Showing papers by "University of Tennessee Health Science Center published in 2014"
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University of Iowa1, University of Alabama at Birmingham2, University of Tennessee Health Science Center3, Johns Hopkins University4, Kaiser Permanente5, Medical University of South Carolina6, University of Missouri7, University of Colorado Denver8, New York University9, University of North Carolina at Chapel Hill10, Duke University11, Mayo Clinic12, University of Pennsylvania13, Case Western Reserve University14, National Institutes of Health15
TL;DR: Although this guideline provides evidence-based recommendations for the management of high BP and should meet the clinical needs of most patients, these recommendations are not a substitute for clinical judgment, and decisions about care must carefully consider and incorporate the clinical characteristics and circumstances of each individual patient.
Abstract: Hypertension is the most common condition seen in primary care and leads to myocardial infarction, stroke, renal failure, and death if not detected early and treated appropriately. Patients want to be assured that blood pressure (BP) treatment will reduce their disease burden, while clinicians want guidance on hypertension management using the best scientific evidence. This report takes a rigorous, evidence-based approach to recommend treatment thresholds, goals, and medications in the management of hypertension in adults. Evidence was drawn from randomized controlled trials, which represent the gold standard for determining efficacy and effectiveness. Evidence quality and recommendations were graded based on their effect on important outcomes. There is strong evidence to support treating hypertensive persons aged 60 years or older to a BP goal of less than 150/90 mm Hg and hypertensive persons 30 through 59 years of age to a diastolic goal of less than 90 mm Hg; however, there is insufficient evidence in hypertensive persons younger than 60 years for a systolic goal, or in those younger than 30 years for a diastolic goal, so the panel recommends a BP of less than 140/90 mm Hg for those groups based on expert opinion. The same thresholds and goals are recommended for hypertensive adults with diabetes or nondiabetic chronic kidney disease (CKD) as for the general hypertensive population younger than 60 years. There is moderate evidence to support initiating drug treatment with an angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, calcium channel blocker, or thiazide-type diuretic in the nonblack hypertensive population, including those with diabetes. In the black hypertensive population, including those with diabetes, a calcium channel blocker or thiazide-type diuretic is recommended as initial therapy. There is moderate evidence to support initial or add-on antihypertensive therapy with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in persons with CKD to improve kidney outcomes. Although this guideline provides evidence-based recommendations for the management of high BP and should meet the clinical needs of most patients, these recommendations are not a substitute for clinical judgment, and decisions about care must carefully consider and incorporate the clinical characteristics and circumstances of each individual patient.
7,119 citations
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Boston Children's Hospital1, University of California, San Diego2, University of California, San Francisco3, Oregon Health & Science University4, Northwestern University5, University of Tennessee Health Science Center6, University of British Columbia7, Children's Memorial Hospital8, New York University9, Case Western Reserve University10, Mayo Clinic11, Wake Forest University12, University of Pennsylvania13, University of Nottingham14, University of Alabama at Birmingham15, Rafael Advanced Defense Systems16, American Academy of Dermatology17, Seattle Children's18
TL;DR: Treatment of atopic dermatitis with nonpharmacologic interventions and pharmacologic topical therapies are reviewed and suggestions on dosing and monitoring are given based on available evidence.
Abstract: Atopic dermatitis is a common and chronic, pruritic inflammatory skin condition that can affect all age groups. This evidence-based guideline addresses important clinical questions that arise in its management. In this second of 4 sections, treatment of atopic dermatitis with nonpharmacologic interventions and pharmacologic topical therapies are reviewed. Where possible, suggestions on dosing and monitoring are given based on available evidence.
889 citations
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TL;DR: In this article, the authors analyzed 127 pediatric HGGs, including diffuse intrinsic pontine gliomas (DIPGs) and non-brainstem HGG (NBS-HGGs), by whole-genome, whole-exome and/or transcriptome sequencing.
Abstract: Pediatric high-grade glioma (HGG) is a devastating disease with a less than 20% survival rate 2 years after diagnosis. We analyzed 127 pediatric HGGs, including diffuse intrinsic pontine gliomas (DIPGs) and non-brainstem HGGs (NBS-HGGs), by whole-genome, whole-exome and/or transcriptome sequencing. We identified recurrent somatic mutations in ACVR1 exclusively in DIPGs (32%), in addition to previously reported frequent somatic mutations in histone H3 genes, TP53 and ATRX, in both DIPGs and NBS-HGGs. Structural variants generating fusion genes were found in 47% of DIPGs and NBS-HGGs, with recurrent fusions involving the neurotrophin receptor genes NTRK1, NTRK2 and NTRK3 in 40% of NBS-HGGs in infants. Mutations targeting receptor tyrosine kinase-RAS-PI3K signaling, histone modification or chromatin remodeling, and cell cycle regulation were found in 68%, 73% and 59% of pediatric HGGs, respectively, including in DIPGs and NBS-HGGs. This comprehensive analysis provides insights into the unique and shared pathways driving pediatric HGG within and outside the brainstem.
848 citations
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Johns Hopkins University1, University of Calgary2, The George Institute for Global Health3, University of Sydney4, Royal Prince Alfred Hospital5, University of Salerno6, Geisinger Medical Center7, Saarland University8, Tufts Medical Center9, University of Minnesota10, University of California, San Diego11, Veterans Health Administration12, University of Tennessee Health Science Center13, University of Aberdeen14, Teikyo University15, Tohoku University16, Shiga University of Medical Science17, Tel Aviv University18, Virginia Commonwealth University19, National Health Research Institutes20, China Medical University (Taiwan)21, University Medical Center Groningen22, University of Paris-Sud23
TL;DR: Declines in estimated GFR smaller than a doubling of serum creatinine concentration occurred more commonly and were strongly and consistently associated with the risk of ESRD and mortality, supporting consideration of lesser declines in Estimated GFR (such as a 30% reduction over 2 years) as an alternative end point for CKD progression.
Abstract: IMPORTANCE: The established chronic kidney disease (CKD) progression end point of end-stage renal disease (ESRD) or a doubling of serum creatinine concentration (corresponding to a change in estimated glomerular filtration rate [GFR] of −57% or greater) is a late event.OBJECTIVE: To characterize the association of decline in estimated GFR with subsequent progression to ESRD with implications for using lesser declines in estimated GFR as potential alternative end points for CKD progression. Because most people with CKD die before reaching ESRD, mortality risk also was investigated.DATA SOURCES AND STUDY SELECTION: Individual meta-analysis of 1.7 million participants with 12,344 ESRD events and 223,944 deaths from 35 cohorts in the CKD Prognosis Consortium with a repeated measure of serum creatinine concentration over 1 to 3 years and outcome data.DATA EXTRACTION AND SYNTHESIS: Transfer of individual participant data or standardized analysis of outputs for random-effects meta-analysis conducted between July 2012 and September 2013, with baseline estimated GFR values collected from 1975 through 2012.MAIN OUTCOMES AND MEASURES: End-stage renal disease (initiation of dialysis or transplantation) or all-cause mortality risk related to percentage change in estimated GFR over 2 years, adjusted for potential confounders and first estimated GFR.RESULTS: The adjusted hazard ratios (HRs) of ESRD and mortality were higher with larger estimated GFR decline. Among participants with baseline estimated GFR of less than 60 mL/min/1.73 m2, the adjusted HRs for ESRD were 32.1 (95% CI, 22.3-46.3) for changes of −57% in estimated GFR and 5.4 (95% CI, 4.5-6.4) for changes of −30%. However, changes of −30% or greater (6.9% [95% CI, 6.4%-7.4%] of the entire consortium) were more common than changes of −57% (0.79% [95% CI, 0.52%-1.06%]). This association was strong and consistent across the length of the baseline period (1 to 3 years), baseline estimated GFR, age, diabetes status, or albuminuria. Average adjusted 10-year risk of ESRD (in patients with a baseline estimated GFR of 35 mL/min/1.73 m2) was 99% (95% CI, 95%-100%) for estimated GFR change of −57%, was 83% (95% CI, 71%-93%) for estimated GFR change of −40%, and was 64% (95% CI, 52%-77%) for estimated GFR change of −30% vs 18% (95% CI, 15%-22%) for estimated GFR change of 0%. Corresponding mortality risks were 77% (95% CI, 71%-82%), 60% (95% CI, 56%-63%), and 50% (95% CI, 47%-52%) vs 32% (95% CI, 31%-33%), showing a similar but weaker pattern.CONCLUSIONS AND RELEVANCE: Declines in estimated GFR smaller than a doubling of serum creatinine concentration occurred more commonly and were strongly and consistently associated with the risk of ESRD and mortality, supporting consideration of lesser declines in estimated GFR (such as a 30% reduction over 2 years) as an alternative end point for CKD progression.
742 citations
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University of Connecticut1, University of Adelaide2, Winthrop-University Hospital3, University of Texas MD Anderson Cancer Center4, City of Hope National Medical Center5, Virginia Commonwealth University6, University of Tennessee Health Science Center7, National and Kapodistrian University of Athens8, Brigham and Women's Hospital9, University of Rochester10
685 citations
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Seattle Children's1, Mayo Clinic2, New York University3, University of California, San Francisco4, University of British Columbia5, Northwestern University6, Case Western Reserve University7, Wake Forest University8, Oregon Health & Science University9, University of Pennsylvania10, University of Tennessee Health Science Center11, Boston Children's Hospital12, University of San Diego13, University of Nottingham14, University of Alabama at Birmingham15, American Academy of Dermatology16
TL;DR: The treatment of atopic dermatitis with phototherapy and systemic immunomodulators, antimicrobials, and antihistamines is reviewed in this article, including indications for use and the risk-benefit profile of each treatment option.
Abstract: Atopic dermatitis is a chronic, pruritic inflammatory dermatosis that affects up to 25% of children and 2% to 3% of adults This guideline addresses important clinical questions that arise in atopic dermatitis management and care, providing recommendations based on the available evidence In this third of 4 sections, treatment of atopic dermatitis with phototherapy and systemic immunomodulators, antimicrobials, and antihistamines is reviewed, including indications for use and the risk-benefit profile of each treatment option
632 citations
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TL;DR: The current knowledge of the roles TLRs play in antiviral innate immune responses is reviewed, examples of TLR-mediated viral recognition are discussed, and strategies used by viruses to antagonize the host antiviral inherent immune responses are described.
516 citations
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University of Genoa1, Nova Southeastern University2, Nippon Medical School3, The Catholic University of America4, University of Tennessee Health Science Center5, Seconda Università degli Studi di Napoli6, University of Montpellier7, National Institutes of Health8, Erasmus University Rotterdam9, University of Colorado Denver10, Federal University of Paraná11, University of Aberdeen12, University of Missouri–Kansas City13, University of Zurich14, University of Turku15, National University of Singapore16, Mahidol University17, Humboldt University of Berlin18
TL;DR: “Raising public awareness about sublingual immunotherapy”, as a need for patients, and strategies to increase awareness of allergen immunotherapy (AIT) among patients, the medical community, all healthcare stakeholders, and public opinion are reported in detail.
515 citations
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TL;DR: The study was underpowered because it did not meet the planned accrual target, and OS was higher than predicted in both arms, but IC cannot be recommended routinely in patients with N2 or N3 locally advanced SCCHN.
Abstract: Purpose Induction chemotherapy (IC) before radiotherapy lowers distant failure (DF) rates in locally advanced squamous cell carcinoma of the head and neck (SCCHN). The goal of this phase III trial was to determine whether IC before chemoradiotherapy (CRT) further improves survival compared with CRT alone in patients with N2 or N3 disease. Patients and Methods Treatment-naive patients with nonmetastatic N2 or N3 SCCHN were randomly assigned to CRT alone (CRT arm; docetaxel, fluorouracil, and hydroxyurea plus radiotherapy 0.15 Gy twice per day every other week) versus two 21-day cycles of IC (docetaxel 75 mg/m2 on day 1, cisplatin 75 mg/m2 on day 1, and fluorouracil 750 mg/m2 on days 1 to 5) followed by the same CRT regimen (IC + CRT arm). The primary end point was overall survival (OS). Secondary end points included DF-free survival, failure pattern, and recurrence-free survival (RFS). Results A total of 285 patients were randomly assigned. The most common grade 3 to 4 toxicities during IC were febrile neu...
421 citations
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TL;DR: The Systolic Blood Pressure Intervention Trial will provide important information on the risks and benefits of intensive blood pressure treatment targets in a diverse sample of high-risk participants, including those with prior cardiovascular disease, chronic kidney disease, and those aged ≥75 years.
Abstract: Background:High blood pressure is an important public health concern because it is highly prevalent and a risk factor for adverse health outcomes, including coronary heart disease, stroke, decompensated heart failure, chronic kidney disease, and decline in cognitive function. Observational studies show a progressive increase in risk associated with blood pressure above 115/75 mm Hg. Prior research has shown that reducing elevated systolic blood pressure lowers the risk of subsequent clinical complications from cardiovascular disease. However, the optimal systolic blood pressure to reduce blood pressure–related adverse outcomes is unclear, and the benefit of treating to a level of systolic blood pressure well below 140 mm Hg has not been proven in a large, definitive clinical trial.Purpose:To describe the design considerations of the Systolic Blood Pressure Intervention Trial (SPRINT) and the baseline characteristics of trial participants.Methods:The Systolic Blood Pressure Intervention Trial is a multicen...
417 citations
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University of California, San Francisco1, University of South Florida2, University of Tennessee Health Science Center3, Northwestern University4, Memorial Sloan Kettering Cancer Center5, Seattle Cancer Care Alliance6, City of Hope National Medical Center7, Fox Chase Cancer Center8, Duke University9, Pancreatic Cancer Action Network10, University of Michigan11, Washington University in St. Louis12, Johns Hopkins University13, Stanford University14, University of California, San Diego15, Roswell Park Cancer Institute16, Vanderbilt University17, University of Utah18, Ohio State University19, Harvard University20, University of Alabama at Birmingham21, University of Nebraska Medical Center22, University of Colorado Boulder23, University of Texas MD Anderson Cancer Center24, Brigham and Women's Hospital25, National Comprehensive Cancer Network26
TL;DR: These NCCN Guidelines Insights summarize major discussion points from the 2014 NCCn Pancreatic Adenocarcinoma Panel meeting, which focused mainly on the management of borderline resectable and locally advanced disease.
Abstract: The NCCN Guidelines for Pancreatic Adenocarcinoma discuss the diagnosis and management of adenocarcinomas of the exocrine pancreas and are intended to assist with clinical decision-making. These NCCN Guidelines Insights summarize major discussion points from the 2014 NCCN Pancreatic Adenocarcinoma Panel meeting. The panel discussion focused mainly on the management of borderline resectable and locally advanced disease. In particular, the panel discussed the definition of borderline resectable disease, role of neoadjuvant therapy in borderline disease, role of chemoradiation in locally advanced disease, and potential role of newer, more active chemotherapy regimens in both settings.
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TL;DR: The integrated data from CLASH experiments in the PolymiRTS database is integrated to provide more complete and accurate miRNA–mRNA interactions and other significant new features include small insertions and deletions in miRNA seed regions and miRNA target sites.
Abstract: Polymorphisms in microRNAs (miRNAs) and their target sites (PolymiRTS) are known to disrupt miRNA function, leading to the development of disease and variation in physiological and behavioral phenotypes. Here, we describe recent updates to the PolymiRTS database (http://compbio.uthsc.edu/miRSNP), an integrated platform for analyzing the functional impact of genetic polymorphisms in miRNA seed regions and miRNA target sites. Recent advances in genomic technologies have made it possible to identify miRNA-mRNA binding sites from direct mapping experiments such as CLASH (cross linking, ligation and sequencing of hybrids). We have integrated data from CLASH experiments in the PolymiRTS database to provide more complete and accurate miRNA-mRNA interactions. Other significant new features include (i) small insertions and deletions in miRNA seed regions and miRNA target sites, (ii) TargetScan context + score differences for assessing the impact of polymorphic miRNA-mRNA interactions and (iii) biological pathways. The browse and search pages of PolymiRTS allow users to explore the relations between the PolymiRTSs and gene expression traits, physiological and behavioral phenotypes, human diseases and biological pathways.
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Baylor College of Medicine1, Ohio State University2, University of Florida3, Thomas Jefferson University4, University of Tennessee Health Science Center5, Indiana University – Purdue University Indianapolis6, University of Pennsylvania7, University of South Florida8, University of Texas Medical Branch9
TL;DR: This study provides level 1 data, suggesting that elimination of intraperitoneal drainage in all cases of PD increases the frequency and severity of complications.
Abstract: Objective To test by randomized prospective multicenter trial the hypothesis that pancreaticoduodenectomy (PD) without the use of intraperitoneal drainage does not increase the frequency or severity of complications. Background Some surgeons have abandoned the use of drains placed during pancreas resection. Methods We randomized 137 patients to PD with (n = 68, drain group) and without (n = 69, no-drain group) the use of intraperitoneal drainage and compared the safety of this approach and spectrum of complications between the 2 groups. Results There were no differences between drain and no-drain cohorts in demographics, comorbidities, pathology, pancreatic duct size, pancreas texture, baseline quality of life, or operative technique. PD without intraperitoneal drainage was associated with an increase in the number of complications per patient [1 (0-2) vs 2 (1-4), P = 0.029]; an increase in the number of patients who had at least 1 ≥grade 2 complication [35 (52%) vs 47 (68%), P = 0.047]; and a higher average complication severity [2 (0-2) vs 2 (1-3), P = 0.027]. PD without intraperitoneal drainage was associated with a higher incidence of gastroparesis, intra-abdominal fluid collection, intra-abdominal abscess (10% vs 25%, P = 0.027), severe (≥grade 2) diarrhea, need for a postoperative percutaneous drain, and a prolonged length of stay. The Data Safety Monitoring Board stopped the study early because of an increase in mortality from 3% to 12% in the patients undergoing PD without intraperitoneal drainage. Conclusions This study provides level 1 data, suggesting that elimination of intraperitoneal drainage in all cases of PD increases the frequency and severity of complications.
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Roswell Park Cancer Institute1, Brigham and Women's Hospital2, Duke University3, Ohio State University4, University of Utah5, Memorial Sloan Kettering Cancer Center6, University of Nebraska–Lincoln7, University of Washington8, Fox Chase Cancer Center9, University of California, San Diego10, Washington University in St. Louis11, Northwestern University12, Harvard University13, Vanderbilt University14, University of Michigan15, Moffitt Cancer Center16, University of Colorado Boulder17, University of Tennessee Health Science Center18, University of California, San Francisco19, University of Texas MD Anderson Cancer Center20, Johns Hopkins University21, University of Alabama at Birmingham22, Stanford University23, City of Hope National Medical Center24
TL;DR: Significant updates for early disease include distinction between active surveillance and observation, a new section on principles of imaging, and revisions to radiation recommendations.
Abstract: Prostate cancer has surpassed lung cancer as the most common cancer in men in the United States. The NCCN Guidelines for Prostate Cancer provide multidisciplinary recommendations on the clinical management of patients with prostate cancer based on clinical evidence and expert consensus. NCCN Panel guidance on treatment decisions for patients with localized disease is represented in this version. Significant updates for early disease include distinction between active surveillance and observation, a new section on principles of imaging, and revisions to radiation recommendations. The full version of these guidelines, including treatment of patients with advanced disease, can be found online at the NCCN website.
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TL;DR: It is demonstrated that O-GlcNAcylation regulates cancer cell metabolic reprograming and survival stress signaling via regulation of HIF-1α and its transcriptional target GLUT1.
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TL;DR: The widely used Alkylating Agent Dose (AAD) score is derived from the drug dose distribution of the study population and thus cannot be used for comparisons across populations as each will have a unique distribution of drug doses.
Abstract: BACKGROUND
Estimation of the risk of adverse long-term outcomes such as second malignant neoplasms and infertility often requires reproducible quantification of exposures. The method for quantification should be easily utilized and valid across different study populations. The widely used Alkylating Agent Dose (AAD) score is derived from the drug dose distribution of the study population and thus cannot be used for comparisons across populations as each will have a unique distribution of drug doses.
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TL;DR: The obesity paradox in ESRD is unlikely to be due to residual confounding alone and has biologic plausibility, but well-designed studies exploring the causes and consequences of the reverse epidemiology of cardiovascular risk factors, including the obesity paradox, among ESRd patients could provide more information on mechanisms.
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TL;DR: Treatment with GS-5806 reduced the viral load and the severity of clinical disease in a challenge study of healthy adults, and adverse events, including low neutrophil counts and increased levels of alanine aminotransferase, were more common among participants receiving the drug.
Abstract: Background Respiratory syncytial virus (RSV) is a common cause of infant hospitalizations and is increasingly recognized as a cause of considerable morbidity and mortality. No accepted antiviral treatment exists. Methods We conducted a double-blind, placebo-controlled study of GS-5806, an oral RSV-entry inhibitor, in healthy adults who received a clinical challenge strain of RSV intranasally. Participants were monitored for 12 days. At the time of a positive test for RSV infection or 5 days after inoculation, whichever occurred first, participants were randomly assigned to receive GS-5806 or placebo in one of seven sequential cohorts. Cohorts 1 to 4 received a first dose of 50 mg of GS-5806 and then 25 mg daily for the next 4 days, cohort 5 received a first dose of 50 mg and then 25 mg daily for the next 2 days, cohort 6 received one 100-mg dose, and cohort 7 received a first dose of 10 mg and then 5 mg daily for the next 4 days. Dose selection for cohorts 5, 6, and 7 occurred after an interim analysis of...
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TL;DR: Coenzyme Q10 was safe and well tolerated in this population, but showed no evidence of clinical benefit, and the study was terminated after a prespecified futility criterion was reached.
Abstract: Importance Coenzyme Q10 (CoQ10), an antioxidant that supports mitochondrial function, has been shown in preclinical Parkinson disease (PD) models to reduce the loss of dopamine neurons, and was safe and well tolerated in early-phase human studies. A previous phase II study suggested possible clinical benefit. Objective To examine whether CoQ10 could slow disease progression in early PD. Design, Setting, and Participants A phase III randomized, placebo-controlled, double-blind clinical trial at 67 North American sites consisting of participants 30 years of age or older who received a diagnosis of PD within 5 years and who had the following inclusion criteria: the presence of a rest tremor, bradykinesia, and rigidity; a modified Hoehn and Yahr stage of 2.5 or less; and no anticipated need for dopaminergic therapy within 3 months. Exclusion criteria included the use of any PD medication within 60 days, the use of any symptomatic PD medication for more than 90 days, atypical or drug-induced parkinsonism, a Unified Parkinson’s Disease Rating Scale (UPDRS) rest tremor score of 3 or greater for any limb, a Mini-Mental State Examination score of 25 or less, a history of stroke, the use of certain supplements, and substantial recent exposure to CoQ10. Of 696 participants screened, 78 were found to be ineligible, and 18 declined participation. Interventions The remaining 600 participants were randomly assigned to receive placebo, 1200 mg/d of CoQ10, or 2400 mg/d of CoQ10; all participants received 1200 IU/d of vitamin E. Main Outcomes and Measures Participants were observed for 16 months or until a disability requiring dopaminergic treatment. The prospectively defined primary outcome measure was the change in total UPDRS score (Parts I-III) from baseline to final visit. The study was powered to detect a 3-point difference between an active treatment and placebo. Results The baseline characteristics of the participants were well balanced, the mean age was 62.5 years, 66% of participants were male, and the mean baseline total UPDRS score was 22.7. A total of 267 participants required treatment (94 received placebo, 87 received 1200 mg/d of CoQ10, and 86 received 2400 mg/d of CoQ10), and 65 participants (29 who received placebo, 19 who received 1200 mg/d of CoQ10, and 17 who received 2400 mg/d of CoQ10) withdrew prematurely. Treatments were well tolerated with no safety concerns. The study was terminated after a prespecified futility criterion was reached. At study termination, both active treatment groups showed slight adverse trends relative to placebo. Adjusted mean changes (worsening) in total UPDRS scores from baseline to final visit were 6.9 points (placebo), 7.5 points (1200 mg/d of CoQ10; P = .49 relative to placebo), and 8.0 points (2400 mg/d of CoQ10; P = .21 relative to placebo). Conclusions and Relevance Coenzyme Q10 was safe and well tolerated in this population, but showed no evidence of clinical benefit. Trial Registration clinicaltrials.gov Identifier:NCT00740714
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Seattle Children's1, University of California, San Diego2, University of British Columbia3, Case Western Reserve University4, University of California, San Francisco5, Northwestern University6, New York University7, Mayo Clinic8, Wake Forest University9, Oregon Health & Science University10, University of Pennsylvania11, University of Tennessee Health Science Center12, University of Nottingham13, University of Alabama at Birmingham14, Rafael Advanced Defense Systems15, American Academy of Dermatology16
TL;DR: Treatments for flare prevention and adjunctive and complementary therapies and approaches are reviewed and suggestions on use are given based on available evidence.
Abstract: Atopic dermatitis is a common, chronic inflammatory dermatosis that can affect all age groups. This evidence-based guideline addresses important clinical questions that arise in its management. In this final section, treatments for flare prevention and adjunctive and complementary therapies and approaches are reviewed. Suggestions on use are given based on available evidence.
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TL;DR: It is demonstrated that the neonatal mouse cochlea is capable of spontaneous hair cell regeneration after damage in vivo, which might shed light on the competence of supporting cells to regenerate hair cells and on the factors that promote the survival of newly regenerated hair cells.
Abstract: Loss of cochlear hair cells in mammals is currently believed to be permanent, resulting in hearing impairment that affects more than 10% of the population. Here, we developed two genetic strategies to ablate neonatal mouse cochlear hair cells in vivo. Both Pou4f3 DTR/+ and Atoh1-CreER TM ; ROSA26 DTA/+ alleles allowed selective and inducible hair cell ablation. After hair cell loss was induced at birth, we observed spontaneous regeneration of hair cells. Fate-mapping experiments demonstrated that neighboring supporting cells acquired a hair cell fate, which increased in a basal to apical gradient, averaging over 120 regenerated hair cells per cochlea. The normally mitotically quiescent supporting cells proliferated after hair cell ablation. Concurrent fate mapping and labeling with mitotic tracers showed that regenerated hair cells were derived by both mitotic regeneration and direct transdifferentiation. Over time, regenerated hair cells followed a similar pattern of maturation to normal hair cell development, including the expression of prestin, a terminal differentiation marker of outer hair cells, although many new hair cells eventually died. Hair cell regeneration did not occur when ablation was induced at one week of age. Our findings demonstrate that the neonatal mouse cochlea is capable of spontaneous hair cell regeneration after damage in vivo. Thus, future studies on the neonatal cochlea might shed light on the competence of supporting cells to regenerate hair cells and on the factors that promote the survival of newly regenerated hair cells.
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TL;DR: The American Brachytherapy Society (ABS) as mentioned in this paper developed a set of guidelines for plaque brachythermytherapy of choroidal melanoma and retinoblastoma.
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TL;DR: MTX-related clinical neurotoxicity is transient, and most patients can receive subsequent MTX without recurrence of acute or subacute symptoms, and all symptomatic patients and one in five asymptomatic patients develop leukoencephalopathy that can persist until the end of therapy.
Abstract: Purpose Methotrexate (MTX) can cause significant clinical neurotoxicity and asymptomatic leukoencephalopathy. We sought to identify clinical, pharmacokinetic, and genetic risk factors for these MTX-related toxicities during childhood acute lymphoblastic leukemia (ALL) therapy and provide data on safety of intrathecal and high-dose MTX rechallenge in patients with neurotoxicity. Patients and Methods Prospective brain magnetic resonance imaging was performed at four time points for 369 children with ALL treated in a contemporary study that included five courses of high-dose MTX and 13 to 25 doses of triple intrathecal therapy. Logistic regression modeling was used to evaluate clinical and pharmacokinetic factors, and a genome-wide association study (GWAS) was performed to identify germline polymorphisms for their association with neurotoxicities. Results Fourteen patients (3.8%) developed MTX-related clinical neurotoxicity. Of 13 patients rechallenged with intrathecal and/or high-dose MTX, 12 did not experience recurrence of neurotoxicity. Leukoencephalopathy was found in 73 (20.6%) of 355 asymptomatic patients and in all symptomatic patients and persisted in 74% of asymptomatic and 58% of symptomatic patients at the end of therapy. A high 42-hour plasma MTX to leucovorin ratio (measure of MTX exposure) was associated with increased risk of leukoencephalopathy in multivariable analysis (P .038). GWAS revealed polymorphisms in genes enriched for neurodevelopmental pathways with plausible mechanistic roles in neurotoxicity.
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Illawarra Health & Medical Research Institute1, Pasteur Institute2, QIMR Berghofer Medical Research Institute3, St. Vincent's Institute of Medical Research4, University of Queensland5, Royal Children's Hospital6, New York Medical College7, University of Tennessee Health Science Center8, Centers for Disease Control and Prevention9, Telethon Institute for Child Health Research10, Université libre de Bruxelles11
TL;DR: A functional classification based on 48 emm-clusters containing closely related M proteins that share binding and structural properties is proposed and will facilitate the design of future studies of M protein function, streptococcal virulence, epidemiological surveillance, and vaccine development.
Abstract: Streptococcus pyogenes ranks among the main causes of mortality from bacterial infections worldwide. Currently there is no vaccine to prevent diseases such as rheumatic heart disease and invasive streptococcal infection. The streptococcal M protein that is used as the substrate for epidemiological typing is both a virulence factor and a vaccine antigen. Over 220 variants of this protein have been described, making comparisons between proteins difficult, and hindering M protein-based vaccine development. A functional classification based on 48 emm-clusters containing closely related M proteins that share binding and structural properties is proposed. The need for a paradigm shift from type-specific immunity against S. pyogenes to emm-cluster based immunity for this bacterium should be further investigated. Implementation of this emm-cluster-based system as a standard typing scheme for S. pyogenes will facilitate the design of future studies of M protein function, streptococcal virulence, epidemiological surveillance, and vaccine development.
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Cornell University1, Washington University in St. Louis2, University of Groningen3, University of Zurich4, University of Illinois at Urbana–Champaign5, Oxford Brookes University6, Auburn University7, University of Houston8, United States Department of Health and Human Services9, University of Tennessee Health Science Center10, Harvard University11, University College London12
TL;DR: The house fly genome provides a rich resource for enabling work on innovative methods of insect control, for understanding the mechanisms of insecticide resistance, genetic adaptation to high pathogen loads, and for exploring the basic biology of this important pest.
Abstract: Adult house flies, Musca domestica L., are mechanical vectors of more than 100 devastating diseases that have severe consequences for human and animal health. House fly larvae play a vital role as decomposers of animal wastes, and thus live in intimate association with many animal pathogens. We have sequenced and analyzed the genome of the house fly using DNA from female flies. The sequenced genome is 691 Mb. Compared with Drosophila melanogaster, the genome contains a rich resource of shared and novel protein coding genes, a significantly higher amount of repetitive elements, and substantial increases in copy number and diversity of both the recognition and effector components of the immune system, consistent with life in a pathogen-rich environment. There are 146 P450 genes, plus 11 pseudogenes, in M. domestica, representing a significant increase relative to D. melanogaster and suggesting the presence of enhanced detoxification in house flies. Relative to D. melanogaster, M. domestica has also evolved an expanded repertoire of chemoreceptors and odorant binding proteins, many associated with gustation. This represents the first genome sequence of an insect that lives in intimate association with abundant animal pathogens. The house fly genome provides a rich resource for enabling work on innovative methods of insect control, for understanding the mechanisms of insecticide resistance, genetic adaptation to high pathogen loads, and for exploring the basic biology of this important pest. The genome of this species will also serve as a close out-group to Drosophila in comparative genomic studies.
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Northwestern University1, University of California, San Francisco2, Ohio State University3, Vanderbilt University4, City of Hope National Medical Center5, Fox Chase Cancer Center6, Brigham and Women's Hospital7, University of Tennessee Health Science Center8, University of Nebraska Medical Center9, University of Alabama10, Seattle Cancer Care Alliance11, University of Colorado Boulder12, University of California, San Diego13, Roswell Park Cancer Institute14, University of Texas MD Anderson Cancer Center15, Harvard University16, Memorial Sloan Kettering Cancer Center17, University of Utah18, Washington University in St. Louis19, University of South Florida20, Johns Hopkins University21, Duke University22
TL;DR: The NCCN Guidelines for Colon Cancer address diagnosis, pathologic staging, surgical management, perioperative treatment, posttreatment surveillance, management of recurrent and metastatic disease, and survivorship.
Abstract: The NCCN Guidelines for Colon Cancer address diagnosis, pathologic staging, surgical management, perioperative treatment, posttreatment surveillance, management of recurrent and metastatic disease,and survivorship This portion of the guidelines focuses on the use of systemic therapy in metastatic disease The management of metastatic colorectal cancer involves a continuum of care in which patients are exposed sequentially to a variety of active agents, either in combinations or as single agents Choice of therapy is based on the goals of treatment, the type and timing of prior therapy, the different efficacy and toxicity profiles of the drugs, the mutational status of the tumor, and patient preference
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TL;DR: This study identifies a novel signaling pathway, in which 20(OH)D3 and 20,23( OH)2D3 act as antagonists or inverse agonists of RORα and RORγ, that opens new possibilities for local (skin) or systemic regulation.
Abstract: RORα and RORγ are expressed in human skin cells that produce the noncalcemic 20-hydroxyvitamin D3 [20(OH)D3] and 20,23-dihydroxyvitamin D3 [20,23(OH)2D3]. Chinese hamster ovary (CHO) cells stably expressing a Tet-on RORα or RORγ expression vector and a ROR-responsive element (RORE)-LUC reporter, and a mammalian 2-hybrid model examining the interaction between the ligand binding domain (LBD) of RORα or RORγ with an LBD-interacting LXXLL-peptide, were used to study ROR-antagonist activities. These assays revealed that 20(OH)D3 and 20,23(OH)2D3 function as antagonists of RORα and RORγ. Moreover, 20(OH)D3 inhibited the activation of the promoter of the Bmal1 and G6pase genes, targets of RORα, and 20(OH)D3 and 20,23(OH)2D3 inhibited Il17 promoter activity in Jurkat cells overexpressing RORα or RORγ. Molecular modeling using crystal structures of the LBDs of RORα and RORγ revealed docking scores for 20(OH)D3, 20,23(OH)2D3 and 1,25(OH)2D3 similar to those of the natural ligands, predicting good binding to the receptor. Notably, 20(OH)D3, 20,23(OH)2D3, and 1,25(OH)2D3 inhibited RORE-mediated activation of a reporter in keratinocytes and melanoma cells and inhibited IL-17 production by immune cells. Our study identifies a novel signaling pathway, in which 20(OH)D3 and 20,23(OH)2D3 act as antagonists or inverse agonists of RORα and RORγ, that opens new possibilities for local (skin) or systemic regulation.-Slominski, A. T., Kim, T.-K., Takeda, Y., Janjetovic, Z., Broz˙yna, A. A., Skobowiat, C., Wang, J., Postlethwaite, A., Li, W., Tuckey, R. C., Jetten, A. M. RORα and ROR γ are expressed in human skin and serve as receptors for endogenously produced noncalcemic 20-hydroxy- and 20,23-dihydroxyvitamin D.
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TL;DR: Insight is given into how SNPs impact gene regulation and the notion that peripheral blood may be a reliable correlate of physiological processes in other tissues is supported.
Abstract: Individual genotypes at specific loci can result in different patterns of DNA methylation. These methylation quantitative trait loci (meQTLs) influence methylation across extended genomic regions and may underlie direct SNP associations or gene-environment interactions. We hypothesized that the detection of meQTLs varies with ancestral population, developmental stage, and tissue type. We explored this by analyzing seven datasets that varied by ancestry (African American vs. Caucasian), developmental stage (neonate vs. adult), and tissue type (blood vs. four regions of postmortem brain) with genome-wide DNA methylation and SNP data. We tested for meQTLs by constructing linear regression models of methylation levels at each CpG site on SNP genotypes within 50 kb under an additive model controlling for multiple tests. Most meQTLs mapped to intronic regions, although a limited number appeared to occur in synonymous or nonsynonymous coding SNPs. We saw significant overlap of meQTLs between ancestral groups, developmental stages, and tissue types, with the highest rates of overlap within the four brain regions. Compared with a random group of SNPs with comparable frequencies, meQTLs were more likely to be 1) represented among the most associated SNPs in the WTCCC bipolar disorder results and 2) located in microRNA binding sites. These data give us insight into how SNPs impact gene regulation and support the notion that peripheral blood may be a reliable correlate of physiological processes in other tissues.
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TL;DR: Results indicate that PLGA-CUR NPs efficiently internalize in prostate cancer cells and release biologically active CUR in cytosolic compartment of cells for effective therapeutic activity and can significantly accumulate and exhibit superior anticancer activity in prostatecancer.
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TL;DR: This document provides evidence-based guidance for clinical practices involving PN prescribing, order review, and preparation using consensus prior to review and approval by the American Society for Parenteral and Enteral Nutrition Board of Directors.
Abstract: Background Parenteral nutrition (PN) is a high-alert medication available for patient care within a complex clinical process. Beyond application of best practice recommendations to guide safe use and optimize clinical outcome, several issues are better addressed through evidence-based policies, procedures, and practices. This document provides evidence-based guidance for clinical practices involving PN prescribing, order review, and preparation. Method A systematic review of the best available evidence was used by an expert work group to answer a series of questions about PN prescribing, order review, compounding, labeling, and dispensing. Concepts from the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) format were applied as appropriate. The specific clinical guideline recommendations were developed using consensus prior to review and approval by the American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) Board of Directors. The following questions were addressed: (1) Does education of prescribers improve PN ordering? (2) What is the maximum safe osmolarity of PN admixtures intended for peripheral vein administration? (3) What are the appropriate calcium intake and calcium-phosphate ratios in PN for optimal neonatal bone mineralization? (4) What are the clinical advantages or disadvantages of commercially available premade ("premixed") multichambered PN formulations compared with traditional/customized PN formulations? (5) What are the clinical (infection, catheter occlusion) advantages or disadvantages of 2-in-1 compared with 3-in-1 PN admixtures? (6) What macronutrient dosing limits are expected to provide for the most stable 3-in-1 admixtures? (7) What are the most appropriate recommendations for optimizing calcium (gluconate) and (Na- or K-) phosphate compatibility in PN admixtures? (8) What micronutrient contamination is present in parenteral stock solutions currently used to compound PN admixtures? (9) Is it safe to use the PN admixture as a vehicle for non-nutrient medication delivery? (10) Should heparin be included in the PN admixture to reduce the risk of central vein thrombosis? (11) What methods of repackaging intravenous fat emulsion (IVFE) into smaller patient-specific volumes are safe? (12) What beyond-use date should be used for (a) IVFE dispensed for separate infusion in the original container and (b) repackaged IVFE?