Qualitative and quantitative formal model-based safety analysis : push the safety button

Magdeburg, Univ., Fak. für Informatik, Diss., 2011

Evaluation of Sexual Dimorphism in the Efficacy and Safety of Simvastatin/Atorvastatin Therapy in a Southern Brazilian Cohort

Background: Dyslipidemia is the primary risk factor for cardiovascular disease, and statins have been effective in controlling lipid levels. Sex differences in the pharmacokinetics and pharmacodynamics of statins contribute to interindividual variations in drug efficacy and toxicity. Objective: To evaluate the presence of sexual dimorphism in the efficacy and safety of simvastatin/atorvastatin treatment. Methods: Lipid levels of 495 patients (331 women and 164 men) were measured at baseline and after 6 ± 3 months of simvastatin/atorvastatin treatment to assess the efficacy and safety profiles of both drugs. Results: Women had higher baseline levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) compared with men (p < 0.0001). After treatment, women exhibited a greater decrease in plasma TC and LDL-C levels compared with men. After adjustment for covariates, baseline levels of TC and LDL-C influenced more than 30% of the efficacy of lipid-lowering therapy (p < 0.001), regardless of sex. Myalgia [with or without changes in creatine phosphokinase (CPK) levels] occurred more frequently in women (25.9%; p = 0.002), whereas an increase in CPK and/or abnormal liver function was more frequent in in men (17.9%; p = 0.017). Conclusions: Our results show that baseline TC and LDL-C levels are the main predictors of simvastatin/atorvastatin therapy efficacy, regardless of sex. In addition, they suggest the presence of sexual dimorphism in the safety of simvastatin/atorvastatin. The effect of sex differences on receptors, transporter proteins, and gene expression pathways needs to be better evaluated and characterized to confirm these observations.

System-analytic safety evaluation of the hydrogen cycle for energetic utilization

Hydrogen, energy, safety, risk, production, transport, storage, filling station, fuelcell

Robust learning in safety-related domains : machine learning methods for solving safety-related application problems

Magdeburg, Univ., Fak. für Informatik, Diss., 2009

Optimal design for dose finding studies on safety and efficacy

Magdeburg, Univ., Fak. für Mathematik, Diss., 2009

Reproducibility and Reliability of the Quality of Life Questionnaire in Patients With Atrial Fibrillation

Abstract Background: Studies have shown the impact of atrial fibrillation (AF) on the patients' quality of life. Specific questionnaires enable the evaluation of relevant events. We previously developed a questionnaire to assess the quality of life of patients with AF (AFQLQ version 1), which was reviewed in this study, and new domains were added. Objective: To demonstrate the reproducibility of the AFQLQ version 2 (AFQLQ v.2), which included the domains of fatigue, illness perception and well-being. Methods: We applied 160 questionnaires (AFQLQ v.2 and SF-36) to 40 patients, at baseline and 15 days after, to measure inter- and intraobserver reproducibility. The analysis of quality of life stability was determined by test-retest, applying the Bartko intraclass correlation coefficient (ICC). Internal consistency was assessed by Cronbach's alpha test. Results: The total score of the test-retest (n = 40) had an ICC of 0.98 in the AFQLQ v.2, and of 0.94 in the SF36. In assessing the intra- and interobserver reproducibility of the AFQLQ v.2, the ICC reliability was 0.98 and 0.97, respectively. The internal consistency had a Cronbach's alpha coefficient of 0.82, compatible with good agreement of the AFQLQ v.2. Conclusion: The AFQLQ v.2 performed better than its previous version. Similarly, the domains added contributed to make it more comprehensive and robust to assess the quality of life of patients with AF.

maintenance model for systems with phase-type distributed times to failure

Magdeburg, Univ., Fak. für Mathematik, Diss., 2010

Assessing the role of Piccolo and Bassoon zinc finger domains on synapse vesicle recycling and maintenance

Magdeburg, Univ., Fak. für Naturwiss., Diss., 2013

Increasing the efficiency of utilization of soil and fertilizer phosphorus in the subtropical and tropical agricultural systems C

As a rule, soils of the subtropical and tropical regions, in which rainfall is not limiting, are acidic, and low in phosphorus, and, to a less extent, in other macro and micronutrients as well, such a sulfur, boron and zinc. The establishment of a permanent agricultural prac. tice therefore, demands relatively high usage of liming and phosphatic fertilization, to begin with. Several approaches, not mutually exclusive, could be used in order to increase the efficiency of utilization of soil and fertilizer phosphorus so that, goal of diminishing costs of production is reached. The use of liming materials bringing up pH to 6.0-6.5 causes the conversion of iron and aluminum phosphates to more available calcium phosphates; on the other hand, by raising calcium saturation in the exchange complex, it improves the development and operation if the root system which allows c or a higher utilization of all soil nutrients, including phosphorus, and helps of stand water deficits which may occur. The role of mycorrhizal fungi should be considered as a way of increasing soil and fertilizer P utilization, as well as the limitations thereof. Screening of and breeding for varieties with higher efficiency of uptake and utilization of soil and fertilizer phosphorus leads to a reduction in cost of inputs and to higher benefit/cost ratios. Corrective fertilization using ground rock phosphate helps to saturate the fixation power of the soil thereby reducing, as a consequence, the need for phosphorus in the maintenance fertilization. Maintenance fertilization, in which soluble phos-phatic sources are used, could be improved by several means whose performance has been proved: limimg, granula tion, placement, use of magnesium salts. Last, cost of phosphate fertilization could be further reduced, without impairing yields, through impairing yields, through changes in technology designed to obtain products better adapted to local conditions and to the availability or raw materials and energy sources.

Maintenance of rattlesnakes in captivity / by James B. Murphy and Barry L. Armstrong.

no.3 (1978)

Validity, reliability and responsiveness of the French language translation of the Western Ontario Shoulder Instability Index (WOSI).

BACKGROUND: The WOSI (Western Ontario Shoulder Instability Index) is a self-administered quality of life questionnaire designed to be used as a primary outcome measure in clinical trials on shoulder instability, as well as to measure the effect of an intervention on any particular patient. It is validated and is reliable and sensitive. As it is designed to measure subjective outcome, it is important that translation should be methodologically rigorous, as it is subject to both linguistic and cultural interpretation. OBJECTIVE: To produce a French language version of the WOSI that is culturally adapted to both European and North American French-speaking populations. MATERIALS AND METHODS: A validated protocol was used to create a French language WOSI questionnaire (WOSI-Fr) that would be culturally acceptable for both European and North American French-speaking populations. Reliability and responsiveness analyses were carried out, and the WOSI-Fr was compared to the F-QuickDASH-D/S (Disability of the Arm, Shoulder and Hand-French translation), and Walch-Duplay scores. RESULTS: A French language version of the WOSI (WOSI-Fr) was accepted by a multinational committee. The WOSI-Fr was then validated using a total of 144 native French-speaking subjects from Canada and Switzerland. Comparison of results on two WOSI-Fr questionnaires completed at a mean interval of 16 days showed that the WOSI-Fr had strong reliability, with a Pearson and interclass correlation of r=0.85 (P=0.01) and ICC=0.84 [95% CI=0.78-0.88]. Responsiveness, at a mean 378.9 days after surgical intervention, showed strong correlation with that of the F-QuickDASH-D/S, with r=0.67 (P<0.01). Moreover, a standardized response means analysis to calculate effect size for both the WOSI-Fr and the F-QuickDASH-D/S showed that the WOSI-Fr had a significantly greater ability to detect change (SRM 1.55 versus 0.87 for the WOSI-Fr and F-QuickDASH-D/S respectively, P<0.01). The WOSI-Fr showed fair correlation with the Walch-Duplay. DISCUSSION: A French-language translation of the WOSI questionnaire was created and validated for use in both Canadian and Swiss French-speaking populations. This questionnaire will facilitate outcome assessment in French-speaking settings, collaboration in multinational studies and comparison between studies performed in different countries. TYPE OF STUDY: Multicenter cohort study. LEVEL OF EVIDENCE: II.

Comprehensive Expression Analyses of Neural Cell-Type-Specific miRNAs Identify New Determinants of the Specification and Maintenance of Neuronal Phenotypes.

MicroRNAs (miRNAs) have been shown to play important roles in both brain development and the regulation of adult neural cell functions. However, a systematic analysis of brain miRNA functions has been hindered by a lack of comprehensive information regarding the distribution of miRNAs in neuronal versus glial cells. To address this issue, we performed microarray analyses of miRNA expression in the four principal cell types of the CNS (neurons, astrocytes, oligodendrocytes, and microglia) using primary cultures from postnatal d 1 rat cortex. These analyses revealed that neural miRNA expression is highly cell-type specific, with 116 of the 351 miRNAs examined being differentially expressed fivefold or more across the four cell types. We also demonstrate that individual neuron-enriched or neuron-diminished RNAs had a significant impact on the specification of neuronal phenotype: overexpression of the neuron-enriched miRNAs miR-376a and miR-434 increased the differentiation of neural stem cells into neurons, whereas the opposite effect was observed for the glia-enriched miRNAs miR-223, miR-146a, miR-19, and miR-32. In addition, glia-enriched miRNAs were shown to inhibit aberrant glial expression of neuronal proteins and phenotypes, as exemplified by miR-146a, which inhibited neuroligin 1-dependent synaptogenesis. This study identifies new nervous system functions of specific miRNAs, reveals the global extent to which the brain may use differential miRNA expression to regulate neural cell-type-specific phenotypes, and provides an important data resource that defines the compartmentalization of brain miRNAs across different cell types.

Associations of short-term particle and noise exposures with markers of cardiovascular and respiratory health among highway maintenance workers

BACKGROUND: Highway maintenance workers are constantly and simultaneously exposed to traffic-related particle and noise emissions, and both have been linked to increased cardiovascular morbidity and mortality in population-based epidemiology studies. OBJECTIVES: We aimed to investigate short-term health effects related to particle and noise exposure. METHODS: We monitored 18 maintenance workers, during as many as five 24-hour periods from a total of 50 observation days. We measured their exposure to fine particulate matter (PM2.5), ultrafine particles, noise, and the cardiopulmonary health endpoints: blood pressure, pro-inflammatory and pro-thrombotic markers in the blood, lung function and fractional exhaled nitric oxide (FeNO) measured approximately 15 hours post-work. Heart rate variability was assessed during a sleep period approximately 10 hours post-work. RESULTS: PM2.5 exposure was significantly associated with C-reactive protein and serum amyloid A, and negatively associated with tumor necrosis factor α. None of the particle metrics were significantly associated with von Willebrand factor or tissue factor expression. PM2.5 and work noise were associated with markers of increased heart rate variability, and with increased HF and LF power. Systolic and diastolic blood pressure on the following morning were significantly associated with noise exposure after work, and non-significantly associated with PM2.5. We observed no significant associations between any of the exposures and lung function or FeNO. CONCLUSIONS: Our findings suggest that exposure to particles and noise during highway maintenance work might pose a cardiovascular health risk. Actions to reduce these exposures could lead to better health for this population of workers.