Appropriate treatment for Crohn's disease: methodology and summary results of a multidisciplinary international expert panel approach--EPACT.

BACKGROUND/AIMS: For many therapeutic decisions in Crohn's disease (CD), high-grade evidence is lacking. To assist clinical decision-making, explicit panel-based appropriateness criteria were developed by an international, multidisciplinary expert panel. METHODS: 10 gastroenterologists, 3 surgeons and 2 general practitioners from 12 European countries assessed the appropriateness of therapy for CD using the RAND Appropriateness Method. Their assessment was based on the study of a recent literature review of the subject, combined with their own expert clinical judgment. Panelists rated clinical indications and treatment options using a 9-point scale (1 = extremely inappropriate; 9 = extremely appropriate). These scenarios were then discussed in detail at the panel meeting and re-rated. Median ratings and disagreement were used to aggregate ratings into three assessment categories: appropriate (A), uncertain (U) and inappropriate (I). RESULTS: 569 specific indications were rated, dealing with 9 clinical presentations: mild/moderate luminal CD (n = 104), severe CD (n = 126), steroid-dependent CD (n = 25), steroid-refractory CD (n = 37), fistulizing CD (n = 49), fibrostenotic CD (n = 35), maintenance of medical remission of CD (n = 84), maintenance of surgical remission (n = 78), drug safety in pregnancy (n = 24) and use of infliximab (n = 7). Overall, 146 indications (26%) were judged appropriate, 129 (23%) uncertain and 294 (52%) inappropriate. Frank disagreement was low (14% overall) with the greatest disagreement (54% of scenarios) being observed for treatment of steroid-refractory disease. CONCLUSIONS: Detailed explicit appropriateness criteria for the appropriate use of therapy for CD were developed for the first time by a European expert panel. Disease location, severity and previous treatments were the main factors taken into account. User-friendly access to EPACT criteria is available via an Internet site, www.epact.ch, allowing prospective evaluation and improvement of appropriateness of current CD therapy.

Reconsideration of dimensions and curve fitting practice in economics ellaborating on Georgescu-Roegen’s economic methodology

This paper is to examine the proper use of dimensions and curve fitting practices elaborating on Georgescu-Roegen’s economic methodology in relation to the three main concerns of his epistemological orientation. Section 2 introduces two critical issues in relation to dimensions and curve fitting practices in economics in view of Georgescu-Roegen’s economic methodology. Section 3 deals with the logarithmic function (ln z) and shows that z must be a dimensionless pure number, otherwise it is nonsensical. Several unfortunate examples of this analytical error are presented including macroeconomic data analysis conducted by a representative figure in this field. Section 4 deals with the standard Cobb-Douglas function. It is shown that the operational meaning cannot be obtained for capital or labor within the Cobb-Douglas function. Section 4 also deals with economists "curve fitting fetishism". Section 5 concludes thispaper with several epistemological issues in relation to dimensions and curve fitting practices in economics.

Multimodel inference and multimodel averaging in empirical modeling of occupational exposure levels.

Empirical modeling of exposure levels has been popular for identifying exposure determinants in occupational hygiene. Traditional data-driven methods used to choose a model on which to base inferences have typically not accounted for the uncertainty linked to the process of selecting the final model. Several new approaches propose making statistical inferences from a set of plausible models rather than from a single model regarded as 'best'. This paper introduces the multimodel averaging approach described in the monograph by Burnham and Anderson. In their approach, a set of plausible models are defined a priori by taking into account the sample size and previous knowledge of variables influent on exposure levels. The Akaike information criterion is then calculated to evaluate the relative support of the data for each model, expressed as Akaike weight, to be interpreted as the probability of the model being the best approximating model given the model set. The model weights can then be used to rank models, quantify the evidence favoring one over another, perform multimodel prediction, estimate the relative influence of the potential predictors and estimate multimodel-averaged effects of determinants. The whole approach is illustrated with the analysis of a data set of 1500 volatile organic compound exposure levels collected by the Institute for work and health (Lausanne, Switzerland) over 20 years, each concentration having been divided by the relevant Swiss occupational exposure limit and log-transformed before analysis. Multimodel inference represents a promising procedure for modeling exposure levels that incorporates the notion that several models can be supported by the data and permits to evaluate to a certain extent model selection uncertainty, which is seldom mentioned in current practice.

Complementarities between mathematical and computational modeling: the case of the repeated Prisoners' Dilemma

We study the properties of the well known Replicator Dynamics when applied to a finitely repeated version of the Prisoners' Dilemma game. We characterize the behavior of such dynamics under strongly simplifying assumptions (i.e. only 3 strategies are available) and show that the basin of attraction of defection shrinks as the number of repetitions increases. After discussing the difficulties involved in trying to relax the 'strongly simplifying assumptions' above, we approach the same model by means of simulations based on genetic algorithms. The resulting simulations describe a behavior of the system very close to the one predicted by the replicator dynamics without imposing any of the assumptions of the mathematical model. Our main conclusion is that mathematical and computational models are good complements for research in social sciences. Indeed, while computational models are extremely useful to extend the scope of the analysis to complex scenarios hard to analyze mathematically, formal models can be useful to verify and to explain the outcomes of computational models.

Quantitation of HIV-1 RNA Viral Load Using NASBA Methodology and Comparison with other Surrogate Markers for Disease Progression

In this study, HIV-1 viral load quantitation determined by Nucleic Acid Sequence Based Amplification (NASBA) was compared with other surrogate disease progression markers (antigen p24, CD4/CD8 cell counts and b-2 microglobulin) in 540 patients followed up at São Paulo, SP, Brazil. HIV-1 RNA detection was statistically associated with the presence of antigen p24, but the viral RNA was also detected in 68% of the antigen p24 negative samples, confirming that NASBA is much more sensitive than the determination of antigen p24. Regarding other surrogate markers, no statistically significant association with the detection of viral RNA was found. The reproducibility of this viral load assay was assessed by 14 runs of the same sample, using different reagents batches. Viral load values in this sample ranged from 5.83 to 6.27 log (CV = 36 %), less than the range (0.5 log) established to the determination of significant viral load changes.

The stabilizing effects of the acquired immunity on the schistosomiasis transmission modeling - the sensitivity Analysis

A mathematical model is proposed to analyze the effects of acquired immunity on the transmission of schistosomiasis in the human host. From this model the prevalence curve dependent on four parameters can be obtained. These parameters were estimated fitting the data by the maximum likelihood method. The model showed a good retrieving capacity of real data from two endemic areas of schistosomiasis: Touros, Brazil (Schistosoma mansoni) and Misungwi, Tanzania (S. haematobium). Also, the average worm burden per person and the dispersion of parasite per person in the community can be obtained from the model. In this paper, the stabilizing effects of the acquired immunity assumption in the model are assessed in terms of the epidemiological variables as follows. Regarded to the prevalence curve, we calculate the confidence interval, and related to the average worm burden and the worm dispersion in the community, the sensitivity analysis (the range of the variation) of both variables with respect to their parameters is performed.

Turnaround across diverse global supply chains using shared metrics and change methodology: The Case of Amer Sports Corporation

Purpose - The purpose of this paper is to document the outcome of a global three-year long supply chain improvement initiative at a multi-national producer of branded sporting goods that is transforming from a holding structure to an integrated company. The case company is comprised of seven internationally well-known sport brands, which form a diverse set of independent sub-cases, on which the same supply chain metrics and change project approach was applied to improve supply chain performance. Design/methodology/approach - By using in-depth case study and statistical analysis the paper analyzes across the brands how supply chain complexity (SKU count), supply chain type (make or buy) and seasonality affect completeness and punctuality of deliveries, and inventory as the change project progresses. Findings - Results show that reduction in supply chain complexity improves delivery performance, but has no impact on inventory. Supply chain type has no impact on service level, but brands with in-house production are better in improving inventory than those with outsourced production. Non-seasonal business units improve service faster than seasonal ones, yet there is no impact on inventory. Research limitations/implications - The longitudinal data used for the analysis is biased with the general business trend, yet the rich data from different cases and three-years of data collection enables generalizations to a certain level. Practical implications - The in-depth case study serves as an example for other companies on how to initiate a supply chain improvement project across business units with tangible results. Originality/value - The seven sub-cases with their different characteristics on which the same improvement initiative was applied sets a unique ground for longitudinal analysis to study supply chain complexity, type and seasonality.

Synchronous versus asynchronous modeling of gene regulatory networks.

MOTIVATION: In silico modeling of gene regulatory networks has gained some momentum recently due to increased interest in analyzing the dynamics of biological systems. This has been further facilitated by the increasing availability of experimental data on gene-gene, protein-protein and gene-protein interactions. The two dynamical properties that are often experimentally testable are perturbations and stable steady states. Although a lot of work has been done on the identification of steady states, not much work has been reported on in silico modeling of cellular differentiation processes. RESULTS: In this manuscript, we provide algorithms based on reduced ordered binary decision diagrams (ROBDDs) for Boolean modeling of gene regulatory networks. Algorithms for synchronous and asynchronous transition models have been proposed and their corresponding computational properties have been analyzed. These algorithms allow users to compute cyclic attractors of large networks that are currently not feasible using existing software. Hereby we provide a framework to analyze the effect of multiple gene perturbation protocols, and their effect on cell differentiation processes. These algorithms were validated on the T-helper model showing the correct steady state identification and Th1-Th2 cellular differentiation process. AVAILABILITY: The software binaries for Windows and Linux platforms can be downloaded from http://si2.epfl.ch/~garg/genysis.html.

Preliminary regional rockfall hazard mapping using LIDAR-based slope frequency distribution and CONEFALL modeling

A factor limiting preliminary rockfall hazard mapping at regional scale is often the lack of knowledge of potential source areas. Nowadays, high resolution topographic data (LiDAR) can account for realistic landscape details even at large scale. With such fine-scale morphological variability, quantitative geomorphometric analyses become a relevant approach for delineating potential rockfall instabilities. Using digital elevation model (DEM)-based ?slope families? concept over areas of similar lithology and cliffs and screes zones available from the 1:25,000 topographic map, a susceptibility rockfall hazard map was drawn up in the canton of Vaud, Switzerland, in order to provide a relevant hazard overview. Slope surfaces over morphometrically-defined thresholds angles were considered as rockfall source zones. 3D modelling (CONEFALL) was then applied on each of the estimated source zones in order to assess the maximum runout length. Comparison with known events and other rockfall hazard assessments are in good agreement, showing that it is possible to assess rockfall activities over large areas from DEM-based parameters and topographical elements.

Functional analysis and structural modeling of human APOBEC3G reveal the role of evolutionarily conserved elements in the inhibition of human immunodeficiency virus type 1 infection and Alu transposition.

Retroelements are important evolutionary forces but can be deleterious if left uncontrolled. Members of the human APOBEC3 family of cytidine deaminases can inhibit a wide range of endogenous, as well as exogenous, retroelements. These enzymes are structurally organized in one or two domains comprising a zinc-coordinating motif. APOBEC3G contains two such domains, only the C terminal of which is endowed with editing activity, while its N-terminal counterpart binds RNA, promotes homo-oligomerization, and is necessary for packaging into human immunodeficiency virus type 1 (HIV-1) virions. Here, we performed a large-scale mutagenesis-based analysis of the APOBEC3G N terminus, testing mutants for (i) inhibition of vif-defective HIV-1 infection and Alu retrotransposition, (ii) RNA binding, and (iii) oligomerization. Furthermore, in the absence of structural information on this domain, we used homology modeling to examine the positions of functionally important residues and of residues found to be under positive selection by phylogenetic analyses of primate APOBEC3G genes. Our results reveal the importance of a predicted RNA binding dimerization interface both for packaging into HIV-1 virions and inhibition of both HIV-1 infection and Alu transposition. We further found that the HIV-1-blocking activity of APOBEC3G N-terminal mutants defective for packaging can be almost entirely rescued if their virion incorporation is forced by fusion with Vpr, indicating that the corresponding region of APOBEC3G plays little role in other aspects of its action against this pathogen. Interestingly, residues forming the APOBEC3G dimer interface are highly conserved, contrasting with the rapid evolution of two neighboring surface-exposed amino acid patches, one targeted by the Vif protein of primate lentiviruses and the other of yet-undefined function.

Treeline and climate change : analyzing and modeling patterns and shifts in the Swiss Alps

Summary: Global warming has led to an average earth surface temperature increase of about 0.7 °C in the 20th century, according to the 2007 IPCC report. In Switzerland, the temperature increase in the same period was even higher: 1.3 °C in the Northern Alps anal 1.7 °C in the Southern Alps. The impacts of this warming on ecosystems aspecially on climatically sensitive systems like the treeline ecotone -are already visible today. Alpine treeline species show increased growth rates, more establishment of young trees in forest gaps is observed in many locations and treelines are migrating upwards. With the forecasted warming, this globally visible phenomenon is expected to continue. This PhD thesis aimed to develop a set of methods and models to investigate current and future climatic treeline positions and treeline shifts in the Swiss Alps in a spatial context. The focus was therefore on: 1) the quantification of current treeline dynamics and its potential causes, 2) the evaluation and improvement of temperaturebased treeline indicators and 3) the spatial analysis and projection of past, current and future climatic treeline positions and their respective elevational shifts. The methods used involved a combination of field temperature measurements, statistical modeling and spatial modeling in a geographical information system. To determine treeline shifts and assign the respective drivers, neighborhood relationships between forest patches were analyzed using moving window algorithms. Time series regression modeling was used in the development of an air-to-soil temperature transfer model to calculate thermal treeline indicators. The indicators were then applied spatially to delineate the climatic treeline, based on interpolated temperature data. Observation of recent forest dynamics in the Swiss treeline ecotone showed that changes were mainly due to forest in-growth, but also partly to upward attitudinal shifts. The recent reduction in agricultural land-use was found to be the dominant driver of these changes. Climate-driven changes were identified only at the uppermost limits of the treeline ecotone. Seasonal mean temperature indicators were found to be the best for predicting climatic treelines. Applying dynamic seasonal delimitations and the air-to-soil temperature transfer model improved the indicators' applicability for spatial modeling. Reproducing the climatic treelines of the past 45 years revealed regionally different attitudinal shifts, the largest being located near the highest mountain mass. Modeling climatic treelines based on two IPCC climate warming scenarios predicted major shifts in treeline altitude. However, the currently-observed treeline is not expected to reach this limit easily, due to lagged reaction, possible climate feedback effects and other limiting factors. Résumé: Selon le rapport 2007 de l'IPCC, le réchauffement global a induit une augmentation de la température terrestre de 0.7 °C en moyenne au cours du 20e siècle. En Suisse, l'augmentation durant la même période a été plus importante: 1.3 °C dans les Alpes du nord et 1.7 °C dans les Alpes du sud. Les impacts de ce réchauffement sur les écosystèmes - en particuliers les systèmes sensibles comme l'écotone de la limite des arbres - sont déjà visibles aujourd'hui. Les espèces de la limite alpine des forêts ont des taux de croissance plus forts, on observe en de nombreux endroits un accroissement du nombre de jeunes arbres s'établissant dans les trouées et la limite des arbres migre vers le haut. Compte tenu du réchauffement prévu, on s'attend à ce que ce phénomène, visible globalement, persiste. Cette thèse de doctorat visait à développer un jeu de méthodes et de modèles pour étudier dans un contexte spatial la position présente et future de la limite climatique des arbres, ainsi que ses déplacements, au sein des Alpes suisses. L'étude s'est donc focalisée sur: 1) la quantification de la dynamique actuelle de la limite des arbres et ses causes potentielles, 2) l'évaluation et l'amélioration des indicateurs, basés sur la température, pour la limite des arbres et 3) l'analyse spatiale et la projection de la position climatique passée, présente et future de la limite des arbres et des déplacements altitudinaux de cette position. Les méthodes utilisées sont une combinaison de mesures de température sur le terrain, de modélisation statistique et de la modélisation spatiale à l'aide d'un système d'information géographique. Les relations de voisinage entre parcelles de forêt ont été analysées à l'aide d'algorithmes utilisant des fenêtres mobiles, afin de mesurer les déplacements de la limite des arbres et déterminer leurs causes. Un modèle de transfert de température air-sol, basé sur les modèles de régression sur séries temporelles, a été développé pour calculer des indicateurs thermiques de la limite des arbres. Les indicateurs ont ensuite été appliqués spatialement pour délimiter la limite climatique des arbres, sur la base de données de températures interpolées. L'observation de la dynamique forestière récente dans l'écotone de la limite des arbres en Suisse a montré que les changements étaient principalement dus à la fermeture des trouées, mais aussi en partie à des déplacements vers des altitudes plus élevées. Il a été montré que la récente déprise agricole était la cause principale de ces changements. Des changements dus au climat n'ont été identifiés qu'aux limites supérieures de l'écotone de la limite des arbres. Les indicateurs de température moyenne saisonnière se sont avérés le mieux convenir pour prédire la limite climatique des arbres. L'application de limites dynamiques saisonnières et du modèle de transfert de température air-sol a amélioré l'applicabilité des indicateurs pour la modélisation spatiale. La reproduction des limites climatiques des arbres durant ces 45 dernières années a mis en évidence des changements d'altitude différents selon les régions, les plus importants étant situés près du plus haut massif montagneux. La modélisation des limites climatiques des arbres d'après deux scénarios de réchauffement climatique de l'IPCC a prédit des changements majeurs de l'altitude de la limite des arbres. Toutefois, l'on ne s'attend pas à ce que la limite des arbres actuellement observée atteigne cette limite facilement, en raison du délai de réaction, d'effets rétroactifs du climat et d'autres facteurs limitants.

Application de la modélisation moléculaire à de nouvelles approches thérapeutiques du cancer [Application of molecular modeling to new therapeutic cancer approaches].

Recent progress in the experimental determination of protein structures allow to understand, at a very detailed level, the molecular recognition mechanisms that are at the basis of the living matter. This level of understanding makes it possible to design rational therapeutic approaches, in which effectors molecules are adapted or created de novo to perform a given function. An example of such an approach is drug design, were small inhibitory molecules are designed using in silico simulations and tested in vitro. In this article, we present a similar approach to rationally optimize the sequence of killer T lymphocytes receptors to make them more efficient against melanoma cells. The architecture of this translational research project is presented together with its implications both at the level of basic research as well as in the clinics.

A methodology to event reconstruction from trace images

The widespread use of digital imaging devices for surveillance (CCTV) and entertainment (e.g., mobile phones, compact cameras) has increased the number of images recorded and opportunities to consider the images as traces or documentation of criminal activity. The forensic science literature focuses almost exclusively on technical issues and evidence assessment [1]. Earlier steps in the investigation phase have been neglected and must be considered. This article is the first comprehensive description of a methodology to event reconstruction using images. This formal methodology was conceptualised from practical experiences and applied to different contexts and case studies to test and refine it. Based on this practical analysis, we propose a systematic approach that includes a preliminary analysis followed by four main steps. These steps form a sequence for which the results from each step rely on the previous step. However, the methodology is not linear, but it is a cyclic, iterative progression for obtaining knowledge about an event. The preliminary analysis is a pre-evaluation phase, wherein potential relevance of images is assessed. In the first step, images are detected and collected as pertinent trace material; the second step involves organising and assessing their quality and informative potential. The third step includes reconstruction using clues about space, time and actions. Finally, in the fourth step, the images are evaluated and selected as evidence. These steps are described and illustrated using practical examples. The paper outlines how images elicit information about persons, objects, space, time and actions throughout the investigation process to reconstruct an event step by step. We emphasise the hypothetico-deductive reasoning framework, which demonstrates the contribution of images to generating, refining or eliminating propositions or hypotheses. This methodology provides a sound basis for extending image use as evidence and, more generally, as clues in investigation and crime reconstruction processes.