192 research outputs found
Novel Genome-Editing Tools to Model and Correct Primary Immunodeficiencies
No full textSevere combined immunodeficiency (SCID) and other severe non-SCID primary immunodeficiencies (non-SCID PID) can be treated by allogeneic hematopoietic stem cell (HSC) transplantation, but when histocompatibility leukocyte antigen-matched donors are lacking, this can be a high-risk procedure. Correcting the patient’s own HSCs with gene therapy offers an attractive alternative. Gene therapies currently being used in clinical settings insert a functional copy of the entire gene by means of a viral vector. With this treatment, severe complications may result due to integration within oncogenes. A promising alternative is the use of endonucleases such as ZFNs, TALENs, and CRISPR/Cas9 to introduce a double-stranded break in the DNA and thus induce homology-directed repair. With these genome-editing tools a correct copy can be inserted in a precisely targeted “safe harbor.” They can also be used to correct pathogenic mutations in situ and to develop cellular or animal models needed to study the pathogenic effects of specific genetic defects found in immunodeficient patients. This review discusses the advantages and disadvantages of these endonucleases in gene correction and modeling with an emphasis on CRISPR/Cas9, which offers the most promise due to its efficacy and versatility.Version of Recor
Clinical efficacy and safety of statins in managing cardiovascular risk
No full textNavin K Kapur1, Kiran Musunuru21Division of Cardiology, Tufts University – New England Medical Center; Boston, MA, USA; 2Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, USAAbstract: Since their introduction in the 1980s, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have emerged as the one of the best-selling medication classes to date, with numerous trials demonstrating powerful efficacy in preventing cardiovascular outcomes. As our understanding of low-density lipoprotein cholesterol (LDL-C) and atherosclerosis continues to grow, the concept of ‘lower is better’ has corresponded with a ‘more is better’ approach to statin-based therapy. This review provides a detailed understanding of the clinical efficacy and safety of statins with a particular emphasis on the third generation drug, rosuvastatin.Keywords: low density lipoprotein cholesterol (LDL-C), efficacy, safety, HMGCo-A reductase inhibitors, rosuvastati
Influence of Process Parameters on Health Outcome
No full textIn the recent years, healthcare organizations have realized that quality in providing service is critical for their survival in this competitive world. This increased attention to service quality has forced many health care providers to reevaluate their systems to stay in business. The main purpose of this study is to test the hypothesis “Process Quality predicts the Product quality (patient satisfaction) in the healthcare domain”. The objective of this study was three- fold. The first objective is to analyze historical data both on patient satisfaction and on provider attributes to yield process parameters for a particular area in a hospital. The second objective is to demonstrate and validate the concept that Process quality predicts product quality in health care domains. The third objective is to use a survey tool which yields significant process parameters and demonstrating the method to improve them using lean six sigma methodologies.
Three data sets consisting of responses to patient, employee and physician questionnaires were taken. The ANOVA and Regression Analysis were performed on raw data to enumerate the relation between final outcome measures and their respective attributes. The Regression Analysis was repeated using the combined quantitative composites derived from each of the 3 data sets independently via dimension reduction by factor analysis. The analyses identified several potential key dimensions that were used to develop a generic survey for the patients, physicians and nurses. A preliminary analysis was done to validate the model by partnering with a health care facility.
The ANOVA performed on the generic survey data have shown that the category of the respondent as the most important variable. The multiple regression analysis on the raw data and attributes has shown that the hospital security and adequate medication provided by the providers is significantly affecting the dependent variable: Recommending hospital to others. Moreover from the linear regression analysis, the variables ‘treating each other with courtesy and respect’, ‘feel safe & secure’ ‘flexibility in scheduling work hours’ and ‘balancing of family life and work’ had the highest coefficients which are at 0.001 level. It concludes that dimensions also contribute the most to the variation in health outcomes.
Advisor: Ram R. Bish
Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke
No full textGenetic factors have been implicated in stroke risk, but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) for ischemic stroke and its subtypes in 3,548 affected individuals and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 affected individuals and 6,281 controls. We replicated previous associations for cardioembolic stroke near PITX2 and ZFHX3 and for large vessel stroke at a 9p21 locus. We identified a new association for large vessel stroke within HDAC9 (encoding histone deacetylase 9) on chromosome 7p21.1 (including further replication in an additional 735 affected individuals and 28,583 controls) (rs11984041; combined P = 1.87 × 10<sup>−11</sup>; odds ratio (OR) = 1.42, 95% confidence interval (CI) = 1.28–1.57). All four loci exhibited evidence for heterogeneity of effect across the stroke subtypes, with some and possibly all affecting risk for only one subtype. This suggests distinct genetic architectures for different stroke subtypes
Master of Science
No full textthesisFor more than twenty years, the introduction of reliability-based analysis into roadway geometric design has been investigated. This type of probabilistic geometric design analysis is well suited to explicitly address the level of variability and randomness associated with design inputs when compared to a more deterministic design approach. In this study, reliability analysis was used to estimate the probability distribution of operational performance that might result from basic number of lanes decisions made to achieve a design level of service on a freeway. The concept is demonstrated using data from Interstate 15 and Interstate 80 in Utah. The basic traffic count data used for analysis were obtained from Utah Department of Transportation (UDOT). To account for the uncertainty in the design inputs, statistical distributions were developed and reliability analysis was carried out using Monte Carlo simulation. A statistical software Minitab was used to develop statistical distributions of design inputs involving variability from the traffic count data. Minitab was also used to run Monte Carlo simulation by generating random samples of the design inputs. The outcome of this probabilistic analysis is a distribution of vehicle density for a given number of lanes during the design hour. The main benefit of reliability analysis is that it enables designers to explicitly consider uncertainties in their decision-making and to illustrate specific values of the distributions that correspond their target level of service (e.g., the 65th through 85th percentile density corresponds to the design level of service). The results demonstrate how uncertainty in estimates of K (i.e., the percent of daily traffic in the design hour), directional distribution, percent heavy-vehicles, and free-flow speed significantly contribute to the variation in the vehicle density on a freeway
Population genomics of cardiometabolic traits: design of the University College London-London School of Hygiene and Tropical Medicine-Edinburgh-Bristol (UCLEB) Consortium.
No full textSubstantial advances have been made in identifying common genetic variants influencing cardiometabolic traits and disease outcomes through genome wide association studies. Nevertheless, gaps in knowledge remain and new questions have arisen regarding the population relevance, mechanisms, and applications for healthcare. Using a new high-resolution custom single nucleotide polymorphism (SNP) array (Metabochip) incorporating dense coverage of genomic regions linked to cardiometabolic disease, the University College-London School-Edinburgh-Bristol (UCLEB) consortium of highly-phenotyped population-based prospective studies, aims to: (1) fine map functionally relevant SNPs; (2) precisely estimate individual absolute and population attributable risks based on individual SNPs and their combination; (3) investigate mechanisms leading to altered risk factor profiles and CVD events; and (4) use Mendelian randomisation to undertake studies of the causal role in CVD of a range of cardiovascular biomarkers to inform public health policy and help develop new preventative therapies
Biological, clinical and population relevance of 95 loci for blood lipids
No full textPlasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P<5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD
Crystal structures of Nova-1 and Nova-2 K-homology RNA-binding domains
No full textAbstractBackground: Nova-1 and Nova-2 are related neuronal proteins that were initially cloned using antisera obtained from patients with the autoimmune neurological disease paraneoplastic opsoclonus-myoclonus ataxia (POMA). Both of these disease gene products contain three RNA-binding motifs known as K-homology or KH domains, and their RNA ligands have been identified via binding-site selection experiments. The KH motif structure has been determined previously using NMR spectroscopy, but not using X-ray crystallography. Many proteins contain more than one KH domain, yet there is no published structural information regarding the behavior of such multimers.Results: We have obtained the first X-ray crystallographic structures of KH-domain-containing proteins. Structures of the third KH domains (KH3) of Nova-1 and Nova-2 were determined by multiple isomorphous replacement and molecular replacement at 2.6 Å and 2.0 Å, respectively. These highly similar RNA-binding motifs form a compact protease-resistant domain resembling an open-faced sandwich, consisting of a three-stranded antiparallel β sheet topped by three α helices. In both Nova crystals, the lattice is composed of symmetric tetramers of KH3 domains that are created by two dimer interfaces.Conclusions: The crystal structures of both Nova KH3 domains are similar to the previously determined NMR structures. The most significant differences among the KH domains involve changes in the positioning of one or more of the α helices with respect to the βsheet, particularly in the NMR structure of the KH1 domain of the Fragile X disease protein FMR-1. Loop regions in the KH domains are clearly visible in the crystal structure, unlike the NMR structures, revealing the conformation of the invariant Gly–X–X–Gly segment that is thought to participate in RNA-binding and of the variable region. The tetrameric arrangements of the Nova KH3 domains provide insights into how KH domains may interact with each other in proteins containing multiple KH motifs
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