy group (71% vs. 26%). Median progression-free survival in the combination 150/2 group was 9.4 months, as compared with 5.8 months in the monotherapy group (hazard ratio for progression or death, 0.39; 95% confidence interval, 0.25 to 0.62; P<0.001). The rate of complete or partial response with combination 150/2 therapy was 76%, as compared with 54% with monotherapy (P = 0.03). Conclusions Da braf e nib and tra me ti nib were safely combined at full monotherapy doses. The rate of pyrexia was increased with combination therapy, whereas the rate of proliferative skin lesions was nonsignificantly reduced. Progression-free survival was significantly improved. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT01072175.)
Harvard University1, National Institutes of Health2, Northwestern University3, Washington University in St. Louis4, Alzheimer's Association5, Mayo Clinic6, University of California, San Diego7, SUNY Downstate Medical Center8, University of Kentucky9, Rush University Medical Center10, University of Ulm11, University of Pennsylvania12, University of California, Los Angeles13, University of Washington14
TL;DR: The new guidelines recognize the pre‐clinical stage of AD, enhance the assessment of AD to include amyloid accumulation as well as neurofibrillary change and neuritic plaques, and establish protocols for the neuropathologic assessment of Lewy body disease, vascular brain injury, hippocampal sclerosis, and TDP‐43 inclusions.
Abstract: A consensus panel from the United States and Europe was convened recently to update and revise the 1997 consensus guidelines for the neuropathologic evaluation of Alzheimer's disease (AD) and other diseases of brain that are common in the elderly. The new guidelines recognize the pre-clinical stage of AD, enhance the assessment of AD to include amyloid accumulation as well as neurofibrillary change and neuritic plaques, establish protocols for the neuropathologic assessment of Lewy body disease, vascular brain injury, hippocampal sclerosis, and TDP-43 inclusions, and recommend standard approaches for the workup of cases and their clinico-pathologic correlation.
TL;DR: The Human Microbiome Project (HMP) Consortium has established a population-scale framework which catalyzed significant development of metagenomic protocols resulting in a broad range of quality-controlled resources and data including standardized methods for creating, processing and interpreting distinct types of high-throughput metagenomics data available to the scientific community as mentioned in this paper.
Abstract: A variety of microbial communities and their genes (microbiome) exist throughout the human body, playing fundamental roles in human health and disease. The NIH funded Human Microbiome Project (HMP) Consortium has established a population-scale framework which catalyzed significant development of metagenomic protocols resulting in a broad range of quality-controlled resources and data including standardized methods for creating, processing and interpreting distinct types of high-throughput metagenomic data available to the scientific community. Here we present resources from a population of 242 healthy adults sampled at 15 to 18 body sites up to three times, which to date, have generated 5,177 microbial taxonomic profiles from 16S rRNA genes and over 3.5 Tb of metagenomic sequence. In parallel, approximately 800 human-associated reference genomes have been sequenced. Collectively, these data represent the largest resource to date describing the abundance and variety of the human microbiome, while providing a platform for current and future studies.
Gonzaga University1, King Saud University2, Northside Hospital3, Praxis4, Foothills Medical Centre5, Cornell University6, National Research Council7, Harvard University8, University of Pennsylvania9, Icahn School of Medicine at Mount Sinai10, University of Jena11, Pierre-and-Marie-Curie University12, University of California, Davis13, University of South Carolina14
TL;DR: This document reflects the overall results of the first consensus conference on “point-of-care” lung ultrasound and utilizes the RAND appropriateness method for panel judgment and decisions/consensus.
Abstract: The purpose of this study is to provide evidence-based and expert consensus recommendations for lung ultrasound with focus on emergency and critical care settings. A multidisciplinary panel of 28 experts from eight countries was involved. Literature was reviewed from January 1966 to June 2011. Consensus members searched multiple databases including Pubmed, Medline, OVID, Embase, and others. The process used to develop these evidence-based recommendations involved two phases: determining the level of quality of evidence and developing the recommendation. The quality of evidence is assessed by the grading of recommendation, assessment, development, and evaluation (GRADE) method. However, the GRADE system does not enforce a specific method on how the panel should reach decisions during the consensus process. Our methodology committee decided to utilize the RAND appropriateness method for panel judgment and decisions/consensus. Seventy-three proposed statements were examined and discussed in three conferences held in Bologna, Pisa, and Rome. Each conference included two rounds of face-to-face modified Delphi technique. Anonymous panel voting followed each round. The panel did not reach an agreement and therefore did not adopt any recommendations for six statements. Weak/conditional recommendations were made for 2 statements, and strong recommendations were made for the remaining 65 statements. The statements were then recategorized and grouped to their current format. Internal and external peer-review processes took place before submission of the recommendations. Updates will occur at least every 4 years or whenever significant major changes in evidence appear. This document reflects the overall results of the first consensus conference on “point-of-care” lung ultrasound. Statements were discussed and elaborated by experts who published the vast majority of papers on clinical use of lung ultrasound in the last 20 years. Recommendations were produced to guide implementation, development, and standardization of lung ultrasound in all relevant settings.
Columbia University1, Cleveland Clinic2, University of British Columbia3, Cedars-Sinai Medical Center4, Lenox Hill Hospital5, Boston Children's Hospital6, Emory University7, MedStar Washington Hospital Center8, Stanford University9, University of Pennsylvania10, University of Virginia11, Mayo Clinic12, Scripps Health13, Duke University14, Primary Children's Hospital15, University of London16, Edwards Lifesciences Corporation17
TL;DR: A 2-year follow-up of patients in the PARTNER trial supports TAVR as an alternative to surgery in high-risk patients, but paravalvular regurgitation was more frequent after T AVR and was associated with increased late mortality.
Abstract: The rates of death from any cause were similar in the TAVR and surgery groups (hazard ratio with TAVR, 0.90; 95% confidence interval [CI], 0.71 to 1.15; P = 0.41) and at 2 years (Kaplan–Meier analysis) were 33.9% in the TAVR group and 35.0% in the surgery group (P = 0.78). The frequency of all strokes during follow-up did not differ significantly between the two groups (hazard ratio, 1.22; 95% CI, 0.67 to 2.23; P = 0.52). At 30 days, strokes were more frequent with TAVR than with surgical replacement (4.6% vs. 2.4%, P = 0.12); subsequently, there were 8 additional strokes in the TAVR group and 12 in the surgery group. Improvement in valve areas was similar with TAVR and surgical replacement and was maintained for 2 years. Paravalvular regurgitation was more frequent after TAVR (P<0.001), and even mild paravalvular regurgitation was associated with increased late mortality (P<0.001). Conclusions A 2-year follow-up of patients in the PARTNER trial supports TAVR as an alternative to surgery in high-risk patients. The two treatments were similar with respect to mortality, reduction in symptoms, and improved valve hemodynamics, but paravalvular regurgitation was more frequent after TAVR and was associated with increased late mortality. (Funded by Edwards Lifesciences; ClinicalTrials.gov number, NCT00530894.)
Vanderbilt University1, University of Texas MD Anderson Cancer Center2, University of Pennsylvania3, University of Colorado Denver4, New York University5, University of South Florida6, Peter MacCallum Cancer Centre7, Baylor University Medical Center8, University of Pittsburgh9, Harvard University10, University of Newcastle11, University of California, Los Angeles12, Hoffmann-La Roche13, Veterans Health Administration14, Plexxikon15
TL;DR: Vemurafenib induces clinical responses in more than half of patients with previously treated BRAF V600-mutant metastatic melanoma, and the median overall survival in this study with a long follow-up was approximately 16 months.
Abstract: Approximately 50% of melanomas harbor activating (V600) mutations in the serine– threonine protein kinase B-RAF (BRAF). The oral BRAF inhibitor vemurafenib (PLX4032) frequently produced tumor regressions in patients with BRAF V600– mutant metastatic melanoma in a phase 1 trial and improved overall survival in a phase 3 trial. METHODS We designed a multicenter phase 2 trial of vemurafenib in patients with previously treated BRAF V600–mutant metastatic melanoma to investigate the efficacy of vem urafenib with respect to overall response rate (percentage of treated patients with a tumor response), duration of response, and overall survival. The primary end point was the overall response rate as ascertained by the independent review committee; overall survival was a secondary end point. RESULTS A total of 132 patients had a median follow-up of 12.9 months (range, 0.6 to 20.1). The confirmed overall response rate was 53% (95% confidence interval [CI], 44 to 62; 6% with a complete response and 47% with a partial response), the median duration of response was 6.7 months (95% CI, 5.6 to 8.6), and the median progression-free survival was 6.8 months (95% CI, 5.6 to 8.1). Primary progression was observed in only 14% of patients. Some patients had a response after receiving vemurafenib for more than 6 months. The median overall survival was 15.9 months (95% CI, 11.6 to 18.3). The most common adverse events were grade 1 or 2 arthralgia, rash, photosensitivity, fatigue, and alopecia. Cutaneous squamous-cell carcinomas (the majority, keratoacanthoma type) were diagnosed in 26% of patients. CONCLUSIONS Vemurafenib induces clinical responses in more than half of patients with previously treated BRAF V600–mutant metastatic melanoma. In this study with a long follow-up, the median overall survival was approximately 16 months. (Funded by Hoffmann–La Roche; ClinicalTrials.gov number, NCT00949702.)
University of Washington1, National Institutes of Health2, Northwestern University3, Washington University in St. Louis4, Mayo Clinic5, Harvard University6, University of California, San Diego7, SUNY Downstate Medical Center8, University of Kentucky9, Rush University Medical Center10, University of Ulm11, University of Pennsylvania12, University of California, Los Angeles13
TL;DR: A practical guide for the implementation of recently revised National Institute on Aging–Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer’s disease is presented.
Abstract: We present a practical guide for the implementation of recently revised National Institute on Aging–Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease (AD). Major revisions from previous consensus criteria are: (1) recognition that AD neuropathologic changes may occur in the apparent absence of cognitive impairment, (2) an “ABC” score for AD neuropathologic change that incorporates histopathologic assessments of amyloid β deposits (A), staging of neurofibrillary tangles (B), and scoring of neuritic plaques (C), and (3) more detailed approaches for assessing commonly co-morbid conditions such as Lewy body disease, vascular brain injury, hippocampal sclerosis, and TAR DNA binding protein (TDP)-43 immunoreactive inclusions. Recommendations also are made for the minimum sampling of brain, preferred staining methods with acceptable alternatives, reporting of results, and clinico-pathologic correlations.
TL;DR: It is found that in wild-type nontransgenic mice, a single intrastriatal inoculation of synthetic α- Syn fibrils led to the cell-to-cell transmission of pathologic α-Syn and Parkinson’s-like Lewy pathology in anatomically interconnected regions.
Abstract: Parkinson's disease is characterized by abundant α-synuclein (α-Syn) neuronal inclusions, known as Lewy bodies and Lewy neurites, and the massive loss of midbrain dopamine neurons. However, a cause-and-effect relationship between Lewy inclusion formation and neurodegeneration remains unclear. Here, we found that in wild-type nontransgenic mice, a single intrastriatal inoculation of synthetic α-Syn fibrils led to the cell-to-cell transmission of pathologic α-Syn and Parkinson's-like Lewy pathology in anatomically interconnected regions. Lewy pathology accumulation resulted in progressive loss of dopamine neurons in the substantia nigra pars compacta, but not in the adjacent ventral tegmental area, and was accompanied by reduced dopamine levels culminating in motor deficits. This recapitulation of a neurodegenerative cascade thus establishes a mechanistic link between transmission of pathologic α-Syn and the cardinal features of Parkinson's disease.
Andrew P. Morris1, Benjamin F. Voight2, Benjamin F. Voight3, Tanya M. Teslovich4 +229 more•Institutions (53)
TL;DR: This article conducted a meta-analysis of genetic variants on the Metabochip, including 34,840 cases and 114,981 controls, overwhelmingly of European descent, and identified ten previously unreported T2D susceptibility loci, including two showing sex-differentiated association.
Abstract: To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip, including 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two showing sex-differentiated association. Genome-wide analyses of these data are consistent with a long tail of additional common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signaling and cell cycle regulation, in diabetes pathogenesis.
Harvard University1, Broad Institute2, University of Pennsylvania3, National Institutes of Health4, Boston University5, Lund University6, University of Copenhagen7, University of Texas Health Science Center at Houston8, deCODE genetics9, Queen Mary University of London10, University of Lübeck11, Glenfield Hospital12, University of Leicester13, University of Oxford14, University of Cambridge15, University of Ottawa16, University of Iceland17, Population Health Research Institute18, McGill University19, Vanderbilt University20, University of Missouri–Kansas City21, University of Münster22, University of Verona23, Queen's University Belfast24, MedStar Washington Hospital Center25, GlaxoSmithKline26, University of Helsinki27, Karolinska Institutet28, University of Mainz29, Utrecht University30, University of Groningen31, University of Michigan32, Centro Nacional de Investigaciones Cardiovasculares33, United States Department of Agriculture34, University of North Carolina at Chapel Hill35, University of Regensburg36, Katholieke Universiteit Leuven37, University of Edinburgh38, University of Kiel39, University of Leeds40, Aarhus University41, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico42, University of Washington43, Wellcome Trust Sanger Institute44
TL;DR: In this paper, a Mendelian randomisation analysis was performed to compare the effect of HDL cholesterol, LDL cholesterol, and genetic score on risk of myocardial infarction.
Abstract: Methods We performed two mendelian randomisation analyses. First, we used as an instrument a single nucleotide polymorphism (SNP) in the endothelial lipase gene (LIPG Asn396Ser) and tested this SNP in 20 studies (20 913 myocardial infarction cases, 95 407 controls). Second, we used as an instrument a genetic score consisting of 14 common SNPs that exclusively associate with HDL cholesterol and tested this score in up to 12 482 cases of myocardial infarction and 41 331 controls. As a positive control, we also tested a genetic score of 13 common SNPs exclusively associated with LDL cholesterol. – ¹³) but similar levels of other lipid and non-lipid risk factors for myocardial infarction compared with noncarriers. This diff erence in HDL cholesterol is expected to decrease risk of myocardial infarction by 13% (odds ratio [OR] 0·87, 95% CI 0·84–0·91). However, we noted that the 396Ser allele was not associated with risk of myocardial infarction (OR 0·99, 95% CI 0·88–1·11, p=0·85). From observational epidemiology, an increase of 1 SD in HDL cholesterol was associated with reduced risk of myocardial infarction (OR 0·62, 95% CI 0·58–0·66). However, a 1 SD increase in HDL cholesterol due to genetic score was not associated with risk of myocardial infarction (OR 0·93, 95% CI 0·68–1·26, p=0·63). For LDL cholesterol, the estimate from observational epidemiology (a 1 SD increase in LDL cholesterol associated with OR 1·54, 95% CI 1·45–1·63) was concordant with that from genetic score (OR 2·13, 95% CI 1·69–2·69, p=2×10
University of Louisville1, Rush University Medical Center2, University of North Carolina at Chapel Hill3, University of Amsterdam4, University of Pennsylvania5, Mayo Clinic6, University of Göttingen7, Columbia University Medical Center8, University of Cambridge9, Stavanger University Hospital10, Autonomous University of Barcelona11, Ikerbasque12, Newcastle University13, Istanbul University14
TL;DR: These diagnostic criteria will support future research efforts to identify at the earliest stage those PD patients at increased risk of progressive cognitive decline and dementia who may benefit from clinical interventions at a predementia stage.
Abstract: Mild cognitive impairment is common in nondemented Parkinson's disease (PD) patients and may be a harbinger of dementia. In view of its importance, the Movement Disorder Society commissioned a task force to delineate diagnostic criteria for mild cognitive impairment in PD. The proposed diagnostic criteria are based on a literature review and expert consensus. This article provides guidelines to characterize the clinical syndrome and methods for its diagnosis. The criteria will require validation, and possibly refinement, as additional research improves our understanding of the epidemiology, presentation, neurobiology, assessment, and long-term course of this clinical syndrome. These diagnostic criteria will support future research efforts to identify at the earliest stage those PD patients at increased risk of progressive cognitive decline and dementia who may benefit from clinical interventions at a predementia stage.
TL;DR: It is suggested that inflammation enhances cancer progression in part by facilitating EMT and entry into the circulation and tagged cells invaded and entered the bloodstream unexpectedly early, before frank malignancy could be detected by rigorous histologic analysis.
Memorial Sloan Kettering Cancer Center1, Cornell University2, University of South Florida3, Harvard University4, Yeshiva University5, Columbia University6, Stanford University7, Indiana University8, Mayo Clinic9, Case Western Reserve University10, Technion – Israel Institute of Technology11, University of Pennsylvania12
TL;DR: Genetic predictors of outcome that improved risk stratification among patients with AML, independently of age, white-cell count, induction dose, and post-remission therapy, are identified and the significance of these predictors in an independent cohort is validated.
Abstract: We identified at least one somatic alteration in 97.3% of the patients. We found that internal tandem duplication in FLT3 (FLT3-ITD), partial tandem duplication in MLL (MLL-PTD), and mutations in ASXL1 and PHF6 were associated with reduced overall survival (P = 0.001 for FLT3-ITD, P = 0.009 for MLL-PTD, P = 0.05 for ASXL1, and P = 0.006 for PHF6); CEBPA and IDH2 mutations were associated with improved overall survival (P = 0.05 for CEBPA and P = 0.01 for IDH2). The favorable effect of NPM1 mutations was restricted to patients with co-occurring NPM1 and IDH1 or IDH2 mutations. We identified genetic predictors of outcome that improved risk stratification among patients with AML, independently of age, white-cell count, induction dose, and post-remission therapy, and validated the significance of these predictors in an independent cohort. High-dose daunorubicin, as compared with standarddose daunorubicin, improved the rate of survival among patients with DNMT3A or NPM1 mutations or MLL translocations (P = 0.001) but not among patients with wild-type DNMT3A, NPM1, and MLL (P = 0.67). Conclusions We found that DNMT3A and NPM1 mutations and MLL translocations predicted an improved outcome with high-dose induction chemotherapy in patients with AML. These findings suggest that mutational profiling could potentially be used for risk stratification and to inform prognostic and therapeutic decisions regarding patients with AML. (Funded by the National Cancer Institute and others.)
Harvard University1, Icahn School of Medicine at Mount Sinai2, Carnegie Mellon University3, Broad Institute4, Baylor College of Medicine5, University of Pennsylvania6, Brigham and Women's Hospital7, Vanderbilt University8, Johns Hopkins University9, French Institute of Health and Medical Research10, University of Texas Health Science Center at Houston11, University of Illinois at Chicago12, University of Pittsburgh13
TL;DR: Results from de novo events and a large parallel case–control study provide strong evidence in favour of CHD8 and KATNAL2 as genuine autism risk factors and support polygenic models in which spontaneous coding mutations in any of a large number of genes increases risk by 5- to 20-fold.
Abstract: Autism spectrum disorders (ASD) are believed to have genetic and environmental origins, yet in only a modest fraction of individuals can specific causes be identified. To identify further genetic risk factors, here we assess the role of de novo mutations in ASD by sequencing the exomes of ASD cases and their parents (n = 175 trios). Fewer than half of the cases (46.3%) carry a missense or nonsense de novo variant, and the overall rate of mutation is only modestly higher than the expected rate. In contrast, the proteins encoded by genes that harboured de novo missense or nonsense mutations showed a higher degree of connectivity among themselves and to previous ASD genes as indexed by protein-protein interaction screens. The small increase in the rate of de novo events, when taken together with the protein interaction results, are consistent with an important but limited role for de novo point mutations in ASD, similar to that documented for de novo copy number variants. Genetic models incorporating these data indicate that most of the observed de novo events are unconnected to ASD; those that do confer risk are distributed across many genes and are incompletely penetrant (that is, not necessarily sufficient for disease). Our results support polygenic models in which spontaneous coding mutations in any of a large number of genes increases risk by 5- to 20-fold. Despite the challenge posed by such models, results from de novo events and a large parallel case-control study provide strong evidence in favour of CHD8 and KATNAL2 as genuine autism risk factors.
TL;DR: This paper examined how emotion shapes virality and found that content that evokes high-arousal positive (awe) or negative (anger or anxiety) emotions is more viral.
Abstract: Why are certain pieces of online content (e.g., advertisements, videos, news articles) more viral than others? This article takes a psychological approach to understanding diffusion. Using a unique data set of all the New York Times articles published over a three-month period, the authors examine how emotion shapes virality. The results indicate that positive content is more viral than negative content, but the relationship between emotion and social transmission is more complex than valence alone. Virality is partially driven by physiological arousal. Content that evokes high-arousal positive (awe) or negative (anger or anxiety) emotions is more viral. Content that evokes low-arousal, or deactivating, emotions (e.g., sadness) is less viral. These results hold even when the authors control for how surprising, interesting, or practically useful content is (all of which are positively linked to virality), as well as external drivers of attention (e.g., how prominently content was featured). Experi...