FluxSimulator: An R package to simulate isotopomer distributions in metabolic networks

The representation of biochemical knowledge in terms of fluxes (transformation rates) in a metabolic network is often a crucial step in the development of new drugs and efficient bioreactors. Mass spectroscopy (MS) and nuclear magnetic resonance spectroscopy (NMRS) in combination with 13C labeled substrates are experimental techniques resulting in data that may be used to quantify fluxes in the metabolic network underlying a process. The massive amount of data generated by spectroscopic experiments increasingly requires software which models the dynamics of the underlying biological system. In this work we present an approach to handle isotopomer distributions in metabolic networks using an object-oriented programming approach, implemented using S4 classes in R. The developed package is called FluxSimulator and provides a user friendly interface to specify the topological information of the metabolic network as well as carbon atom transitions in plain text files. The package automatically derives the mathematical representation of the formulated network, and assembles a set of ordinary differential equations (ODEs) describing the change of each isotopomer pool over time. These ODEs are subsequently solved numerically. In a case study FluxSimulator was applied to an example network. Our results indicate that the package is able to reproduce exact changes in isotopomer compositions of the metabolite pools over time at given flux rates

Trajectories of Cognitive Symptoms in Sick-Listed Cancer Survivors

Many non-central nervous system (CNS) cancer survivors experience cognitive symptoms, which may affect their self-perceived work ability. Little is known about trajectories of self-perceived cognitive functioning in cancer survivors in the period after work disability assessment. Therefore, we evaluated: (1) trajectories of self-reported cognitive functioning, in cancer survivors with work capacity, (2) differences in trajectories of self-reported cognitive functioning between three work disability groups, and (3) explanatory factors of trajectories of self-reported cognitive functioning. Participants (n = 206) were assessed on self-reported cognitive functioning at three time points between two and four years after first day of sick leave. A statistically significant improvement in cognitive functioning was found in the total group (β = 4.62, SE = 0.91, p < 0.001). When comparing cancer survivors in different work disability groups, similar trajectories of cognitive functioning were observed. Fatigue was the only factor found to be associated with the reported trajectory (β = -0.23, SE = 0.086, p = 0.08). Self-perceived cognitive functioning scores remained considerably lower than the mean score of the general Dutch population, indicating that cognitive symptoms are a persistent problem in sick-listed cancer survivors and that evidence-based treatment options are warranted

Properties of the Bose glass phase in irradiated superconductors near the matching field

Structural and transport properties of interacting localized flux lines in the Bose glass phase of irradiated superconductors are studied by means of Monte Carlo simulations near the matching field B_Phi, where the densities of vortices and columnar defects are equal. For a completely random columnar pin distribution in the xy-plane transverse to the magnetic field, our results show that the repulsive vortex interactions destroy the Mott insulator phase which was predicted to occur at B = B_Phi. On the other hand, for ratios of the penetration depth to average defect distance lambda/d <= 1, characteristic remnants of the Mott insulator singularities remain visible in experimentally accessible quantities as the magnetization, the bulk modulus, and the magnetization relaxation, when B is varied near B_Phi. For spatially more regular disorder, e.g., a nearly triangular defect distribution, we find that the Mott insulator phase can survive up to considerably large interaction range \lambda/d, and may thus be observable in experiments.Comment: RevTex, 17 pages, eps files for 12 figures include

Effects of changes in early retirement policies on labor force participation: the differential effects for vulnerable groups

Objectives This study investigated the effects of a national early retirement reform, which was implemented in 2006 and penalized early retirement, on paid employment and different exit pathways and examined whether these effects differ by gender, income level and health status. Methods This study included all Dutch individuals in paid employment born six months before (control group) and six months after (intervention group) the cut-off date of the reform (1 January 1950) that fiscally penalized early retirement. A regression discontinuity design combined with restricted mean survival time analysis was applied to evaluate the effect of penalizing early retirement on labor force participation from age 60 until workers reached the retirement age of 65 years, while accounting for secular trends around the threshold. Results The intervention grou

Socio-economic inequalities in the effectiveness of workplace health promotion programmes on body mass index: An individual participant data meta-analysis

This individual participant data meta-analysis assessed the effectiveness of workplace health promotion programmes on body mass index (BMI) across socio-economic groups and whether study and intervention characteristics explained inequalities in effectiveness. Studies were eligible if they assessed the effect of a workplace health promotion programme on BMI in the Netherlands, included workers of at least two different socio-economic positions (SEPs) and had a study design with premeasurement and postmeasurement and control condition. Data of 13 studies presenting 16 interventions (5183 participants) were harmonized. In a two-stage meta-analysis, the interaction between intervention and SEP on BMI was tested with linear mixed models for each study. Subsequently, the interaction terms were pooled. The influence of study and intervention characteristics on the effectiveness of workplace health promotion programmes was evaluated using meta-regression analyses. Compared with control conditions, workplace health promotion programmes overall showed a statistically non-significant 0.12 kg/m2 (95% CI: −0.01, 0.25) decrease in BMI, which did not differ across SEP. Interventions evaluated within randomized controlled trials, agentic interventions, those that focused on high-risk groups, included a counselling component, consisted of more than five sessions, or were offered at the individual level did statistically significantly reduce BMI. No evidence was found for intervention-generated SEP inequalities

The role of personal characteristics, work environment and context in working beyond retirement: a mixed-methods study

Objective: To investigate the role of personal characteristics, work environment and context in working beyond retirement. Methods: In the current study, a mixed-methods design was applied including quantitative survey data and semi-structured telephone interviews. Respondents (N = 568) were selected from the Study on Transitions in Employment, Ability and Motivation (STREAM). Personal characteristics, work characteristics and contextual factors were measured using a questionnaire at baseline. Concurrently, qualitative data of 30 persons aged over 65 years were gathered. Logistic regression analyses were used to identify quantitative associations and thematic analyses were used for qualitative purposes. Results: Quantitative data revealed that being in good physical health (OR = 1.80), developmental proactivity (OR = 1.38), interesting work (OR = 2.02), appreciation (OR = 1.62) and voluntary work (OR = 1.58) were associated with working beyond the statutory retirement age. Additionally, qualitative findings suggested that working beyond retirement was mainly driven by the desire to contribute to society (e.g., mentor younger co

Influence of chronic diseases on societal participation in paid work, volunteering and informal caregiving in Europe: A 12-year follow-up study

Background: This study aims to provide insight into (1) the associations between having a chronic disease and participation in paid work, volunteer activities or informal care, (2) the associations between the onset of a chronic disease and these forms of societal participation, and (3) whether these associations differ across educational level and gender. Methods: The study population consisted of n=21 875 respondents of the Survey of Health, Ageing and Retirement in Europe aged between 50 years and the country-specific retirement age. The influence of having and the onset of a chronic disease on societal participation was analysed using a hybrid Poisson regression model, combining fixed and random effects, and presented by relative risks (RRs). Results: Individuals with a chronic disease were less likely to participate in paid work (RR: 0.69; 95% CI 0.67 to 0.71) and volunteer activities (RR: 0.92; 95% CI 0.88 to 0.97), but more likely to give informal care (RR: 1.05; 95% CI 1.01 to 1.08). Onset of a chronic disease was associated with a higher likelihood to quit paid work (RR: 0.91; 95% CI 0.86 to 0.97) and to give informal care (RR: 1.08; 95% CI 1.01 to 1.16). Lower educated individuals with a chronic disease or with the onset of a chronic disease were less likely to have paid work than higher educated individuals. Conclusion: Individuals with a chronic disease were less likely to participate in paid work and volunteer activities, and more likely to provide informal care. Educational inequalities were present for paid work. More insight into which factors hinder societal participation among individuals with a chronic disease is needed

Evaluation of occupational health interventions using a randomized controlled trial: Challenges and alternative research designs

Occupational health researchers regularly conduct evaluative intervention research for which a randomized controlled trial (RCT) may not be the most appropriate design (eg, effects of policy measures, organizational interventions on work schedules). This article demonstrates the appropriateness of alternative designs for the evaluation of occupational health interventions, which permit causal inferences, formulated along two study design approaches: experimental (stepped-wedge) and observational (propensity scores, instrumental variables, multiple baseline design, interrupted time series, difference-in-difference, and regression discontinuity). For each design, the unique characteristics are presented including the advantages and disadvantages compared to the RCT, illustrated by empirical examples in occupational health. This overview shows that several appropriate alternatives for the RCT design are feasible and available, which may provide sufficiently strong evidence to guide decisions on implementation of interventions in workplaces. Researchers are encouraged to continue exploring these designs and thus contribute to evidence-based occupational health

Identification of regulatory variants associated with genetic susceptibility to meningococcal disease

Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA - a NF-kB subunit, master regulator of the response to infection - under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes

Plasma lipid profiles discriminate bacterial from viral infection in febrile children

Fever is the most common reason that children present to Emergency Departments. Clinical signs and symptoms suggestive of bacterial infection are often non-specific, and there is no definitive test for the accurate diagnosis of infection. The 'omics' approaches to identifying biomarkers from the host-response to bacterial infection are promising. In this study, lipidomic analysis was carried out with plasma samples obtained from febrile children with confirmed bacterial infection (n = 20) and confirmed viral infection (n = 20). We show for the first time that bacterial and viral infection produces distinct profile in the host lipidome. Some species of glycerophosphoinositol, sphingomyelin, lysophosphatidylcholine and cholesterol sulfate were higher in the confirmed virus infected group, while some species of fatty acids, glycerophosphocholine, glycerophosphoserine, lactosylceramide and bilirubin were lower in the confirmed virus infected group when compared with confirmed bacterial infected group. A combination of three lipids achieved an area under the receiver operating characteristic (ROC) curve of 0.911 (95% CI 0.81 to 0.98). This pilot study demonstrates the potential of metabolic biomarkers to assist clinicians in distinguishing bacterial from viral infection in febrile children, to facilitate effective clinical management and to the limit inappropriate use of antibiotics