Ab initio modeling and molecular dynamics simulation of the alpha 1b-adrenergic receptor activation.

This work describes the ab initio procedure employed to build an activation model for the alpha 1b-adrenergic receptor (alpha 1b-AR). The first version of the model was progressively modified and complicated by means of a many-step iterative procedure characterized by the employment of experimental validations of the model in each upgrading step. A combined simulated (molecular dynamics) and experimental mutagenesis approach was used to determine the structural and dynamic features characterizing the inactive and active states of alpha 1b-AR. The latest version of the model has been successfully challenged with respect to its ability to interpret and predict the functional properties of a large number of mutants. The iterative approach employed to describe alpha 1b-AR activation in terms of molecular structure and dynamics allows further complications of the model to allow prediction and interpretation of an ever-increasing number of experimental data.

Numerical simulation of combined heat transfer phenomena (conduction, convection, and radiation). Application to he optimisation of thermal systems

Thermal systems interchanging heat and mass by conduction, convection, radiation (solar and thermal ) occur in many engineering applications like energy storage by solar collectors, window glazing in buildings, refrigeration of plastic moulds, air handling units etc. Often these thermal systems are composed of various elements for example a building with wall, windows, rooms, etc. It would be of particular interest to have a modular thermal system which is formed by connecting different modules for the elements, flexibility to use and change models for individual elements, add or remove elements without changing the entire code. A numerical approach to handle the heat transfer and fluid flow in such systems helps in saving the full scale experiment time, cost and also aids optimisation of parameters of the system. In subsequent sections are presented a short summary of the work done until now on the orientation of the thesis in the field of numerical methods for heat transfer and fluid flow applications, the work in process and the future work.

Hydrogeophysical data integration at larger scales: Application of Bayesian sequential simulation for the characterization of heterogeneous alluvial aquifers

Knowledge of the spatial distribution of hydraulic conductivity (K) within an aquifer is critical for reliable predictions of solute transport and the development of effective groundwater management and/or remediation strategies. While core analyses and hydraulic logging can provide highly detailed information, such information is inherently localized around boreholes that tend to be sparsely distributed throughout the aquifer volume. Conversely, larger-scale hydraulic experiments like pumping and tracer tests provide relatively low-resolution estimates of K in the investigated subsurface region. As a result, traditional hydrogeological measurement techniques contain a gap in terms of spatial resolution and coverage, and they are often alone inadequate for characterizing heterogeneous aquifers. Geophysical methods have the potential to bridge this gap. The recent increased interest in the application of geophysical methods to hydrogeological problems is clearly evidenced by the formation and rapid growth of the domain of hydrogeophysics over the past decade (e.g., Rubin and Hubbard, 2005).

Effort, reward and self-reported mental health: a simulation study on negative affectivity bias.

Background : In the present article, we propose an alternative method for dealing with negative affectivity (NA) biases in research, while investigating the association between a deleterious psychosocial environment at work and poor mental health. First, we investigated how strong NA must be to cause an observed correlation between the independent and dependent variables. Second, we subjectively assessed whether NA can have a large enough impact on a large enough number of subjects to invalidate the observed correlations between dependent and independent variables.Methods : We simulated 10,000 populations of 300 subjects each, using the marginal distribution of workers in an actual population that had answered the Siegrist's questionnaire on effort and reward imbalance (ERI) and the General Health Questionnaire (GHQ).Results : The results of the present study suggested that simulated NA has a minimal effect on the mean scores for effort and reward. However, the correlations between the effort and reward imbalance (ERI) ratio and the GHQ score might be important, even in simulated populations with a limited NA.Conclusions : When investigating the relationship between the ERI ratio and the GHQ score, we suggest the following rules for the interpretation of the results: correlations with an explained variance of 5% and below should be considered with caution; correlations with an explained variance between 5% and 10% may result from NA, although this effect does not seem likely; and correlations with an explained variance of 10% and above are not likely to be the result of NA biases. [Authors]

Fitness to drive and cannabis: Validation of two blood THCCOOH thresholds to distinguish occasional users from heavy smokers.

Many studies based on either an experimental or an epidemiological approach, have shown that the ability to drive is impaired when the driver is under the influence of cannabis. Baseline performances of heavy users remain impaired even after several weeks of abstinence. Symptoms of cannabis abuse and dependence are generally considered incompatible with safe driving. Recently, it has been shown that traffic safety can be increased by reporting the long-term unfit drivers to the driver licensing authorities and referring the cases for further medical assessment. Evaluation of the frequency of cannabis use is a prerequisite for a reliable medical assessment of the fitness to drive. In a previous paper we advocated the use of two thresholds based on 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (THCCOOH) concentration in whole blood to help to distinguish occasional cannabis users (≤3μg/L) from heavy regular smokers (≥40μg/L). These criteria were established on the basis of results obtained in a controlled cannabis smoking study with placebo, carried out with two groups of young male volunteers; the first group was characterized by a heavy use (≥10 joints/month) while the second group was made up of occasional users smoking at most 1 joint/week. However, to date, these cutoffs have not been adequately assessed under real conditions. Their validity can now be evaluated and confirmed with 146 traffic offenders' real cases in which the whole blood cannabinoid concentrations and the frequency of cannabis use are known. The two thresholds were not challenged by the presence of ethanol (40% of cases) and of other therapeutic and illegal drugs (24%). Thus, we propose the following procedure that can be very useful in the Swiss context but also in other countries with similar traffic policies: if the whole blood THCCOOH concentration is higher than 40μg/L, traffic offenders must be directed first and foremost toward medical assessment of their fitness to drive. This evaluation is not recommended if the THCCOOH concentration is lower than 3μg/L and if the self-rated frequency of cannabis use is less than 1 time/week. A THCCOOH level between these two thresholds cannot be reliably interpreted. In such a case, further medical assessment and follow-up of the fitness to drive are also suggested, but with lower priority.

Microsatellites can be misleading: an empirical and simulation study.

It has been long recognized that highly polymorphic genetic markers can lead to underestimation of divergence between populations when migration is low. Microsatellite loci, which are characterized by extremely high mutation rates, are particularly likely to be affected. Here, we report genetic differentiation estimates in a contact zone between two chromosome races of the common shrew (Sorex araneus), based on 10 autosomal microsatellites, a newly developed Y-chromosome microsatellite, and mitochondrial DNA. These results are compared to previous data on proteins and karyotypes. Estimates of genetic differentiation based on F- and R-statistics are much lower for autosomal microsatellites than for all other genetic markers. We show by simulations that this discrepancy stems mainly from the high mutation rate of microsatellite markers for F-statistics and from deviations from a single-step mutation model for R-statistics. The sex-linked genetic markers show that all gene exchange between races is mediated by females. The absence of male-mediated gene flow most likely results from male hybrid sterility.

How Heavy Is A Job?: A Critical Survey of Job Evaluation as a Payment Device.

With salaries subjected to scrutiny more than ever, it is increasingly important that the process by which they are determined be understood and justifiable. Both public and private organisations now routinely rely on so-called “job evaluation” as a means of constructing an appropriate pay-scale and as such it is ever more necessary that we appreciate how this system works and that we recognise its limits. Only with such an understanding of the way in which salaries are set can we hope to have a meaningful discussion of their economic function. This paper aims to expound the details of job evaluation both in theory and in practice, and critically assess its shortcomings. In Section 1 below we describe the job evaluation system and in Section 2 we briefly outline the history and the usage of the system in both the private and the public sector. In Section 3 we theoretically analyse the often unstated but nonetheless implicit assumptions made by practitioners of the art of job evaluation. Section 4 applies the analysis of Section 3 to review a particular and important case study, namely The Senior Salaries Review of the Welsh Assembly 2004. Section 5 concludes.

The Impact of Population Ageing on House Prices: A Micro-simulation Approach

This paper attempts to estimate the impact of population ageing on house prices. There is considerable debate about whether population ageing puts downwards or upwards pressure on house prices. The empirical approach differs from earlier studies of this relationship, which are mainly regression analyses of macro time-series data. A micro-simulation methodology is adopted that combines a macro-level house price model with a micro-level household formation model. The case study is Scotland, a country that is expected to age rapidly in the future. The parameters of the household formation model are estimated with panel data from the British Household Panel Survey covering the period 1999-2008. The estimates are then used to carry out a set of simulations. The simulations are based on a set of population projections that represent a considerable range in the rate of population ageing. The main finding from the simulations is that population ageing—or more generally changes in age structure—is not likely a main determinant of house prices, at least in Scotland.

No healthy heart for heavy drinkers: a population-based study in Switzerland

Background: Low to moderate alcohol consumption has been associated with lower coronary heart disease (CHD) risk, an effect mainly mediated by an increase in HDL-cholesterol levels. However, data on the CHD risk associated with high alcohol consumption are conflicting. Methods: In a population-based study of 5,769 men and women, aged 35-75 years, without cardiovascular disease in Switzerland, last week alcohol consumption was categorized into 0, 1-6, 7-13, 14-20, 21-27, 28-34, 035 drinks/week and into nondrinkers (0 drink/week), moderate (1-13), high (14-34) and very high drinkers (035). Blood pressure, lipids and high sensitivity C-reactive protein (hs-CRP) were measured, and the 10-year CHD risk was calculated according to the Framingham risk score. Results: 73% (n = 4,214) of the participants consumed alcohol; 16% (n = 909) were considered as high drinkers and 2% (n = 119) as very high drinkers. In multivariate analysis, increasing alcohol consumption was associated with higher HDL-cholesterol (from 1.57 ± 0.01 [adjusted mean ± SE] in nondrinkers to 1.88 ± 0.03 mmol/L in very high drinkers); triglycerides (1.17 ± 1.01 to 1.32 ± 1.05 mmol/L), and systolic and diastolic blood pressure rose significantly (127.4 ± 0.4 to 132.2 ± 1.4 and 78.7 ± 0.3 to 81.7 ± 0.9 mm Hg, respectively, all p for trend <0.001). Predicted 10-year CHD risk increased from 4.31 ± 0.10 to 4.90 ± 0.37 (p = 0.03) with increasing alcohol use, with a J-shaped relationship. Conclusion: As measured by the 10-year CHD risk, the protective effect of alcohol consumption disappears in very high drinkers, namely because the beneficial increase in HDL-cholesterol may be blunt by a rise in blood pressure levels.

Cell-based computational modeling of vascular morphogenesis using Tissue Simulation Toolkit.

Computational modeling has become a widely used tool for unraveling the mechanisms of higher level cooperative cell behavior during vascular morphogenesis. However, experimenting with published simulation models or adding new assumptions to those models can be daunting for novice and even for experienced computational scientists. Here, we present a step-by-step, practical tutorial for building cell-based simulations of vascular morphogenesis using the Tissue Simulation Toolkit (TST). The TST is a freely available, open-source C++ library for developing simulations with the two-dimensional cellular Potts model, a stochastic, agent-based framework to simulate collective cell behavior. We will show the basic use of the TST to simulate and experiment with published simulations of vascular network formation. Then, we will present step-by-step instructions and explanations for building a recent simulation model of tumor angiogenesis. Demonstrated mechanisms include cell-cell adhesion, chemotaxis, cell elongation, haptotaxis, and haptokinesis.

Simulation-based systematic review of imatinib population pharmacokinetics and PK-PD relationships in chronic myeloid leukemia (CML) patients

Objectives: Several population pharmacokinetic (PPK) and pharmacokinetic-pharmacodynamic (PK-PD) analyses have been performed with the anticancer drug imatinib. Inspired by the approach of meta-analysis, we aimed to compare and combine results from published studies in a useful way - in particular for improving the clinical interpretation of imatinib concentration measurements in the scope of therapeutic drug monitoring (TDM). Methods: Original PPK analyses and PK-PD studies (PK surrogate: trough concentration Cmin; PD outcomes: optimal early response and specific adverse events) were searched systematically on MEDLINE. From each identified PPK model, a predicted concentration distribution under standard dosage was derived through 1000 simulations (NONMEM), after standardizing model parameters to common covariates. A "reference range" was calculated from pooled simulated concentrations in a semi-quantitative approach (without specific weighting) over the whole dosing interval. Meta-regression summarized relationships between Cmin and optimal/suboptimal early treatment response. Results: 9 PPK models and 6 relevant PK-PD reports in CML patients were identified. Model-based predicted median Cmin ranged from 555 to 1388 ng/ml (grand median: 870 ng/ml and inter-quartile range: 520-1390 ng/ml). The probability to achieve optimal early response was predicted to increase from 60 to 85% from 520 to 1390 ng/ml across PK-PD studies (odds ratio for doubling Cmin: 2.7). Reporting of specific adverse events was too heterogeneous to perform a regression analysis. The general frequency of anemia, rash and fluid retention increased however consistently with Cmin, but less than response probability. Conclusions: Predicted drug exposure may differ substantially between various PPK analyses. In this review, heterogeneity was mainly attributed to 2 "outlying" models. The established reference range seems to cover the range where both good efficacy and acceptable tolerance are expected for most patients. TDM guided dose adjustment appears therefore justified for imatinib in CML patients. Its usefulness remains now to be prospectively validated in a randomized trial.

Agent based simulation to optimise emergency departments

Nowadays, many of the health care systems are large and complex environments and quite dynamic, specifically Emergency Departments, EDs. It is opened and working 24 hours per day throughout the year with limited resources, whereas it is overcrowded. Thus, is mandatory to simulate EDs to improve qualitatively and quantitatively their performance. This improvement can be achieved modelling and simulating EDs using Agent-Based Model, ABM and optimising many different staff scenarios. This work optimises the staff configuration of an ED. In order to do optimisation, objective functions to minimise or maximise have to be set. One of those objective functions is to find the best or optimum staff configuration that minimise patient waiting time. The staff configuration comprises: doctors, triage nurses, and admissions, the amount and sort of them. Staff configuration is a combinatorial problem, that can take a lot of time to be solved. HPC is used to run the experiments, and encouraging results were obtained. However, even with the basic ED used in this work the search space is very large, thus, when the problem size increases, it is going to need more resources of processing in order to obtain results in an acceptable time.

Artificial Snow Optimization in Winter Sport Destinations Using a Multi-agent Simulation

This paper presents the Juste-Neige system for predicting the snow height on the ski runs of a resort using a multi-agent simulation software. Its aim is to facilitate snow cover management in order to i) reduce the production cost of artificial snow and to improve the profit margin for the companies managing the ski resorts; and ii) to reduce the water and energy consumption, and thus to reduce the environmental impact, by producing only the snow needed for a good skiing experience. The software provides maps with the predicted snow heights for up to 13 days. On these maps, the areas most exposed to snow erosion are highlighted. The software proceeds in three steps: i) interpolation of snow height measurements with a neural network; ii) local meteorological forecasts for every ski resort; iii) simulation of the impact caused by skiers using a multi-agent system. The software has been evaluated in the Swiss ski resort of Verbier and provides useful predictions.