Showing papers by "University of Maryland, Baltimore published in 2013"
Stanford University1, Maine Medical Center2, University of California, San Francisco3, Veterans Health Administration4, McGill University5, University of Texas at Austin6, Scripps Health7, Northeastern University8, University of Chicago9, University of Washington10, University of Wisconsin-Madison11, University of Maryland, Baltimore12, University of Cincinnati13, University of Virginia14, Baylor University Medical Center15, Virginia Commonwealth University16, Université de Montréal17, McMaster University18
TL;DR: These guidelines provide a roadmap for developing integrated, evidence-based, and patient-centered protocols for preventing and treating pain, agitation, and delirium in critically ill patients.
Abstract: Objective:To revise the “Clinical Practice Guidelines for the Sustained Use of Sedatives and Analgesics in the Critically Ill Adult” published in Critical Care Medicine in 2002.Methods:The American College of Critical Care Medicine assembled a 20-person, multidisciplinary, multi-institutional task f
3,005 citations
University of Maryland, Baltimore1, Centers for Disease Control and Prevention2, International Centre for Diarrhoeal Disease Research, Bangladesh3, Aga Khan University4, Medical Research Council5, University of Barcelona6, GlaxoSmithKline7, United States Department of Veterans Affairs8, Center for Drug Evaluation and Research9, Norwegian Institute of Public Health10, University of Bergen11, Royal Children's Hospital12
TL;DR: Interventions targeting five pathogens can substantially reduce the burden of moderate-to-severe diarrhoea and suggest new methods and accelerated implementation of existing interventions (rotavirus vaccine and zinc) are needed to prevent disease and improve outcomes.
2,766 citations
Saint Louis University1, French Institute of Health and Medical Research2, Charité3, University of Erlangen-Nuremberg4, The Catholic University of America5, Wright State University6, Columbia University7, University of Maryland, Baltimore8, University of Toronto9, Pennsylvania State University10, Dalhousie University11, University of Antwerp12, Johns Hopkins University13
TL;DR: For the purposes of optimally managing individuals with physical frailty, all persons older than 70 years and all individuals with significant weight loss (>5%) due to chronic disease should be screened for frailty.
2,751 citations
Cristen J. Willer1, Ellen M. Schmidt1, Sebanti Sengupta1, Gina M. Peloso2 +316 more•Institutions (87)
TL;DR: It is found that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index.
Abstract: Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 × 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.
2,585 citations
TL;DR: It is shown that metagenomeSeq outperforms the tools currently used in this field and relies on a novel normalization technique and a statistical model that accounts for undersampling in large-scale marker-gene studies.
Abstract: We introduce a methodology to assess differential abundance in sparse high-throughput microbial marker-gene survey data. Our approach, implemented in the metagenomeSeq Bioconductor package, relies on a novel normalization technique and a statistical model that accounts for undersampling-a common feature of large-scale marker-gene studies. Using simulated data and several published microbiota data sets, we show that metagenomeSeq outperforms the tools currently used in this field.
1,664 citations
Beth Israel Deaconess Medical Center1, Harvard University2, University of Pavia3, University of Maryland, Baltimore4, Columbia University5, Royal Hallamshire Hospital6, University of Tampere7, Imperial College London8, University of Oslo9, Mayo Clinic10, University of Naples Federico II11, University of Salerno12
TL;DR: A multidisciplinary task force of 16 physicians from seven countries used the electronic database PubMed to review the literature for CD-related terms and suggested a definition for each term, followed by feedback through a web survey on definitions and discussions during a meeting in Oslo.
Abstract: Objective The literature suggests a lack of consensus on the use of terms related to coeliac disease (CD) and gluten. Design A multidisciplinary task force of 16 physicians from seven countries used the electronic database PubMed to review the literature for CD-related terms up to January 2011. Teams of physicians then suggested a definition for each term, followed by feedback of these definitions through a web survey on definitions, discussions during a meeting in Oslo and phone conferences. In addition to ‘CD’, the following descriptors of CD were evaluated (in alphabetical order): asymptomatic, atypical, classical, latent, non-classical, overt, paediatric classical, potential, refractory, silent, subclinical, symptomatic, typical, CD serology, CD autoimmunity, genetically at risk of CD, dermatitis herpetiformis, gluten, gluten ataxia, gluten intolerance, gluten sensitivity and gliadin-specific antibodies. Results CD was defined as ‘a chronic small intestinal immune-mediated enteropathy precipitated by exposure to dietary gluten in genetically predisposed individuals’. Classical CD was defined as ‘CD presenting with signs and symptoms of malabsorption. Diarrhoea, steatorrhoea, weight loss or growth failure is required.’ ‘Gluten-related disorders’ is the suggested umbrella term for all diseases triggered by gluten and the term gluten intolerance should not to be used. Other definitions are presented in the paper. Conclusion This paper presents the Oslo definitions for CD-related terms.
1,324 citations
University of Maryland, Baltimore1, University of California, San Diego2, Toronto Western Hospital3, University of Edinburgh4, University College London5, University of Brescia6, University of California, San Francisco7, University of Pennsylvania8, National Institutes of Health9, University of Western Ontario10, Case Western Reserve University11, St. Joseph's Hospital and Medical Center12, University of Paris13
TL;DR: Clinical CBD phenotypes and features were combined to create 2 sets of criteria: more specific clinical research criteria for probable CBD and broader criteria for possible CBD that are more inclusive but have a higher chance to detect other tau-based pathologies.
Abstract: Current criteria for the clinical diagnosis of pathologically confirmed corticobasal degeneration (CBD) no longer reflect the expanding understanding of this disease and its clinicopathologic correlations. An international consortium of behavioral neurology, neuropsychology, and movement disorders specialists developed new criteria based on consensus and a systematic literature review. Clinical diagnoses (early or late) were identified for 267 nonoverlapping pathologically confirmed CBD cases from published reports and brain banks. Combined with consensus, 4 CBD phenotypes emerged: corticobasal syndrome (CBS), frontal behavioral-spatial syndrome (FBS), nonfluent/agrammatic variant of primary progressive aphasia (naPPA), and progressive supranuclear palsy syndrome (PSPS). Clinical features of CBD cases were extracted from descriptions of 209 brain bank and published patients, providing a comprehensive description of CBD and correcting common misconceptions. Clinical CBD phenotypes and features were combined to create 2 sets of criteria: more specific clinical research criteria for probable CBD and broader criteria for possible CBD that are more inclusive but have a higher chance to detect other tau-based pathologies. Probable CBD criteria require insidious onset and gradual progression for at least 1 year, age at onset ≥50 years, no similar family history or known tau mutations, and a clinical phenotype of probable CBS or either FBS or naPPA with at least 1 CBS feature. The possible CBD category uses similar criteria but has no restrictions on age or family history, allows tau mutations, permits less rigorous phenotype fulfillment, and includes a PSPS phenotype. Future validation and refinement of the proposed criteria are needed.
1,253 citations
University of Pittsburgh1, Veterans Health Administration2, University of Washington3, Emory University4, Baylor College of Medicine5, Icahn School of Medicine at Mount Sinai6, Yale University7, University of Maryland, Baltimore8, University of Vermont9, University of California, Los Angeles10, University of South Carolina11, National Institutes of Health12
TL;DR: Investigating whether HIV is associated with an increased risk of acute myocardial infarction after adjustment for all standard Framingham risk factors among a large cohort of HIV-positive and demographically and behaviorally similar uninfected veterans in care found infections with HIV are associated with a 50% increased risk beyond that explained by recognized risk factors.
Abstract: Importance Whether people infected with human immunodeficiency virus (HIV) are at an increased risk of acute myocardial infarction (AMI) compared with uninfected people is not clear. Without demographically and behaviorally similar uninfected comparators and without uniformly measured clinical data on risk factors and fatal and nonfatal AMI events, any potential association between HIV status and AMI may be confounded. Objective To investigate whether HIV is associated with an increased risk of AMI after adjustment for all standard Framingham risk factors among a large cohort of HIV-positive and demographically and behaviorally similar (ie, similar prevalence of smoking, alcohol, and cocaine use) uninfected veterans in care. Design and Setting Participants in the Veterans Aging Cohort Study Virtual Cohort from April 1, 2003, through December 31, 2009. Participants After eliminating those with baseline cardiovascular disease, we analyzed data on HIV status, age, sex, race/ethnicity, hypertension, diabetes mellitus, dyslipidemia, smoking, hepatitis C infection, body mass index, renal disease, anemia, substance use, CD4 cell count, HIV-1 RNA, antiretroviral therapy, and incidence of AMI. Main Outcome Measure Acute myocardial infarction. Results We analyzed data on 82 459 participants. During a median follow-up of 5.9 years, there were 871 AMI events. Across 3 decades of age, the mean (95% CI) AMI events per 1000 person-years was consistently and significantly higher for HIV-positive compared with uninfected veterans: for those aged 40 to 49 years, 2.0 (1.6-2.4) vs 1.5 (1.3-1.7); for those aged 50 to 59 years, 3.9 (3.3-4.5) vs 2.2 (1.9-2.5); and for those aged 60 to 69 years, 5.0 (3.8-6.7) vs 3.3 (2.6-4.2) (P Conclusions and Relevance Infection with HIV is associated with a 50% increased risk of AMI beyond that explained by recognized risk factors.
1,100 citations
Mayo Clinic1, University of Pittsburgh2, Autonomous University of Barcelona3, University of Alberta4, Karolinska University Hospital5, University of Florida6, New York Methodist Hospital7, United States Department of Veterans Affairs8, George Washington University9, University of Duisburg-Essen10, Albert Einstein College of Medicine11, Virginia Commonwealth University12, Otto-von-Guericke University Magdeburg13, Vrije Universiteit Brussel14, Ghent University Hospital15, Hospital of the University of Pennsylvania16, University of Chicago17, Duke University18, University of Maryland, Baltimore19, RWTH Aachen University20, St. John Providence Health System21, University of California, San Diego22, St Thomas' Hospital23, Beth Israel Deaconess Medical Center24, Medical University of Vienna25, Tampa General Hospital26, Goethe University Frankfurt27
TL;DR: Two novel markers for AKI have been identified and validated in independent multicenter cohorts and are superior to existing markers, provide additional information over clinical variables and add mechanistic insight into AKI.
Abstract: Introduction: Acute kidney injury (AKI) can evolve quickly and clinical measures of function often fail to detect AKI at a time when interventions are likely to provide benefit. Identifying early markers of kidney damage has been difficult due to the complex nature of human AKI, in which multiple etiologies exist. The objective of this study was to identify and validate novel biomarkers of AKI. Methods: We performed two multicenter observational studies in critically ill patients at risk for AKI - discovery and validation. The top two markers from discovery were validated in a second study (Sapphire) and compared to a number of previously described biomarkers. In the discovery phase, we enrolled 522 adults in three distinct cohorts including patients with sepsis, shock, major surgery, and trauma and examined over 300 markers. In the Sapphire validation study, we enrolled 744 adult subjects with critical illness and without evidence of AKI at enrollment; the final analysis cohort was a heterogeneous sample of 728 critically ill patients. The primary endpoint was moderate to severe AKI (KDIGO stage 2 to 3) within 12 hours of sample collection. Results: Moderate to severe AKI occurred in 14% of Sapphire subjects. The two top biomarkers from discovery were validated. Urine insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2), both inducers of G1 cell cycle arrest, a key mechanism implicated in AKI, together demonstrated an AUC of 0.80 (0.76 and 0.79 alone). Urine [TIMP-2]·[IGFBP7] was significantly superior to all previously described markers of AKI (P 0.72. Furthermore, [TIMP2]·[IGFBP7] significantly improved risk stratification when added to a nine-variable clinical model when analyzed using Cox proportional hazards model, generalized estimating equation, integrated discrimination improvement or net reclassification improvement. Finally, in sensitivity analyses [TIMP-2]·[IGFBP7] remained significant and superior to all other markers regardless of changes in reference creatinine method.
997 citations
TL;DR: It is reported that contamination of the cytoplasm by lipopolysaccharide (LPS) is the signal that triggers caspase-11 activation in mice, and this data reveal a new pathway for detecting cy toplasmic LPS.
Abstract: Inflammatory caspases, such as caspase-1 and -11, mediate innate immune detection of pathogens. Caspase-11 induces pyroptosis, a form of programmed cell death, and specifically defends against bacterial pathogens that invade the cytosol. During endotoxemia, however, excessive caspase-11 activation causes shock. We report that contamination of the cytoplasm by lipopolysaccharide (LPS) is the signal that triggers caspase-11 activation in mice. Specifically, caspase-11 responds to penta- and hexa-acylated lipid A, whereas tetra-acylated lipid A is not detected, providing a mechanism of evasion for cytosol-invasive Francisella. Priming the caspase-11 pathway in vivo resulted in extreme sensitivity to subsequent LPS challenge in both wild-type and Tlr4-deficient mice, whereas Casp11-deficient mice were relatively resistant. Together, our data reveal a new pathway for detecting cytoplasmic LPS.
965 citations
TL;DR: Clinical testing of engineered T cells expressing an affinity-enhanced TCR against HLA-A*01-restricted MAGE-A3 demonstrated that TCR-engineered T cells can have serious and not readily predictable off-target and organ-specific toxicities and highlight the need for improved methods to define the specificity of engineeredTCRs.
University of Pittsburgh1, Veterans Health Administration2, Loyola University Chicago3, Boston University4, University of New Mexico5, University of Arizona6, Arizona State University7, University of Texas Southwestern Medical Center8, University of Maryland, Baltimore9, Oregon Health & Science University10, Yale University11
TL;DR: Combination therapy with an ACE inhibitor and an ARB was associated with an increased risk of adverse events among patients with diabetic nephropathy and safety outcomes included mortality, hyperkalemia, and acute kidney injury.
Abstract: Background Combination therapy with angiotensin-converting–enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) decreases proteinuria; however, its safety and effect on the progression of kidney disease are uncertain. Methods We provided losartan (at a dose of 100 mg per day) to patients with type 2 diabetes, a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 300, and an estimated glomerular filtration rate (GFR) of 30.0 to 89.9 ml per minute per 1.73 m 2 of body-surface area and then randomly assigned them to receive lisinopril (at a dose of 10 to 40 mg per day) or placebo. The primary end point was the first occurrence of a change in the estimated GFR (a decline of ≥30 ml per minute per 1.73 m 2 if the initial estimated GFR was ≥60 ml per minute per 1.73 m 2 or a decline of ≥50% if the initial estimated GFR was <60 ml per minute per 1.73 m 2 ), end-stage renal disease (ESRD), or death. The secondary renal end point was the first occurrence of a decline in the estimated GFR or ESRD. Safety outcomes included mortality, hyperkalemia, and acute kidney injury. Results The study was stopped early owing to safety concerns. Among 1448 randomly assigned patients with a median follow-up of 2.2 years, there were 152 primary endpoint events in the monotherapy group and 132 in the combination-therapy group (hazard ratio with combination therapy, 0.88; 95% confidence interval [CI], 0.70 to 1.12; P = 0.30). A trend toward a benefit from combination therapy with respect to the secondary end point (hazard ratio, 0.78; 95% CI, 0.58 to 1.05; P = 0.10) decreased with time (P = 0.02 for nonproportionality). There was no benefit with respect to mortality (hazard ratio for death, 1.04; 95% CI, 0.73 to 1.49; P = 0.75) or cardiovascular events. Combination therapy increased the risk of hyperkalemia (6.3 events per 100 person-years, vs. 2.6 events per 100 person-years with monotherapy; P<0.001) and acute kidney injury (12.2 vs. 6.7 events per 100 person-years, P<0.001). Conclusions Combination therapy with an ACE inhibitor and an ARB was associated with an increased risk of adverse events among patients with diabetic nephropathy. (Funded by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development; VA NEPHRON-D ClinicalTrials.gov number, NCT00555217.)
UCL Institute of Child Health1, National Institutes of Health2, University of Helsinki3, VU University Amsterdam4, University of Graz5, Harvard University6, University of Cambridge7, McGill University8, Wake Forest University9, Peninsula College of Medicine and Dentistry10, University of Gothenburg11, University of Edinburgh12, University of Zagreb13, University of Maryland, Baltimore14, University of Oxford15, Churchill Hospital16, Wellcome Trust Centre for Human Genetics17, University of Oulu18, Heidelberg University19, Uppsala University20, Western General Hospital21, King's College London22, NHS Blood and Transplant23, Wellcome Trust Sanger Institute24, University of Southampton25, University of London26, GlaxoSmithKline27, University College London28
TL;DR: A mendelian randomization study based on data from multiple cohorts conducted by Karani Santhanakrishnan Vimaleswaran and colleagues re-examines the causal nature of the relationship between vitamin D levels and obesity.
Abstract: BACKGROUND: Obesity is associated with vitamin D deficiency, and both are areas of active public health concern. We explored the causality and direction of the relationship between body mass index (BMI) and 25-hydroxyvitamin D [25(OH)D] using genetic markers as instrumental variables (IVs) in bi-directional Mendelian randomization (MR) analysis. METHODS AND FINDINGS: We used information from 21 adult cohorts (up to 42,024 participants) with 12 BMI-related SNPs (combined in an allelic score) to produce an instrument for BMI and four SNPs associated with 25(OH)D (combined in two allelic scores, separately for genes encoding its synthesis or metabolism) as an instrument for vitamin D. Regression estimates for the IVs (allele scores) were generated within-study and pooled by meta-analysis to generate summary effects. Associations between vitamin D scores and BMI were confirmed in the Genetic Investigation of Anthropometric Traits (GIANT) consortium (n = 123,864). Each 1 kg/m(2) higher BMI was associated with 1.15% lower 25(OH)D (p = 6.52×10⁻²⁷). The BMI allele score was associated both with BMI (p = 6.30×10⁻⁶²) and 25(OH)D (-0.06% [95% CI -0.10 to -0.02], p = 0.004) in the cohorts that underwent meta-analysis. The two vitamin D allele scores were strongly associated with 25(OH)D (p≤8.07×10⁻⁵⁷ for both scores) but not with BMI (synthesis score, p = 0.88; metabolism score, p = 0.08) in the meta-analysis. A 10% higher genetically instrumented BMI was associated with 4.2% lower 25(OH)D concentrations (IV ratio: -4.2 [95% CI -7.1 to -1.3], p = 0.005). No association was seen for genetically instrumented 25(OH)D with BMI, a finding that was confirmed using data from the GIANT consortium (p≥0.57 for both vitamin D scores). CONCLUSIONS: On the basis of a bi-directional genetic approach that limits confounding, our study suggests that a higher BMI leads to lower 25(OH)D, while any effects of lower 25(OH)D increasing BMI are likely to be small. Population level interventions to reduce BMI are expected to decrease the prevalence of vitamin D deficiency.
National Institutes of Health1, Center for Drug Evaluation and Research2, Silver Spring Networks3, Johns Hopkins University4, Carolinas Medical Center5, Cornell University6, National Development and Research Institutes7, University of Maryland, Baltimore8, University of California, Irvine9, Veterans Health Administration10
TL;DR: RNA sequencing in primary human hepatocytes activated with synthetic double-stranded RNA to mimic HCV infection provides new insights into the genetic regulation of HCV clearance and its clinical management.
Abstract: Chronic infection with hepatitis C virus (HCV) is a common cause of liver cirrhosis and cancer. We performed RNA sequencing in primary human hepatocytes activated with synthetic double-stranded RNA to mimic HCV infection. Upstream of IFNL3 (IL28B) on chromosome 19q13.13, we discovered a new transiently induced region that harbors a dinucleotide variant ss469415590 (TT or ΔG), which is in high linkage disequilibrium with rs12979860, a genetic marker strongly associated with HCV clearance. ss469415590[ΔG] is a frameshift variant that creates a novel gene, designated IFNL4, encoding the interferon-λ4 protein (IFNL4), which is moderately similar to IFNL3. Compared to rs12979860, ss469415590 is more strongly associated with HCV clearance in individuals of African ancestry, although it provides comparable information in Europeans and Asians. Transient overexpression of IFNL4 in a hepatoma cell line induced STAT1 and STAT2 phosphorylation and the expression of interferon-stimulated genes. Our findings provide new insights into the genetic regulation of HCV clearance and its clinical management.
Icahn School of Medicine at Mount Sinai1, Stanford University2, Vanderbilt University3, Pierre-and-Marie-Curie University4, Brigham and Women's Hospital5, University of Florida6, American Association of Colleges of Pharmacy7, University of Maryland, Baltimore8, United States Department of Veterans Affairs9
TL;DR: In this article, an expanded literature review showed that CYP2C19 loss-of-function alleles confer increased risks for serious adverse cardiovascular (CV) events among clopidogrel-treated patients with acute coronary syndromes (ACSs) undergoing percutaneous coronary intervention (PCI).
Abstract: Cytochrome P450 (CYP)2C19 catalyzes the bioactivation of the antiplatelet prodrug clopidogrel, and CYP2C19 loss-of-function alleles impair formation of active metabolites, resulting in reduced platelet inhibition. In addition, CYP2C19 loss-of-function alleles confer increased risks for serious adverse cardiovascular (CV) events among clopidogrel-treated patients with acute coronary syndromes (ACSs) undergoing percutaneous coronary intervention (PCI). Guideline updates include emphasis on appropriate indication for CYP2C19 genotype–directed antiplatelet therapy, refined recommendations for specific CYP2C19 alleles, and additional evidence from an expanded literature review (updates at http://www.pharmgkb.org).
TL;DR: It is suggested that triglyceride-rich lipoproteins causally influence risk for CAD, and the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk.
Abstract: Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 × 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.
University of Texas MD Anderson Cancer Center1, Radiation Therapy Oncology Group2, University of Lausanne3, University of Texas Health Science Center at Houston4, Medical College of Wisconsin5, Tel Aviv Sourasky Medical Center6, Johns Hopkins University7, University of Edinburgh8, Maastricht University9, University Hospitals Bristol NHS Foundation Trust10, Rambam Health Care Campus11, Ohio State University12, Emory University13, University of Maryland, Baltimore14
TL;DR: This study did not demonstrate improved efficacy for DD temozolomide for newly diagnosed GBM, regardless of methylation status, but it did confirm the prognostic significance of MGMT methylation.
Abstract: Purpose Radiotherapy with concomitant and adjuvant temozolomide is the standard of care for newly diagnosed glioblastoma (GBM) O 6 -methylguanine-DNA methyltransferase (MGMT) methylation status may be an important determinant of treatment response Dose-dense (DD) temozolomide results in prolonged depletion of MGMT in blood mononuclear cells and possibly in tumor This trial tested whether DD temozolomide improves overall survival (OS) or progression-free survival (PFS) in patients with newly diagnosed GBM Patients and Methods This phase III trial enrolled patients older than age 18 years with a Karnofsky performance score of 60 with adequate tissue Stratification included clinical factors and tumor MGMT methylation status Patients were randomly assigned to standard temozolomide (arm 1) or DD temozolomide (arm 2) for 6 to 12 cycles The primary end point was OS Secondary analyses evaluated the impact of MGMT status
University of Memphis1, National Institutes of Health2, Duke University3, University of California, San Diego4, National Science Foundation5, Robert Wood Johnson Foundation6, Northwestern University7, University of Southern California8, University of Illinois at Chicago9, University of California, Davis10, University of Michigan11, University of Maryland, Baltimore12, University of Pittsburgh13, University of California, Los Angeles14
TL;DR: Current evaluation standards are described to describe current evaluation standards, discuss future possibilities, and set a grand goal for the emerging field of mHealth research.
TL;DR: There is a dose-dependent immunological threshold for establishing high-level protection against malaria that can be achieved with IV administration of a vaccine that is safe and meets regulatory standards.
Abstract: Consistent, high-level, vaccine-induced protection against human malaria has only been achieved by inoculation of Plasmodium falciparum (Pf) sporozoites (SPZ) by mosquito bites. We report that the PfSPZ Vaccine--composed of attenuated, aseptic, purified, cryopreserved PfSPZ--was safe and well tolerated when administered four to six times intravenously (IV) to 40 adults. Zero of six subjects receiving five doses and three of nine subjects receiving four doses of 1.35 × 10(5) PfSPZ Vaccine and five of six nonvaccinated controls developed malaria after controlled human malaria infection (P = 0.015 in the five-dose group and P = 0.028 for overall, both versus controls). PfSPZ-specific antibody and T cell responses were dose-dependent. These data indicate that there is a dose-dependent immunological threshold for establishing high-level protection against malaria that can be achieved with IV administration of a vaccine that is safe and meets regulatory standards.
University of Pennsylvania1, University of Florida2, Primary Children's Hospital3, Washington University in St. Louis4, National Institutes of Health5, Mayo Clinic6, University of Texas Medical Branch7, Marshfield Clinic8, University of California, San Francisco9, Henry Ford Health System10, University of Maryland, Baltimore11, University of Alabama at Birmingham12, Vanderbilt University13, Tulane University14, Icahn School of Medicine at Mount Sinai15, Duke University16, Yeshiva University17, University of Utah18, Harvard University19
TL;DR: Genotype-guided dosing of warfarin did not improve anticoagulation control during the first 4 weeks of therapy and there was a significant interaction between dosing strategy and race.
Abstract: Background The clinical utility of genotype-guided (pharmacogenetically based) dosing of warfarin has been tested only in small clinical trials or observational studies, with equivocal results. Methods We randomly assigned 1015 patients to receive doses of warfarin during the first 5 days of therapy that were determined according to a dosing algorithm that included both clinical variables and genotype data or to one that included clinical variables only. All patients and clinicians were unaware of the dose of warfarin during the first 4 weeks of therapy. The primary outcome was the percentage of time that the international normalized ratio (INR) was in the therapeutic range from day 4 or 5 through day 28 of therapy. Results At 4 weeks, the mean percentage of time in the therapeutic range was 45.2% in the genotype-guided group and 45.4% in the clinically guided group (adjusted mean difference, [genotype-guided group minus clinically guided group], −0.2; 95% confidence interval, −3.4 to 3.1; P=0.91). There ...
TL;DR: New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.
Abstract: Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.
University of Maryland, Baltimore1, Johns Hopkins University2, University of Pennsylvania3, University of Wisconsin-Madison4, University of California, San Francisco5, Kaiser Permanente6, University of Toronto7, National Institutes of Health8, University of Utah9, Case Western Reserve University10, University of Illinois at Chicago11, Wake Forest University12, University of Michigan13, Science Applications International Corporation14, George Washington University15, Tulane University16, Georgetown University17
TL;DR: Renal risk variants in APOL1 were associated with the higher rates of end-stage renal disease and progression of chronic kidney disease that were observed in black patients as compared with white patients, regardless of diabetes status.
Abstract: Methods In two studies, we examined the effects of variants in the gene encoding apolipoprotein L1 (APOL1) on the progression of chronic kidney disease. In the African American Study of Kidney Disease and Hypertension (AASK), we evaluated 693 black patients with chronic kidney disease attributed to hypertension. In the Chronic Renal Insufficiency Cohort (CRIC) study, we evaluated 2955 white patients and black patients with chronic kidney disease (46% of whom had diabetes) according to whether they had 2 copies of high-risk APOL1 variants (APOL1 high-risk group) or 0 or 1 copy (APOL1 low-risk group). In the AASK study, the primary outcome was a composite of end-stage renal disease or a doubling of the serum creatinine level. In the CRIC study, the primary outcomes were the slope in the estimated glomerular filtration rate (eGFR) and the composite of end-stage renal disease or a reduction of 50% in the eGFR from baseline. Results In the AASK study, the primary outcome occurred in 58.1% of the patients in the APOL1 high-risk group and in 36.6% of those in the APOL1 low-risk group (hazard ratio in the high-risk group, 1.88; P<0.001). There was no interaction between APOL1 status and trial interventions or the presence of baseline proteinuria. In the CRIC study, black patients in the APOL1 high-risk group had a more rapid decline in the eGFR and a higher risk of the composite renal outcome than did white patients, among those with diabetes and those without diabetes (P<0.001 for all comparisons). Conclusions Renal risk variants in APOL1 were associated with the higher rates of end-stage renal disease and progression of chronic kidney disease that were observed in black patients as compared with white patients, regardless of diabetes status. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others.)
Virginia Mason Medical Center1, University of Konstanz2, Ontario Institute for Cancer Research3, University of Oxford4, Michigan State University5, University of Utah6, The Feinstein Institute for Medical Research7, Hofstra University8, Marine Biological Laboratory9, Icahn School of Medicine at Mount Sinai10, Stowers Institute for Medical Research11, University of Kansas12, University of New Hampshire13, University of Washington14, University of Toronto15, Emory University16, Harvard University17, Medical Research Council18, Wellcome Trust Sanger Institute19, California Institute of Technology20, University of Oklahoma21, Kalamazoo College22, University of Maryland, Baltimore23, University of Iowa24, Children's Hospital Oakland Research Institute25, Washington University in St. Louis26
TL;DR: Analyses of the assembly indicate that two whole-genome duplications likely occurred before the divergence of ancestral lamprey and gnathostome lineages, and help define key evolutionary events within vertebrate lineages.
Abstract: Lampreys are representatives of an ancient vertebrate lineage that diverged from our own ∼500 million years ago. By virtue of this deeply shared ancestry, the sea lamprey (P. marinus) genome is uniquely poised to provide insight into the ancestry of vertebrate genomes and the underlying principles of vertebrate biology. Here, we present the first lamprey whole-genome sequence and assembly. We note challenges faced owing to its high content of repetitive elements and GC bases, as well as the absence of broad-scale sequence information from closely related species. Analyses of the assembly indicate that two whole-genome duplications likely occurred before the divergence of ancestral lamprey and gnathostome lineages. Moreover, the results help define key evolutionary events within vertebrate lineages, including the origin of myelin-associated proteins and the development of appendages. The lamprey genome provides an important resource for reconstructing vertebrate origins and the evolutionary events that have shaped the genomes of extant organisms.
TL;DR: The AOSpine TL injury classification system is clinically relevant according to the consensus agreement of the international team of spine trauma experts and requires prospective observational data collection documenting use of the classification system, therapeutic decision making, and clinical follow-up evaluation by a large number of surgeons from different countries.
Abstract: STUDY DESIGN Reliability and agreement study, retrospective case series. OBJECTIVE To develop a widely accepted, comprehensive yet simple classification system with clinically acceptable intra- and interobserver reliability for use in both clinical practice and research. SUMMARY OF BACKGROUND DATA Although the Magerl classification and thoracolumbar injury classification system (TLICS) are both well-known schemes to describe thoracolumbar (TL) fractures, no TL injury classification system has achieved universal international adoption. This lack of consensus limits communication between clinicians and researchers complicating the study of these injuries and the development of treatment algorithms. METHODS A simple and reproducible classification system of TL injuries was developed using a structured international consensus process. This classification system consists of a morphologic classification of the fracture, a grading system for the neurological status, and description of relevant patient-specific modifiers. Forty cases with a broad range of injuries were classified independently twice by group members 1 month apart and analyzed for classification reliability using the Kappa coefficient (κ). RESULTS The morphologic classification is based on 3 main injury patterns: type A (compression), type B (tension band disruption), and type C (displacement/translation) injuries. Reliability in the identification of a morphologic injury type was substantial (κ= 0.72). CONCLUSION The AOSpine TL injury classification system is clinically relevant according to the consensus agreement of our international team of spine trauma experts. Final evaluation data showed reasonable reliability and accuracy, but further clinical validation of the proposed system requires prospective observational data collection documenting use of the classification system, therapeutic decision making, and clinical follow-up evaluation by a large number of surgeons from different countries.
TL;DR: A genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry finds a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
Abstract: Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
TL;DR: It is reported that the oncogenic melanocyte lineage-specification transcription factor MITF drives PGC1α (PPARGC1A) overexpression in a subset of human melanomas and derived cell lines.
TL;DR: A T cell engineered to target one such antigen—MAGE A3—cross-reacts with a peptide from a muscle protein, Titin, which is likely the cause of the off-target toxicity.
Abstract: MAGE A3, which belongs to the family of cancer-testis antigens, is an attractive target for adoptive therapy given its reactivation in various tumors and limited expression in normal tissues. We developed an affinity-enhanced T cell receptor (TCR) directed to a human leukocyte antigen (HLA)–A*01–restricted MAGE A3 antigen (EVDPIGHLY) for use in adoptive therapy. Extensive preclinical investigations revealed no off-target antigen recognition concerns; nonetheless, administration to patients of T cells expressing the affinity-enhanced MAGE A3 TCR resulted in a serious adverse event (SAE) and fatal toxicity against cardiac tissue. We present a description of the preclinical in vitro functional analysis of the MAGE A3 TCR, which failed to reveal any evidence of off-target activity, and a full analysis of the post-SAE in vitro investigations, which reveal cross-recognition of an off-target peptide. Using an amino acid scanning approach, a peptide from the muscle protein Titin (ESDPIVAQY) was identified as an alternative target for the MAGE A3 TCR and the most likely cause of in vivo toxicity. These results demonstrate that affinity-enhanced TCRs have considerable effector functions in vivo and highlight the potential safety concerns for TCR-engineered T cells. Strategies such as peptide scanning and the use of more complex cell cultures are recommended in preclinical studies to mitigate the risk of off-target toxicity in future clinical investigations.
TL;DR: It is shown that bothersome pain afflicts half of the community‐dwelling US older adult population and is associated with significant reduction in physical function, particularly in those with multisite pain, and this pattern remained unchanged when accounting for cognitive performance, dementia, proxy responses, and residential care living status.
Abstract: This study sought to determine the prevalence and impact of pain in a nationally representative sample of older adults in the United States. Data from the 2011 National Health and Aging Trends Study were analyzed. In-person interviews were conducted in 7601 adults ages ≥65 years. The response rate was 71.0% and all analyses were weighted to account for the sampling design. The overall prevalence of bothersome pain in the last month was 52.9%, afflicting 18.7 million older adults in the United States. Pain did not vary across age groups (P = 0.21), and this pattern remained unchanged when accounting for cognitive performance, dementia, proxy responses, and residential care living status. Pain prevalence was higher in women and in older adults with obesity, musculoskeletal conditions, and depressive symptoms (P < 0.001). The majority (74.9%) of older adults with pain endorsed multiple sites of pain. Several measures of physical capacity, including grip strength and lower-extremity physical performance, were associated with pain and multisite pain. For example, self-reported inability to walk 3 blocks was 72% higher in participants with than without pain (adjusted prevalence ratio 1.72 [95% confidence interval 1.56-1.90]). Participants with 1, 2, 3, and ≥4 sites of pain had gait speeds that were 0.01, 0.03, 0.05, and 0.08 meters per second slower, respectively, than older adults without pain, adjusting for disease burden and other potential confounders (P < 0.001). In summary, bothersome pain in the last month was reported by half of the older adult population of the United States in 2011 and was strongly associated with decreased physical function.
University of Florida1, University of Düsseldorf2, Washington University in St. Louis3, University of New Mexico4, University of Pennsylvania5, Vanderbilt University6, New York University7, Creedmoor Psychiatric Center8, Cardiff University9, University of Iowa10, University of California, San Diego11, Harvard University12, Veterans Health Administration13, Maastricht University Medical Centre14, King's College London15, University of Maryland, Baltimore16
TL;DR: The essence of the broad DSM-IV definition of schizophrenia is retained and changes in its definition should improve diagnosis and characterization of individuals with schizophrenia and facilitate measurement-based treatment and concurrently provide a more useful platform for research that will elucidate its nature.
Book•
07 Aug 2013
TL;DR: Model results indicate that the 1930s drought was caused by anomalous tropical sea surface temperatures during that decade and that interactions between the atmosphere and the land surface increased its severity.
Abstract: During the 1930s, the United States experienced one of the most devastating droughts of the past century. The drought affected almost two-thirds of the country and parts of Mexico and Canada and was infamous for the numerous dust storms that occurred in the southern Great Plains. In this study, we present model results that indicate that the drought was caused by anomalous tropical sea surface temperatures during that decade and that interactions between the atmosphere and the land surface increased its severity. We also contrast the 1930s drought with other North American droughts of the 20th century.