Population pharmacokinetic-pharmacodynamic modelling of angiotensin receptor blockade in healthy volunteers.

OBJECTIVE: To compare the pharmacokinetic and pharmacodynamic characteristics of angiotensin II receptor antagonists as a therapeutic class. DESIGN: Population pharmacokinetic-pharmacodynamic modelling study. METHODS: The data of 14 phase I studies with 10 different drugs were analysed. A common population pharmacokinetic model (two compartments, mixed zero- and first-order absorption, two metabolite compartments) was applied to the 2685 drug and 900 metabolite concentration measurements. A standard nonlinear mixed effect modelling approach was used to estimate the drug-specific parameters and their variabilities. Similarly, a pharmacodynamic model was applied to the 7360 effect measurements, i.e. the decrease of peak blood pressure response to intravenous angiotensin challenge recorded by finger photoplethysmography. The concentration of drug and metabolite in an effect compartment was assumed to translate into receptor blockade [maximum effect (Emax) model with first-order link]. RESULTS: A general pharmacokinetic-pharmacodynamic (PK-PD) model for angiotensin antagonism in healthy individuals was successfully built up for the 10 drugs studied. Representatives of this class share different pharmacokinetic and pharmacodynamic profiles. Their effects on blood pressure are dose-dependent, but the time course of the effect varies between the drugs. CONCLUSIONS: The characterisation of PK-PD relationships for these drugs gives the opportunity to optimise therapeutic regimens and to suggest dosage adjustments in specific conditions. Such a model can be used to further refine the use of this class of drugs.

Recovering Euclidean deformable models from stereo-motion

In this paper we present a novel structure from motion (SfM) approach able to infer 3D deformable models from uncalibrated stereo images. Using a stereo setup dramatically improves the 3D model estimation when the observed 3D shape is mostly deforming without undergoing strong rigid motion. Our approach first calibrates the stereo system automatically and then computes a single metric rigid structure for each frame. Afterwards, these 3D shapes are aligned to a reference view using a RANSAC method in order to compute the mean shape of the object and to select the subset of points on the object which have remained rigid throughout the sequence without deforming. The selected rigid points are then used to compute frame-wise shape registration and to extract the motion parameters robustly from frame to frame. Finally, all this information is used in a global optimization stage with bundle adjustment which allows to refine the frame-wise initial solution and also to recover the non-rigid 3D model. We show results on synthetic and real data that prove the performance of the proposed method even when there is no rigid motion in the original sequence

Targeting anticancer therapy : clinical and preclinical approaches

AbstractCancer treatment has shifted from cytotoxic and nonspecific chemotherapy to chronic treatment with targeted molecular therapies. These new classes of drugs directed against cancer-specific molecules and signaling pathways, act at a particular level of the tumor cell development. However, in both types of therapeutic approaches (standard cytotoxic chemotherapy and targeted signal transduction inhibitions), toxicity and side effects can occur. The aim of this thesis was to investigate various approaches to improve the activity and tolerability of cancer treatment, in a clinical setting, a) by molecular targeting through the use of tyrosine kinase inhibitors (TKIs), whose dosage can be adapted to each patient according to plasma levels, and, b) in a preclinical model, by tissue targeting with locoregional administration of cytotoxic chemotherapy to increase drug exposure in the target tissue while reducing systemic toxicity of the treatment.A comprehensive program for the Therapeutic Drug Monitoring (TDM) of the new class of targeted anticancer drugs of TKIs in patient's blood has been therefore initiated comprising the setting up, validation and clinical application of a multiplex assay by liquid chromatography coupled to tandem mass spectrometry of TKIs in plasma from cancer patients. Information on drugs exposure may be clinically useful for an optimal follow-up of patients' anticancer treatment, especially in case of less than optimal clinical response, occurrence of adverse drug reaction effects and the numerous risks of drug-drug interactions. In this context, better knowledge of the potential drug interactions between TKIs and widely prescribed co- medications is of critical importance for clinicians, to improve their daily care of cancer patients. For one of the first TKI imatinib, TDM interpretation is nowadays based on total plasma concentrations but, only the unbound (free) form is likely to enter cell to exert its pharmacological action. Pharmacokinetic analysis of the total and free plasma level of imatinib measured simultaneously in patients have allowed to refine and validate a population pharmacokinetic model integrating factors influencing in patients the exposure of pharmacological active species. The equation developed from this model may be used for extrapolating free imatinib plasma concentration based on the total plasma levels that are currently measured in TDM from patients. Finally, the specific influence of Pglycoprotein on the intracellular disposition of TKIs has been studies in cell systems using the siRNA silencing approach.Another approach to enhance the selectivity of anticancer treatment may be achieved by the loco-regional administration of a cytostatic agent to the target organ while sparing non- affected tissues. Isolated lung perfusion (ILP) was designed for the treatment of loco-regional malignancies of the lung but clinical results have been so far disappointing. It has been shown in a preclinical model in rats that ILP with the cytotoxic agent doxorubicin alone allows a high drug uptake in lung tissue, and a low systemic toxicity, but was characterized by a high spatial tissular heterogeneity in drug exposure and doxorubicin uptake in tumor was comparatively smaller than in normal lung tissue. Photodynamic therapy (PDT) is a new approach for the treatment of superficial tumors, and implies the application of a sensitizer activated by a laser light at a specific wavelength, that disrupts endothelial barrier of tumor vessels to increase locally the distribution of cytostatics into the tumor tissue. PDT pre-treatment before intravenous administration of liposomal doxorubicin was indeed shown to selectively increase drug uptake in tumors in a rat model of sarcoma tumors to the lung.RésuméLe traitement de certains cancers s'est progressivement transformé et est passé de la chimiothérapie, cytotoxique et non spécifique, au traitement chronique des patients avec des thérapies moléculaires ciblées. Ces médicaments ont une action ciblée en interférant à un niveau spécifique du développement de la cellule tumorale. Dans les deux types d'approches thérapeutiques (chimiothérapie cytotoxique et traitements ciblés), on est confronté à la présence de toxicité et aux effets secondaires du traitement anticancéreux. Le but de cette thèse a donc été d'étudier diverses approches visant à améliorer l'efficacité et la tolérabilité du traitement anticancéreux, a) dans le cadre d'une recherche clinique, par le ciblage moléculaire grâce aux inhibiteurs de tyrosines kinases (TKIs) dont la posologie est adaptée à chaque patient, et b) dans un modèle préclinique, par le ciblage tissulaire grâce à l'administration locorégionale de chimiothérapie cytotoxique, afin d'augmenter l'exposition dans le tissu cible et de réduire la toxicité systémique du traitement.Un programme de recherche sur le suivi thérapeutique (Therapeutic Drug Monitoring, TDM) des inhibiteurs de tyrosine kinases a été ainsi mis en place et a impliqué le développement, la validation et l'application clinique d'une méthode multiplex par chromatographie liquide couplée à la spectrométrie de masse en tandem des TKIs chez les patients souffrant de cancer. L'information fournie par le TDM sur l'exposition des patients aux traitements ciblés est cliniquement utile et est susceptible d'optimiser la dose administrée, notamment dans les cas où la réponse clinique au traitement des patients est sous-optimale, en présence d'effets secondaires du traitement ciblé, ou lorsque des risques d'interactions médicamenteuses sont suspectés. Dans ce contexte, l'étude des interactions entre les TKIs et les co-médications couramment associées est utile pour les cliniciens en charge d'améliorer au jour le jour la prise en charge du traitement anticancéreux. Pour le premier TKI imatinib, l'interprétation TDM est actuellement basée sur la mesure des concentrations plasmatiques totales alors que seule la fraction libre (médicament non lié aux protéines plasmatiques circulantes) est susceptible de pénétrer dans la cellule pour exercer son action pharmacologique. L'analyse pharmacocinétique des taux plasmatiques totaux et libres d'imatinib mesurés simultanément chez les patients a permis d'affiner et de valider un modèle de pharmacocinétique de population qui intègre les facteurs influençant l'exposition à la fraction de médicament pharmacologiquement active. L'équation développée à partir de ce modèle permet d'extrapoler les concentrations libres d'imatinib à partir des concentrations plasmatiques totales qui sont actuellement mesurées lors du TDM des patients. Finalement, l'influence de la P-glycoprotéine sur la disposition cellulaire des TKIs a été étudiée dans un modèle cellulaire utilisant l'approche par la technologie du siRNA permettant de bloquer sélectivement l'expression du gène de cette protéine d'efflux des médicaments.Une autre approche pour augmenter la sélectivité du traitement anticancéreux consiste en une administration loco-régionale d'un agent cytostatique directement au sein de l'organe cible tout en préservant les tissus sains. La perfusion isolée du poumon (ILP) a été conçue pour le traitement loco-régional des cancers affectant les tissus pulmonaires mais les résultats cliniques ont été jusqu'à ce jour décevants. Dans des modèles précliniques chez le rat, il a pu être démontré que l'ILP avec la doxorubicine, un agent cytotoxique, administré seul, permet une exposition élevée au niveau du tissu pulmonaire, et une faible toxicité systémique. Toutefois, cette technique est caractérisée par une importante variabilité de la distribution dans les tissus pulmonaires et une pénétration du médicament au sein de la tumeur comparativement plus faible que dans les tissus sains.La thérapie photodynamique (PDT) est une nouvelle approche pour le traitement des tumeurs superficielles, qui consiste en l'application d'un agent sensibilisateur activé par une lumière laser de longueur d'onde spécifique, qui perturbe l'intégrité physiologique de la barrière endothéliale des vaisseaux alimentant la tumeur et permet d'augmenter localement la pénétration des agents cytostatiques.Nos études ont montré qu'un pré-traitement par PDT permet d'augmenter sélectivement l'absorption de doxorubicine dans les tumeurs lors d'administration i.v. de doxorubicine liposomale dans un modèle de sarcome de poumons de rongeurs.Résumé large publicDepuis une dizaine d'année, le traitement de certains cancers s'est progressivement transformé et les patients qui devaient jusqu'alors subir des chimiothérapies, toxiques et non spécifiques, peuvent maintenant bénéficier de traitements chroniques avec des thérapies ciblées. Avec les deux types d'approches thérapeutiques, on reste cependant confronté à la toxicité et aux effets secondaires du traitement.Le but de cette thèse a été d'étudier chez les patients et dans des modèles précliniques les diverses approches visant à améliorer l'activité et la tolérance des traitements à travers un meilleur ciblage de la thérapie anticancéreuse. Cet effort de recherche nous a conduits à nous intéresser à l'optimisation du traitement par les inhibiteurs de tyrosines kinases (TKIs), une nouvelle génération d'agents anticancéreux ciblés agissant sélectivement sur les cellules tumorales, en particulier chez les patients souffrant de leucémie myéloïde chronique et de tumeurs stromales gastro-intestinales. L'activité clinique ainsi que la toxicité de ces TKIs paraissent dépendre non pas de la dose de médicament administrée, mais de la quantité de médicaments circulant dans le sang auxquelles les tumeurs cancéreuses sont exposées et qui varient beaucoup d'un patient à l'autre. A cet effet, nous avons développé une méthode par chromatographie couplée à la spectrométrie de masse pour mesurer chez les patients les taux de médicaments de la classe des TKIs dans la perspective de piloter le traitement par une approche de suivi thérapeutique (Therapeutic Drug Monitoring, TDM). Le TDM repose sur la mesure de la quantité de médicament dans le sang d'un patient dans le but d'adapter individuellement la posologie la plus appropriée: des quantités insuffisantes de médicament dans le sang peuvent conduire à un échec thérapeutique alors qu'un taux sanguin excessif peut entraîner des manifestations toxiques.Dans une seconde partie préclinique, nous nous sommes concentrés sur l'optimisation de la chimiothérapie loco-régionale dans un modèle de sarcome du poumon chez le rat, afin d'augmenter l'exposition dans la tumeur tout en réduisant la toxicité dans les tissus non affectés.La perfusion isolée du poumon (ILP) permet d'administrer un médicament anticancéreux cytotoxique comme la doxorubicine, sélectivement au niveau le tissu pulmonaire où sont généralement localisées les métastases de sarcome. L'administration par ILP de doxorubicine, toxique pour le coeur, a permis une forte accumulation des médicaments dans le poumon, tout en épargnant le coeur. Il a été malheureusement constaté que la doxorubicine ne pénètre que faiblement dans la tumeur sarcomateuse, témoignant des réponses cliniques décevantes observées avec cette approche en clinique. Nous avons ainsi étudié l'impact sur la pénétration tumorale de l'association d'une chimiothérapie cytotoxique avec la thérapie photodynamique (PDT) qui consiste en l'irradiation spécifique du tissu-cible cancéreux, après l'administration d'un agent photosensibilisateur. Dans ce modèle animal, nous avons observé qu'un traitement par PDT permet effectivement d'augmenter de façon sélective l'accumulation de doxorubicine dans les tumeurs lors d'administration intraveineuse de médicament.

Mosaico mediterráneo. El Arte como herramienta de diálogo intercultural

El presente trabajo de investigación doctoral reflexiona sobre el aporte de las prácticas artísticas contemporáneas en los procesos de diálogo entre culturas en el Mediterráneo. En las dinámicas de percepción, acercamiento y (re)conocimiento del otro y de las culturas otras, todos los medios informativos y de comunicación pueden ser, por un lado, válidos y efectivos como, por otro, pueden desviar de la verdad y difundir fácilmente numerosos prejuicios. Frente a la “síntesis” operada por los medios de comunicación tradicionales, donde “el Otro” es a menudo objeto de representaciones estereotipadas, las prácticas artísticas, en su sentido más amplio, contraponen un “análisis” que puede permitir, en diferentes casos, la eliminación de las barreras y un mayor acercamiento a la cultura otra. En la presente investigación se quiere trazar un itinerario teórico que parte de las hipótesis orientalistas, pasa por las filosofías del encuentro con el otro; los estudios sobre la participación; las actuales reflexiones sobre la estética relacional; las definiciones históricas y socio-políticas del Mediterráneo; hasta llegar a reconocer en el arte, en la creación artística, el medio de comunicación más eficaz y penetrante a la hora de refinar el conocimiento y (re)descubrir los diferentes aspectos de las culturas de los países y de los pueblos del Mediterráneo. En el espacio plural del Mediterráneo las prácticas artísticas y creativas actuales actúan como un campo de experimentación y un territorio de debate valioso e importante para el desarrollo del discurso intercultural.

Validation of a modified fluorimetric assay for the screening of trichomonacidal drugs

A fluorimetric microassay that uses a redox dye to determine the viability of the flagellate Trichomonas vaginalis has been optimised to provide a more sensitive method to evaluate potential trichomonacidal compounds. Resazurin has been used in recent years to test drugs against different parasites, including trichomonadid protozoa; however, the reproducibility of these resazurin-based methods in our laboratory has been limited because the flagellate culture medium spontaneously reduces the resazurin. The objective of this work was to refine the fluorimetric microassay method previously developed by other research groups to reduce the fluorescence background generated by the media and increase the sensitivity of the screening assay. The experimental conditions, time of incubation, resazurin concentration and media used in the microtitre plates were adjusted. Different drug sensitivity studies against T. vaginalis were developed using the 5-nitroimidazole reference drugs, new 5-nitroindazolinones and 5-nitroindazole synthetic derivatives. Haemocytometer count results were compared with the resazurin assay using a 10% solution of 3 mM resazurin dissolved in phosphate buffered saline with glucose (1 mg/mL). The fluorimetric assay and the haemocytometer counts resulted in similar percentages of trichomonacidal activity in all the experiments, demonstrating that the fluorimetric microtitre assay has the necessary accuracy for high-throughput screening of new drugs against T. vaginalis.

Development and validation of a risk score predicting substantial weight gain over 5 years in middle-aged European men and women.

BACKGROUND Identifying individuals at high risk of excess weight gain may help targeting prevention efforts at those at risk of various metabolic diseases associated with weight gain. Our aim was to develop a risk score to identify these individuals and validate it in an external population. METHODS We used lifestyle and nutritional data from 53°758 individuals followed for a median of 5.4 years from six centers of the European Prospective Investigation into Cancer and Nutrition (EPIC) to develop a risk score to predict substantial weight gain (SWG) for the next 5 years (derivation sample). Assuming linear weight gain, SWG was defined as gaining ≥ 10% of baseline weight during follow-up. Proportional hazards models were used to identify significant predictors of SWG separately by EPIC center. Regression coefficients of predictors were pooled using random-effects meta-analysis. Pooled coefficients were used to assign weights to each predictor. The risk score was calculated as a linear combination of the predictors. External validity of the score was evaluated in nine other centers of the EPIC study (validation sample). RESULTS Our final model included age, sex, baseline weight, level of education, baseline smoking, sports activity, alcohol use, and intake of six food groups. The model's discriminatory ability measured by the area under a receiver operating characteristic curve was 0.64 (95% CI = 0.63-0.65) in the derivation sample and 0.57 (95% CI = 0.56-0.58) in the validation sample, with variation between centers. Positive and negative predictive values for the optimal cut-off value of ≥ 200 points were 9% and 96%, respectively. CONCLUSION The present risk score confidently excluded a large proportion of individuals from being at any appreciable risk to develop SWG within the next 5 years. Future studies, however, may attempt to further refine the positive prediction of the score.

Development of a new tool for assessing health-related quality of life in patients with primary hyperparathyroidism.

BACKGROUND Several studies in recent years have evaluated Health Related Quality of Life (HRQoL) of patients with primary hyperparathyroidism (PHPT). No disease specific questionnaires are available to assess the impact of the disease. The aim of this research is to describe the development of a new disease specific Quality of Life (QoL) questionnaire for use specifically with PHPT patients. METHODS A conceptual model was developed describing the impact of the disease and its symptoms on QoL domains. A literature review was conducted to identify the most relevant domains. A focus group with experts was used to validate the domains; 24 patients were also interviewed to complement the information from the patient's perspective. A content analysis of the interviews was performed to identify items related with the impact of the disease, leading to PHPQoL-V.1 which was presented to a sample of 67 patients. Reliability was assessed by Cronbach's coefficient alpha and item-total score correlations. Validity was assessed by a factor analysis performed to determine the number of domains. Rasch analysis was carried out in order to refine the questionnaire items. RESULTS 259 items were extracted from the interviews that were subsequently reduced to 34 items. Cronbach's coefficient alpha was 0.92. The factor analysis extracted two domains (physical and emotional). After Rasch analysis the questionnaire PHPQoL-V.2 kept 16 items (9 physical and 7 emotional). The questionnaire was developed in a Spanish population and the final version was translated to English through translation and back-translation. CONCLUSION The first disease specific HRQoL questionnaire for PHPT patients (PHPQoL-16) has been developed. Validation studies designed to assess measurement properties of this tool are currently underway.

Pathology of peripheral T-cell lymphomas: where do we stand?

Peripheral T-cell lymphomas (PTCLs) are heterogeneous and uncommon malignancies characterized by a usually aggressive clinical course. The current World Health Organization (WHO) classification delineates many entities grouped according to the clinical presentation as predominantly leukemic, cutaneous, extranodal, or nodal diseases. Yet, few genetic lesions serve as entity-defining markers. Using high-throughput methods, new recurrent genetic and molecular alterations are being discovered that are expected to refine the current classification and serve as diagnostic genetic markers and targets for novel therapies. There is increasing evidence that certain cellular subsets, in particular follicular helper T cells and gamma delta T cells, represent important defining markers and/or determinants of the biology of certain entities; nevertheless, the cellular derivation of many PTCL entities remains poorly characterized and there is evidence of plasticity in terms of cellular derivation (alpha-beta, gamma-delta, natural killer [NK]) especially in several extranodal entities with a cytotoxic profile. While most clonal NK/T-cell proliferations are in general highly malignant, some more indolent forms of NK or T-cell lympho-proliferations are being identified.

Comparative analysis of human and mouse expression data illuminates tissue-specific evolutionary patterns of miRNAs.

MicroRNAs (miRNAs) constitute an important class of gene regulators. While models have been proposed to explain their appearance and expansion, the validation of these models has been difficult due to the lack of comparative studies. Here, we analyze miRNA evolutionary patterns in two mammals, human and mouse, in relation to the age of miRNA families. In this comparative framework, we confirm some predictions of previously advanced models of miRNA evolution, e.g. that miRNAs arise more frequently de novo than by duplication, or that the number of protein-coding gene targeted by miRNAs decreases with evolutionary time. We also corroborate that miRNAs display an increase in expression level with evolutionary time, however we show that this relation is largely tissue-dependent, and especially low in embryonic or nervous tissues. We identify a bias of tag-sequencing techniques regarding the assessment of breadth of expression, leading us, contrary to predictions, to find more tissue-specific expression of older miRNAs. Together, our results refine the models used so far to depict the evolution of miRNA genes. They underline the role of tissue-specific selective forces on the evolution of miRNAs, as well as the potential co-evolution patterns between miRNAs and the protein-coding genes they target.

Automatic landmarks detection in breast reconstruction aesthetic assessment.

This paper addresses a fully automatic landmarks detection method for breast reconstruction aesthetic assessment. The set of landmarks detected are the supraesternal notch (SSN), armpits, nipples, and inframammary fold (IMF). These landmarks are commonly used in order to perform anthropometric measurements for aesthetic assessment. The methodological approach is based on both illumination and morphological analysis. The proposed method has been tested with 21 images. A good overall performance is observed, although several improvements must be achieved in order to refine the detection of nipples and SSNs.

Examining the information content of time-lapse crosshole GPR data collected under different infiltration conditions to estimate unsaturated soil hydraulic properties

Time-lapse geophysical data acquired during transient hydrological experiments are being increasingly employed to estimate subsurface hydraulic properties at the field scale. In particular, crosshole ground-penetrating radar (GPR) data, collected while water infiltrates into the subsurface either by natural or artificial means, have been demonstrated in a number of studies to contain valuable information concerning the hydraulic properties of the unsaturated zone. Previous work in this domain has considered a variety of infiltration conditions and different amounts of time-lapse GPR data in the estimation procedure. However, the particular benefits and drawbacks of these different strategies as well as the impact of a variety of key and common assumptions remain unclear. Using a Bayesian Markov-chain-Monte-Carlo stochastic inversion methodology, we examine in this paper the information content of time-lapse zero-offset-profile (ZOP) GPR traveltime data, collected under three different infiltration conditions, for the estimation of van Genuchten-Mualem (VGM) parameters in a layered subsurface medium. Specifically, we systematically analyze synthetic and field GPR data acquired under natural loading and two rates of forced infiltration, and we consider the value of incorporating different amounts of time-lapse measurements into the estimation procedure. Our results confirm that, for all infiltration scenarios considered, the ZOP GPR traveltime data contain important information about subsurface hydraulic properties as a function of depth, with forced infiltration offering the greatest potential for VGM parameter refinement because of the higher stressing of the hydrological system. Considering greater amounts of time-lapse data in the inversion procedure is also found to help refine VGM parameter estimates. Quite importantly, however, inconsistencies observed in the field results point to the strong possibility that posterior uncertainties are being influenced by model structural errors, which in turn underlines the fundamental importance of a systematic analysis of such errors in future related studies.

On the origin and scope of the second language speech production disadvatage

Los hablantes bilingües tienen un acceso al léxico más lento y menos robusto que los monolingües, incluso cuando hablan en su lengua materna y dominante. Este fenómeno, comúnmente llamado “la desventaja bilingüe” también se observa en hablantes de una segunda lengua en comparación con hablantes de una primera lengua. Una causa que posiblemente contribuya a estas desventajas es el uso de control inhibitorio durante la producción del lenguaje: la inhibición de palabras coactivadas de la lengua actualmente no en uso puede prevenir intrusiones de dicha lengua, pero al mismo tiempo ralentizar la producción del lenguaje. El primer objetivo de los estudios descritos en este informe era testear esta hipótesis mediante diferentes predicciones generadas por teorías de control inhibitorio del lenguaje. Un segundo objetivo era investigar la extensión de la desventaja bilingüe dentro y fuera de la producción de palabras aisladas, así como avanzar en el conocimiento de las variables que la modulan. En lo atingente al primer objetivo, la evidencia obtenida es incompatible con un control inhibitorio global, desafiando la idea de mecanismos específicos en el hablante bilingüe utilizados para la selección léxica. Esto implica que una explicación común para el control de lenguaje y la desventaja bilingüe en el acceso al léxico es poco plausible. En cuanto al segundo objetivo, los resultados muestran que (a) la desventaja bilingüe no tiene un impacto al acceso a la memoria; (b) la desventaja bilingüe extiende a la producción del habla conectada; y (c) similitudes entre lenguas a diferentes niveles de representación así como la frecuencia de uso son factores que modulan la desventaja bilingüe.   

Discovery and refinement of loci associated with lipid levels.

Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 × 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.

Bayesian Markov chain Monte Carlo inversion of geophysical data for the purpose of estimating the hydraulic properties of the unsaturated zone

Ground-penetrating radar (GPR) has the potential to provide valuable information on hydrological properties of the vadose zone because of their strong sensitivity to soil water content. In particular, recent evidence has suggested that the stochastic inversion of crosshole GPR data within a coupled geophysical-hydrological framework may allow for effective estimation of subsurface van-Genuchten-Mualem (VGM) parameters and their corresponding uncertainties. An important and still unresolved issue, however, is how to best integrate GPR data into a stochastic inversion in order to estimate the VGM parameters and their uncertainties, thus improving hydrological predictions. Recognizing the importance of this issue, the aim of the research presented in this thesis was to first introduce a fully Bayesian inversion called Markov-chain-Monte-carlo (MCMC) strategy to perform the stochastic inversion of steady-state GPR data to estimate the VGM parameters and their uncertainties. Within this study, the choice of the prior parameter probability distributions from which potential model configurations are drawn and tested against observed data was also investigated. Analysis of both synthetic and field data collected at the Eggborough (UK) site indicates that the geophysical data alone contain valuable information regarding the VGM parameters. However, significantly better results are obtained when these data are combined with a realistic, informative prior. A subsequent study explore in detail the dynamic infiltration case, specifically to what extent time-lapse ZOP GPR data, collected during a forced infiltration experiment at the Arrenaes field site (Denmark), can help to quantify VGM parameters and their uncertainties using the MCMC inversion strategy. The findings indicate that the stochastic inversion of time-lapse GPR data does indeed allow for a substantial refinement in the inferred posterior VGM parameter distributions. In turn, this significantly improves knowledge of the hydraulic properties, which are required to predict hydraulic behaviour. Finally, another aspect that needed to be addressed involved the comparison of time-lapse GPR data collected under different infiltration conditions (i.e., natural loading and forced infiltration conditions) to estimate the VGM parameters using the MCMC inversion strategy. The results show that for the synthetic example, considering data collected during a forced infiltration test helps to better refine soil hydraulic properties compared to data collected under natural infiltration conditions. When investigating data collected at the Arrenaes field site, further complications arised due to model error and showed the importance of also including a rigorous analysis of the propagation of model error with time and depth when considering time-lapse data. Although the efforts in this thesis were focused on GPR data, the corresponding findings are likely to have general applicability to other types of geophysical data and field environments. Moreover, the obtained results allow to have confidence for future developments in integration of geophysical data with stochastic inversions to improve the characterization of the unsaturated zone but also reveal important issues linked with stochastic inversions, namely model errors, that should definitely be addressed in future research.

Sistemas heterogéneos adaptativos basados en el contexto

Delivery context-aware adaptative heterogenous systems. Currently, many types of devices that have gained access to the network is large and diverse. The different capabilities and characteristics of them, in addition to the different characteristics and preferences of users, have generated a new goal to overcome: how to adapt the contents taking into account this heterogeneity, known as the “delivery context.” The concepts of adaptation and accessibility have been widely discussed and have resulted in many proposals, standards and techniques designed to solve the problem, making it necessary to refine the analysis of the issue to be considered in the process of adaptation. We present a tour of the various proposals and standards that have marked the area of heterogeneous systems works, and others who have worked since the real-time interaction through agents based platforms. All targeted to solve a common goal: the delivery context