Traceability for Mutation Analysis in Model Transformation

International audienceModel transformation can't be directly tested using program techniques. Those have to be adapted to model characteristics. In this paper we focus on one test technique: mutation analysis. This technique aims to qualify a test data set by analyzing the execution results of intentionally faulty program versions. If the degree of qualification is not satisfactory, the test data set has to be improved. In the context of model, this step is currently relatively fastidious and manually performed. We propose an approach based on traceability mechanisms in order to ease the test model set improvement in the mutation analysis process. We illustrate with a benchmark the quick automatic identification of the input model to change. A new model is then created in order to raise the quality of the test data set

Dihydroartemisinin-Piperaquine and Artemether-Lumefantrine for Treating Uncomplicated Malaria in African Children: A Randomised, Non-Inferiority Trial

BACKGROUND: Artemisinin combination therapies (ACTs) are currently the preferred option for treating uncomplicated malaria. Dihydroartemisinin-piperaquine (DHA-PQP) is a promising fixed-dose ACT with limited information on its safety and efficacy in African children. METHODOLOGY/PRINCIPAL FINDINGS: The non-inferiority of DHA-PQP versus artemether-lumefantrine (AL) in children 6-59 months old with uncomplicated P. falciparum malaria was tested in five African countries (Burkina Faso, Kenya, Mozambique, Uganda and Zambia). Patients were randomised (2:1) to receive either DHA-PQP or AL. Non-inferiority was assessed using a margin of -5% for the lower limit of the one-sided 97.5% confidence interval on the treatment difference (DHA-PQP vs. AL) of the day 28 polymerase chain reaction (PCR) corrected cure rate. Efficacy analysis was performed in several populations, and two of them are presented here: intention-to-treat (ITT) and enlarged per-protocol (ePP). 1553 children were randomised, 1039 receiving DHA-PQP and 514 AL. The PCR-corrected day 28 cure rate was 90.4% (ITT) and 94.7% (ePP) in the DHA-PQP group, and 90.0% (ITT) and 95.3% (ePP) in the AL group. The lower limits of the one-sided 97.5% CI of the difference between the two treatments were -2.80% and -2.96%, in the ITT and ePP populations, respectively. In the ITT population, the Kaplan-Meier estimate of the proportion of new infections up to Day 42 was 13.55% (95% CI: 11.35%-15.76%) for DHA-PQP vs 24.00% (95% CI: 20.11%-27.88%) for AL (p<0.0001). CONCLUSIONS/SIGNIFICANCE: DHA-PQP is as efficacious as AL in treating uncomplicated malaria in African children from different endemicity settings, and shows a comparable safety profile. The occurrence of new infections within the 42-day follow up was significantly lower in the DHA-PQP group, indicating a longer post-treatment prophylactic effect. TRIAL REGISTRATION: Controlled-trials.com ISRCTN16263443

Unexpected High Digestion Rate of Cooked Starch by the Ct-Maltase-Glucoamylase Small Intestine Mucosal α-Glucosidase Subunit

For starch digestion to glucose, two luminal α-amylases and four gut mucosal α-glucosidase subunits are employed. The aim of this research was to investigate, for the first time, direct digestion capability of individual mucosal α-glucosidases on cooked (gelatinized) starch. Gelatinized normal maize starch was digested with N- and C-terminal subunits of recombinant mammalian maltase-glucoamylase (MGAM) and sucrase-isomaltase (SI) of varying amounts and digestion periods. Without the aid of α-amylase, Ct-MGAM demonstrated an unexpected rapid and high digestion degree near 80%, while other subunits showed 20 to 30% digestion. These findings suggest that Ct-MGAM assists α-amylase in digesting starch molecules and potentially may compensate for developmental or pathological amylase deficiencies

Crystal structure of a tripartite complex between C3dg, C-terminal domains of factor H and OspE of Borrelia burgdorferi

Complement is an important part of innate immunity. The alternative pathway of complement is activated when the main opsonin, C3b coats non-protected surfaces leading to opsonisation, phagocytosis and cell lysis. The alternative pathway is tightly controlled to prevent autoactivation towards host cells. The main regulator of the alternative pathway is factor H (FH), a soluble glycoprotein that terminates complement activation in multiple ways. FH recognizes host cell surfaces via domains 19–20 (FH19-20). All microbes including Borrelia burgdorferi, the causative agent of Lyme borreliosis, must evade complement activation to allow the infectious agent to survive in its host. One major mechanism that Borrelia uses is to recruit FH from host. Several outer surface proteins (Osp) have been described to bind FH via the C-terminus, and OspE is one of them. Here we report the structure of the tripartite complex formed by OspE, FH19-20 and C3dg at 3.18 Å, showing that OspE and C3dg can bind simultaneously to FH19-20. This verifies that FH19-20 interacts via the “common microbial binding site” on domain 20 with OspE and simultaneously and independently via domain 19 with C3dg. The spatial organization of the tripartite complex explains how OspE on the bacterial surface binds FH19-20, leaving FH fully available to protect the bacteria against complement. Additionally, formation of tripartite complex between FH, microbial protein and C3dg might enable enhanced protection, particularly on those regions on the bacteria where previous complement activation led to deposition of C3d. This might be especially important for slow-growing bacteria that cause chronic disease like Borrelia burgdorferi.Peer reviewe

Factors influencing nurses' compliance with Standard Precautions in order to avoid occupational exposure to microorganisms: A focus group study

<p>Abstract</p> <p>Background</p> <p>Nurses may acquire an infection during the provision of nursing care because of occupational exposure to microorganisms. Relevant literature reports that, compliance with Standard Precautions (a set of guidelines that can protect health care professionals from being exposed to microorganisms) is low among nurses. Additionally, high rates of exposure to microorganisms among nurses via several modes (needlesticks, hand contamination with blood, exposure to air-transmitted microorganisms) occur. The aim of the study was to study the factors that influence nurses' compliance with Standard Precaution in order to avoid occupational exposure to pathogens, by employing a qualitative research design.</p> <p>Method</p> <p>A focus group approach was used to explore the issue under study. Four focus groups (N = 30) were organised to elicit nurses' perception of the factors that influence their compliance with Standard Precautions. The Health Belief Model (HBM) was used as the theoretical framework and the data were analysed according to predetermined criteria.</p> <p>Results</p> <p>Following content analysis, factors that influence nurses' compliance emerged. Most factors could be applied to one of the main domains of the HBM: benefits, barriers, severity, susceptibility, cues to action, and self-efficacy.</p> <p>Conclusions</p> <p>Changing current behavior requires knowledge of the factors that may influence nurses' compliance with Standard Precautions. This knowledge will facilitate in the implementation of programs and preventive actions that contribute in avoiding of occupational exposure.</p

Joint effects of known type 2 diabetes susceptibility loci in genome-wide association study of Singapore Chinese: The Singapore Chinese health study

Background: Genome-wide association studies (GWAS) have identified genetic factors in type 2 diabetes (T2D), mostly among individuals of European ancestry. We tested whether previously identified T2D-associated single nucleotide polymorphisms (SNPs) replicate and whether SNPs in regions near known T2D SNPs were associated with T2D within the Singapore Chinese Health Study. Methods: 2338 cases and 2339 T2D controls from the Singapore Chinese Health Study were genotyped for 507,509 SNPs. Imputation extended the genotyped SNPs to 7,514,461 with high estimated certainty (r2>0.8). Replication of known index SNP associations in T2D was attempted. Risk scores were computed as the sum of index risk alleles. SNPs in regions ±100 kb around each index were tested for associations with T2D in conditional fine-mapping analysis. Results: Of 69 index SNPs, 20 were genotyped directly and genotypes at 35 others were well imputed. Among the 55 SNPs with data, disease associations were replicated (at p<0.05) for 15 SNPs, while 32 more were directionally consistent with previous reports. Risk score was a significant predictor with a 2.03 fold higher risk CI (1.69-2.44) of T2D comparing the highest to lowest quintile of risk allele burden (p = 5.72×10-14). Two improved SNPs around index rs10923931 and 5 new candidate SNPs around indices rs10965250 and rs1111875 passed simple Bonferroni corrections for significance in conditional analysis. Nonetheless, only a small fraction (2.3% on the disease liability scale) of T2D burden in Singapore is explained by these SNPs. Conclusions: While diabetes risk in Singapore Chinese involves genetic variants, most disease risk remains unexplained. Further genetic work is ongoing in the Singapore Chinese population to identify unique common variants not already seen in earlier studies. However rapid increases in T2D risk have occurred in recent decades in this population, indicating that dynamic environmental influences and possibly gene by environment interactions complicate the genetic architecture of this disease. © 2014 Chen et al

Search for three-jet resonances in pp Collisions at √s=7 TeV

This article is published Open Access at sciencedirect.com. It is distributed under the terms of the Creative Commons Attribution License 3.0.-- et al.Results are reported from a search for the production of three-jet resonances in pp collisions at a center-of-mass energy √s=7  TeV. The study uses the data sample collected by the CMS experiment at the LHC in 2011, corresponding to an integrated luminosity of 5.0fb -1. Events with high jet multiplicity and a large scalar sum of jet transverse momenta are analyzed for the presence of resonances in the three-jet invariant mass spectrum. No evidence for a narrow resonance is found in the data, and limits are set on the cross section for gluino pair production in an R-parity-violating supersymmetry model, for gluino masses greater than 280 GeV. Assuming a branching fraction for gluino decay into three jets of 100%, gluino masses below 460 GeV are excluded at 95% confidence level. These results significantly extend the range of previous limits. © 2012 CERN.European Commission; Federal Ministry of Science, Research and Economy (Austria); ); Agency for Innovation by Science and Technology (Belgium); Conselho Nacional de Desenvolvimento Científico e Tecnológico (Brasil); Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Brasil); Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro; Fundação de Amparo à Pesquisa do Estado de São Paulo; Ministry of Science and Technology of the People's Republic of China; National Natural Science Foundation of China; Colciencias (Colombia); Ministry of Science, Education and Sports of the Republic of Croatia; Research Promotion Foundation (Cyprus); Centre National de la Recherche Scientifique (France); Bundesministerium für Bildung und Forschung (Deutschland); Deutsche Forschungsgemeinschaft; General Secretariat of Research and Technology (Greece); Helsinki Institute of Physics; National Office for Research and Technology (Hungary); Institute for Research in Fundamental Sciences (Iran); Science Foundation Ireland; Istituto Nazionale di Fisica Nucleare (Italia); Compagnia di San Paolo (Italia); National Research Foundation of Korea; Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (México); Consejo Nacional de Ciencia y Tecnología (México); Secretaría de Educación Pública (México); Universidad Autónoma de San Luis Potosí; Ministry of Science and Innovation (New Zealand); Pakistan Atomic Energy Commission; National Science Center (Poland); Fundação para a Ciência e a Tecnologia (Portugal); Joint Institute for Nuclear Research (Russia); Russian Foundation for Basic Research; Ministry of Education, Science and Technological Development (Serbia); Ministerio de Ciencia e Innovación (España); Swiss National Science Foundation.Peer Reviewe

Pharmacogenetics: data, concepts and tools to improve drug discovery and drug treatment

Variation in the human genome is a most important cause of variable response to drugs and other xenobiotics. Susceptibility to almost all diseases is determined to some extent by genetic variation. Driven by the advances in molecular biology, pharmacogenetics has evolved within the past 40 years from a niche discipline to a major driving force of clinical pharmacology, and it is currently one of the most actively pursued disciplines in applied biomedical research in general. Nowadays we can assess more than 1,000,000 polymorphisms or the expression of more than 25,000 genes in each participant of a clinical study – at affordable costs. This has not yet significantly changed common therapeutic practices, but a number of physicians are starting to consider polymorphisms, such as those in CYP2C9, CYP2C19, CYP2D6, TPMT and VKORC1, in daily medical practice. More obviously, pharmacogenetics has changed the practices and requirements in preclinical and clinical drug research; large clinical trials without a pharmacogenomic add-on appear to have become the minority. This review is about how the discipline of pharmacogenetics has evolved from the analysis of single proteins to current approaches involving the broad analyses of the entire genome and of all mRNA species or all metabolites and other approaches aimed at trying to understand the entire biological system. Pharmacogenetics and genomics are becoming substantially integrated fields of the profession of clinical pharmacology, and education in the relevant methods, knowledge and concepts form an indispensable part of the clinical pharmacology curriculum and the professional life of pharmacologists from early drug discovery to pharmacovigilance

A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes

dentification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 x 10(-8)) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.Peer reviewe