Pharmacokinetic and pharmacodynamic assessment of valganciclovir in solid organ transplant recipients

RESUME : Valganciclovir (Valcyte®) is an orally administered ester prodrug of the standard anticytomegalovirus (CMV) drug ganciclovir. This drug enabled an important reduction of the burden of CMV morbidity and mortality in solid organ transplant recipients. Prevention of CMV infection and treatment of CMV disease requires drug administration during many weeks. Oral drug administration is therefore convenient. Valganciclovir has been developed to overcome the poor oral availability of ganciclovir, which limits its concentration exposure after oral administration and thus its efficacy. This prodrug crosses efficiently the intestinal barrier, is then hydrolyzed into ganciclovir, providing exposure similar to intravenous ganciclovir. Valganciclovir is now preferred for the prophylaxis and treatment of CMV infection in solid organ transplant recipients. Nevertheless, adequate dosage adjustment is necessary to optimize its use, avoiding either insufficient or exaggerate exposure related to differences in its pharmacokinetic profile between patients. The main goal of this thesis was to better describe the pharmacokinetic and pharmacodynamic profile of valganciclovir in solid organ transplant recipients, to assess their reproducibility and their predictability, and thus to evaluate the current recommendations for valganciclovir dosage adjustment and the potential contribution of routine therapeutic drug monitoring (TDM) to patients' management. A total of 437 ganciclovir plasma concentration data from 65 transplant patients (41 kidney, 12 lung, 10 heart and 2 liver recipients, 58 under oral valganciclovir prophylaxis, 8 under oral valganciclovir treatment and 2 under intravenous ganciclovir) were measured using a validated chromatographic method (HPLC) developed for this study. The results were analyzed by non-linear mixed effect modeling (NONMEM). A two-compartment model with first-order absorption appropriately described the data. Systemic clearance was markedly influenced by GFR, with further differences between graft types and sex (CL/GFR = 1.7 in kidney, 0.9 in heart and 1.2 in lung and liver recipients) with interpatient variability (CV%) of 26% and interoccasion variability of 12%. Body weight and sex influenced central volume of distribution (V1 = 0.34 l/kg in males and 0.27 l/kg in females) with an interpatient variability of 20%. Residual intrapatient variability was 21 %. No significant drug interaction influenced GCV disposition. VGC prophylactic efficacy and tolerability were good, without detectable dependence on GCV profile. In conclusion, this analysis highlights the importance of thorough adjustment of VGC dosage to renal function and body weight. Considering the good predictability and reproducibility of GCV profile after oral VGC in solid organ transplant recipients, routine TDM does not appear to be clinically indicated. However, GCV plasma measurement may still be helpful in specific clinical situations such as documentation of appropriate exposure in patients with potentially compromised absorption, or lack of response to CMV disease treatment, or under renal replacement therapy. RESUME : Le valganciclovir (Valcyte®) est un promédicament oral du ganciclovir qui est un anti-infectieux de référence contre les infections à cytomegalovirus (CMV). Cet antiviral a permis de réduire les effets délétères de cette infection jusqu'ici responsable d'une importante morbidité et mortalité chez les transplantés d'organe. La prévention et le traitement de l'infection à CMV sont donc nécessaires mais requièrent l'administration d'un agent antiviral sur une longue période. Un médicament administré par voie orale représente donc un avantage évident. Le valganciclovir a été développé dans le but d'améliorer la faible absorption orale du ganciclovir, et donc son efficacité. Cet ester valylique du ganciclovir traverse plus facilement la barrière gastro-intestinale, puis est hydrolysé en ganciclovir dans la circulation sanguine, produisant une exposition comparable à celle d'une perfusion intraveineuse de ganciclovir. De ce fait, le valganciclovir est devenu largement utilisé pour la prophylaxie mais aussi le traitement de l'infection à CMV. Néanmoins une utilisation optimale de ce nouveau médicament nécessite de bonnes connaissances sur son profil pharmacocinétique afin d'établir un schéma de dose adapté pour éviter tant une surexposition qu'une sous-exposition résultant des différences d'élimination entre les patients. Le but de cette thèse a été d'étudier le profil pharmacocinétique et pharmacodynamique du valganciclovir chez les transplantés d'organe ainsi que sa reproductibilité et sa prédictibilité. Il s'agissait d'apprécier de manière critique le schéma actuellement recommandé pour l'adaptation des doses de valganciclovir, mais aussi la contribution éventuelle d'un suivi des concentrations sanguines en routine. Un total de 437 taux sanguins de ganciclovir ont été mesurés, provenant de 65 patients transplantés d'organe (41 rénaux, 12 pulmonaires, 10 cardiaques et 2 hépatiques, 58 sous une prophylaxie orale de valganciclovir, 8 sous un traitement de valganciclovir et 2 sous un traitement intraveineux). Une méthode de chromatographie liquide à haute performance a été développée et validée pour cette étude. Les résultats ont été ensuite analysés par modélisation non linéaire à effets mixtes (NONMEM). Un modèle à deux compartiments avec absorption de premier ordre a permis de décrire les données. La clairance systémique était principalement influencée par le débit de filtration glomérulaire (GFR), avec une différence entre les types de greffe et les sexes (CL/GFR = 1.7 chez les greffés rénaux, 0.9 pour les greffés cardiaques et 1.2 pour le groupe des greffés pulmonaires et hépatiques) avec un variabilité inter-individuelle de 26% (CV%) et une variabilité inter-occasion de 12%. Le poids corporel ainsi que le sexe avaient une influence sur le volume central de distribution (V1 = 0.34 l/kg chez les hommes et 0.27 l/kg chez les femmes) avec une variabilité inter-individuelle de 20%. La variabilité intra-individuelle résiduelle était de 21 %. Aucune interaction médicamenteuse n'a montré d'influence sur le profil du ganciclovir. La prophylaxie avec le valganciclovir s'est révélée efficace et bien tolérée. En conclusion, cette analyse souligne l'importance d'une adaptation de la dose du valganciclovir à la fonction rénale et au poids du patient. Au vu de la bonne reproductibilité et prédictibilité du profil pharmacocinétique du ganciclovir chez les patients transplantés recevant du valganciclovir, un suivi des concentrations sanguines en routine ne semble pas cliniquement indiqué. Néanmoins, la mesure des taux plasmatiques de ganciclovir peut être utile dans certaines situations particulières, comme la vérification d'une exposition appropriée chez des patients susceptibles d'absorption insuffisante, ou ne répondant pas au traitement d'une infection à CMV ou encore sous épuration extra-rénale. RESUME LARGE PUBLIC : Le valganciclovir est un précurseur capable de libérer du ganciclovir, récemment développé pour améliorer la faible absorption orale de ce dernier. Une fois le valganciclovir absorbé, le ganciclovir libéré dans la circulation sanguine devient efficace contre les infections à cytomégalovirus. Ce virus largement répandu est responsable de maladies insidieuses et parfois graves chez les personnes présentant une baisse des défenses immunitaires, comme les greffés d'organe recevant un traitement anti-rejet. Le ganciclovir est administré pendant plusieurs mois consécutifs soit pour prévenir une infection après la transplantation, soit pour traiter une infection déclarée. La facilité d'administration du valganciclovir par voie orale représente un avantage sur une administration du ganciclovir par perfusion, qui nécessite une hospitalisation. Toutefois, la voie orale peut être une source supplémentaire de variabilité chez les patients, avec un impact potentiel sur l'efficacité ou la toxicité du médicament. Le but de cette étude a été - de décrire le devenir de ce médicament dans le corps humain (dont l'étude relève de la discipline de la pharmacocinétique) - de définir les facteurs cliniques pouvant expliquer les différences de concentration sanguine observées entre les patients sous une posologie donnée - d'explorer les relations entre les concentrations du médicament dans le sang et son efficacité ou la survenue d'effets indésirables (dont l'étude relève de la discipline de la pharmacodynamie). Cette étude a nécessité le développement et la validation, d'une méthode d'analyse pour mesurer la concentration sanguine du ganciclovir, puis son application à 437 échantillons provenant de 65 patients transplantés d'organe solide (41 rénaux, 12 pulmonaires, 10 cardiaques et 2 hépatiques) recevant du valganciclovir. Les résultats des mesures effectuées ont été analysés à l'aide d'un outil mathématique afin d'élaborer un modèle du devenir du médicament dans le sang chez chaque patient et à chaque occasion. Cette étude a permis d'évaluer chez des patients recevant le valganciclovir, la vitesse à laquelle l'organisme absorbe, distribue, puis élimine le médicament. La vitesse d'élimination dépendait étroitement de la fonction rénale, du type de greffe et du sexe alors que la distribution dépendait du poids et du sexe du patient. La variabilité non expliquée par ces facteurs cliniques était modérée et vraisemblablement sans conséquence clinique évidente soit sur l'efficacité ou la tolérance, qui se révèlent très satisfaisantes chez les patients de l'étude. Les observations n'ont pas révélé de relation entre les concentrations de médicament et l'efficacité thérapeutique ou la survenue d'effets indésirables, confirmant que les doses relativement faibles utilisées dans notre collectif de patients suffisaient à produire une exposition reproductible à des concentrations adéquates. En conclusion, le profil (et par conséquent l'absorption) du valganciclovir chez les patients transplantés semble bien prédictible après une adaptation de la dose à la fonction rénale et au poids du patient. Un contrôle systématique des concentrations sanguines n'est probablement pas indiqué en routine, mais cette mesure peut présenter un intérêt dans certaines conditions particulières.

Characterization of cerebral glucose dynamics in vivo with a four-state conformational model of transport at the blood-brain barrier.

Determination of brain glucose transport kinetics in vivo at steady-state typically does not allow distinguishing apparent maximum transport rate (T(max)) from cerebral consumption rate. Using a four-state conformational model of glucose transport, we show that simultaneous dynamic measurement of brain and plasma glucose concentrations provide enough information for independent and reliable determination of the two rates. In addition, although dynamic glucose homeostasis can be described with a reversible Michaelis-Menten model, which is implicit to the large iso-inhibition constant (K(ii)) relative to physiological brain glucose content, we found that the apparent affinity constant (K(t)) was better determined with the four-state conformational model of glucose transport than with any of the other models tested. Furthermore, we confirmed the utility of the present method to determine glucose transport and consumption by analysing the modulation of both glucose transport and consumption by anaesthesia conditions that modify cerebral activity. In particular, deep thiopental anaesthesia caused a significant reduction of both T(max) and cerebral metabolic rate for glucose consumption. In conclusion, dynamic measurement of brain glucose in vivo in function of plasma glucose allows robust determination of both glucose uptake and consumption kinetics.

Key locations for soybean genotype assessment in Central Brazil

The objective of this work was to identify key locations for the establishment of soybean (Glycine max) genetic breeding programs, in the Central Region of Brazil. Grain yield data of three maturity groups of soybean genotypes, from regional trials conducted over three years, at 18 locations in Brazilian Cerrado were used. A key location for the early phases of the breeding program was defined as the site that best classifies the winning genotypes in the region. Key locations for the final phases were defined as those sites that best represent each environmental stratum, in relation to the adaptability of the respective winning genotype. This adaptability was estimated by additive main effects and multiplicative interaction (AMMI) model analysis, using the distance between the score of each location in a stratum and the score of the winning genotype, which characterizes such stratum in an AMMI biplot. The locations that best classified the winning genotypes over space and time were Mineiros, Placas and Rio Verde. For the final phases of genotype selection, with data from the three maturity group, the recommended locations were: Buritis, Chapadão do Céu, Iraí, Pamplona, Placas, Planaltina, Rio Verde, Sacramento, Senador Canedo, Uberaba, and Uberlândia.

State of the science and the way forward for the ecotoxicological assessment of contaminated land

Over the past two decades, soil ecotoxicologists have made strides in utilizing the basic concepts and advancements in soil zoology and ecology. They have applied the existing tools, and developed new ones to investigate how chemical contamination can affect soil ecosystems, including the degradation or destruction of soil quality and habitats or the diminishment of belowground biodiversity. Soil ecotoxicologists are applying a suite of standard protocols, originally developed as laboratory tests with single chemicals (e.g., pesticides), and further enhancing both the approaches and protocols for the assessment of contaminated lands. However, ecological relevance of some approaches remains unresolved. The authors discuss the main challenges for a coherent ecotoxicological assessment of soil ecosystems amid contaminated lands, and provide recommendations on how to integrate the effects of physical and chemical soil properties, the variations in the diversity of soil invertebrates, and the interactions among organisms of various trophic levels. The review examines new international approaches and test methods using examples from three continents (in particular research conducted in Brazil), and provides recommendations for improving ecological relevance of ecotoxicological investigations of contaminated lands.

Image quality assessment in digital mammography: part II. NPWE as a validated alternative for contrast detail analysis.

Assessment of image quality for digital x-ray mammography systems used in European screening programs relies mainly on contrast-detail CDMAM phantom scoring and requires the acquisition and analysis of many images in order to reduce variability in threshold detectability. Part II of this study proposes an alternative method based on the detectability index (d') calculated for a non-prewhitened model observer with an eye filter (NPWE). The detectability index was calculated from the normalized noise power spectrum and image contrast, both measured from an image of a 5 cm poly(methyl methacrylate) phantom containing a 0.2 mm thick aluminium square, and the pre-sampling modulation transfer function. This was performed as a function of air kerma at the detector for 11 different digital mammography systems. These calculated d' values were compared against threshold gold thickness (T) results measured with the CDMAM test object and against derived theoretical relationships. A simple relationship was found between T and d', as a function of detector air kerma; a linear relationship was found between d' and contrast-to-noise ratio. The values of threshold thickness used to specify acceptable performance in the European Guidelines for 0.10 and 0.25 mm diameter discs were equivalent to threshold calculated detectability indices of 1.05 and 6.30, respectively. The NPWE method is a validated alternative to CDMAM scoring for use in the image quality specification, quality control and optimization of digital x-ray systems for screening mammography.

An assurance-based model to holistically assess the information security posture

EXECUTIVE SUMMARY : Evaluating Information Security Posture within an organization is becoming a very complex task. Currently, the evaluation and assessment of Information Security are commonly performed using frameworks, methodologies and standards which often consider the various aspects of security independently. Unfortunately this is ineffective because it does not take into consideration the necessity of having a global and systemic multidimensional approach to Information Security evaluation. At the same time the overall security level is globally considered to be only as strong as its weakest link. This thesis proposes a model aiming to holistically assess all dimensions of security in order to minimize the likelihood that a given threat will exploit the weakest link. A formalized structure taking into account all security elements is presented; this is based on a methodological evaluation framework in which Information Security is evaluated from a global perspective. This dissertation is divided into three parts. Part One: Information Security Evaluation issues consists of four chapters. Chapter 1 is an introduction to the purpose of this research purpose and the Model that will be proposed. In this chapter we raise some questions with respect to "traditional evaluation methods" as well as identifying the principal elements to be addressed in this direction. Then we introduce the baseline attributes of our model and set out the expected result of evaluations according to our model. Chapter 2 is focused on the definition of Information Security to be used as a reference point for our evaluation model. The inherent concepts of the contents of a holistic and baseline Information Security Program are defined. Based on this, the most common roots-of-trust in Information Security are identified. Chapter 3 focuses on an analysis of the difference and the relationship between the concepts of Information Risk and Security Management. Comparing these two concepts allows us to identify the most relevant elements to be included within our evaluation model, while clearing situating these two notions within a defined framework is of the utmost importance for the results that will be obtained from the evaluation process. Chapter 4 sets out our evaluation model and the way it addresses issues relating to the evaluation of Information Security. Within this Chapter the underlying concepts of assurance and trust are discussed. Based on these two concepts, the structure of the model is developed in order to provide an assurance related platform as well as three evaluation attributes: "assurance structure", "quality issues", and "requirements achievement". Issues relating to each of these evaluation attributes are analysed with reference to sources such as methodologies, standards and published research papers. Then the operation of the model is discussed. Assurance levels, quality levels and maturity levels are defined in order to perform the evaluation according to the model. Part Two: Implementation of the Information Security Assurance Assessment Model (ISAAM) according to the Information Security Domains consists of four chapters. This is the section where our evaluation model is put into a welldefined context with respect to the four pre-defined Information Security dimensions: the Organizational dimension, Functional dimension, Human dimension, and Legal dimension. Each Information Security dimension is discussed in a separate chapter. For each dimension, the following two-phase evaluation path is followed. The first phase concerns the identification of the elements which will constitute the basis of the evaluation: ? Identification of the key elements within the dimension; ? Identification of the Focus Areas for each dimension, consisting of the security issues identified for each dimension; ? Identification of the Specific Factors for each dimension, consisting of the security measures or control addressing the security issues identified for each dimension. The second phase concerns the evaluation of each Information Security dimension by: ? The implementation of the evaluation model, based on the elements identified for each dimension within the first phase, by identifying the security tasks, processes, procedures, and actions that should have been performed by the organization to reach the desired level of protection; ? The maturity model for each dimension as a basis for reliance on security. For each dimension we propose a generic maturity model that could be used by every organization in order to define its own security requirements. Part three of this dissertation contains the Final Remarks, Supporting Resources and Annexes. With reference to the objectives of our thesis, the Final Remarks briefly analyse whether these objectives were achieved and suggest directions for future related research. Supporting resources comprise the bibliographic resources that were used to elaborate and justify our approach. Annexes include all the relevant topics identified within the literature to illustrate certain aspects of our approach. Our Information Security evaluation model is based on and integrates different Information Security best practices, standards, methodologies and research expertise which can be combined in order to define an reliable categorization of Information Security. After the definition of terms and requirements, an evaluation process should be performed in order to obtain evidence that the Information Security within the organization in question is adequately managed. We have specifically integrated into our model the most useful elements of these sources of information in order to provide a generic model able to be implemented in all kinds of organizations. The value added by our evaluation model is that it is easy to implement and operate and answers concrete needs in terms of reliance upon an efficient and dynamic evaluation tool through a coherent evaluation system. On that basis, our model could be implemented internally within organizations, allowing them to govern better their Information Security. RÉSUMÉ : Contexte général de la thèse L'évaluation de la sécurité en général, et plus particulièrement, celle de la sécurité de l'information, est devenue pour les organisations non seulement une mission cruciale à réaliser, mais aussi de plus en plus complexe. A l'heure actuelle, cette évaluation se base principalement sur des méthodologies, des bonnes pratiques, des normes ou des standards qui appréhendent séparément les différents aspects qui composent la sécurité de l'information. Nous pensons que cette manière d'évaluer la sécurité est inefficiente, car elle ne tient pas compte de l'interaction des différentes dimensions et composantes de la sécurité entre elles, bien qu'il soit admis depuis longtemps que le niveau de sécurité globale d'une organisation est toujours celui du maillon le plus faible de la chaîne sécuritaire. Nous avons identifié le besoin d'une approche globale, intégrée, systémique et multidimensionnelle de l'évaluation de la sécurité de l'information. En effet, et c'est le point de départ de notre thèse, nous démontrons que seule une prise en compte globale de la sécurité permettra de répondre aux exigences de sécurité optimale ainsi qu'aux besoins de protection spécifiques d'une organisation. Ainsi, notre thèse propose un nouveau paradigme d'évaluation de la sécurité afin de satisfaire aux besoins d'efficacité et d'efficience d'une organisation donnée. Nous proposons alors un modèle qui vise à évaluer d'une manière holistique toutes les dimensions de la sécurité, afin de minimiser la probabilité qu'une menace potentielle puisse exploiter des vulnérabilités et engendrer des dommages directs ou indirects. Ce modèle se base sur une structure formalisée qui prend en compte tous les éléments d'un système ou programme de sécurité. Ainsi, nous proposons un cadre méthodologique d'évaluation qui considère la sécurité de l'information à partir d'une perspective globale. Structure de la thèse et thèmes abordés Notre document est structuré en trois parties. La première intitulée : « La problématique de l'évaluation de la sécurité de l'information » est composée de quatre chapitres. Le chapitre 1 introduit l'objet de la recherche ainsi que les concepts de base du modèle d'évaluation proposé. La maniéré traditionnelle de l'évaluation de la sécurité fait l'objet d'une analyse critique pour identifier les éléments principaux et invariants à prendre en compte dans notre approche holistique. Les éléments de base de notre modèle d'évaluation ainsi que son fonctionnement attendu sont ensuite présentés pour pouvoir tracer les résultats attendus de ce modèle. Le chapitre 2 se focalise sur la définition de la notion de Sécurité de l'Information. Il ne s'agit pas d'une redéfinition de la notion de la sécurité, mais d'une mise en perspectives des dimensions, critères, indicateurs à utiliser comme base de référence, afin de déterminer l'objet de l'évaluation qui sera utilisé tout au long de notre travail. Les concepts inhérents de ce qui constitue le caractère holistique de la sécurité ainsi que les éléments constitutifs d'un niveau de référence de sécurité sont définis en conséquence. Ceci permet d'identifier ceux que nous avons dénommés « les racines de confiance ». Le chapitre 3 présente et analyse la différence et les relations qui existent entre les processus de la Gestion des Risques et de la Gestion de la Sécurité, afin d'identifier les éléments constitutifs du cadre de protection à inclure dans notre modèle d'évaluation. Le chapitre 4 est consacré à la présentation de notre modèle d'évaluation Information Security Assurance Assessment Model (ISAAM) et la manière dont il répond aux exigences de l'évaluation telle que nous les avons préalablement présentées. Dans ce chapitre les concepts sous-jacents relatifs aux notions d'assurance et de confiance sont analysés. En se basant sur ces deux concepts, la structure du modèle d'évaluation est développée pour obtenir une plateforme qui offre un certain niveau de garantie en s'appuyant sur trois attributs d'évaluation, à savoir : « la structure de confiance », « la qualité du processus », et « la réalisation des exigences et des objectifs ». Les problématiques liées à chacun de ces attributs d'évaluation sont analysées en se basant sur l'état de l'art de la recherche et de la littérature, sur les différentes méthodes existantes ainsi que sur les normes et les standards les plus courants dans le domaine de la sécurité. Sur cette base, trois différents niveaux d'évaluation sont construits, à savoir : le niveau d'assurance, le niveau de qualité et le niveau de maturité qui constituent la base de l'évaluation de l'état global de la sécurité d'une organisation. La deuxième partie: « L'application du Modèle d'évaluation de l'assurance de la sécurité de l'information par domaine de sécurité » est elle aussi composée de quatre chapitres. Le modèle d'évaluation déjà construit et analysé est, dans cette partie, mis dans un contexte spécifique selon les quatre dimensions prédéfinies de sécurité qui sont: la dimension Organisationnelle, la dimension Fonctionnelle, la dimension Humaine, et la dimension Légale. Chacune de ces dimensions et son évaluation spécifique fait l'objet d'un chapitre distinct. Pour chacune des dimensions, une évaluation en deux phases est construite comme suit. La première phase concerne l'identification des éléments qui constituent la base de l'évaluation: ? Identification des éléments clés de l'évaluation ; ? Identification des « Focus Area » pour chaque dimension qui représentent les problématiques se trouvant dans la dimension ; ? Identification des « Specific Factors » pour chaque Focus Area qui représentent les mesures de sécurité et de contrôle qui contribuent à résoudre ou à diminuer les impacts des risques. La deuxième phase concerne l'évaluation de chaque dimension précédemment présentées. Elle est constituée d'une part, de l'implémentation du modèle général d'évaluation à la dimension concernée en : ? Se basant sur les éléments spécifiés lors de la première phase ; ? Identifiant les taches sécuritaires spécifiques, les processus, les procédures qui auraient dû être effectués pour atteindre le niveau de protection souhaité. D'autre part, l'évaluation de chaque dimension est complétée par la proposition d'un modèle de maturité spécifique à chaque dimension, qui est à considérer comme une base de référence pour le niveau global de sécurité. Pour chaque dimension nous proposons un modèle de maturité générique qui peut être utilisé par chaque organisation, afin de spécifier ses propres exigences en matière de sécurité. Cela constitue une innovation dans le domaine de l'évaluation, que nous justifions pour chaque dimension et dont nous mettons systématiquement en avant la plus value apportée. La troisième partie de notre document est relative à la validation globale de notre proposition et contient en guise de conclusion, une mise en perspective critique de notre travail et des remarques finales. Cette dernière partie est complétée par une bibliographie et des annexes. Notre modèle d'évaluation de la sécurité intègre et se base sur de nombreuses sources d'expertise, telles que les bonnes pratiques, les normes, les standards, les méthodes et l'expertise de la recherche scientifique du domaine. Notre proposition constructive répond à un véritable problème non encore résolu, auquel doivent faire face toutes les organisations, indépendamment de la taille et du profil. Cela permettrait à ces dernières de spécifier leurs exigences particulières en matière du niveau de sécurité à satisfaire, d'instancier un processus d'évaluation spécifique à leurs besoins afin qu'elles puissent s'assurer que leur sécurité de l'information soit gérée d'une manière appropriée, offrant ainsi un certain niveau de confiance dans le degré de protection fourni. Nous avons intégré dans notre modèle le meilleur du savoir faire, de l'expérience et de l'expertise disponible actuellement au niveau international, dans le but de fournir un modèle d'évaluation simple, générique et applicable à un grand nombre d'organisations publiques ou privées. La valeur ajoutée de notre modèle d'évaluation réside précisément dans le fait qu'il est suffisamment générique et facile à implémenter tout en apportant des réponses sur les besoins concrets des organisations. Ainsi notre proposition constitue un outil d'évaluation fiable, efficient et dynamique découlant d'une approche d'évaluation cohérente. De ce fait, notre système d'évaluation peut être implémenté à l'interne par l'entreprise elle-même, sans recourir à des ressources supplémentaires et lui donne également ainsi la possibilité de mieux gouverner sa sécurité de l'information.

Tumor necrosis factor-alpha mediates changes in tissue protein turnover in a rat cancer cachexia model.

Rats bearing the Yoshida AH-130 ascites hepatoma showed enhanced fractional rates of protein degradation in gastrocnemius muscle, heart, and liver, while fractional synthesis rates were similar to those in non-tumor bearing rats. This hypercatabolic pattern was associated with marked perturbations of the hormonal homeostasis and presence of tumor necrosis factor in the circulation. The daily administration of a goat anti-murine TNF IgG to tumor-bearing rats decreased protein degradation rates in skeletal muscle, heart, and liver as compared with tumor-bearing rats receiving a nonimmune goat IgG. The anti-TNF treatment was also effective in attenuating early perturbations in insulin and corticosterone homeostasis. Although these results suggest that tumor necrosis factor plays a significant role in mediating the changes in protein turnover and hormone levels elicited by tumor growth, the inability of such treatment to prevent a reduction in body weight implies that other mediators or tumor-related events were also involved.

The effect of scale in daily precipitation hazard assessment

Daily precipitation is recorded as the total amount of water collected by a rain-gauge in 24 h. Events are modelled as a Poisson process and the 24 h precipitation by a Generalised Pareto Distribution (GPD) of excesses. Hazard assessment is complete when estimates of the Poisson rate and the distribution parameters, together with a measure of their uncertainty, are obtained. The shape parameter of the GPD determines the support of the variable: Weibull domain of attraction (DA) corresponds to finite support variables as should be for natural phenomena. However, Fréchet DA has been reported for daily precipitation, which implies an infinite support and a heavy-tailed distribution. Bayesian techniques are used to estimate the parameters. The approach is illustrated with precipitation data from the Eastern coast of the Iberian Peninsula affected by severe convective precipitation. The estimated GPD is mainly in the Fréchet DA, something incompatible with the common sense assumption of that precipitation is a bounded phenomenon. The bounded character of precipitation is then taken as a priori hypothesis. Consistency of this hypothesis with the data is checked in two cases: using the raw-data (in mm) and using log-transformed data. As expected, a Bayesian model checking clearly rejects the model in the raw-data case. However, log-transformed data seem to be consistent with the model. This fact may be due to the adequacy of the log-scale to represent positive measurements for which differences are better relative than absolute

A numeric model to simulate solar individual ultraviolet exposure.

Exposure to solar ultraviolet (UV) light is the main causative factor for skin cancer. UV exposure depends on environmental and individual factors. Individual exposure data remain scarce and development of alternative assessment methods is greatly needed. We developed a model simulating human exposure to solar UV. The model predicts the dose and distribution of UV exposure received on the basis of ground irradiation and morphological data. Standard 3D computer graphics techniques were adapted to develop a rendering engine that estimates the solar exposure of a virtual manikin depicted as a triangle mesh surface. The amount of solar energy received by each triangle was calculated, taking into account reflected, direct and diffuse radiation, and shading from other body parts. Dosimetric measurements (n = 54) were conducted in field conditions using a foam manikin as surrogate for an exposed individual. Dosimetric results were compared to the model predictions. The model predicted exposure to solar UV adequately. The symmetric mean absolute percentage error was 13%. Half of the predictions were within 17% range of the measurements. This model provides a tool to assess outdoor occupational and recreational UV exposures, without necessitating time-consuming individual dosimetry, with numerous potential uses in skin cancer prevention and research.

Defining risk thresholds for a 10-year probability of hip fracture model that combines clinical risk factors and quantitative ultrasound: results using the EPISEM cohort.

Using a large prospective cohort of over 12,000 women, we determined 2 thresholds (high risk and low risk of hip fracture) to use in a 10-yr hip fracture probability model that we had previously described, a model combining the heel stiffness index measured by quantitative ultrasound (QUS) and a set of easily determined clinical risk factors (CRFs). The model identified a higher percentage of women with fractures as high risk than a previously reported risk score that combined QUS and CRF. In addition, it categorized women in a way that was quite consistent with the categorization that occurred using dual X-ray absorptiometry (DXA) and the World Health Organization (WHO) classification system; the 2 methods identified similar percentages of women with and without fractures in each of their 3 categories, but the 2 identified only in part the same women. Nevertheless, combining our composite probability model with DXA in a case findings strategy will likely further improve the detection of women at high risk of fragility hip fracture. We conclude that the currently proposed model may be of some use as an alternative to the WHO classification criteria for osteoporosis, at least when access to DXA is limited.

Validation of a model to predict adverse outcomes in patients with pulmonary embolism.

AIMS: To validate a model for quantifying the prognosis of patients with pulmonary embolism (PE). The model was previously derived from 10 534 US patients. METHODS AND RESULTS: We validated the model in 367 patients prospectively diagnosed with PE at 117 European emergency departments. We used baseline data for the model's 11 prognostic variables to stratify patients into five risk classes (I-V). We compared 90-day mortality within each risk class and the area under the receiver operating characteristic curve between the validation and the original derivation samples. We also assessed the rate of recurrent venous thrombo-embolism and major bleeding within each risk class. Mortality was 0% in Risk Class I, 1.0% in Class II, 3.1% in Class III, 10.4% in Class IV, and 24.4% in Class V and did not differ between the validation and the original derivation samples. The area under the curve was larger in the validation sample (0.87 vs. 0.78, P=0.01). No patients in Classes I and II developed recurrent thrombo-embolism or major bleeding. CONCLUSION: The model accurately stratifies patients with PE into categories of increasing risk of mortality and other relevant complications. Patients in Risk Classes I and II are at low risk of adverse outcomes and are potential candidates for outpatient treatment.

Use of anisotropic modelling in electrical impedance tomography: description of method and preliminary assessment of utility in imaging brain function in the adult human head.

Electrical Impedance Tomography (EIT) is an imaging method which enables a volume conductivity map of a subject to be produced from multiple impedance measurements. It has the potential to become a portable non-invasive imaging technique of particular use in imaging brain function. Accurate numerical forward models may be used to improve image reconstruction but, until now, have employed an assumption of isotropic tissue conductivity. This may be expected to introduce inaccuracy, as body tissues, especially those such as white matter and the skull in head imaging, are highly anisotropic. The purpose of this study was, for the first time, to develop a method for incorporating anisotropy in a forward numerical model for EIT of the head and assess the resulting improvement in image quality in the case of linear reconstruction of one example of the human head. A realistic Finite Element Model (FEM) of an adult human head with segments for the scalp, skull, CSF, and brain was produced from a structural MRI. Anisotropy of the brain was estimated from a diffusion tensor-MRI of the same subject and anisotropy of the skull was approximated from the structural information. A method for incorporation of anisotropy in the forward model and its use in image reconstruction was produced. The improvement in reconstructed image quality was assessed in computer simulation by producing forward data, and then linear reconstruction using a sensitivity matrix approach. The mean boundary data difference between anisotropic and isotropic forward models for a reference conductivity was 50%. Use of the correct anisotropic FEM in image reconstruction, as opposed to an isotropic one, corrected an error of 24 mm in imaging a 10% conductivity decrease located in the hippocampus, improved localisation for conductivity changes deep in the brain and due to epilepsy by 4-17 mm, and, overall, led to a substantial improvement on image quality. This suggests that incorporation of anisotropy in numerical models used for image reconstruction is likely to improve EIT image quality.

Morbillivirus glycoprotein expression induces ER stress, alters Ca2+ homeostasis and results in the release of vasostatin.

Although the pathology of Morbillivirus in the central nervous system (CNS) is well described, the molecular basis of neurodegenerative events still remains poorly understood. As a model to explore Morbillivirus-mediated CNS dysfunctions, we used canine distemper virus (CDV) that we inoculated into two different cell systems: a monkey cell line (Vero) and rat primary hippocampal neurons. Importantly, the recombinant CDV used in these studies not only efficiently infects both cell types but recapitulates the uncommon, non-cytolytic cell-to-cell spread mediated by virulent CDVs in brain of dogs. Here, we demonstrated that both CDV surface glycoproteins (F and H) markedly accumulated in the endoplasmic reticulum (ER). This accumulation triggered an ER stress, characterized by increased expression of the ER resident chaperon calnexin and the proapoptotic transcription factor CHOP/GADD 153. The expression of calreticulin (CRT), another ER resident chaperon critically involved in the response to misfolded proteins and in Ca(2+) homeostasis, was also upregulated. Transient expression of recombinant CDV F and H surface glycoproteins in Vero cells and primary hippocampal neurons further confirmed a correlation between their accumulation in the ER, CRT upregulation, ER stress and disruption of ER Ca(2+) homeostasis. Furthermore, CDV infection induced CRT fragmentation with re-localisation of a CRT amino-terminal fragment, also known as vasostatin, on the surface of infected and neighbouring non-infected cells. Altogether, these results suggest that ER stress, CRT fragmentation and re-localization on the cell surface may contribute to cytotoxic effects and ensuing cell dysfunctions triggered by Morbillivirus, a mechanism that might potentially be relevant for other neurotropic viruses.

Local alignment refinement using structural assessment.

Homology modeling is the most commonly used technique to build a three-dimensional model for a protein sequence. It heavily relies on the quality of the sequence alignment between the protein to model and related proteins with a known three dimensional structure. Alignment quality can be assessed according to the physico-chemical properties of the three dimensional models it produces.In this work, we introduce fifteen predictors designed to evaluate the properties of the models obtained for various alignments. They consist of an energy value obtained from different force fields (CHARMM, ProsaII or ANOLEA) computed on residue selected around misaligned regions. These predictors were evaluated on ten challenging test cases. For each target, all possible ungapped alignments are generated and their corresponding models are computed and evaluated.The best predictor, retrieving the structural alignment for 9 out of 10 test cases, is based on the ANOLEA atomistic mean force potential and takes into account residues around misaligned secondary structure elements. The performance of the other predictors is significantly lower. This work shows that substantial improvement in local alignments can be obtained by careful assessment of the local structure of the resulting models.

Assessment of the 10-year probability of osteoporotic hip fracture combining clinical risk factors and heel bone ultrasound: the EPISEM prospective cohort of 12,958 elderly women.

This study aimed to develop a hip screening tool that combines relevant clinical risk factors (CRFs) and quantitative ultrasound (QUS) at the heel to determine the 10-yr probability of hip fractures in elderly women. The EPISEM database, comprised of approximately 13,000 women 70 yr of age, was derived from two population-based white European cohorts in France and Switzerland. All women had baseline data on CRFs and a baseline measurement of the stiffness index (SI) derived from QUS at the heel. Women were followed prospectively to identify incident fractures. Multivariate analysis was performed to determine the CRFs that contributed significantly to hip fracture risk, and these were used to generate a CRF score. Gradients of risk (GR; RR/SD change) and areas under receiver operating characteristic curves (AUC) were calculated for the CRF score, SI, and a score combining both. The 10-yr probability of hip fracture was computed for the combined model. Three hundred seven hip fractures were observed over a mean follow-up of 3.2 yr. In addition to SI, significant CRFs for hip fracture were body mass index (BMI), history of fracture, an impaired chair test, history of a recent fall, current cigarette smoking, and diabetes mellitus. The average GR for hip fracture was 2.10 per SD with the combined SI + CRF score compared with a GR of 1.77 with SI alone and of 1.52 with the CRF score alone. Thus, the use of CRFs enhanced the predictive value of SI alone. For example, in a woman 80 yr of age, the presence of two to four CRFs increased the probability of hip fracture from 16.9% to 26.6% and from 52.6% to 70.5% for SI Z-scores of +2 and -3, respectively. The combined use of CRFs and QUS SI is a promising tool to assess hip fracture probability in elderly women, especially when access to DXA is limited.