University of Colorado Denver

About: University of Colorado Denver is a education organization based out in Denver, Colorado, United States. It is known for research contribution in the topics: Population & Health care. The organization has 27444 authors who have published 57213 publications receiving 2539937 citations. The organization is also known as: CU Denver & UCD.

Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program.

Abstract: The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes)1 In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals) These rare variants provide insights into mutational processes and recent human evolutionary history The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 001% The goals, resources and design of the NHLBI Trans-Omics for Precision Medicine (TOPMed) programme are described, and analyses of rare variants detected in the first 53,831 samples provide insights into mutational processes and recent human evolutionary history

Incidence and Prognosis of Resistant Hypertension in Hypertensive Patients

Abstract: Background—Despite a recent American Heart Association (AHA) consensus statement emphasizing the importance of resistant hypertension, the incidence and prognosis of this condition are largely unknown. Methods and Results—This retrospective cohort study in 2 integrated health plans included patients with incident hypertension in whom treatment was begun between 2002 and 2006. Patients were followed up for the development of resistant hypertension based on AHA criteria of uncontrolled blood pressure despite use of ≥3 antihypertensive medications, with data collected on prescription filling information and blood pressure measurement. We determined incident cardiovascular events (death or incident myocardial infarction, heart failure, stroke, or chronic kidney disease) in patients with and without resistant hypertension with adjustment for patient and clinical characteristics. Among 205 750 patients with incident hypertension, 1.9% developed resistant hypertension within a median of 1.5 years from initial tr...

gp100 peptide vaccine and interleukin-2 in patients with advanced melanoma.

Abstract: Background Stimulating an immune response against cancer with the use of vaccines remains a challenge. We hypothesized that combining a melanoma vaccine with interleukin-2, an immune activating agent, could improve outcomes. In a previous phase 2 study, patients with metastatic melanoma receiving high-dose interleukin-2 plus the gp100:209-217(210M) peptide vaccine had a higher rate of response than the rate that is expected among patients who are treated with interleukin-2 alone. Methods We conducted a randomized, phase 3 trial involving 185 patients at 21 centers. Eligibility criteria included stage IV or locally advanced stage III cutaneous melanoma, expression of HLA*A0201, an absence of brain metastases, and suitability for high-dose interleukin-2 therapy. Patients were randomly assigned to receive interleukin-2 alone (720,000 IU per kilogram of body weight per dose) or gp100:209-217(210M) plus incomplete Freund's adjuvant (Montanide ISA-51) once per cycle, followed by interleukin-2. The primary end p...

Emtricitabine-tenofovir concentrations and pre-exposure prophylaxis efficacy in men who have sex with men.

Abstract: Drug concentrations associated with protection from HIV-1 acquisition have not been determined. We evaluated drug concentrations among men who have sex with men in a substudy of the iPrEx trial (1). In this randomized placebo-controlled trial, daily oral doses of emtricitabine/tenofovir disoproxil fumarate were used as pre-exposure prophylaxis (PrEP) in men who have sex with men. Drug was detected less frequently in blood plasma and in viable cryopreserved peripheral blood mononuclear cells (PBMCs) in HIV-infected cases at the visit when HIV was first discovered compared with controls at the matched time point of the study (8% versus 44%; P < 0.001) and in the 90 days before that visit (11% versus 51%; P < 0.001). An intracellular concentration of the active form of tenofovir, tenofovir-diphosphate (TFV-DP), of 16 fmol per million PBMCs was associated with a 90% reduction in HIV acquisition relative to the placebo arm. Directly observed dosing in a separate study, the STRAND trial, yielded TFV-DP concentrations that, when analyzed according to the iPrEx model, corresponded to an HIV-1 risk reduction of 76% for two doses per week, 96% for four doses per week, and 99% for seven doses per week. Prophylactic benefits were observed over a range of doses and drug concentrations, suggesting ways to optimize PrEP regimens for this population.

Use of Pharmacogenetic and Clinical Factors to Predict the Therapeutic Dose of Warfarin

Abstract: Initiation of warfarin therapy using trial-and-error dosing is problematic. Our goal was to develop and validate a pharmacogenetic algorithm. In the derivation cohort of 1,015 participants, the independent predictors of therapeutic dose were: VKORC1 polymorphism -1639/3673 G>A (-28% per allele), body surface area (BSA) (+11% per 0.25 m(2)), CYP2C9(*)3 (-33% per allele), CYP2C9(*)2 (-19% per allele), age (-7% per decade), target international normalized ratio (INR) (+11% per 0.5 unit increase), amiodarone use (-22%), smoker status (+10%), race (-9%), and current thrombosis (+7%). This pharmacogenetic equation explained 53-54% of the variability in the warfarin dose in the derivation and validation (N= 292) cohorts. For comparison, a clinical equation explained only 17-22% of the dose variability (P < 0.001). In the validation cohort, we prospectively used the pharmacogenetic-dosing algorithm in patients initiating warfarin therapy, two of whom had a major hemorrhage. To facilitate use of these pharmacogenetic and clinical algorithms, we developed a nonprofit website, http://www.WarfarinDosing.org.