Showing papers by "University of Colorado Denver published in 2017"
Cornell University1, University of Colorado Denver2, Aix-Marseille University3, The Royal Marsden NHS Foundation Trust4, University of Michigan5, Swansea University6, German Cancer Research Center7, Cross Cancer Institute8, University of Zurich9, Princess Margaret Cancer Centre10, Netherlands Cancer Institute11, University of Sydney12, Katholieke Universiteit Leuven13, Complutense University of Madrid14, Peter MacCallum Cancer Centre15, University of Paris16, University of Melbourne17, Northwestern University18, Bristol-Myers Squibb19, University of Duisburg-Essen20
TL;DR: Among patients with advanced melanoma, significantly longer overall survival occurred with combination therapy with nivolumab plus ipilimumab or with n ivolumAB alone than with ipil optimumab alone.
Abstract: BackgroundNivolumab combined with ipilimumab resulted in longer progression-free survival and a higher objective response rate than ipilimumab alone in a phase 3 trial involving patients with advanced melanoma. We now report 3-year overall survival outcomes in this trial. MethodsWe randomly assigned, in a 1:1:1 ratio, patients with previously untreated advanced melanoma to receive nivolumab at a dose of 1 mg per kilogram of body weight plus ipilimumab at a dose of 3 mg per kilogram every 3 weeks for four doses, followed by nivolumab at a dose of 3 mg per kilogram every 2 weeks; nivolumab at a dose of 3 mg per kilogram every 2 weeks plus placebo; or ipilimumab at a dose of 3 mg per kilogram every 3 weeks for four doses plus placebo, until progression, the occurrence of unacceptable toxic effects, or withdrawal of consent. Randomization was stratified according to programmed death ligand 1 (PD-L1) status, BRAF mutation status, and metastasis stage. The two primary end points were progression-free survival a...
3,794 citations
Gregory A. Roth1, Catherine O. Johnson1, Amanuel Alemu Abajobir2, Foad Abd-Allah3 +170 more•Institutions (99)
TL;DR: The GBD (Global Burden of Disease) 2015 study integrated data on disease incidence, prevalence, and mortality to produce consistent, up-to-date estimates for cardiovascular burden, finding that CVDs remain a major cause of health loss for all regions of the world.
2,525 citations
Seattle Children's1, Case Western Reserve University2, University of Maryland, Baltimore3, University of Missouri–Kansas City4, Indiana University5, University of Colorado Denver6, Boston Children's Hospital7, University of British Columbia8, Thomas Jefferson University9, American Academy of Pediatrics10, Alfred I. duPont Hospital for Children11, Morehouse College12, Harvard University13, University of Texas Health Science Center at Houston14, University of Pittsburgh15, Columbia University Medical Center16, Cincinnati Children's Hospital Medical Center17
TL;DR: These pediatric hypertension guidelines are an update to the 2004 report and include revised recommendations on when to perform echocardiography in the evaluation of newly diagnosed hypertensive pediatric patients (generally only before medication initiation), along with a revised definition of left ventricular hypertrophy.
Abstract: These pediatric hypertension guidelines are an update to the 2004 “Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents.” Significant changes in these guidelines include (1) the replacement of the term “prehypertension” with the term “elevated blood pressure,” (2) new normative pediatric blood pressure (BP) tables based on normal-weight children, (3) a simplified screening table for identifying BPs needing further evaluation, (4) a simplified BP classification in adolescents ≥13 years of age that aligns with the forthcoming American Heart Association and American College of Cardiology adult BP guidelines, (5) a more limited recommendation to perform screening BP measurements only at preventive care visits, (6) streamlined recommendations on the initial evaluation and management of abnormal BPs, (7) an expanded role for ambulatory BP monitoring in the diagnosis and management of pediatric hypertension, and (8) revised recommendations on when to perform echocardiography in the evaluation of newly diagnosed hypertensive pediatric patients (generally only before medication initiation), along with a revised definition of left ventricular hypertrophy. These guidelines include 30 Key Action Statements and 27 additional recommendations derived from a comprehensive review of almost 15 000 published articles between January 2004 and July 2016. Each Key Action Statement includes level of evidence, benefit-harm relationship, and strength of recommendation. This clinical practice guideline, endorsed by the American Heart Association, is intended to foster a patient- and family-centered approach to care, reduce unnecessary and costly medical interventions, improve patient diagnoses and outcomes, support implementation, and provide direction for future research.
2,082 citations
TL;DR: Prevention and early detection of lung cancer with an emphasis on lung cancer screening is discussed, and the importance of smoking prevention and cessation is acknowledged.
2,027 citations
TL;DR: As compared with crizotinib, alectinib showed superior efficacy and lower toxicity in primary treatment of ALK‐positive NSCLC and independent review committee–assessed progression‐free survival were consistent with those for the primary end point.
Abstract: BackgroundAlectinib, a highly selective inhibitor of anaplastic lymphoma kinase (ALK), has shown systemic and central nervous system (CNS) efficacy in the treatment of ALK-positive non–small-cell lung cancer (NSCLC). We investigated alectinib as compared with crizotinib in patients with previously untreated, advanced ALK-positive NSCLC, including those with asymptomatic CNS disease. MethodsIn a randomized, open-label, phase 3 trial, we randomly assigned 303 patients with previously untreated, advanced ALK-positive NSCLC to receive either alectinib (600 mg twice daily) or crizotinib (250 mg twice daily). The primary end point was investigator-assessed progression-free survival. Secondary end points were independent review committee–assessed progression-free survival, time to CNS progression, objective response rate, and overall survival. ResultsDuring a median follow-up of 17.6 months (crizotinib) and 18.6 months (alectinib), an event of disease progression or death occurred in 62 of 152 patients (41%) in ...
1,665 citations
TL;DR: A way forward is suggested for the effective targeting of autophagy by understanding the context-dependent roles of autophile and by capitalizing on modern approaches to clinical trial design.
Abstract: Autophagy is a mechanism by which cellular material is delivered to lysosomes for degradation, leading to the basal turnover of cell components and providing energy and macromolecular precursors. Autophagy has opposing, context-dependent roles in cancer, and interventions to both stimulate and inhibit autophagy have been proposed as cancer therapies. This has led to the therapeutic targeting of autophagy in cancer to be sometimes viewed as controversial. In this Review, we suggest a way forwards for the effective targeting of autophagy by understanding the context-dependent roles of autophagy and by capitalizing on modern approaches to clinical trial design.
1,606 citations
New York University1, National and Kapodistrian University of Athens2, University of Barcelona3, Texas Oncology4, Complutense University of Madrid5, Aix-Marseille University6, University of Toronto7, University of Oxford8, University of Queensland9, University of Colorado Denver10, Emory University11, Cross Cancer Institute12, Centre Hospitalier Universitaire de Toulouse13, Georgetown University14, University of Sydney15, University of Washington16, University of Paris17, Nagoya University18, Seoul National University19, Bristol-Myers Squibb20, The Royal Marsden NHS Foundation Trust21
TL;DR: Among patients undergoing resection of stage IIIB, IIIC, or IV melanoma, adjuvant therapy with nivolumab resulted in significantly longer recurrence‐free survival and a lower rate of grade 3 or 4 adverse events than adjuant therapy with ipilimumab.
Abstract: BackgroundNivolumab and ipilimumab are immune checkpoint inhibitors that have been approved for the treatment of advanced melanoma. In the United States, ipilimumab has also been approved as adjuvant therapy for melanoma on the basis of recurrence-free and overall survival rates that were higher than those with placebo in a phase 3 trial. We wanted to determine the efficacy of nivolumab versus ipilimumab for adjuvant therapy in patients with resected advanced melanoma. MethodsIn this randomized, double-blind, phase 3 trial, we randomly assigned 906 patients (≥15 years of age) who were undergoing complete resection of stage IIIB, IIIC, or IV melanoma to receive an intravenous infusion of either nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks (453 patients) or ipilimumab at a dose of 10 mg per kilogram every 3 weeks for four doses and then every 12 weeks (453 patients). The patients were treated for a period of up to 1 year or until disease recurrence, a report of unacceptable toxic ef...
1,549 citations
Queen Mary University of London1, Winthrop-University Hospital2, Karolinska Institutet3, Boston Children's Hospital4, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico5, Harvard University6, University of Colorado Denver7, McMaster University8, University of Auckland9, Katholieke Universiteit Leuven10, University of Tampere11, University of Birmingham12, Pennsylvania State University13, University of Otago14, QIMR Berghofer Medical Research Institute15, Dartmouth College16, Menzies Research Institute17, Medical University of Łódź18, University of Delhi19, Jikei University School of Medicine20
TL;DR: Vitamin D supplementation was safe and it protected against acute respiratory tract infection overall and patients who were very vitamin D deficient and those not receiving bolus doses experienced the most benefit.
Abstract: Objectives To assess the overall effect of vitamin D supplementation on risk of acute respiratory tract infection, and to identify factors modifying this effect. Design Systematic review and meta-analysis of individual participant data (IPD) from randomised controlled trials. Data sources Medline, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, ClinicalTrials.gov, and the International Standard Randomised Controlled Trials Number registry from inception to December 2015. Eligibility criteria for study selection Randomised, double blind, placebo controlled trials of supplementation with vitamin D 3 or vitamin D 2 of any duration were eligible for inclusion if they had been approved by a research ethics committee and if data on incidence of acute respiratory tract infection were collected prospectively and prespecified as an efficacy outcome. Results 25 eligible randomised controlled trials (total 11 321 participants, aged 0 to 95 years) were identified. IPD were obtained for 10 933 (96.6%) participants. Vitamin D supplementation reduced the risk of acute respiratory tract infection among all participants (adjusted odds ratio 0.88, 95% confidence interval 0.81 to 0.96; P for heterogeneity Conclusions Vitamin D supplementation was safe and it protected against acute respiratory tract infection overall. Patients who were very vitamin D deficient and those not receiving bolus doses experienced the most benefit. Systematic review registration PROSPERO CRD42014013953.
1,431 citations
TL;DR: These findings guide which normalization and differential abundance techniques to use based on the data characteristics of a given study.
Abstract: Data from 16S ribosomal RNA (rRNA) amplicon sequencing present challenges to ecological and statistical interpretation. In particular, library sizes often vary over several ranges of magnitude, and the data contains many zeros. Although we are typically interested in comparing relative abundance of taxa in the ecosystem of two or more groups, we can only measure the taxon relative abundance in specimens obtained from the ecosystems. Because the comparison of taxon relative abundance in the specimen is not equivalent to the comparison of taxon relative abundance in the ecosystems, this presents a special challenge. Second, because the relative abundance of taxa in the specimen (as well as in the ecosystem) sum to 1, these are compositional data. Because the compositional data are constrained by the simplex (sum to 1) and are not unconstrained in the Euclidean space, many standard methods of analysis are not applicable. Here, we evaluate how these challenges impact the performance of existing normalization methods and differential abundance analyses. Effects on normalization: Most normalization methods enable successful clustering of samples according to biological origin when the groups differ substantially in their overall microbial composition. Rarefying more clearly clusters samples according to biological origin than other normalization techniques do for ordination metrics based on presence or absence. Alternate normalization measures are potentially vulnerable to artifacts due to library size. Effects on differential abundance testing: We build on a previous work to evaluate seven proposed statistical methods using rarefied as well as raw data. Our simulation studies suggest that the false discovery rates of many differential abundance-testing methods are not increased by rarefying itself, although of course rarefying results in a loss of sensitivity due to elimination of a portion of available data. For groups with large (~10×) differences in the average library size, rarefying lowers the false discovery rate. DESeq2, without addition of a constant, increased sensitivity on smaller datasets ( 20 samples per group) but also critically the only method tested that has a good control of false discovery rate. These findings guide which normalization and differential abundance techniques to use based on the data characteristics of a given study.
1,292 citations
San Antonio River Authority1, Ljubljana University Medical Centre2, University of Amsterdam3, University of Colorado Denver4, University of Washington5, King's College London6, Vita-Salute San Raffaele University7, Stanford University8, University of Padua9, Harvard University10, University of Sheffield11, University of Cambridge12, Shanghai Jiao Tong University13, Princess Margaret Hospital for Children14, University of Virginia15, JDRF16, University of East Anglia17, Copenhagen University Hospital18, University of Montpellier19, Yale University20
TL;DR: This article summarizes the ATTD consensus recommendations and represents the current understanding of how CGM results can affect outcomes.
Abstract: Measurement of glycated hemoglobin (HbA1c) has been the traditional method for assessing glycemic control. However, it does not reflect intra- and interday glycemic excursions that may lead to acute events (such as hypoglycemia) or postprandial hyperglycemia, which have been linked to both microvascular and macrovascular complications. Continuous glucose monitoring (CGM), either from real-time use (rtCGM) or intermittently viewed (iCGM), addresses many of the limitations inherent in HbA1c testing and self-monitoring of blood glucose. Although both provide the means to move beyond the HbA1c measurement as the sole marker of glycemic control, standardized metrics for analyzing CGM data are lacking. Moreover, clear criteria for matching people with diabetes to the most appropriate glucose monitoring methodologies, as well as standardized advice about how best to use the new information they provide, have yet to be established. In February 2017, the Advanced Technologies & Treatments for Diabetes (ATTD) Congress convened an international panel of physicians, researchers, and individuals with diabetes who are expert in CGM technologies to address these issues. This article summarizes the ATTD consensus recommendations and represents the current understanding of how CGM results can affect outcomes.
1,173 citations
Cornell University1, Memorial Sloan Kettering Cancer Center2, University of Texas MD Anderson Cancer Center3, University of Colorado Denver4, Harvard University5, NewYork–Presbyterian Hospital6, Northwestern University7, Sarah Cannon Research Institute8, University of Texas Southwestern Medical Center9, City of Hope National Medical Center10, Cleveland Clinic11, University of Miami12, Stanford University13, Institut Gustave Roussy14, Université Paris-Saclay15, University of Oxford16, Celgene17, Agios Pharmaceuticals18
TL;DR: Inducing differentiation of myeloblasts, not cytotoxicity, seems to drive the clinical efficacy of enasidenib, a first-in-class, oral, selective inhibitor of mutant-IDH2 enzymes.
29 Jun 2017
TL;DR: Vitamin B12 deficiency causes reversible megaloblastic anemia, demyelinating disease, or both; current assays have insufficient sensitivity and specificity; methylmalonic acid levels are useful to confirm diagnosis.
Abstract: Vitamin B12 deficiency causes reversible megaloblastic anemia, demyelinating disease, or both. Current assays have insufficient sensitivity and specificity; methylmalonic acid levels are useful to confirm diagnosis. Parenteral or high-dose oral vitamin B12 is effective therapy.
TL;DR: It is demonstrated that Nkx2.2 functions as an integral component of a modular regulatory program to correctly specify pancreatic islet cell fates.
Abstract: Many pancreatic transcription factors that are essential for islet cell differentiation have been well characterized; however, because they are often expressed in several different cell populations, their functional hierarchy remains unclear. To parse out the spatiotemporal regulation of islet cell differentiation, we used a Neurog3-Cre allele to ablate Nkx2.2, one of the earliest and most broadly expressed islet transcription factors, specifically in the Neurog3+ endocrine progenitor lineage (Nkx2.2△endo). Remarkably, many essential components of the β cell transcriptional network that were down-regulated in the Nkx2.2KO mice, were maintained in the Nkx2.2△endo mice - yet the Nkx2.2△endo mice displayed defective β cell differentiation and recapitulated the Nkx2.2KO phenotype. This suggests that Nkx2.2 is not only required in the early pancreatic progenitors, but has additional essential activities within the endocrine progenitor population. Consistently, we demonstrate Nkx2.2 functions as an integral component of a modular regulatory program to correctly specify pancreatic islet cell fates.
San Francisco VA Medical Center1, University of California, San Francisco2, University of Colorado Denver3, McMaster University4, University of North Carolina at Chapel Hill5, Icahn School of Medicine at Mount Sinai6, Erasmus University Medical Center7, University of Washington8, Kingston General Hospital9
TL;DR: A multidisciplinary Delphi panel developed a consensus definition for ACP for adults that can be used to inform implementation and measurement of ACP clinical, research, and policy initiatives.
Christian R. Marshall, Daniel P. Howrigan1, Daniel P. Howrigan2, Daniele Merico +326 more•Institutions (98)
TL;DR: In this article, a centralized analysis pipeline was applied to a SCZ cohort of 21,094 cases and 20,227 controls, and a global enrichment of copy number variants (CNVs) was observed in cases (odds ratio (OR) = 1.11, P = 5.7 × 10-15), which persisted after excluding loci implicated in previous studies.
Abstract: Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (odds ratio (OR) = 1.11, P = 5.7 × 10-15), which persisted after excluding loci implicated in previous studies (OR = 1.07, P = 1.7 × 10-6). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 × 10-11) and neurobehavioral phenotypes in mouse (OR = 1.18, P = 7.3 × 10-5). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by nonallelic homologous recombination.
TL;DR: This update of a previously published Cochrane review sought to critically appraise and summarise current evidence on the effectiveness and resource use of CGA for older adults admitted to hospital, and to estimate its cost-effectiveness.
Abstract: Background
Comprehensive geriatric assessment (CGA) is a multi-dimensional, multi-disciplinary diagnostic and therapeutic process conducted to determine the medical, mental, and functional problems of older people with frailty so that a co-ordinated and integrated plan for treatment and follow-up can be developed. This is an update of a previously published Cochrane review.
Objectives
We sought to critically appraise and summarise current evidence on the effectiveness and resource use of CGA for older adults admitted to hospital, and to use these data to estimate its cost-effectiveness.
Search methods
We searched CENTRAL, MEDLINE, Embase, three other databases, and two trials registers on 5 October 2016; we also checked reference lists and contacted study authors.
Selection criteria
We included randomised trials that compared inpatient CGA (delivered on geriatric wards or by mobile teams) versus usual care on a general medical ward or on a ward for older people, usually admitted to hospital for acute care or for inpatient rehabilitation after an acute admission.
Data collection and analysis
We followed standard methodological procedures expected by Cochrane and Effective Practice and Organisation of Care (EPOC). We used the GRADE approach to assess the certainty of evidence for the most important outcomes. For this update, we requested individual patient data (IPD) from trialists, and we conducted a survey of trialists to obtain details of delivery of CGA. We calculated risk ratios (RRs), mean differences (MDs), or standardised mean differences (SMDs), and combined data using fixed-effect meta-analysis. We estimated cost-effectiveness by comparing inpatient CGA versus hospital admission without CGA in terms of cost per quality-adjusted life year (QALY) gained, cost per life year (LY) gained, and cost per life year living at home (LYLAH) gained.
Main results
We included 29 trials recruiting 13,766 participants across nine, mostly high-income countries. CGA increases the likelihood that patients will be alive and in their own homes at 3 to 12 months' follow-up (risk ratio (RR) 1.06, 95% confidence interval (CI) 1.01 to 1.10; 16 trials, 6799 participants; high-certainty evidence), results in little or no difference in mortality at 3 to 12 months' follow-up (RR 1.00, 95% CI 0.93 to 1.07; 21 trials, 10,023 participants; high-certainty evidence), decreases the likelihood that patients will be admitted to a nursing home at 3 to 12 months follow-up (RR 0.80, 95% CI 0.72 to 0.89; 14 trials, 6285 participants; high-certainty evidence) and results in little or no difference in dependence (RR 0.97, 95% CI 0.89 to 1.04; 14 trials, 6551 participants; high-certainty evidence). CGA may make little or no difference to cognitive function (SMD ranged from -0.22 to 0.35 (5 trials, 3534 participants; low-certainty evidence)). Mean length of stay ranged from 1.63 days to 40.7 days in the intervention group, and ranged from 1.8 days to 42.8 days in the comparison group. Healthcare costs per participant in the CGA group were on average GBP 234 (95% CI GBP -144 to GBP 605) higher than in the usual care group (17 trials, 5303 participants; low-certainty evidence). CGA may lead to a slight increase in QALYs of 0.012 (95% CI -0.024 to 0.048) at GBP 19,802 per QALY gained (3 trials; low-certainty evidence), a slight increase in LYs of 0.037 (95% CI 0.001 to 0.073), at GBP 6305 per LY gained (4 trials; low-certainty evidence), and a slight increase in LYLAH of 0.019 (95% CI -0.019 to 0.155) at GBP 12,568 per LYLAH gained (2 trials; low-certainty evidence). The probability that CGA would be cost-effective at a GBP 20,000 ceiling ratio for QALY, LY, and LYLAH was 0.50, 0.89, and 0.47, respectively (17 trials, 5303 participants; low-certainty evidence).
Authors' conclusions
Older patients are more likely to be alive and in their own homes at follow-up if they received CGA on admission to hospital. We are uncertain whether data show a difference in effect between wards and teams, as this analysis was underpowered. CGA may lead to a small increase in costs, and evidence for cost-effectiveness is of low-certainty due to imprecision and inconsistency among studies. Further research that reports cost estimates that are setting-specific across different sectors of care are required.
University of Toronto1, University of Düsseldorf2, German Cancer Research Center3, University of Pittsburgh4, Ontario Institute for Cancer Research5, Seoul National University6, University of Warsaw7, University of Lyon8, Mayo Clinic9, The Chinese University of Hong Kong10, Johns Hopkins University11, University of Alabama at Birmingham12, Fred Hutchinson Cancer Research Center13, University of Washington14, University of California, San Francisco15, McMaster University16, Hamilton Health Sciences17, Vanderbilt University18, University of Colorado Denver19, Semmelweis University20, Erasmus University Rotterdam21, University of Ulsan22, Kitasato University23, Mexican Social Security Institute24, Masaryk University25, Emory University26, University of Debrecen27, University of Naples Federico II28, Washington University in St. Louis29, McGill University30, Montreal Children's Hospital31, Virginia Commonwealth University32, Chonnam National University33, University of Queensland34, University of Calgary35, University of São Paulo36, University of Cincinnati37, University of Arkansas for Medical Sciences38, The Catholic University of America39, University of California, Los Angeles40, University of Sydney41, Kumamoto University42, Saint Louis University43, Case Western Reserve University44
TL;DR: Similarity network fusion (SNF) applied to genome-wide DNA methylation and gene expression data across 763 primary samples identifies very homogeneous clusters of patients, supporting the presence of medulloblastoma subtypes.
TL;DR: Three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease are observed, providing additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's Disease.
Abstract: We identified rare coding variants associated with Alzheimer's disease in a three-stage case–control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10−4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10−8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10−10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10−10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10−14, OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein–protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.
Mayo Clinic1, Yale University2, Case Western Reserve University3, Children's National Medical Center4, University of California, San Diego5, University of Miami6, Virginia Commonwealth University7, University of Calgary8, Cleveland Clinic9, University of Gothenburg10, University of British Columbia11, Saint Louis University12, Johns Hopkins University13, Dartmouth College14, University of Washington15, University of Texas MD Anderson Cancer Center16, Veterans Health Administration17, Royal Melbourne Hospital18, Cedars-Sinai Medical Center19, University of Colorado Denver20
TL;DR: Fred M. Kusumoto,MD, FHRS, FACC, Chair, Mark H. Schoenfeld, MD, F hrs, F ACC, FAHA, CCDS, Vice-Chair, Bruce L. Wilkoff, MD; Ulrika M. Birgersdotter-Green, MD.
TL;DR: It is found that few randomized trials have successfully changed what people think and feel about vaccines, and those that succeeded were minimally effective in increasing uptake.
Abstract: Vaccination is one of the great achievements of the 20th century, yet persistent public-health problems include inadequate, delayed, and unstable vaccination uptake. Psychology offers three general propositions for understanding and intervening to increase uptake where vaccines are available and affordable. The first proposition is that thoughts and feelings can motivate getting vaccinated. Hundreds of studies have shown that risk beliefs and anticipated regret about infectious disease correlate reliably with getting vaccinated; low confidence in vaccine effectiveness and concern about safety correlate reliably with not getting vaccinated. We were surprised to find that few randomized trials have successfully changed what people think and feel about vaccines, and those few that succeeded were minimally effective in increasing uptake. The second proposition is that social processes can motivate getting vaccinated. Substantial research has shown that social norms are associated with vaccination, but few int...
Oregon Health & Science University1, Emory University2, Centers for Disease Control and Prevention3, University of Colorado Denver4, California Department of Public Health5, Foundation for Innovative New Diagnostics6, McGill University7, University of Southampton8, Vanderbilt University9, University of Arkansas for Medical Sciences10
TL;DR: Twenty-three evidence-based recommendations about diagnostic testing for latent tuberculosis infection, pulmonary tuberculosis, and extrapulmonary tuberculosis are provided and six of the recommendations are strong, whereas the remaining 17 are conditional.
Abstract: Background Individuals infected with Mycobacterium tuberculosis (Mtb) may develop symptoms and signs of disease (tuberculosis disease) or may have no clinical evidence of disease (latent tuberculosis infection [LTBI]). Tuberculosis disease is a leading cause of infectious disease morbidity and mortality worldwide, yet many questions related to its diagnosis remain. Methods A task force supported by the American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America searched, selected, and synthesized relevant evidence. The evidence was then used as the basis for recommendations about the diagnosis of tuberculosis disease and LTBI in adults and children. The recommendations were formulated, written, and graded using the Grading, Recommendations, Assessment, Development and Evaluation (GRADE) approach. Results Twenty-three evidence-based recommendations about diagnostic testing for latent tuberculosis infection, pulmonary tuberculosis, and extrapulmonary tuberculosis are provided. Six of the recommendations are strong, whereas the remaining 17 are conditional. Conclusions These guidelines are not intended to impose a standard of care. They provide the basis for rational decisions in the diagnosis of tuberculosis in the context of the existing evidence. No guidelines can take into account all of the often compelling unique individual clinical circumstances.
University of Pittsburgh1, Riley Hospital for Children2, Washington University in St. Louis3, Baylor College of Medicine4, Texas Tech University5, Northwestern University6, University of British Columbia7, Medical College of Wisconsin8, Saint Barnabas Medical Center9, University of Pennsylvania10, University College London11, University of Alberta12, Duke University13, McMaster University14, Yeshiva University15, University of Michigan16, Laval University17, Kaiser Permanente18, Emory University19, University of Maryland, Baltimore20, Cornell University21, Nationwide Children's Hospital22, Children's Mercy Hospital23, Texas Tech University Health Sciences Center at El Paso24, University of Florida25, St Mary's Hospital26, University of Rochester27, University of Washington28, Stanford University29, University of California, San Diego30, Valley Hospital31, University of Melbourne32, Royal Children's Hospital33, Loma Linda University34, Great Ormond Street Hospital35, Boston Children's Hospital36, Austral University37, University of Colorado Denver38, Nemours Foundation39
TL;DR: A major new recommendation in the 2014 update of the 2007 American College of Critical Care Medicine “Clinical Guidelines for Hemodynamic Support of Neonates and Children with Septic Shock” is consideration of institution—specific use of a recognition bundle containing a trigger tool for rapid identification of patients with septic shock.
Abstract: Objectives:The American College of Critical Care Medicine provided 2002 and 2007 guidelines for hemodynamic support of newborn and pediatric septic shock Provide the 2014 update of the 2007 American College of Critical Care Medicine “Clinical Guidelines for Hemodynamic Support of Neonates and Child
TL;DR: Among patients with advanced heart failure, implantation of a fully magnetically levitated centrifugal‐flow pump was associated with better outcomes at 6 months than was implanted of an axial‐ flow pump, primarily because of the lower rate of reoperation for pump malfunction.
Abstract: BackgroundContinuous-flow left ventricular assist systems increase the rate of survival among patients with advanced heart failure but are associated with the development of pump thrombosis. We investigated the effects of a new magnetically levitated centrifugal continuous-flow pump that was engineered to avert thrombosis. MethodsWe randomly assigned patients with advanced heart failure to receive either the new centrifugal continuous-flow pump or a commercially available axial continuous-flow pump. Patients could be enrolled irrespective of the intended goal of pump support (bridge to transplantation or destination therapy). The primary end point was a composite of survival free of disabling stroke (with disabling stroke indicated by a modified Rankin score >3; scores range from 0 to 6, with higher scores indicating more severe disability) or survival free of reoperation to replace or remove the device at 6 months after implantation. The trial was powered for noninferiority testing of the primary end poi...
Cincinnati Children's Hospital Medical Center1, Janeway Children's Health and Rehabilitation Centre2, Baylor College of Medicine3, Yale University4, Boston Children's Hospital5, University of Colorado Denver6, University of Cincinnati7, Hospital for Sick Children8, University of Toronto9, Memorial University of Newfoundland10, Ottawa Hospital Research Institute11, University of California, San Diego12, Emory University13
TL;DR: This guideline is designed to guide screening and clinical care of children with nonalcoholic fatty liver disease and is a management challenge for general pediatric practitioners, subspecialists and for health systems.
Abstract: Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent chronic liver disease that occurs in the setting of insulin resistance and increased adiposity. It has rapidly evolved into the most common liver disease seen in the pediatric population and is a management challenge for general pediatric practitioners, subspecialists, and for health systems. In this guideline, the expert committee on NAFLD reviewed and summarized the available literature, formulating recommendations to guide screening and clinical care of children with NAFLD.
TL;DR: In this article, a consensus committee of 32 experts in CF diagnosis from 9 countries to develop clear and actionable consensus guidelines on the diagnosis of CF and to clarify diagnostic criteria and terminology for other disorders associated with CFTR mutations.
Royal College of Surgeons in Ireland1, University of Manchester2, Netherlands Cancer Institute3, Autonomous University of Barcelona4, Katholieke Universiteit Leuven5, University of Glasgow6, University of Cambridge7, Masaryk University8, Utrecht University9, University of Lausanne10, Curie Institute11, University of Paris12, University of Colorado Denver13, Harvard University14, University of Groningen15, University of Oslo16, Catalan Institution for Research and Advanced Studies17, University of Turin18
TL;DR: Patient derived xenografts (PDXs) have emerged as an important platform to elucidate new treatments and biomarkers in oncology as mentioned in this paper, and the ability of PDX models to predict clinical outcomes is being improved through mouse humanization strategies and the implementation of co-clinical trials, within which patients and PDXs reciprocally inform therapeutic decisions.
Abstract: Patient-derived xenografts (PDXs) have emerged as an important platform to elucidate new treatments and biomarkers in oncology. PDX models are used to address clinically relevant questions, including the contribution of tumour heterogeneity to therapeutic responsiveness, the patterns of cancer evolutionary dynamics during tumour progression and under drug pressure, and the mechanisms of resistance to treatment. The ability of PDX models to predict clinical outcomes is being improved through mouse humanization strategies and the implementation of co-clinical trials, within which patients and PDXs reciprocally inform therapeutic decisions. This Opinion article discusses aspects of PDX modelling that are relevant to these questions and highlights the merits of shared PDX resources to advance cancer medicine from the perspective of EurOPDX, an international initiative devoted to PDX-based research.
TL;DR: Recent progress in elucidating the molecular mechanisms by which lncRNAs modulate gene expression is reviewed, including the act of lnc RNA transcription rather than the lncRNA product that appears to be regulatory.
Abstract: It has recently become apparent that RNA, itself the product of transcription, is a major regulator of the transcriptional process. In particular, long noncoding RNAs (lncRNAs), which are so numerous in eukaryotes, function in many cases as transcriptional regulators. These RNAs function through binding to histone-modifying complexes, to DNA binding proteins (including transcription factors), and even to RNA polymerase II. In other cases, it is the act of lncRNA transcription rather than the lncRNA product that appears to be regulatory. We review recent progress in elucidating the molecular mechanisms by which lncRNAs modulate gene expression and future opportunities in this research field.
York University1, Royal Berkshire NHS Foundation Trust2, RMIT University3, University of Washington4, University of Gothenburg5, Churchill Hospital6, JDRF7, Université de Montréal8, University of Dundee9, University College London Hospitals NHS Foundation Trust10, University of California, Irvine11, AstraZeneca12, Princess Margaret Hospital for Children13, Telethon Institute for Child Health Research14, University of Western Australia15, University of Colorado Denver16, University of Southern California17, Boston Children's Hospital18, Joslin Diabetes Center19
TL;DR: This Review provides an up-to-date consensus on exercise management for individuals with type 1 diabetes who exercise regularly, including glucose targets for safe and effective exercise, and nutritional and insulin dose adjustments to protect against exercise-related glucose excursions.
TL;DR: In this article, insights into the mechanisms of mitochondrial dysfunction in heart failure are presented, along with an overview of emerging treatments with the potential to improve the function of the failing heart by targeting mitochondria.
Abstract: Heart failure is a pressing worldwide public-health problem with millions of patients having worsening heart failure. Despite all the available therapies, the condition carries a very poor prognosis. Existing therapies provide symptomatic and clinical benefit, but do not fully address molecular abnormalities that occur in cardiomyocytes. This shortcoming is particularly important given that most patients with heart failure have viable dysfunctional myocardium, in which an improvement or normalization of function might be possible. Although the pathophysiology of heart failure is complex, mitochondrial dysfunction seems to be an important target for therapy to improve cardiac function directly. Mitochondrial abnormalities include impaired mitochondrial electron transport chain activity, increased formation of reactive oxygen species, shifted metabolic substrate utilization, aberrant mitochondrial dynamics, and altered ion homeostasis. In this Consensus Statement, insights into the mechanisms of mitochondrial dysfunction in heart failure are presented, along with an overview of emerging treatments with the potential to improve the function of the failing heart by targeting mitochondria.
TL;DR: HCL therapy was safe during in-home use by adolescents and adults and the study phase demonstrated increased time in target, and reductions in HbA1c, hyperglycemia and hypoglycemia, compared to baseline.
Abstract: Background: The safety and effectiveness of the in-home use of a hybrid closed-loop (HCL) system that automatically increases, decreases, and suspends insulin delivery in response to continuous glucose monitoring were investigated. Methods: Adolescents (n = 30, ages 14–21 years) and adults (n = 94, ages 22–75 years) with type 1 diabetes participated in a multicenter (nine sites in the United States, one site in Israel) pivotal trial. The Medtronic MiniMed® 670G system was used during a 2-week run-in phase without HCL control, or Auto Mode, enabled (Manual Mode) and, thereafter, with Auto Mode enabled during a 3-month study phase. A supervised hotel stay (6 days/5 nights) that included a 24-h frequent blood sample testing with a reference measurement (i-STAT) occurred during the study phase. Results: Adolescents (mean ± standard deviation [SD] 16.5 ± 2.29 years of age and 7.7 ± 4.15 years of diabetes) used the system for a median 75.8% (interquartile range [IQR] 68.0%–88.4%) of the time (2977 pati...