Model-based Segmentation and Image Fusion of 3D Computed Tomography and 3D Ultrasound of the Eye for Radiotherapy Planning

For radiotherapy treatment planning of retinoblastoma inchildhood, Computed Tomography (CT) represents thestandard method for tumor volume delineation, despitesome inherent limitations. CT scan is very useful inproviding information on physical density for dosecalculation and morphological volumetric information butpresents a low sensitivity in assessing the tumorviability. On the other hand, 3D ultrasound (US) allows ahigh accurate definition of the tumor volume thanks toits high spatial resolution but it is not currentlyintegrated in the treatment planning but used only fordiagnosis and follow-up. Our ultimate goal is anautomatic segmentation of gross tumor volume (GTV) in the3D US, the segmentation of the organs at risk (OAR) inthe CT and the registration of both. In this paper, wepresent some preliminary results in this direction. Wepresent 3D active contour-based segmentation of the eyeball and the lens in CT images; the presented approachincorporates the prior knowledge of the anatomy by usinga 3D geometrical eye model. The automated segmentationresults are validated by comparing with manualsegmentations. Then, for the fusion of 3D CT and USimages, we present two approaches: (i) landmark-basedtransformation, and (ii) object-based transformation thatmakes use of eye ball contour information on CT and USimages.

Model-based iterative reconstruction in pediatric chest CT: assessment of image quality in a prospective study of children with cystic fibrosis.

BACKGROUND: The potential effects of ionizing radiation are of particular concern in children. The model-based iterative reconstruction VEO(TM) is a technique commercialized to improve image quality and reduce noise compared with the filtered back-projection (FBP) method. OBJECTIVE: To evaluate the potential of VEO(TM) on diagnostic image quality and dose reduction in pediatric chest CT examinations. MATERIALS AND METHODS: Twenty children (mean 11.4 years) with cystic fibrosis underwent either a standard CT or a moderately reduced-dose CT plus a minimum-dose CT performed at 100 kVp. Reduced-dose CT examinations consisted of two consecutive acquisitions: one moderately reduced-dose CT with increased noise index (NI = 70) and one minimum-dose CT at CTDIvol 0.14 mGy. Standard CTs were reconstructed using the FBP method while low-dose CTs were reconstructed using FBP and VEO. Two senior radiologists evaluated diagnostic image quality independently by scoring anatomical structures using a four-point scale (1 = excellent, 2 = clear, 3 = diminished, 4 = non-diagnostic). Standard deviation (SD) and signal-to-noise ratio (SNR) were also computed. RESULTS: At moderately reduced doses, VEO images had significantly lower SD (P < 0.001) and higher SNR (P < 0.05) in comparison to filtered back-projection images. Further improvements were obtained at minimum-dose CT. The best diagnostic image quality was obtained with VEO at minimum-dose CT for the small structures (subpleural vessels and lung fissures) (P < 0.001). The potential for dose reduction was dependent on the diagnostic task because of the modification of the image texture produced by this reconstruction. CONCLUSIONS: At minimum-dose CT, VEO enables important dose reduction depending on the clinical indication and makes visible certain small structures that were not perceptible with filtered back-projection.

Update on the non-prewhitening model observer in computed tomography for the assessment of the adaptive statistical and model-based iterative reconstruction algorithms.

The state of the art to describe image quality in medical imaging is to assess the performance of an observer conducting a task of clinical interest. This can be done by using a model observer leading to a figure of merit such as the signal-to-noise ratio (SNR). Using the non-prewhitening (NPW) model observer, we objectively characterised the evolution of its figure of merit in various acquisition conditions. The NPW model observer usually requires the use of the modulation transfer function (MTF) as well as noise power spectra. However, although the computation of the MTF poses no problem when dealing with the traditional filtered back-projection (FBP) algorithm, this is not the case when using iterative reconstruction (IR) algorithms, such as adaptive statistical iterative reconstruction (ASIR) or model-based iterative reconstruction (MBIR). Given that the target transfer function (TTF) had already shown it could accurately express the system resolution even with non-linear algorithms, we decided to tune the NPW model observer, replacing the standard MTF by the TTF. It was estimated using a custom-made phantom containing cylindrical inserts surrounded by water. The contrast differences between the inserts and water were plotted for each acquisition condition. Then, mathematical transformations were performed leading to the TTF. As expected, the first results showed a dependency of the image contrast and noise levels on the TTF for both ASIR and MBIR. Moreover, FBP also proved to be dependent of the contrast and noise when using the lung kernel. Those results were then introduced in the NPW model observer. We observed an enhancement of SNR every time we switched from FBP to ASIR to MBIR. IR algorithms greatly improve image quality, especially in low-dose conditions. Based on our results, the use of MBIR could lead to further dose reduction in several clinical applications.

N-acetylcysteine normalizes neurochemical changes in the glutathione-deficient schizophrenia mouse model during development.

BACKGROUND: Glutathione (GSH) is the major cellular redox-regulator and antioxidant. Redox-imbalance due to genetically impaired GSH synthesis is among the risk factors for schizophrenia. Here we used a mouse model with chronic GSH deficit induced by knockout (KO) of the key GSH-synthesizing enzyme, glutamate-cysteine ligase modulatory subunit (GCLM).¦METHODS: With high-resolution magnetic resonance spectroscopy at 14.1 T, we determined the neurochemical profile of GCLM-KO, heterozygous, and wild-type mice in anterior cortex throughout development in a longitudinal study design.¦RESULTS: Chronic GSH deficit was accompanied by an elevation of glutamine (Gln), glutamate (Glu), Gln/Glu, N-acetylaspartate, myo-Inositol, lactate, and alanine. Changes were predominantly present at prepubertal ages (postnatal days 20 and 30). Treatment with N-acetylcysteine from gestation on normalized most neurochemical alterations to wild-type level.¦CONCLUSIONS: Changes observed in GCLM-KO anterior cortex, notably the increase in Gln, Glu, and Gln/Glu, were similar to those reported in early schizophrenia, emphasizing the link between redox imbalance and the disease and validating the model. The data also highlight the prepubertal period as a sensitive time for redox-related neurochemical changes and demonstrate beneficial effects of early N-acetylcysteine treatment. Moreover, the data demonstrate the translational value of magnetic resonance spectroscopy to study brain disease in preclinical models.

The Hydrophobic interaction: modeling hydrophobic interactions and aggregation of non-polar particles in aqueous solutions

Malgré son importance dans notre vie de tous les jours, certaines propriétés de l?eau restent inexpliquées. L'étude des interactions entre l'eau et les particules organiques occupe des groupes de recherche dans le monde entier et est loin d'être finie. Dans mon travail j'ai essayé de comprendre, au niveau moléculaire, ces interactions importantes pour la vie. J'ai utilisé pour cela un modèle simple de l'eau pour décrire des solutions aqueuses de différentes particules. Récemment, l?eau liquide a été décrite comme une structure formée d?un réseau aléatoire de liaisons hydrogènes. En introduisant une particule hydrophobe dans cette structure à basse température, certaines liaisons hydrogènes sont détruites ce qui est énergétiquement défavorable. Les molécules d?eau s?arrangent alors autour de cette particule en formant une cage qui permet de récupérer des liaisons hydrogènes (entre molécules d?eau) encore plus fortes : les particules sont alors solubles dans l?eau. A des températures plus élevées, l?agitation thermique des molécules devient importante et brise les liaisons hydrogènes. Maintenant, la dissolution des particules devient énergétiquement défavorable, et les particules se séparent de l?eau en formant des agrégats qui minimisent leur surface exposée à l?eau. Pourtant, à très haute température, les effets entropiques deviennent tellement forts que les particules se mélangent de nouveau avec les molécules d?eau. En utilisant un modèle basé sur ces changements de structure formée par des liaisons hydrogènes j?ai pu reproduire les phénomènes principaux liés à l?hydrophobicité. J?ai trouvé une région de coexistence de deux phases entre les températures critiques inférieure et supérieure de solubilité, dans laquelle les particules hydrophobes s?agrègent. En dehors de cette région, les particules sont dissoutes dans l?eau. J?ai démontré que l?interaction hydrophobe est décrite par un modèle qui prend uniquement en compte les changements de structure de l?eau liquide en présence d?une particule hydrophobe, plutôt que les interactions directes entre les particules. Encouragée par ces résultats prometteurs, j?ai étudié des solutions aqueuses de particules hydrophobes en présence de co-solvants cosmotropiques et chaotropiques. Ce sont des substances qui stabilisent ou déstabilisent les agrégats de particules hydrophobes. La présence de ces substances peut être incluse dans le modèle en décrivant leur effet sur la structure de l?eau. J?ai pu reproduire la concentration élevée de co-solvants chaotropiques dans le voisinage immédiat de la particule, et l?effet inverse dans le cas de co-solvants cosmotropiques. Ce changement de concentration du co-solvant à proximité de particules hydrophobes est la cause principale de son effet sur la solubilité des particules hydrophobes. J?ai démontré que le modèle adapté prédit correctement les effets implicites des co-solvants sur les interactions de plusieurs corps entre les particules hydrophobes. En outre, j?ai étendu le modèle à la description de particules amphiphiles comme des lipides. J?ai trouvé la formation de différents types de micelles en fonction de la distribution des regions hydrophobes à la surface des particules. L?hydrophobicité reste également un sujet controversé en science des protéines. J?ai défini une nouvelle échelle d?hydrophobicité pour les acides aminés qui forment des protéines, basée sur leurs surfaces exposées à l?eau dans des protéines natives. Cette échelle permet une comparaison meilleure entre les expériences et les résultats théoriques. Ainsi, le modèle développé dans mon travail contribue à mieux comprendre les solutions aqueuses de particules hydrophobes. Je pense que les résultats analytiques et numériques obtenus éclaircissent en partie les processus physiques qui sont à la base de l?interaction hydrophobe.<br/><br/>Despite the importance of water in our daily lives, some of its properties remain unexplained. Indeed, the interactions of water with organic particles are investigated in research groups all over the world, but controversy still surrounds many aspects of their description. In my work I have tried to understand these interactions on a molecular level using both analytical and numerical methods. Recent investigations describe liquid water as random network formed by hydrogen bonds. The insertion of a hydrophobic particle at low temperature breaks some of the hydrogen bonds, which is energetically unfavorable. The water molecules, however, rearrange in a cage-like structure around the solute particle. Even stronger hydrogen bonds are formed between water molecules, and thus the solute particles are soluble. At higher temperatures, this strict ordering is disrupted by thermal movements, and the solution of particles becomes unfavorable. They minimize their exposed surface to water by aggregating. At even higher temperatures, entropy effects become dominant and water and solute particles mix again. Using a model based on these changes in water structure I have reproduced the essential phenomena connected to hydrophobicity. These include an upper and a lower critical solution temperature, which define temperature and density ranges in which aggregation occurs. Outside of this region the solute particles are soluble in water. Because I was able to demonstrate that the simple mixture model contains implicitly many-body interactions between the solute molecules, I feel that the study contributes to an important advance in the qualitative understanding of the hydrophobic effect. I have also studied the aggregation of hydrophobic particles in aqueous solutions in the presence of cosolvents. Here I have demonstrated that the important features of the destabilizing effect of chaotropic cosolvents on hydrophobic aggregates may be described within the same two-state model, with adaptations to focus on the ability of such substances to alter the structure of water. The relevant phenomena include a significant enhancement of the solubility of non-polar solute particles and preferential binding of chaotropic substances to solute molecules. In a similar fashion, I have analyzed the stabilizing effect of kosmotropic cosolvents in these solutions. Including the ability of kosmotropic substances to enhance the structure of liquid water, leads to reduced solubility, larger aggregation regime and the preferential exclusion of the cosolvent from the hydration shell of hydrophobic solute particles. I have further adapted the MLG model to include the solvation of amphiphilic solute particles in water, by allowing different distributions of hydrophobic regions at the molecular surface, I have found aggregation of the amphiphiles, and formation of various types of micelle as a function of the hydrophobicity pattern. I have demonstrated that certain features of micelle formation may be reproduced by the adapted model to describe alterations of water structure near different surface regions of the dissolved amphiphiles. Hydrophobicity remains a controversial quantity also in protein science. Based on the surface exposure of the 20 amino-acids in native proteins I have defined the a new hydrophobicity scale, which may lead to an improvement in the comparison of experimental data with the results from theoretical HP models. Overall, I have shown that the primary features of the hydrophobic interaction in aqueous solutions may be captured within a model which focuses on alterations in water structure around non-polar solute particles. The results obtained within this model may illuminate the processes underlying the hydrophobic interaction.<br/><br/>La vie sur notre planète a commencé dans l'eau et ne pourrait pas exister en son absence : les cellules des animaux et des plantes contiennent jusqu'à 95% d'eau. Malgré son importance dans notre vie de tous les jours, certaines propriétés de l?eau restent inexpliquées. En particulier, l'étude des interactions entre l'eau et les particules organiques occupe des groupes de recherche dans le monde entier et est loin d'être finie. Dans mon travail j'ai essayé de comprendre, au niveau moléculaire, ces interactions importantes pour la vie. J'ai utilisé pour cela un modèle simple de l'eau pour décrire des solutions aqueuses de différentes particules. Bien que l?eau soit généralement un bon solvant, un grand groupe de molécules, appelées molécules hydrophobes (du grecque "hydro"="eau" et "phobia"="peur"), n'est pas facilement soluble dans l'eau. Ces particules hydrophobes essayent d'éviter le contact avec l'eau, et forment donc un agrégat pour minimiser leur surface exposée à l'eau. Cette force entre les particules est appelée interaction hydrophobe, et les mécanismes physiques qui conduisent à ces interactions ne sont pas bien compris à l'heure actuelle. Dans mon étude j'ai décrit l'effet des particules hydrophobes sur l'eau liquide. L'objectif était d'éclaircir le mécanisme de l'interaction hydrophobe qui est fondamentale pour la formation des membranes et le fonctionnement des processus biologiques dans notre corps. Récemment, l'eau liquide a été décrite comme un réseau aléatoire formé par des liaisons hydrogènes. En introduisant une particule hydrophobe dans cette structure, certaines liaisons hydrogènes sont détruites tandis que les molécules d'eau s'arrangent autour de cette particule en formant une cage qui permet de récupérer des liaisons hydrogènes (entre molécules d?eau) encore plus fortes : les particules sont alors solubles dans l'eau. A des températures plus élevées, l?agitation thermique des molécules devient importante et brise la structure de cage autour des particules hydrophobes. Maintenant, la dissolution des particules devient défavorable, et les particules se séparent de l'eau en formant deux phases. A très haute température, les mouvements thermiques dans le système deviennent tellement forts que les particules se mélangent de nouveau avec les molécules d'eau. A l'aide d'un modèle qui décrit le système en termes de restructuration dans l'eau liquide, j'ai réussi à reproduire les phénomènes physiques liés à l?hydrophobicité. J'ai démontré que les interactions hydrophobes entre plusieurs particules peuvent être exprimées dans un modèle qui prend uniquement en compte les liaisons hydrogènes entre les molécules d'eau. Encouragée par ces résultats prometteurs, j'ai inclus dans mon modèle des substances fréquemment utilisées pour stabiliser ou déstabiliser des solutions aqueuses de particules hydrophobes. J'ai réussi à reproduire les effets dûs à la présence de ces substances. De plus, j'ai pu décrire la formation de micelles par des particules amphiphiles comme des lipides dont la surface est partiellement hydrophobe et partiellement hydrophile ("hydro-phile"="aime l'eau"), ainsi que le repliement des protéines dû à l'hydrophobicité, qui garantit le fonctionnement correct des processus biologiques de notre corps. Dans mes études futures je poursuivrai l'étude des solutions aqueuses de différentes particules en utilisant les techniques acquises pendant mon travail de thèse, et en essayant de comprendre les propriétés physiques du liquide le plus important pour notre vie : l'eau.

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.

Population pharmacokinetic modelling and evaluation of different dosage regimens for darunavir and ritonavir in HIV-infected individuals.

OBJECTIVES: Darunavir is a protease inhibitor that is administered with low-dose ritonavir to enhance its bioavailability. It is prescribed at standard dosage regimens of 600/100 mg twice daily in treatment-experienced patients and 800/100 mg once daily in naive patients. A population pharmacokinetic approach was used to characterize the pharmacokinetics of both drugs and their interaction in a cohort of unselected patients and to compare darunavir exposure expected under alternative dosage regimens. METHODS: The study population included 105 HIV-infected individuals who provided darunavir and ritonavir plasma concentrations. Firstly, a population pharmacokinetic analysis for darunavir and ritonavir was conducted, with inclusion of patients' demographic, clinical and genetic characteristics as potential covariates (NONMEM(®)). Then, the interaction between darunavir and ritonavir was studied while incorporating levels of both drugs into different inhibitory models. Finally, model-based simulations were performed to compare trough concentrations (Cmin) between the recommended dosage regimen and alternative combinations of darunavir and ritonavir. RESULTS: A one-compartment model with first-order absorption adequately characterized darunavir and ritonavir pharmacokinetics. The between-subject variability in both compounds was important [coefficient of variation (CV%) 34% and 47% for darunavir and ritonavir clearance, respectively]. Lopinavir and ritonavir exposure (AUC) affected darunavir clearance, while body weight and darunavir AUC influenced ritonavir elimination. None of the tested genetic variants showed any influence on darunavir or ritonavir pharmacokinetics. The simulations predicted darunavir Cmin much higher than the IC50 thresholds for wild-type and protease inhibitor-resistant HIV-1 strains (55 and 550 ng/mL, respectively) under standard dosing in >98% of experienced and naive patients. Alternative regimens of darunavir/ritonavir 1200/100 or 1200/200 mg once daily also had predicted adequate Cmin (>550 ng/mL) in 84% and 93% of patients, respectively. Reduction of darunavir/ritonavir dosage to 600/50 mg twice daily led to a 23% reduction in average Cmin, still with only 3.8% of patients having concentrations below the IC50 for resistant strains. CONCLUSIONS: The important variability in darunavir and ritonavir pharmacokinetics is poorly explained by clinical covariates and genetic influences. In experienced patients, treatment simplification strategies guided by drug level measurements and adherence monitoring could be proposed.

Evidence evaluation in fingerprint comparison and automated fingerprint identification systems: modeling between finger variability

In the context of the investigation of the use of automated fingerprint identification systems (AFIS) for the evaluation of fingerprint evidence, the current study presents investigations into the variability of scores from an AFIS system when fingermarks from a known donor are compared to fingerprints that are not from the same source. The ultimate goal is to propose a model, based on likelihood ratios, which allows the evaluation of mark-to-print comparisons. In particular, this model, through its use of AFIS technology, benefits from the possibility of using a large amount of data, as well as from an already built-in proximity measure, the AFIS score. More precisely, the numerator of the LR is obtained from scores issued from comparisons between impressions from the same source and showing the same minutia configuration. The denominator of the LR is obtained by extracting scores from comparisons of the questioned mark with a database of non-matching sources. This paper focuses solely on the assignment of the denominator of the LR. We refer to it by the generic term of between-finger variability. The issues addressed in this paper in relation to between-finger variability are the required sample size, the influence of the finger number and general pattern, as well as that of the number of minutiae included and their configuration on a given finger. Results show that reliable estimation of between-finger variability is feasible with 10,000 scores. These scores should come from the appropriate finger number/general pattern combination as defined by the mark. Furthermore, strategies of obtaining between-finger variability when these elements cannot be conclusively seen on the mark (and its position with respect to other marks for finger number) have been presented. These results immediately allow case-by-case estimation of the between-finger variability in an operational setting.

MORM--a Petri net based model for assessing OH&S risks in industrial processes: modeling qualitative aspects.

Because of the increase in workplace automation and the diversification of industrial processes, workplaces have become more and more complex. The classical approaches used to address workplace hazard concerns, such as checklists or sequence models, are, therefore, of limited use in such complex systems. Moreover, because of the multifaceted nature of workplaces, the use of single-oriented methods, such as AEA (man oriented), FMEA (system oriented), or HAZOP (process oriented), is not satisfactory. The use of a dynamic modeling approach in order to allow multiple-oriented analyses may constitute an alternative to overcome this limitation. The qualitative modeling aspects of the MORM (man-machine occupational risk modeling) model are discussed in this article. The model, realized on an object-oriented Petri net tool (CO-OPN), has been developed to simulate and analyze industrial processes in an OH&S perspective. The industrial process is modeled as a set of interconnected subnets (state spaces), which describe its constitutive machines. Process-related factors are introduced, in an explicit way, through machine interconnections and flow properties. While man-machine interactions are modeled as triggering events for the state spaces of the machines, the CREAM cognitive behavior model is used in order to establish the relevant triggering events. In the CO-OPN formalism, the model is expressed as a set of interconnected CO-OPN objects defined over data types expressing the measure attached to the flow of entities transiting through the machines. Constraints on the measures assigned to these entities are used to determine the state changes in each machine. Interconnecting machines implies the composition of such flow and consequently the interconnection of the measure constraints. This is reflected by the construction of constraint enrichment hierarchies, which can be used for simulation and analysis optimization in a clear mathematical framework. The use of Petri nets to perform multiple-oriented analysis opens perspectives in the field of industrial risk management. It may significantly reduce the duration of the assessment process. But, most of all, it opens perspectives in the field of risk comparisons and integrated risk management. Moreover, because of the generic nature of the model and tool used, the same concepts and patterns may be used to model a wide range of systems and application fields.

Environmental data mining and modeling based on machine learning algorithms and geostatistics

The paper presents some contemporary approaches to spatial environmental data analysis. The main topics are concentrated on the decision-oriented problems of environmental spatial data mining and modeling: valorization and representativity of data with the help of exploratory data analysis, spatial predictions, probabilistic and risk mapping, development and application of conditional stochastic simulation models. The innovative part of the paper presents integrated/hybrid model-machine learning (ML) residuals sequential simulations-MLRSS. The models are based on multilayer perceptron and support vector regression ML algorithms used for modeling long-range spatial trends and sequential simulations of the residuals. NIL algorithms deliver non-linear solution for the spatial non-stationary problems, which are difficult for geostatistical approach. Geostatistical tools (variography) are used to characterize performance of ML algorithms, by analyzing quality and quantity of the spatially structured information extracted from data with ML algorithms. Sequential simulations provide efficient assessment of uncertainty and spatial variability. Case study from the Chernobyl fallouts illustrates the performance of the proposed model. It is shown that probability mapping, provided by the combination of ML data driven and geostatistical model based approaches, can be efficiently used in decision-making process. (C) 2003 Elsevier Ltd. All rights reserved.

Ultimate test bench for pediatric biventricular assist device based on artificial muscles.

Ventricular assist devices (VADs) are used in treatment for terminal heart failure or as a bridge to transplantation. We created biVAD using the artificial muscles (AMs) that supports both ventricles at the same time. We developed the test bench (TB) as the in vitro evaluating system to enable the measurement of performance. The biVAD exerts different pressure between left and right ventricle like the heart physiologically does. The heart model based on child's heart was constructed in silicone. This model was fitted with the biVAD. Two pipettes containing water with an ultrasonic sensor placed on top of each and attached to ventricles reproduced the preload and the after load of each ventricle by the real-time measurement of the fluid height variation proportionally to the exerted pressure. The LabVIEW software extrapolated the displaced volume and the pressure generated by each side of our biVAD. The development of a standardized protocol permitted the validation of the TB for in vitro evaluation, measurement of the performances of the AM biVAD herein, and reproducibility of data.

Dosing regimen of gentamicin in neonates: evaluation of current guidelines based on a large population pharmacokinetic analysis

Objectives: Gentamicin is among the most commonly prescribed antibiotics in newborns, but large interindividual variability in exposure levels exists. Based on a population pharmacokinetic analysis of a cohort of unselected neonates, we aimed to validate current dosing recommendations from a recent reference guideline (Neofax®). Methods: From 3039 concentrations collected in 994 preterm (median gestational age 32.3 weeks, range 24.2-36.5) and 455 term newborns, treated at the University Hospital of Lausanne between 2006 and 2011, a population pharmacokinetic analysis was performed with NONMEM®. Model-based simulations were used to assess the ability of dosing regimens to bring concentrations into targets: trough ≤ 1mg/L and peak ~ 8mg/L. Results: A two-compartment model best characterized gentamicin pharmacokinetics. Model parameters are presented in the table. Body weight, gestational age and postnatal age positively influence clearance, which decreases under dopamine administration. Body weight and gestational age influence the distribution volume. Model based simulations confirm that preterm infants need doses superior to 4 mg/kg, and extended dosage intervals, up to 48 hours for very preterm newborns, whereas most term newborns would achieve adequate exposure under 4 mg/kg q. 24 h. More than 90% of neonates would achieve trough concentrations below 2 mg/L and peaks above 6 mg/L following most recent guidelines. Conclusions: Simulated gentamicin exposure demonstrates good accordance with recent dosing recommendations for target concentration achievement.