Showing papers by "Research Triangle Park published in 2009"

Computational Topology: An Introduction

Abstract: Combining concepts from topology and algorithms, this book delivers what its title promises: an introduction to the field of computational topology. Starting with motivating problems in both mathematics and computer science and building up from classic topics in geometric and algebraic topology, the third part of the text advances to persistent homology. This point of view is critically important in turning a mostly theoretical field of mathematics into one that is relevant to a multitude of disciplines in the sciences and engineering. The main approach is the discovery of topology through algorithms. The book is ideal for teaching a graduate or advanced undergraduate course in computational topology, as it develops all the background of both the mathematical and algorithmic aspects of the subject from first principles. Thus the text could serve equally well in a course taught in a mathematics department or computer science department.

HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin.

Abstract: Drug-induced liver injury (DILI) is an important cause of serious liver disease. The antimicrobial agent flucloxacillin is a common cause of DILI, but the genetic basis for susceptibility remains unclear. We conducted a genome-wide association (GWA) study using 866,399 markers in 51 cases of flucloxacillin DILI and 282 controls matched for sex and ancestry. The GWA showed an association peak in the major histocompatibility complex (MHC) region with the strongest association (P = 8.7 x 10(-33)) seen for rs2395029[G], a marker in complete linkage disequilibrium (LD) with HLA-B*5701. Further MHC genotyping, which included 64 flucloxacillin-tolerant controls, confirmed the association with HLA-B*5701 (OR = 80.6, P = 9.0 x 10(-19)). The association was replicated in a second cohort of 23 cases. In HLA-B*5701 carrier cases, rs10937275 in ST6GAL1 on chromosome 3 also showed genome-wide significance (OR = 4.1, P = 1.4 x 10(-8)). These findings provide new insights into the mechanism of flucloxacillin DILI and have the potential to substantially improve diagnosis of this serious disease.

A review of Secondary Organic Aerosol (SOA) formation from isoprene

Abstract: . Recent field and laboratory evidence indicates that the oxidation of isoprene, (2-methyl-1,3-butadiene, C5H8) forms secondary organic aerosol (SOA). Global biogenic emissions of isoprene (600 Tg yr−1) are sufficiently large that the formation of SOA in even small yields results in substantial production of atmospheric particulate matter, likely having implications for air quality and climate. Here we present a review of field measurements, experimental work, and modeling studies aimed at understanding the mechanisms, yield, and atmospheric importance of isoprene-derived SOA. SOA yields depend on a number of factors, including organic aerosol loading (Mo), NOx level (RO2 chemistry), and, because of the importance of multigenerational chemistry, the degree of oxidation. These dependences are not always included in SOA modules used in atmospheric transport models, and instead most yield parameterizations rely on a single set of chamber experiments (carried out over a limited range of conditions); this may lead to very different estimates of the atmospheric importance of isoprene SOA. New yield parameterizations, based on all available laboratory data (Mo=0–50 μg m−3), are presented here, so that SOA formation may be computed as a function of Mo, NOx level, and temperature. Current research needs and future research directions are identified.

A Genome-Wide Association Study in Chronic Obstructive Pulmonary Disease (COPD): Identification of Two Major Susceptibility Loci

Abstract: There is considerable variability in the susceptibility of smokers to develop chronic obstructive pulmonary disease (COPD). The only known genetic risk factor is severe deficiency of alpha(1)-antitrypsin, which is present in 1-2% of individuals with COPD. We conducted a genome-wide association study (GWAS) in a homogenous case-control cohort from Bergen, Norway (823 COPD cases and 810 smoking controls) and evaluated the top 100 single nucleotide polymorphisms (SNPs) in the family-based International COPD Genetics Network (ICGN; 1891 Caucasian individuals from 606 pedigrees) study. The polymorphisms that showed replication were further evaluated in 389 subjects from the US National Emphysema Treatment Trial (NETT) and 472 controls from the Normative Aging Study (NAS) and then in a fourth cohort of 949 individuals from 127 extended pedigrees from the Boston Early-Onset COPD population. Logistic regression models with adjustments of covariates were used to analyze the case-control populations. Family-based association analyses were conducted for a diagnosis of COPD and lung function in the family populations. Two SNPs at the alpha-nicotinic acetylcholine receptor (CHRNA 3/5) locus were identified in the genome-wide association study. They showed unambiguous replication in the ICGN family-based analysis and in the NETT case-control analysis with combined p-values of 1.48 x 10(-10), (rs8034191) and 5.74 x 10(-10) (rs1051730). Furthermore, these SNPs were significantly associated with lung function in both the ICGN and Boston Early-Onset COPD populations. The C allele of the rs8034191 SNP was estimated to have a population attributable risk for COPD of 12.2%. The association of hedgehog interacting protein (HHIP) locus on chromosome 4 was also consistently replicated, but did not reach genome-wide significance levels. Genome-wide significant association of the HHIP locus with lung function was identified in the Framingham Heart study (Wilk et al., companion article in this issue of PLoS Genetics; doi:10.1371/journal.pgen.1000429). The CHRNA 3/5 and the HHIP loci make a significant contribution to the risk of COPD. CHRNA3/5 is the same locus that has been implicated in the risk of lung cancer.

The global prevalence of glucose-6-phosphate dehydrogenase deficiency: a systematic review and meta-analysis.

Abstract: Glucose-6-phosphate deficiency is the most prevalent enzyme deficiency, with an estimated 400 million people affected worldwide. This inherited deficiency causes neonatal hyperbilirubinemia and chronic hemolytic anemia. Although most affected individuals are asymptomatic, exposure to oxidative stressors such as certain drugs or infection, can elicit acute hemolysis. To characterize the global prevalence of G6PD deficiency, we conducted a systematic review of the G6PD deficiency literature, drawing studies from various databases, including MEDLINE/Pubmed and Biosis. Selected studies included cross-sectional and longitudinal studies published between 1960 and 2008. Additionally, meta-analytic procedures were employed to assess the degree of heterogeneity amongst prevalence estimates and, where appropriate, pool them. The searches yielded a total of 280 prevalence estimates, corresponding to 88 countries. The highest prevalence rates were reported among Sub-Saharan African countries, even after adjusting for assessment method. Meta-analysis revealed a high degree of heterogeneity for regional and global prevalence estimates. This heterogeneity in reported estimates appeared to be due to differences in G6PD deficiency assessment and diagnostic procedures. The magnitude and variation in global, regional, and country-level prevalence rates of G6PD deficiency are of public health import, particularly in planning programs to improve neonatal health and in the distribution of various medications, especially antimalarial drugs, as G6PD deficiency is most prevalent in malaria-endemic areas.

In Vitro Screening of Environmental Chemicals for Targeted Testing Prioritization: The ToxCast Project

Abstract: There are thousands of environmental chemicals, including many industrial chemicals and pesticidal active and inert ingredients, with the potential for significant human exposures but for which toxicity information is either limited or nonexistent (Judson et al. 2009). This data gap is due largely to the high cost and length of time required to conduct animal testing in rodents and other species. A complete set of regulatory tests for a single chemical (including those for carcinogenicity and for chronic, reproductive, and development toxicity) uses thousands of animals and costs millions of dollars. In addition, traditional animal tests often yield limited information on mechanism of action, and hence on the cellular pathways that could lead to toxicity in humans. Such mechanistic information is key to moving beyond default approaches for extrapolating from high-dose animal toxicity tests to estimation of human risk at realistic exposure levels. There is a pressing need to screen the large backlog of chemicals for their potential toxicity and, ultimately, their contribution to human diseases. The National Research Council (2007) advocated the use of mechanistically informative in vitro assays based on human cells or human cell constituents that measure effects on “toxicity pathways” leading to human disease. The U.S. Environmental Protection Agency (EPA), through its ToxCast program (Dix et al. 2007) and the Tox21 collaboration with the National Toxicology Program and the National Institutes of Health Chemical Genomics Center, is pursuing similar objectives and applying many of the ideas represented in the National Research Council report (Collins et al. 2008; Kavlock et al. 2009). ToxCast is a large-scale experiment using a battery of in vitro, high-throughput screening (HTS) assays, applied to a relatively large and diverse chemical space, to develop methods to predict potential toxicity of environmental chemicals at a fraction of the cost of full-scale animal testing. Three major goals of ToxCast are to a) identify in vitro assays that can reliably indicate alterations in biological processes of relevance to in vivo toxicity; b) develop signatures or prediction models based on multiple assays, along with computed or available chemical properties, that can achieve higher predictive power than single assays or chemical structure alone; and c) use these combined in silico and in vitro assay-based signatures to screen large numbers of previously untested environmental chemicals. The ToxCast data set provides a rich resource for identifying chemically induced changes in biological pathways that are associated with in vivo end points and that could potentially lead to human disease. Chemicals whose properties and assay profiles match these predictive signatures can be prioritized for more in-depth testing, which may include nontraditional, mechanism-focused in vivo tests. In this article, we provide an overview of the entire ToxCast phase I assay results data set and present initial analyses and findings.

A review of nitrogen enrichment effects on three biogenic GHGs: the CO2 sink may be largely offset by stimulated N2O and CH4 emission.

Abstract: Anthropogenic nitrogen (N) enrichment of ecosystems, mainly from fuel combustion and fertilizer application, alters biogeochemical cycling of ecosystems in a way that leads to altered flux of biogenic greenhouse gases (GHGs). Our meta-analysis of 313 observations across 109 studies evaluated the effect of N addition on the flux of three major GHGs: CO(2), CH(4) and N(2)O. The objective was to quantitatively synthesize data from agricultural and non-agricultural terrestrial ecosystems across the globe and examine whether factors, such as ecosystem type, N addition level and chemical form of N addition influence the direction and magnitude of GHG fluxes. Results indicate that N addition increased ecosystem carbon content of forests by 6%, marginally increased soil organic carbon of agricultural systems by 2%, but had no significant effect on net ecosystem CO(2) exchange for non-forest natural ecosystems. Across all ecosystems, N addition increased CH(4) emission by 97%, reduced CH(4) uptake by 38% and increased N(2)O emission by 216%. The net effect of N on the global GHG budget is calculated and this topic is reviewed. Most often N addition is considered to increase forest C sequestration without consideration of N stimulation of GHG production in other ecosystems. However, our study indicated that although N addition increased the global terrestrial C sink, the CO(2) reduction could be largely offset (53-76%) by N stimulation of global CH(4) and N(2)O emission from multiple ecosystems.

flowCore: a Bioconductor package for high throughput flow cytometry.

Abstract: Background: Recent advances in automation technologies have enabled the use of flow cytometry for high throughput screening, generating large complex data sets often in clinical trials or drug discovery settings. However, data management and data analysis methods have not advanced sufficiently far from the initial small-scale studies to support modeling in the presence of multiple covariates. Results: We developed a set of flexible open source computational tools in the R package flowCore to facilitate the analysis of these complex data. A key component of which is having suitable data structures that support the application of similar operations to a collection of samples or a clinical cohort. In addition, our software constitutes a shared and extensible research platform that enables collaboration between bioinformaticians, computer scientists, statisticians, biologists and clinicians. This platform will foster the development of novel analytic methods for flow cytometry. Conclusion: The software has been applied in the analysis of various data sets and its data structures have proven to be highly efficient in capturing and organizing the analytic work flow. Finally, a number of additional Bioconductor packages successfully build on the infrastructure provided by flowCore, open new avenues for flow data analysis.

Role of human milk in extremely low birth weight infants’ risk of necrotizing enterocolitis or death

Abstract: To determine the association between human milk (HM) intake and risk of necrotizing enterocolitis (NEC) or death among infants 401 to 1000 g birth weight. Analysis of 1272 infants in the National Institute of Child Health and Human Development Neonatal Network Glutamine Trial was performed to determine if increasing HM intake was associated with decreased risk of NEC or death. HM intake was defined as the proportion of HM to total intake, to enteral intake and total volume over the first 14 days. Known NEC risk factors were included as covariates in Cox proportional hazard analyses for duration of survival time free of NEC. Among study infants, 13.6% died or developed NEC after 14 days. The likelihood of NEC or death after 14 days was decreased by a factor of 0.83 (95% confidence interval, CI 0.72, 0.96) for each 10% increase in the proportion of total intake as HM. Each 100 ml kg−1 increase in HM intake during the first 14 days was associated with decreased risk of NEC or death (hazard ratio, HR 0.87 (95% CI 0.77, 0.97)). There appeared to be a trend towards a decreased risk of NEC or death among infants who received 100% HM as a proportion to total enteral intake (HM plus formula), although this finding was not statistically significant (HR 0.85 (95% CI 0.60, 1.19)). These data suggest a dose-related association of HM feeding with a reduction of risk of NEC or death after the first 2 weeks of life among extremely low birth weight infants.

A genome-wide investigation of SNPs and CNVs in schizophrenia

Abstract: We report a genome-wide assessment of single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) in schizophrenia. We investigated SNPs using 871 patients and 863 controls, following up the top hits in four independent cohorts comprising 1,460 patients and 12,995 controls, all of European origin. We found no genome-wide significant associations, nor could we provide support for any previously reported candidate gene or genome-wide associations. We went on to examine CNVs using a subset of 1,013 cases and 1,084 controls of European ancestry, and a further set of 60 cases and 64 controls of African ancestry. We found that eight cases and zero controls carried deletions greater than 2 Mb, of which two, at 8p22 and 16p13.11-p12.4, are newly reported here. A further evaluation of 1,378 controls identified no deletions greater than 2 Mb, suggesting a high prior probability of disease involvement when such deletions are observed in cases. We also provide further evidence for some smaller, previously reported, schizophrenia-associated CNVs, such as those in NRXN1 and APBA2. We could not provide strong support for the hypothesis that schizophrenia patients have a significantly greater “load” of large (>100 kb), rare CNVs, nor could we find common CNVs that associate with schizophrenia. Finally, we did not provide support for the suggestion that schizophrenia-associated CNVs may preferentially disrupt genes in neurodevelopmental pathways. Collectively, these analyses provide the first integrated study of SNPs and CNVs in schizophrenia and support the emerging view that rare deleterious variants may be more important in schizophrenia predisposition than common polymorphisms. While our analyses do not suggest that implicated CNVs impinge on particular key pathways, we do support the contribution of specific genomic regions in schizophrenia, presumably due to recurrent mutation. On balance, these data suggest that very few schizophrenia patients share identical genomic causation, potentially complicating efforts to personalize treatment regimens.

College Women's Experiences with Physically Forced, Alcohol- or Other Drug-Enabled, and Drug-Facilitated Sexual Assault Before and Since Entering College

Abstract: Objective: Research has shown associations between college women's alcohol and/or drug consumption and the risk of sexual assault, but few studies have measured the various means by which sexual as...

The prevalence, severity, and impact of opioid-induced bowel dysfunction: results of a US and European Patient Survey (PROBE 1)

Abstract: Objective. This multinational, Internet-based survey was designed to assess the prevalence, frequency, severity, and impact of opioid-induced bowel dysfunction (OBD) in patients receiving opioid therapy for chronic pain and taking laxatives. Design. In total, 322 patients taking daily oral opioids and laxatives completed the 45-item questionnaire. At the time of the survey, 45% of patients reported <3 bowel movements per week. The most prevalent opioid-induced side effects were constipation (81%) and straining to pass a bowel movement (58%). Those side effects considered most bothersome by patients were (in order of rank) constipation, straining, fatigue, small or hard bowel movements, and insomnia. Results. Most of the OBD symptoms specified in the questionnaire were experienced by the majority of patients ≥4 times a week. Constipation was the OBD symptom that was most often reported as severe. Most patients reported that their OBD symptoms had at least a moderate negative impact on their overall quality of life and activities of daily living. A third of patients had missed, decreased or stopped using opioids in order to make it easier to have a bowel movement. Conclusion. The survey findings confirm that OBD occurs frequently, despite the use of laxatives, in individuals taking daily oral opioids for chronic pain. These gastrointestinal symptoms add to the burden already experienced by chronic pain patients, negatively impacting quality of life and, in some cases, affecting opioid treatment itself.

X-Rated Sexual Attitudes and Behaviors Associated With U.S. Early Adolescents' Exposure to Sexually Explicit Media

Abstract: Correlates of use and subsequent sexual attitudes and behaviors predicted by exposure to sexually explicit content (i.e., pornography and erotica) in adult magazines, X-rated movies, and the Internet were examined in a prospective survey of a diverse sample of early adolescents (average age at baseline = 13.6 years; N = 967). Two-thirds (66%) of males and more than one-third (39%) of females had seen at least one form of sexually explicit media in the past year. At baseline, being black, being older, and having less-educated parents, lower socioeconomic status, and high need for sensation were related to greater exposure for both males and females. Longitudinal analyses showed that early exposure for males predicted less progressive gender role attitudes, more permissive sexual norms, sexual harassment perpetration, and having oral sex and sexual intercourse two years later. Early exposure for females predicted subsequently less progressive gender role attitudes, and having oral sex and sexual intercourse...

The Toxicity Data Landscape for Environmental Chemicals

Abstract: ObjectiveThousands of chemicals are in common use, but only a portion of them have undergone significant toxicologic evaluation, leading to the need to prioritize the remainder for targeted testing...

The minimally important difference of the Asthma Control Test.

Abstract: Background The Asthma Control Test (ACT) has been well validated, but a minimally important difference (MID) has not been established. Objective We sought to identify an MID for the ACT. Methods Data come from 4 independent samples of adult asthmatic patients. Distributional methods for determining the MID included 0.5 SD, 1 SEM, and 2 SEM. Anchor-based methods assessed the relationship of differences in ACT scores to (1) self-reported asthma severity, (2) asthma episode frequency in the past 4 weeks, (3) physician ratings of asthma control, (4) physician recommendation of a change in therapy, (5) FEV 1 , (6) the risk over the next 12 months of excess short-acting β-agonist use and exacerbations, and (7) patient-defined changes in asthma course over 3 months. Results Four thousand one hundred eighteen patients completed the ACT. The 0.5 SD criterion for MID ranged from 2.03 to 2.45 points (mean, 2.2 points). The 1 SEM criterion ranged from 1.77 to 2.05 points (mean, 1.88 points), and the 2 SEM criterion ranged from 3.55 to 4.10 points (mean, 3.75 points). Differences in mean ACT scores across patient groups differing on criterion measures ranged from 1.06 to 5.28 points (mean, 3.1 points). Predictive analyses showed that a difference of 3 points on the ACT was associated with a subsequent 76% increased risk (95% CI, 73% to 79%) of excess short-acting β-agonist use and a 33% increased risk (95% CI, 31% to 35%) of exacerbations. Conclusion The data support an MID for the ACT of 3 points.

Pneumonia risk in COPD patients receiving inhaled corticosteroids alone or in combination: TORCH study results

Abstract: Inhaled corticosteroids (ICS) are important in reducing exacerbation frequency associated with chronic obstructive pulmonary disease (COPD). However, little is known about the risk of associated infections. In a post hoc analysis of the TOwards a Revolution in COPD Health (TORCH) study, we analysed and identified potential risk factors for adverse event reports of pneumonia in this randomised, double-blind trial comparing twice-daily inhaled salmeterol (SAL) 50 microg, fluticasone propionate (FP) 500 microg, and the combination (SFC) with placebo in 6,184 patients with moderate-to-severe COPD over 3 yrs. Despite a higher withdrawal rate in the placebo arm, after adjusting for time on treatment, a greater rate of pneumonia was reported in the FP and SFC treatment arms (84 and 88 per 1,000 treatment-yrs, respectively) compared with SAL and placebo (52 and 52 per 1,000 treatment-yrs, respectively). Risk factors for pneumonia were age > or =55 yrs, forced expiratory volume in 1 s <50% predicted, COPD exacerbations in the year prior to the study, worse Medical Research Council dyspnoea scores and body mass index <25 kg.m(-2). No increase in pneumonia deaths with SFC was observed; this could not be concluded for FP. Despite the benefits of ICS-containing regimens in COPD management, healthcare providers should remain vigilant regarding the possible development of pneumonia as a complication in COPD patients receiving such therapies.

Nitrite as regulator of hypoxic signaling in mammalian physiology

Abstract: In this review we consider the effects of endogenous and pharmacological levels of nitrite under conditions of hypoxia. In humans, the nitrite anion has long been considered as metastable intermediate in the oxidation of nitric oxide radicals to the stable metabolite nitrate. This oxidation cascade was thought to be irreversible under physiological conditions. However, a growing body of experimental observations attests that the presence of endogenous nitrite regulates a number of signaling events along the physiological and pathophysiological oxygen gradient. Hypoxic signaling events include vasodilation, modulation of mitochondrial respiration, and cytoprotection following ischemic insult. These phenomena are attributed to the reduction of nitrite anions to nitric oxide if local oxygen levels in tissues decrease. Recent research identified a growing list of enzymatic and nonenzymatic pathways for this endogenous reduction of nitrite. Additional direct signaling events not involving free nitric oxide are proposed. We here discuss the mechanisms and properties of these various pathways and the role played by the local concentration of free oxygen in the affected tissue.

Fixed effects, random effects and GEE: What are the differences?

Abstract: For analyses of longitudinal repeated-measures data, statistical methods include the random effects model, fixed effects model and the method of generalized estimating equations. We examine the assumptions that underlie these approaches to assessing covariate effects on the mean of a continuous, dichotomous or count outcome. Access to statistical software to implement these models has led to widespread application in numerous disciplines. However, careful consideration should be paid to their critical assumptions to ascertain which model might be appropriate in a given setting. To illustrate similarities and differences that might exist in empirical results, we use a study that assessed depressive symptoms in low-income pregnant women using a structured instrument with up to five assessments that spanned the pre-natal and post-natal periods. Understanding the conceptual differences between the methods is important in their proper application even though empirically they might not differ substantively. The choice of model in specific applications would depend on the relevant questions being addressed, which in turn informs the type of design and data collection that would be relevant.

Lamivudine in late pregnancy to prevent perinatal transmission of hepatitis B virus infection: a multicentre, randomized, double-blind, placebo-controlled study.

Abstract: This randomized, double-blind, placebo-controlled study evaluated whether lamivudine given during late pregnancy can reduce hepatitis B virus (HBV) perinatal transmission in highly viraemic mothers. Mothers were randomized to either lamivudine 100 mg or placebo from week 32 of gestation to week 4 postpartum. At birth, infants received recombinant HBV vaccine with or without HBIg and were followed until week 52. One hundred and fifty mothers, with a gestational age of 26-30 weeks and serum HBV DNA >1000 MEq/mL (bDNA assay), were treated. A total of 141 infants received immunoprophylaxis at birth. In lamivudine-treated mothers, 56 infants received vaccine + HBIg (lamivudine + vaccine + HBIg) and 26 infants received vaccine (lamivudine + vaccine). In placebo-treated mothers, 59 infants received vaccine + HBIg (placebo + vaccine + HBIg). At week 52, in the primary analyses where missing data was counted as failures, infants in the lamivudine + vaccine + HBIg group had a significant decrease in incidence of HBsAg seropositivity (10/56, 18%vs 23/59, 39%; P = 0.014) and in detectable HBV DNA (11/56, 20%vs 27/59, 46%; P = 0.003) compared to infants in the placebo + vaccine + HBIg group. Sensitivity analyses to evaluate the impact of missing data at week 52 resulting from a high dropout rate (13% in the lamivudine + vaccine + HBIg group and 31% in the placebo + vaccine + HBIg group) remained consistent with the primary analysis in that lower transmission rates were still observed in the infants of lamivudine-treated mothers, but the differences were not statistically significant. No safety concerns were noted in the lamivudine-treated mothers or their infants. Results of this study suggest that lamivudine reduced HBV transmission from highly viraemic mothers to their infants who received passive/active immunization.

Adjunctive lacosamide for partial-onset seizures: Efficacy and safety results from a randomized controlled trial.

Abstract: Summary Purpose: To evaluate the efficacy and safety of lacosamide (200 and 400 mg/day) when added to one to three concomitant antiepileptic drugs (AEDs) in patients with uncontrolled partial-onset seizures. Methods: This multicenter, double-blind, placebo-controlled trial randomized patients (age 16–70 years) with partial-onset seizures with or without secondary generalization to placebo, lacosamide 200, or lacosamide 400 mg/day. The trial consisted of an 8-week baseline, a 4-week titration, and a 12-week maintenance period. Results: Four hundred eighty-five patients were randomized and received trial medication. Among these, 87% were taking two or more concomitant AEDs. Median percent reduction in seizure frequency per 28 days from baseline to maintenance period (intent-to-treat, ITT) was 20.5% for placebo, 35.3% for lacosamide 200 mg/day (p = 0.02), and 36.4% for 400 mg/day (p = 0.03). In the per protocol population, the reductions were 35.3% for lacosamide 200 mg/day (p = 0.04) and 44.9% for 400 mg/day (p = 0.01) compared to placebo (25.4%). The 50% responder rate for lacosamide 400 mg/day (40.5%) was significant (p = 0.01) over placebo (25.8%), but was not for 200 mg/day (35.0%). In the per protocol population, the 50% responder rate for lacosamide 400 mg/day (46.3%) was significant (p < 0.01) compared with the placebo responder rate (27.5%). Dose-related adverse events (AEs) included dizziness, nausea, and vomiting. Clinically relevant changes in the mean plasma concentrations of commonly used AEDs were not observed. Discussion: Results of this trial demonstrated the efficacy and tolerability of adjunctive lacosamide 200 and 400 mg/day and support that lacosamide may be an advantageous option for the treatment of partial-onset seizures in patients with epilepsy.

Efficacy of salmeterol/fluticasone propionate by GOLD stage of chronic obstructive pulmonary disease: analysis from the randomised, placebo-controlled TORCH study

Abstract: Background: The efficacy of inhaled salmeterol plus fluticasone propionate (SFC) in patients with severe or very severe COPD is well documented. However, there are only limited data about the influence of GOLD severity staging on the effectiveness of SFC, particularly in patients with milder disease. Methods: TORCH was a 3-year, double-blind, placebo-controlled trial of 6112 patients with moderate/severe COPD with pre-bronchodilator FEV1 < 60% predicted (mean age 65 years, 76% male, mean 44% predicted FEV 1 , 43% current smokers). To understand the relative efficacy of SFC and its components by GOLD stages, we conducted a post-hoc analysis of the TORCH dataset using baseline post-bronchodilator FEV1 to segment patients into three groups: moderate COPD (GOLD stage II and above: ³ 50%; n = 2156), severe COPD (GOLD stage III: 30% to < 50%; n = 3019) and very severe COPD (GOLD stage IV: < 30%; n = 937). Results: Compared with placebo, SFC improved post-bronchodilator FEV 1 : 101 ml (95% confidence interval [CI]: 71, 132) in GOLD stage II, 82 ml (95% CI: 60, 104) in GOLD stage III and 96 ml (95% CI: 54, 138) in GOLD stage IV patients, and reduced the rate of exacerbations: 31% (95% CI: 19, 40) in GOLD stage II, 26% (95% CI: 17, 34) in GOLD stage III and 14% (95% CI: -4, 29) in GOLD stage IV. SFC improved health status to a greater extent than other treatments regardless of baseline GOLD stage. Similarly, SFC reduced the risk of death by 33% (hazard ratio [HR] 0.67; 95% CI: 0.45, 0.98) for GOLD stage II, 5% (HR 0.95; 95% CI: 0.73, 1.24) for GOLD stage III, and 30% (HR 0.70; 95% CI: 0.47, 1.05) for GOLD stage IV. The rates of adverse events were similar across treatment arms and increased with disease severity. Overall, there was a higher incidence of pneumonia in the fluticasone propionate and SFC arms, compared with other treatments in all GOLD stages.

Scaling the bandwidth wall: challenges in and avenues for CMP scaling

Abstract: As transistor density continues to grow at an exponential rate in accordance to Moore's law, the goal for many Chip Multi-Processor (CMP) systems is to scale the number of on-chip cores proportionally. Unfortunately, off-chip memory bandwidth capacity is projected to grow slowly compared to the desired growth in the number of cores. This creates a situation in which each core will have a decreasing amount of off-chip bandwidth that it can use to load its data from off-chip memory. The situation in which off-chip bandwidth is becoming a performance and throughput bottleneck is referred to as the bandwidth wall problem.In this study, we seek to answer two questions: (1) to what extent does the bandwidth wall problem restrict future multicore scaling, and (2) to what extent are various bandwidth conservation techniques able to mitigate this problem. To address them, we develop a simple but powerful analytical model to predict the number of on-chip cores that a CMP can support given a limited growth in memory traffic capacity. We find that the bandwidth wall can severely limit core scaling. When starting with a balanced 8-core CMP, in four technology generations the number of cores can only scale to 24, as opposed to 128 cores under proportional scaling, without increasing the memory traffic requirement. We find that various individual bandwidth conservation techniques we evaluate have a wide ranging impact on core scaling, and when combined together, these techniques have the potential to enable super-proportional core scaling for up to 4 technology generations.

Solid-fuel household cook stoves: characterization of performance and emissions.

Abstract: In this study, 14 solid-fuel household cook stove and fuel combinations, including 10 stoves and four fuels, were tested for performance and pollutant emissions using a WBT (Water Boiling Test) protocol. Results from the testing showed that some stoves currently used in the field have improved fuel efficiency and lower pollutant emissions compared with traditional cooking methods. Stoves with smaller-mass components exposed to the heat of fuel combustion tended to take lesser time to boil, have better fuel efficiency, and lower pollutant emissions. The challenge is to design stoves with smaller-mass components that also have acceptable durability, affordable cost, and meet user needs. Results from this study provide stove performance and emissions information to practitioners disseminating stove technology in the field. This information may be useful for improving the design of existing stoves and for developing new stove designs. Comparison of results between laboratories shows that results can be replicated between labs when the same stove and fuel are tested using the WBT protocol. Recommendations were provided to improve the ability to replicate results between labs. Implications of better solid-fuel cook stoves are improved human health, reduced fuel use, reduced deforestation, and reduced global climate change.

Substance use disorder among older adults in the United States in 2020

Abstract: Aims This study aimed to project the number of people aged 50 years or older with substance use disorder (alcohol/ illicit drug dependence or abuse) in the United States in 2020. Design Logistic regression models were applied to estimate parameters predicting past-year substance use disorder using the 2002–06 National Survey on Drug Use and Health data. We applied these parameters to the projected US 2020 population to estimate the number of adults aged 50 or older with substance use disorder in 2020. Setting Non-institutionalized US residences. Participants Representative sample of the US civilian, non-institutionalized population. Measurements Substance use disorder is classified based on criteria in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition. Findings Due to the large population size and high substance use rate of the baby-boom cohort, the number of adults aged 50 or older with substance use disorder is projected to double from 2.8 million (annual average) in 2002–06 to 5.7 million in 2020. Increases are projected for all examined gender, race/ethnicity and age groups. Conclusions Our estimates provide critical information for policymakers to allocate resources and develop prevention and treatment approaches to address future needs of the US older adult population with substance use disorder.

A Bridgeless PFC Boost Rectifier With Optimized Magnetic Utilization

Abstract: The implementation of a bridgeless power factor correction (PFC) boost rectifier with low common-mode noise is presented in this paper. The proposed implementation employs a unique multiple-winding, multicore inductor to increase the utilization of the magnetic material. The operation and performance of the circuit were verified on a 750-W, universal-line experimental prototype operating at 110 kHz.