Coyote (Canis latrans) range expansion in the Central Appalachian Mountains has stimulated interest in ecology of this predator and potential impacts to prey populations. This is particularly true in the Ridge and Valley Region in western Virginia where white-tailed deer (Odocoileus virginianus) populations are restricted by low nutritional carrying capacity and are subject to two other predators, bobcats (Lynx rufus) and American black bears (Ursus americanus), in addition to an active hunter community. I address two primary objectives of the Virginia Appalachian Coyote Study: to investigate 1) spatial ecology and 2) population dynamics of coyote populations in Bath and Rockingham counties. I deployed 21 GPS satellite collars on 19 coyotes over 32 months. I estimated home range size (mean = 13.46 km², range = 1.23 km² - 38.24 km²) across months using biased-random bridges and second-order habitat selection at four scales using eigenanalysis of selection ratios. I developed a metric to classify social status of individuals as either resident or transient based on stability of home range centers over time. I found evidence for class substructure for selection of territories where adult residents had a higher probability of mortality in high productivity/high risk habitats, compared to subadults and transients that were restricted to less productive habitats. I collected scat samples over five scat surveys across 2.5 years and extracted fecal DNA to identify individual coyotes in a mark-recapture framework. I estimated coyote densities in Bath (5.53 – 9.04 coyotes/100 km²) and Rockingham Counties (2.41 – 8.53 coyotes/100 km²) using a spatial capture-recapture model. Six-month apparent survival was lower in Bath County (Φ_Bath = 0.442, 0.259 – 0.643; Φ_Rockingham = 0.863, 0.269 – 0.991). The Bath County population demonstrated persistence despite high mortality and the Rockingham population demonstrated boundedness with recruitment inverse of changes in density. Findings at both sites suggest density-dependence, and tests of territoriality, presence of transients, and territory turnover demonstrate a capacity for immediate local immigration in response to high mortality in Bath County. I suggest that landscape-level habitat management may be a viable strategy to reduce potential conflicts with coyotes in the region. / Ph. D.

[ES] La fibrilación auricular (FA) es una de las arritmias más comunes en la práctica clínica cuyos mecanismos, hasta ahora, no han sido comprendidos en su totalidad. El estudio de dichos mecanismos mediante el estudio de la información clínica, la metodología de estudios computacionales y los algoritmos de inteligencia artificial (IA) que permiten la identificación de nuevos patrones para la personalización de los tratamientos es clave para desvelar las características de la arritmia. Actualmente, el tratamiento de preferencia para los pacientes con FA que ha presentado mayores ratios de efectividad ha sido la ablación cardiaca. Este procedimiento invasivo utiliza un catéter para ablacionar o quemar el área del tejido cardiaco que es responsable del mantenimiento de la arritmia. Para poder identificar dicha área, es indispensable realizar un estudio electrofisiológico para evaluar las señales eléctricas intracavitarias. En el campo de las simulaciones por ordenador, varios estudios han presentado abordajes personalizados que intentan establecer una plataforma complementaria para la planificación de la ablación. En este ámbito, la electrocardiografía por imagen se ha utilizado para la estratificación y caracterización previa de pacientes antes del procedimiento de ablación. Finalmente, los estudios observacionales clínicos permiten la caracterización de la población de FA, ayudando a recoger, no solo datos electrofisiológicos, sino también biomarcadores clínicos directamente relacionados con la prognosis del paciente. Dada toda la información producida durante este tipo de estudios, la IA se ha introducido paulatinamente en este tipo de estudios con el objetivo de identificar patrones o biomarcadores que permitan caracterizar a estos pacientes incluyendo toda la información recogida. Además, los algoritmos de predicción, que permiten estimar el éxito del tratamiento y la prognosis del paciente, han sido desarrollados. Debido a todas estas razones, estos campos han sido estudiados durante el desarrollo de este trabajo. En primer lugar, se realizaron simulaciones por ordenador utilizan-do una población de modelos que permitía evaluar la inducibilidad y mantenimiento de la arritmia en diferentes escenarios. Teniendo en cuenta la gran cantidad de datos derivados de las simulaciones, que incluían la variabilidad introducida en la población y diferentes fármacos, se implementaron algoritmos de IA que extrajeron patrones de los perfiles más proarrítmicos. En segundo lugar, se realizaron simulaciones personalizadas en una cohorte de pacientes, incluyendo las anatomías de las aurículas y considerando diferentes escenarios arrítmicos. Estos experimentos se realizaron con una carga computacional menor comparado con otros estudios y permitieron identificar un biomarcador obtenido de dichos datos que caracterizaba la actividad en la zona de las venas pulmonares y la comparaba con la evolución del paciente 12 meses tras el procedimiento de ablación. Finalmente, se analizó el estudio observacional STRATIFY-AF utilizando la información obtenida del ECGi y combinándola con datos clínicos. Como resultado, se obtuvo un score electrofisiológico que per-mite predecir el tratamiento más exitoso para cada paciente. Los resultados presentados en esta tesis ilustran un claro ejemplo de combinación de diferentes tecnologías, como las simulaciones in silico, con datos clínicos y algoritmos de IA, que pueden ser de gran utilidad para investigar los mecanismos de la arritmia cardiaca. / [CA] La fibril·lació auricular (FA) és una de les arítmies més comunes. En la pràctica clínica els mecanismes de la qual, fins ara, no han sigut compresos en la seua totalitat. L'estudi dels dits mecanismes per mitjà de l'estudi de la informació clínica, la metodologia d'estudis computacionals i els algoritmes d'intel·ligència artificial (IA) que permeten la identificació de nous patrons per a la personalització dels tractaments és clau per a desvelar les característiques de l'arítmia. Actualment, el tractament de preferència per als pacients amb FA que ha presentat majors ràtios d'efectivitat ha sigut l'ablació cardíaca. Este procediment invasiu utilitza un catèter per a ablacionar o cremar l'àrea del teixit cardíac que és responsable del manteniment de l'arítmia. Per a poder identificar la dita àrea, és indispensable realitzar un estudi electrofisiologia per a avaluar els senyals elèctrics intracavitarias. En el camp de les simulacions per ordinador, diversos estudis han presentat abordatges personalitzats que intenten establir una plataforma complementària per a la planificació de l'ablació. En este àmbit, l'electrocardiografia per imatge s'ha utilitzat per a l'estratificació i caracterització prèvia de pacients abans del procediment d'ablació. Finalment, els estudis observacionals clínics permeten la caracterització de la població de FA, ajudant a arreplegar, no sols dades electrofisiològiques, sinó també biomarcadores clínics directament relacionats amb la prognosi del pacient. Donada tota la informació produïda durant este tipus d'estudis, la IA s'ha introduït gradualment en este tipus d'estudis amb l'objectiu d'identificar patrons o biomarcadores que permeten caracteritzar estos pacients incloent tota la informació arreplegada. A més, els algoritmes de predicció, que permeten estimar l'èxit del tractament i la prognosi del pacient, han sigut desenrotllats. A causa de totes estes raons, estos camps han sigut estudiats durant el desenrotllament d'este treball. En primer lloc, es van utilitzar simulacions per ordinador utilitzant una població de models que permetia avaluar la inducibilidad i manteniment de l'arítmia en diferents escenaris. Donada la variabilitat introduïda en la població, en combinació amb diferents fàrmacs, els algoritmes d'IA es van utilitzar per a extraure patrons que identificaven els perfils més proarítmics. En segon lloc, es van realitzar simulacions personalitzades en una cohort de pacients, incloent les anatomies de les aurícules i considerant diferents escenaris arítmics. Estos experiments es van realitzar amb una càrrega computacional menor comparat amb altres estudis i van permetre identificar un biomarcador obtingut de les dits dades que caracteritzava l'activitat en la zona de les venes pulmonars i la comparava amb l'evolució del pacient 12 mesos després del procediment d'ablació. Finalment, l'estudi observacional STRATIFY-AF es va analitzar utilitzant la informació obtinguda de l'ECGi i combinant-la amb dades clíniques. Com resultat, es va obtindre un score electrofisiològic que permet predir el tractament més reeixit per a cada pacient. Els resultats presentats en esta tesi il·lustren, per tant, que la combinació de les tecnologies in silico, junt amb les dades clíniques i el processament de dades disponibles gràcies als algoritmes d'IA poden ser de gran utilitzar per a investigar els mecanismes de l'arítmia cardíaca. / [EN] Atrial Fibrillation (AF) is one of the most common arrhythmias in clinical practice and thus far, the electrophysiological mechanisms underlying its initiation and maintenance are not fully understood. The study of such mechanism including clinical information, computational models and artificial intelligence (AI) algorithms that enable the identification of new patterns for the personalization of the treatments is key to unveil the characteristics of the arrhythmia. At the present, the treatment of choice for AF patients with higher effectiveness has proved to be cardiac ablation. This invasive procedure uses a catheter to ablate or burn the area of the cardiac tissue that is responsible for the maintenance of the arrhythmia. In order to find this specific area, it is indispensable to perform an electrophysiological study to evaluate the intracavitary electrical signals. In the computational field, several studies have presented personalized approaches that aim to stablish a complimentary platform for ablation planning. In this area, electrocardiographic imaging has also been used for the stratification and prior characterization of patients before the ablation procedure. Finally, observational studies enable the characterization of the AF population, enabling to collect, not only electrophysiological data but clinical biomarkers that can be related with the prognosis of the patients. Due to all the information produced during this type of studies, AI has been recently incorporated into these studies, with the main objective of identifying patterns or biomarkers that are able to characterize these patients including all the collected information. In addition, prediction algorithms, that allow to estimate the success of the treatment and prognosis of the patient have also been developed. For this purpose, these three fields of study were explored in this thesis. First, computational simulations using a population of models were performed to evaluate arrhythmia inducibility and maintenance under different scenarios. Due to the variability introduced in the population of models in combination with different drugs, AI algorithms were applied to extract patterns that identified the most proarrhythmic profiles. Secondly, personalized simulations were performed in a cohort of patients including their anatomical cardiac geometries and considering different arrhythmic scenarios. These experiments were achieved with a lowered computational costs and included the identification of a biomarker extracted from the simulation analysis that characterized the activity in the pulmonary vein area and evaluating it with the 12-month ablation outcome. Finally, the STRATIFY-AF observational study was analyzed, using the ECGi information from the patients combined with clinical infor-mation. As a results, a stratification score was obtained to predict the most successful treatment for each of the patients. The results presented in this thesis illustrate that the combination of in silico technologies with clinical data and processing algorithms can be of great utility to further investigate the arrhythmic mechanisms. / Sánchez De La Nava, AM. (2022). Definition of a Sensitivity Profile for Drug Treatment and Identification on Clinical Biomarkers in Atrial Fibrillation [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/184778

Introduction: Examination of subungual pigmented lesions is sometimes a diagnostic challenge for clinicians. Objectives: The study was aimed to investigate characteristic patterns in optical coherence tomography (OCT) of subungual hematomas and determine distinctive features that can differentiate them from subungual melanocytic lesions. Methods: VivoSight® (Michelson Diagnostics, Maidstone, UK) was used to examine 71 subungual hematomas and 11 subungual melanocytic lesions in 69 patients (18 female and 51 male patients). Results: On OCT, bleeding was related to sharply defined black sickle-shaped (p < 0.001) or globular regions (not significant [ns]) with a hyperreflective margin (0.002), a grey center (0.013), hyperreflective lines in the area (ns) or periphery (p = 0.031), peripheral fading (p = 0.029), and red dots in the area (p = 0.001). In the 1 case of melanoma in situ examined, we found curved vessels with irregular sizes and distribution on the dermis of the nailbed, while subungual hematomas and subungual benign nevi presented as clustered red dots and/or regularly distributed curved vessels. Conclusion: Our findings indicate that the use of OCT in addition to dermoscopy provides high-resolution optical imaging information for the diagnosis of subungual hematoma and facilitates the differential diagnosis of subungual hematomas and subungual melanocytic lesions.

[EN] Atrial tachyarrhythmias present a high prevalence in the developed world, and several studies predict that in the coming decades it will be increased. Micro or macro-reentrant mechanisms of the electrical wavefronts that govern the mechanical behavior of the heart are one of the main responsibles for the maintenance of these arrhythmias. Atrial flutter is maintained by a macro-reentry around an anatomical or functional obstacle located in the atria. In the case of atrial fibrillation, the hypothesis which describes high frequency rotors as dominant sources of the fibrillation and responsible for the maintenance of the arrhythmia, has been gaining relevance in the last years. However, the therapies that target high frequency sources have a limited efficacy with current techniques. Radiofrequency ablation allows the destruction of parts of the cardiac tissue resulting in the interruption of the reentrant circuit in case of macro-reentries or the isolation of micro-reentrant circuits. The non-invasive location of reentrant circuits would increment the efficacy of these therapies and would shorten surgery interventions. In parallel, pharmacological therapies modify ionic expressions associated to the excitability and electrical refractoriness of the cardiac tissue with the objective of hindering the maintenance of reentrant behaviors. These therapies require a deep knowledge of the ionic mechanisms underlying the reentrant behavior and its properties in order to be effective. The research in these mechanisms allows the evaluation of new targets for the treatment and thus may improve the efficacy in atrial fibrillation termination. In this thesis, mathematical modeling is used to go forward in the minimization of the limitations associated to these treatments. Body surface potential mapping has been evaluated, both clinically and by means of mathematical simulations for the diagnosis and location of macro-reentrant circuits. The analysis of phase maps obtained from multiple lead electrocardiographic recordings distributed in the whole torso allowed the discrimination between different reentrant circuits. It is the reason why this technique is presented as a tool for the non-invasive location of macro and micro-reentrant circuits. A population of mathematical models designed in this thesis based on the action potentials recordings of atrial cardiomyocites from 149 patients, allowed the evaluation of the ionic mechanisms defining the properties of reentrant behaviors. This study has allowed us defining the blockade of ICaL as a target for the pharmacological treatment. The blockade of this current is associated with the increase of the movement in the core of the rotor which easies the collision of the rotor with other wavefronts or anatomical obstacles promoting the extinction of the reentry. The variability observed between patients modeled in our population has allowed showing and explaining the mechanisms promoting divergent results of a single treatment. This is why the introduction of populations of models will allow the prevention of side effects associated to inter-subject variability and to go forward in the development of individualized therapies. These works are built through a simulation platform of cardiac electrophysiology based in Graphic Processing Units (GPUs) and developed in this thesis. The platform allows the simulation of cellular models, tissues and organs with a realistic geometry and shows features comparable to that of the platforms used by the most relevant electrophysiology research groups at the moment. / [ES] Las taquiarritmias auriculares tienen una alta prevalencia en el mundo desarrollado, además diversos estudios poblacionales indican que en las próximas décadas ésta se verá incrementada. Los mecanismos de micro o macro-reentrada de los frentes de onda eléctricos que rigen el comportamiento mecánico del corazón, se presentan como una de las principales causas del mantenimiento de estas arritmias. El flutter auricular es mantenido por un macro-reentrada alrededor de un obstáculo anatómico o funcional en las aurículas, mientras que en el caso de la fibrilación auricular la hipótesis que define a los rotores de alta frecuencia como elementos dominantes y responsables del mantenimiento de la arritmia se ha ido imponiendo al resto en los últimos años. Sin embargo, las terapias que tienen como objetivo finalizar o aislar estas reentradas tienen todavía una eficacia limitada. La ablación por radiofrecuencia permite eliminar zonas del tejido cardiaco resultando en la interrupción del circuito de reentrada en el caso de macro-reentradas o el aislamiento de comportamientos micro-reentrantes. La localización no invasiva de los circuitos reentrantes incrementaría la eficacia de estas terapias y reduciría la duración de las intervenciones quirúrgicas. Por otro lado, las terapias farmacológicas alteran las expresiones iónicas asociadas a la excitabilidad y la refractoriedad del tejido con el fin de dificultar el mantenimiento de comportamientos reentrantes. Este tipo de terapias exigen incrementar el conocimiento de los mecanismos subyacentes que explican el proceso de reentrada y sus propiedades, la investigación de estos mecanismos permite definir las dianas terapéuticas que mejoran la eficacia en la extinción de estos comportamientos. En esta tesis el modelado matemático se utiliza para dar un paso importante en la minimización de las limitaciones asociadas a estos tratamientos. La cartografía eléctrica de superficie ha sido testada, clínicamente y con simulaciones matemática,s como técnica de diagnóstico y localización de circuitos macro-reentrantes. El análisis de mapas de fase obtenidos a partir de los registros multicanal de derivaciones electrocardiográficas distribuidas en la superficie del torso permite diferenciar distintos circuitos de reentrada. Es por ello que esta técnica de registro y análisis se presenta como una herramienta para la localización no invasiva de circuitos macro y micro-reentrantes. Una población de modelos matemáticos, diseñada en esta tesis a partir de los registros de los potenciales de acción de 149 pacientes, ha permitido evaluar los mecanismos iónicos que definen las propiedades asociadas a los procesos de reentrada. Esto ha permitido apuntar al bloqueo de la corriente ICaL como diana terapéutica. Ésta se asocia al incremento del movimiento del núcleo que facilita el impacto del rotor con otros frentes de onda u obstáculos extinguiéndose así el comportamiento reentrante. La variabilidad entre pacientes reflejada en la población de modelos ha permitido además mostrar los mecanismos por los cuales un mismo tratamiento puede mostrar efectos divergentes, así el uso de poblaciones de modelos matemáticos permitirá prevenir efectos secundarios asociados a la variabilidad entre pacientes y profundizar en el desarrollo de terapias individualizadas. Estos trabajos se cimientan sobre una plataforma de simulación de electrofisiología cardiaca de basado en Unidades de Procesado Gráfico (GPUs) y desarrollada en esta tesis. La plataforma permite la simulación de modelos celulares cardiacos así como de tejidos u órganos con geometría realista, mostrando unas prestaciones comparables con las de las utilizadas por los grupos de investigación más potentes en el campo de la electrofisiología. / [CA] Les taquiarítmies auriculars tenen una alta prevalença en el món desenvolupat, a més diversos estudis poblacionals indiquen que en les pròximes dècades aquesta es veurà incrementada. Els mecanismes de micro o macro-reentrada dels fronts d'ona elèctrics que regeixen el comportament mecànic del cor, es presenten com una de les principals causes del manteniment d'aquestes arítmies. El flutter auricular és mantingut per una macro-reentrada al voltant d'un obstacle anatòmic o funcional en les aurícules, mentre que en el cas de la fibril·lació auricular la hipòtesi que defineix als rotors d'alta freqüència com a elements dominants i responsables del manteniment de l'arítmia s'ha anat imposant a la resta en els últims anys. No obstant això, les teràpies que tenen com a objectiu finalitzar o aïllar aquestes reentrades tenen encara una eficàcia limitada. L'ablació per radiofreqüència permet eliminar zones del teixit cardíac resultant en la interrupció del circuit de reentrada en el cas de macro-reentrades o l'aïllament de comportaments micro-reentrants. La localització no invasiva dels circuits reentrants incrementaria l'eficàcia d'aquestes teràpies i reduiria la durada de les intervencions quirúrgiques. D'altra banda, les teràpies farmacològiques alteren les expressions iòniques associades a la excitabilitat i la refractaritat del teixit amb la finalitat de dificultar el manteniment de comportaments reentrants. Aquest tipus de teràpies exigeixen incrementar el coneixement dels mecanismes subjacents que expliquen el procés de reentrada i les seues propietats, la recerca d'aquests mecanismes permet definir les dianes terapèutiques que milloren l'eficàcia en l'extinció d'aquests comportaments. En aquesta tesi el modelatge matemàtic s'utilitza per a fer un pas important en la minimització de les limitacions associades a aquests tractaments. La cartografia elèctrica de superfície ha sigut testada, clínicament i amb simulacions matemàtiques com a tècnica de diagnòstic i localització de circuits macro-reentrants. L'anàlisi de mapes de fase obtinguts a partir dels registres multicanal de derivacions electrocardiogràfiques distribuïdes en la superfície del tors permet diferenciar diferents circuits de reentrada. És per açò que aquesta tècnica de registre i anàlisi es presenta com una eina per a la localització no invasiva de circuits macro i micro-reentrants. Una població de models matemàtics, dissenyada en aquesta tesi a partir dels registres dels potencials d'acció de 149 pacients, ha permès avaluar els mecanismes iònics que defineixen les propietats associades als processos de reentrada. Açò ha permès apuntar al bloqueig del corrent ICaL com a diana terapèutica. Aquesta s'associa a l'increment del moviment del nucli que facilita l'impacte del rotor amb altres fronts d'ona o obstacles extingint-se així el comportament reentrant. La variabilitat entre pacients reflectida en la població de models ha permès a més mostrar els mecanismes pels quals un mateix tractament pot mostrar efectes divergents, així l'ús de poblacions de models matemàtics permetrà prevenir efectes secundaris associats a la variabilitat entre pacients i aprofundir en el desenvolupament de teràpies individualitzades. Aquests treballs es fonamenten sobre una plataforma de simulació de electrofisiologia cardíaca basat en Unitats de Processament Gràfic (GPUs) i desenvolupada en aquesta tesi. La plataforma permet la simulació de models cel·lulars cardíacs així com de teixits o òrgans amb geometria realista, mostrant unes prestacions comparables amb les de les utilitzades per els grups de recerca més importants en aquesta área. / Liberos Mascarell, A. (2016). Mathematical modeling approaches for the diagnosis and treatment of reentrant atrial tachyarrhythmias [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/62166

L’imagerie par résonance magnétique de diffusion (l’IRMd) est actuellement la seule technique non-invasive pour étudier l’architecture tridimensionnelle des fibres myocardiques du cœur humain à la fois ex vivo et in vivo. Cependant, il est difficile de savoir comment les caractéristiques de diffusion calculées à partir des images de diffusion reflètent les propriétés des microstructures du myocarde à cause de l’absence de la vérité-terrain sans parler de l’influence de divers facteurs tels que la résolution spatiale, le bruit et les artéfacts. L'objectif principal de cette thèse est donc de développer des simulateurs de l’IRM de diffusion basés sur des modèles réalistes afin de simuler, en intégrant différentes modalités d'imagerie, les images pondérées en diffusion des fibres myocardiques à la fois ex vivo et in vivo, et de proposer un outil générique permettant d’évaluer la qualité de l’imagerie et les algorithmes de traitement d’images. Pour atteindre cet objectif, le présent travail se focalise sur quatre parties principales. La première partie concerne la formulation de la théorie de simulation IRMd pour la génération d’images de diffusion et pour les applications sur les modèles simples de fibres cardiaques chez l’homme, et essaie de comprendre la relation sous-jacente entre les propriétés mesurées de la diffusion et les caractéristiques à la fois physiques et structurelles des fibres cardiaques. La seconde partie porte sur la simulation des images de résonance magnétique de diffusion à différentes échelles en s’appuyant sur des données du cœur humain issues de l'imagerie par lumière polarisée. En comparant les propriétés de diffusion à différentes échelles, la relation entre la variation de la microstructure et les propriétés de diffusion observée à l'échelle macroscopique est étudiée. La troisième partie consacre à l’analyse de l'influence des paramètres d'imagerie sur les propriétés de diffusion en utilisant une théorie de simulation améliorée. La dernière partie a pour objectif de modéliser la structure des fibres cardiaques in vivo et de simuler les images de diffusion correspondantes en combinant la structure des fibres cardiaques et le mouvement cardiaque connu a priori. Les simulateurs proposés nous fournissent un outil générique pour générer des images de diffusion simulées qui peuvent être utilisées pour évaluer les algorithmes de traitement d’images, pour optimiser le choix des paramètres d’IRM pour les fibres cardiaque aussi bien ex vivo que in vivo, et pour étudier la relation entre la structure de fibres microscopique et les propriétés de diffusion macroscopiques. / Diffusion magnetic resonance imaging (dMRI) appears currently as the unique imaging modality to investigate noninvasively both ex vivo and in vivo three-dimensional fiber architectures of the human heart. However, it is difficult to know how well the diffusion characteristics calculated from diffusion images reflect the microstructure properties of the myocardium since there is no ground-truth information available and add to that the influence of various factors such as spatial resolution, noise and artifacts, etc. The main objective of this thesis is then to develop realistic model-based dMRI simulators to simulate diffusion-weighted images for both ex vivo and in vivo cardiac fibers by integrating different imaging modalities, and propose a generic tool for the evaluation of imaging quality and image processing algorithms. To achieve this, the present work focuses on four parts. The first part concerns the formulation of basic dMRI simulation theory for diffusion image generation and subsequent applications on simple cardiac fiber models, and tries to elucidate the underlying relationship between the measured diffusion anisotropic properties and the cardiac fiber characteristics, including both physical and structural ones. The second part addresses the simulation of diffusion magnetic resonance images at multiple scales based on the polarized light imaging data of the human heart. Through both qualitative and quantitative comparison between diffusion properties at different simulation scales, the relationship between the microstructure variation and the diffusion properties observed at macroscopic scales is investigated. The third part deals with studying the influence of imaging parameters on diffusion image properties by means of the improved simulation theory. The last part puts the emphasis on the modeling of in vivo cardiac fiber structures and the simulation of the corresponding diffusion images by combining the cardiac fiber structure and the a priori known heart motion. The proposed simulators provide us a generic tool for generating the simulated diffusion images that can be used for evaluating image processing algorithms, optimizing the choice of MRI parameters in both ex vivo and in vivo cardiac fiber imaging, and investigating the relationship between microscopic fiber structure and macroscopic diffusion properties.

Thesis (MScMedSc)--University of Stellenbosch, 2011. / ENGLISH ABSTRACT: An important next step to Tuberculosis control relies on the translation of basic science and modern diagnostic techniques into primary health care clinics. These assays must be rapid, inexpensive, interpretation of results must be easy and they must be simple so that a healthcare worker with limited training can perform the tests under safe conditions. This study consists of four aims. The first aim was to develop a methodology to sterilize sputum specimens for rapid TB diagnosis and drug resistance testing. Candidate bactericides were identified from the literature, and tested for their bactericidal activity in Mycobacterium tuberculosis. We identified ultraseptin®aktiv as a powerful bactericidal agent which sterilizes sputum specimens for subsequent safe handling prior to light emitting diode microscopy and it also provides a DNA template for PCR-based tests. An algorithm has been proposed for the processing of specimens and rapid diagnosis of TB and drug resistant TB while patients wait for results. Recently, the World Health Organization has endorsed the MTBDRplus test for diagnosis of TB and drug resistant TB. However genotypic tests may have more problems than anticipated. With the HIV pandemic, an increase of non-tuberculous mycobacteria has been reported. The sensitivity of genotypic tests in specimens with underlying non-tuberculous mycobacterial species therefore requires further evaluation. This study therefore also aimed at determining the reliability of the MTBDRplus assay for detection of drug resistant TB where non-tuberculous bacterial load is high. Clinically relevant non-tuberculous mycobacterium DNA and DNA from a multi-drug resistant TB isolate were obtained. Ratios of the different NTM with the MDR-TB DNA were made and subjected to the MTBDRplus assay. Known mix NTM and TB infected clinical isolates and sputum sediments were also evaluated for TB and drug resistance detection on the MTBDRplus assay. Under these conditions, this study provides evidence that the MTBDRplus test cannot reliably detect TB and drug resistance TB in specimens with underlying non-tuberculous mycobacteria. Thirdly, to evaluate the sensitivity of the MTBDRplus assay for detecting drug resistance in hetero-resistant isolates, ratios were made using purified DNA from an MDR and pan-susceptible TB isolate. The MTBDRplus assay was then performed on the different ratios. We report that the MTBDRplus assay can efficiently detect wild type DNA in genes associated with resistance during the early evolution of drug resistance. However, in the later stage during treatment when both the wild type and mutants are present, the detection limit for the mutant DNA was 1:55. Due to these results, the MTBDRplus assay should still be further improved or other tests should be developed to address these limitations. And finally to combat cross amplicon contamination during the final steps of genotypic detection with the MTBDRplus assay, a proof of concept for a patentable closed tube line probe device was proposed on the 4th aim. This device can be improved to enable automated drug resistance genotyping of multiple specimens. The results of this study highlight the need for a sensitive inexpensive point of care drug resistance test that does not require intensive training. / AFRIKAANSE OPSOMMING: 'n Belangrike volgende stap om Tuberkulose te beheer is om basiese wetenskap resultate te gebruik sodat moderne diagnose tegnieke ontwikkel kan word wat in primêre gesondheidsorg klinieke toegepas kan word. Hierdie toetse moet vinnig, goedkoop, en die interpretasie van resultate moet maklik wees. Die toetse moet eenvoudig wees sodat 'n gesondheidswerker met beperkte opleiding die toetse onder veilige omstandighede kan uitvoer. Hierdie studie bestaan uit vier doelwitte, waarvan die eerste was om 'n metode te ontwikkel vir die sterilisasie van sputum monsters vir vinnige TB diagnose en die toesting van middelweerstandigheid. Kandidaat kiemdodende middels was geïdentifiseer vanaf die literatuur en die middels se kiekdodende aktiviteit was getoets op Mycobacterium tuberculosis. Ons het ultraseptin®aktiv geïdentifiseer as 'n kragtige kiemdodende middel wat bakteria in sputum monsters steriliseer vir veilige hantering voordat diagnose met 'n lig uitstralende diode mikroskopie gedoen kan word. Hierdie behandeling met ultraseptin®aktiv bied ook 'n DNA templaat vir PCR-gebaseerde toetse. 'n Algoritme is voorgestel vir die hantering van monsters en die vinnige diagnose van sensitiewe- en middel weerstandige Tuberkulose terwyl die pasiënte by die kliniek wag vir die resultate. Onlangs het die Wêreld Gesondheid Organisasie die genotipiese MTBDRplus toets vir die diagnose van Tuberkulose en middel-weerstandige Tuberkulose onderskryf. Hierdie toets word tans op groot skaal in Suid Afrika gebruik. Dit kan egter wees dat genotipiese toetse baie meer probleme kan he as wat aanvanklik verwag is. Die HIV pandemie gaan toenemend gepaard met n toename van nie-tuberkulose mycobacteria. Die sensitiwiteit van genotipiese toetse op monsters met onderliggende nie-tuberkulose mikobakteriese spesies vereis dus verdere evaluasie. Die doel van hierdie studie was ook om die betroubaarheid van die MTBDRplus-toets te bepaal vir die opsporing van middelweerstandige TB waar die nie-tuberkulose bakteriële lading hoog is. DNA van kliniese relevante nie-tuberkulose mikobakteria en multi-middelweerstige TB isolate was bekom. Verskillende verdunnigs van die spesifieke NTM DNA te same met die van MDR-TB DNA is gemaak en onderwerp aan die MTBDRplus toets. Bekende gemengde NTM- en TB geïnfekteerde kliniese isolate en sputum sedimente was ook geevalueer vir die opsporing van TB en middel weerstandigheid met die MTBDRplus toets. Hierdie studie verskaf bewyse dat die MTBDRplus toets nie betroubaar is met die diagnose van sensitiewe- en middel weerstandige Tuberkulose in monsters met onderliggende nie-tuberkulose mycobacteria nie. Verskillende verdunnings van gesuiwerde DNA van MDR en pan-sensitiewe TB isolate is gemaak om die sensitiwiteit van die MTBDRplus toets vir die opsporing van middelweerstandigheid te bepaal. Die MDRDRplus toets is gebruik met hierdie verdunnings. Resultate in hierdie studie toon dat die MTBDRplus toets effektief is met die identifisering van wilde-tipe DNA (dit beteken middel sensitief) in gene wat geassosieer word met middel weerstandigheid gedurende die vroeë ontwikkeling van weerstandigheid. Hier teenoor toon die resultate dat in die later stadium tydens behandeling, wanneer beide die wilde-tipe (sensitief) en mutante DNA (weerstandig) teenwoordig is, is die opsporingslimiet vir die mutante DNA maar 1:55. As gevolg van hierdie resultate raai ons aan dat die MTBDRplus toets nog verder verbeter moet word of dat ander toetse ontwikkel moet word om hierdie beperkinge aan te spreek. Amplikon kruiskontaminasie kan n groot impak hê op die betroubaarheid van enige genotipiese diagnostiese toets. Die finale stappe van MTBDRplus toets behels die gebruik van 'n oop sisteem sodat kontaminasie maklik kan plaasvind. In die 4de doewit 'n konsep vir 'n patenteerbare geslotebuis toestel ontwikkel en die resultate het getoon dat kontaminasie suksesvol uitgeskakel kan word. Hierdie toestel kan verbeter na 'n outomatiese apparaat verbeter word sodat die module genotipering van verskeie monsters moontlik kan maak. Die resultate van hierdie studie beklemtoon die noodsaaklikheid van 'n sensitiewe goedkoop “point of care” diagnostiese toets wat nie intensiewe opleiding benodig nie. / Medical Research Council of South Africa / University of Stellenbosch, Dept. of Molecular Biology and Human Genetics

L'imagerie par résonance magnétique de diffusion (l'IRMd) est actuellement la seule technique non-invasive pour étudier l'architecture tridimensionnelle des fibres myocardiques du cœur humain à la fois ex vivo et in vivo. Cependant, il est difficile de savoir comment les caractéristiques de diffusion calculées à partir des images de diffusion reflètent les propriétés des microstructures du myocarde à cause de l'absence de la vérité-terrain sans parler de l'influence de divers facteurs tels que la résolution spatiale, le bruit et les artéfacts. L'objectif principal de cette thèse est donc de développer des simulateurs de l'IRM de diffusion basés sur des modèles réalistes afin de simuler, en intégrant différentes modalités d'imagerie, les images pondérées en diffusion des fibres myocardiques à la fois ex vivo et in vivo, et de proposer un outil générique permettant d'évaluer la qualité de l'imagerie et les algorithmes de traitement d'images. Pour atteindre cet objectif, le présent travail se focalise sur quatre parties principales. La première partie concerne la formulation de la théorie de simulation IRMd pour la génération d'images de diffusion et pour les applications sur les modèles simples de fibres cardiaques chez l'homme, et essaie de comprendre la relation sous-jacente entre les propriétés mesurées de la diffusion et les caractéristiques à la fois physiques et structurelles des fibres cardiaques. La seconde partie porte sur la simulation des images de résonance magnétique de diffusion à différentes échelles en s'appuyant sur des données du cœur humain issues de l'imagerie par lumière polarisée. En comparant les propriétés de diffusion à différentes échelles, la relation entre la variation de la microstructure et les propriétés de diffusion observée à l'échelle macroscopique est étudiée. La troisième partie consacre à l'analyse de l'influence des paramètres d'imagerie sur les propriétés de diffusion en utilisant une théorie de simulation améliorée. La dernière partie a pour objectif de modéliser la structure des fibres cardiaques in vivo et de simuler les images de diffusion correspondantes en combinant la structure des fibres cardiaques et le mouvement cardiaque connu a priori. Les simulateurs proposés nous fournissent un outil générique pour générer des images de diffusion simulées qui peuvent être utilisées pour évaluer les algorithmes de traitement d'images, pour optimiser le choix des paramètres d'IRM pour les fibres cardiaque aussi bien ex vivo que in vivo, et pour étudier la relation entre la structure de fibres microscopique et les propriétés de diffusion macroscopiques.

<p>Uvod: Iz rezultata brojnih randomiziranih kliničkih studija proizi&scaron;le su smernice u koijma se navodi da je upotreba neinvazivne ventilacije (NIV), uz farmakolo&scaron;ku terapiju, indikovana kod svih bolesnika sa te&scaron;kom egzacerbacijom hronične opstruktivne bolesti pluća (HOBP), i to sa najvi&scaron;im nivoom preporuke. Dokazano je da se upotrebom NIV-a smanjuje broj intubacija, uz smanjenje mortaliteta ali i skraćenje dužine bolničkog lečenja. S obzirom da je nekada ventilatorna potpora bila pružana isključivo u jedinicama intenzivne nege, a da je kapacitet ovakvih odeljenja gotovo stalno popunjen, postavlja se pitanje adekvatnog okruženja unutar bolnice gde se bezbedno i efikasno može primeniti neinvazivna ventilacija, ali gde se i na vreme mogu prepoznati rani znakovi njene neuspe&scaron;ne primene, nakon čega trebaobezbediti pravovremenu endotrahealnu intubaciju. Stoga su rađene brojne studije u cilju izdvajanja ranih prediktora ishoda neinvazivne ventilacije - kako u cilju ranog prepoznavanja neuspeha NIV-a i omogućavanja pravovremene intubacije, tako i u cilju stratifikacije pacijenata sa različitim stepenom rizika za neuspeh, uz obezbeđivanje adekvatnog nivoa nege i monitoringa za sve bolesnike. Ciljevi: Ciljevi istraživanja su da se utvrdi koji pokazatelji koreliraju sa neuspe&scaron;nim ishodom primene neinvazivne mehaničke ventilacije kod bolesnika sa te&scaron;kom egzacerbacijom hronične opstruktivne bolesti pluća, kako bi se kreirao prognostički model ishoda lečenja, te da se se na osnovu prognostičkog modela stratifikuju bolesnici prema stepenu rizika za neuspeh NIV-a i u skladu sa njim predloži adekvatan stepen monitoringa, odnosno kliničko okruženje za bezbedno i efikasno pružanje ventilatorne potpore. Metodologija: U Institutu za plućne bolesti Vojvodine u Sremskoj Kamenici sprovedeno je prospektivno opservaciono istraživanje u trajanju od 39 meseci, u koje je uključeno 250 konsekutivnih bolesnika hospitalizovanih zbog te&scaron;ke egzacerbacije HOBP-a sa respiratornom acidozom. NIV je primenjen u modu pritiskom podržane ventilacije ventilatorima marke Covidien tipa Airox Supportair, uz upotrebu oronazalne maske. Početni parametri su podrazumevali upotrebu ekspiratornog pozitivnog pritiska u disajnim putevima - EPAP-a od 5 cm H2O i inspiratornog pozitivnog pritiska u disajnim putevima IPAPa od 12 cm H20, koji su u potom titrirani ka ciljnim vrednostima IPAPa od 15-20 cmH2O, a u skladu sa kliničkim odgovorom. Za svakog bolesnika evidentirani su: pol, starost, ranija primena dugotrajne oksigenoterapije u kućnim uslovima, primena NIV-a tokom prethodnih hospitalizacija, komorbiditeti preko Charlson indeksa, vreme proteklo od početka hospitalizacije do započinjanja NIV-a, vrednosti pH, bikarbonata, PaCO2 i PaO2 u gasnim analizama arterijske krvi pre započinjanja NIV-a, inicijalna SpO2 i odnos PaO2/FiO2, zatim promena vrednosti pH, PaCO2 i PaO2 u gasnim analizama arterijske krvi sat vremena nakon početka primene NIV-a, inicijalni vitalni parametri - srčana frekvenca, respiratorna frekvenca, stanje svesti procenjeno Glazgov koma skalom (GCS), telesna temperatura, sistolni arterijski pritisak, diureza, a potom zbirni modifikovani ranoupozoravajući bodovni skor (MEWS-modified early warning score), prisustvo i opseg konsolidacija na radiogramu grudnog ko&scaron;a, saradnja bolesnika, te mesto primene NIV-a. Kao primarni ishod istraživanja definisan je neuspeh neinvazivne mehaničke ventilacije: intubacija ili smrtni ishod u toku hospitalizacije uzrokovan respiratornom insuficijencijom. Svaki potencijalni prediktor neuspeha je prvo evaluiran uz pomoć univarijantne analize, a potom su svi faktori rizika za koje je univarijantnom analizom utvrdjena statistička značajnost analizirani uz pomoć multivarijantne logističke regresije, u cilju utvrdjivanja adekvatnih statističkih modela. Rezultati: Od ukupno 250 bolesnika NIV je uspe&scaron;no primenjen kod 164 bolesnika (65.6%). Ukupno 139 (59.3%) bolesnika bilo je mu&scaron;kog pola, a prosečna starost svih ispitanika bila je 67 godina. Bolesnici sa neuspe&scaron;nim ishodom NIV-a imaju, prema univarijantnoj analizi: statistički značajno veće vrednosti Charlson indexa (p=0.002, OR 1.293, 95%CI 1.103-1.516), konsolidacije u &ge;2 kvadranata (p=0.000, OR 5.384, 95%CI 2.487-11.655), duže vreme od početka hospitalizacije do započinjanja NIV-a (p=0.0034, OR 1.005, 95%CI 1.000-1.009), tahikardiju (p=0.031, OR 2.292, 95%CI 1.080-4.864), vrednost GCS &le;11 (p=0.042, OR 1.000, 95%CI 0.165-0.969), veći MEWS skor (p=0.000, OR 1.708, 95%CI 1.410-2.068), niže vrednosti inicijalnog pH (p=0.004, OR 0.002, 95%CI 0.000-0.147), slabiju saradnju (p=0.000, OR 2.102, 95%CI 0.145-0.339). Mesto gde je sprovedena NIV je značajno uticalo na ishod &ndash; &scaron;anse za neuspe&scaron;an ishod su bile dvostruko veće kod bolesnika ventiliranih na op&scaron;tem odeljenju (p=0.006, OR 2.102, 95%CI 1.236-3.574). Kao nezavisni prediktori neuspeha nakon multivarijantne logističke regresije pokazali su se vrednosti Charlson-ovog indexa (p=0.043, OR 1.246, 95%CI 1.007-1.541), MEWS skora (p=0.010, OR 1.394, 95%CI 1.083-1.795), inicijalne vrednosti pH (p=0.030, OR 0.642, 95%CI 0.430-0.958) i stepena saradnje (p=0.000, OR 0.230, 95%CI 0.141-0.376). Zaključci: Bolesnici sa visokim vrednostima Charlson-ovog indeksa (preko 6 bodova) i MEWS-ovog skora (preko 4 boda), te niskom inicijalnom pH vredno&scaron;ću arterijske krvi (ispod 7.29) i niskim stepenom saradnje (manjim od 4) su bolesnici koji imaju povi&scaron;en stepen rizika za neuspe&scaron;an ishod primene neinvazivne ventilacije. Bolesnici visokog stepena rizika treba da se zbrinjavaju i neinvazivno ventiliraju na odeljenjima poluintenzivne i intenzivne nege, dok se bolesnici sa manjim stepenom rizika mogu inicijalno neinvazivno ventilirati i na op&scaron;tim odeljenjima, uz adekvatan monitoring i nadzor obučenog osoblja.</p> / <p>Introduction: Clinical guidelines that have evolved from the results of numerous randomized clinical trials state that the use of non-invasive ventilation (NIV), in addition to pharmacological therapy, is necessary in all patients wih severe exacerbation of chronic obstructive pulmonary disease (COPD) - at the highest level of recommendation. It has been proven that the use of NIV leeds to reduction in mortality, intubation rates, and the length of stay in hospitals. Since ventilatory support in past was only delivered in intensive care units, and bearing in mind that their capacities are limited, there is a question of an adequate setting within a hospital where NIV can be used safely and efficiently, and where potential early signs of failure will be timely recognized and patient intubated, if necessary. Consequently, the studies were performed in order to identify early predictors of NIV outcome &ndash; in order to recognize NIV failure and necessity for transition towards invasive ventilation, but also in order to stratify the patients according to the level of risk, which will then dictate the necessary level of care and monitoring. Goals: This research is aimed at identification of parameters that correlate with failure of non-invasive ventilation in patients with severe exacerbation of COPD, in order to create prognostic model of outcome, which will then enable stratification of patients according to the risk of NIV failure. The model is to be used in order to determine adequate level of care and monitoring, that is, a setting within a hospital, for provision of efficent and safe ventilatory support for all patients. Methods: This 39-month prospective observational study was performed at the Institute for Pulmonary Diseases of Vojvodina in Sremska Kamenica, which included 250 consecutive patients hospitalized due to severe exacerbation of COPD with respiratory acidosis. NIV was applied as pressure support mode of ventilation with the ventilators brand Covidien, type Airox Supportair, with oro-nasal mask. Initial parameters were: expiratory positive airway pressure &ndash; EPAPof 5 cm H2O and inspiratory positive airway pressure - IPAP of 12 cm H20, which were further adjusted towards the IPAP of 15-20 cmH2O, or according to the clinical response. The following data were recorded for each patient: sex, age, earlier longterm oxygen therapy, NIV episode during the previous hospitalizations, co-morbidities through Charlson index, time elapsed from admission to NIV initiation, initial blood gas values: pH, bicarbonates, PaCO2 and PaO2, initial SpO2 and PaO2/FiO2, the subsequent changes inthe blood gas values after one hour: pH, PaCO2 and PaO2, initial vital signs - heart rate, respiratory rate, consciousness level by Glasgow coma scale (GCS), body temperature, sistolic blood pressure, urine output, and then modified early warning score - MEWS, presence of consolidation on chest X-ray, tolerance, setting where NIV was applied. Primary outcome was NIV failure defined as endotracheal intubation or death during hospitalization caused by respiratory failure. All variables were first tested with univariate analysis, and those with statistical significance were further subjected to multivariate logistic regression, in order to generate an adequate statistical model. Results: Amongst the total of 250 patients, NIV was successfully applied in 164 patients (65.6 %). There were 139 (59.3%) male patients, and average age was 67. According to the univariate analysis, patients with NIV failure had: higher Charlson index (p=0.002, OR 1.293, 95%CI 1.103-1.516), consolidation in &ge;2 quadrants (p=0.000, OR 5.384, 95%CI 2.487-11.655), longer time from admission to NIV initiation (p=0.0034, OR 1.005, 95%CI 1.000-1.009), increased heart rate (p=0.031, OR 2.292, 95%CI 1.080-4.864), GCS &le;11 (p=0.042, OR 1.000, 95%CI 0.165-0.969), higher MEWS score (p=0.000, OR 1.708, 95%CI 1.410-2.068), lower initial pH (p=0.004, OR 0.002, 95%CI 0.000-0.147), poorer tolerance (p=0.000, OR 2.102, 95%CI 0.145-0.339). The setting were NIV was applied influenced the outcome &ndash; odds for NIV failure were twice as high for the patients on general wards (p=0.006, OR 2.102, 95%CI 1.236-3.574). After the multivariate logistic regression, the following variables were identified as independent predictors of outcome: Charlson index (p=0.043, OR 1.246, 95%CI 1.007- 1.541), MEWS score (p=0.010, OR 1.394, 95%CI 1.083-1.795), initial pH (p=0.030, OR 0.642, 95%CI 0.430-0.958) and tolerance (p=0.000, OR 0.230, 95%CI 0.141-0.376). Conclusions: Patients with higher Charlson index (&gt; 6 points) and MEWS score (&gt;4 points), lower initial pH (&lt;7.29) and tolerance (&lt;4) are at a higher risk for nonivasive ventilation failure. High-risk patients should be admitted and ventilated at high dependency or intensive care units, while the low-risk patients may receive non-invasive ventilatory support on general wards, with adequate monitoring and under the trained staff supervision.</p>

<p>Uvod: Tematika ove doktorske teze, usmerena je na analizu respiratornih poremećaja tokom spavanja, uzimajući u obzir činjenicu da se većina trudnica žali na poremećaje u ovoj sferi. Akcenti na ovom polju, odnose se na identifikaciju ovih patolo&scaron;kih stanja u trudnoći. Zato se ovi poremećaji moraju posmatrati integrisano sa rizičnim trudnoćama, ne samo kao njihovi pratioci, već najverovatnije i uzročnici i bitni činioci.<br />Cilj istraživanja: Cilj nam je bio da ukažemo na neophodnost primene neinvazivne ventilacije kod selektovane grupe trudnica, koja ima poremećeno disanje tokom spavanja, prema praktičnom kliničkom protokolu koji će, nadamo se, proisteći iz ovog istraživanja<br />Metodologija: Istraživanje je sprovedeno u formi prospektivne studije, na Klinici za ginekologiju i aku&scaron;erstvo, Kliničkog centra Vojvodine i u Centru za medicinu sna, Instituta za plućne bolesti Vojvodine, u periodu: od maja 2009. do juna 2011 godine.i obuhvatilo je finalno 110 trudnica. Studija je po tipu bila kohortna i eksperimentalna, po&scaron;to je identifikovala ispitanice na osnovu prisustva određenog faktora (SDB) i uticaj prisustva, odnosno odsustva predložene terapijske intervencije na tok i ishod trudnoće.<br />Rezultati:<br />- Respiratorni poremećaji tokom spavanja (SDB) su većinom tranzitornog karaktera tokom trudnoće, bez razlike između rizičnih trudnoća i onih uobičajenog toka;<br />- SDB tokom rizičnih trudnoća, uop&scaron;teno gledano, negativno utiču na tok i ishod istih;<br />- Primenom neinvazivne ventilacije (NIV), postiže se signifikatno smanjenje dnevne pospanosti (mereno sa ESS) i pobolj&scaron;anje oksigenacije, te redukcija kardiovaskularnih i metaboličkih komplikacija bez statistički značajne razlike sa i bez NIV-a;<br />- Trudnice lečene sa NIV (grupa 1) imaju duže trajanje gestacije u odnosu na nelečene (grupa 2) bez statistički značajne razlike;<br />- Rezultati Apgar-skora takođe su vi&scaron;ih vrednosti kod grupe 1 u odnosu na grupu 2 (bez NIV-a) bez statistički značajne razlike;<br />- Nije zabeležena statistički značajna razlika telesne mase novorođenčadi između grupe 1 i grupe 2, kao ni kod obe grupe u odnosu na kontrolnu (grupu 3);<br />- Pojava hipertenzivnog sindroma u grupama 1 i 2 je bez signifikantne razlike iako je manje trudnica imalo ovaj sindrom u grupi 1;<br />- Prisustvo SDB nije uticalo na način zavr&scaron;etka porođaja u svim ispitivanim grupama, ali su rizične trudnoće če&scaron;će zavr&scaron;avane operativnim putem.<br />Zaključak: Naučna opravdanost disertacije, ogleda se u tome, da se po prvi put, na na&scaron;im prostorima, uvođenjem neinvazivne ventilacije, kod pacijentkinja sa rizičnim trudnoćama, utiče na parametre perinatalnog ishoda i bolje zdravstveno stanje trudnica i njihovih novorođenčadi. Velika ekspanzija naučnog istraživanja u vodećim svetskim centrima o ovoj problematici, a imajući u vidu izražen trend negativnog prirodnog prira&scaron;taja u na&scaron;oj sredini, navela nas je na neophodnost re&scaron;avanja ovog problema na domaćem terenu, kao jednom od prioriteta u naučno-istraživačkom radu i praktičnom medicinskom delovanju.</p> / <p>Background: The theme of this thesis is focused on the analysis of respiratory disorders during sleep, since most pregnant women complain of sleep disturbances. The goal is to identify pathological respiratory disorders in pregnancy, considering them an integral part of high risk pregnancy, being most likely a cause of some of them, not only a side effect.<br />Objective: The aim of the study was to point out the necessity of application of non-invasive ventilation in selected pregnant women who have disrupted breathing during sleep. Based on the results of this research, a clinical protocol is developed.<br />Method: The research was conducted in the form of prospective studies in the Department of Gynecology and Obstetrics, Clinical Center and the Center for sleep medicine, Institute for Pulmonary Diseases of Vojvodina, in the period from May 2009 through June 2011 godine.U covered the final 110 pregnant women. The study by the type of the cohort and experimental, as the respondent identified by the presence of certain factors (SDB) and the effect of the presence or the absence of the proposed therapeutic interventions on the course and outcome of pregnancy.<br />Results:<br />- respiratory disorders during sleep (SDB) are mostly transitory nature during pregnancy, with no difference between risk pregnancies and those ordinary course;<br />- SDB during high-risk pregnancies, in general, negatively affect the course and outcome of the same;<br />- Application of non-invasive ventilation (NIV), achieved statistical significance reduce daytime sleepiness (measured with the ESS) and improve oxygenation and reduce cardiovascular and metabolic complications with no statistically significant differences with and without NIV;<br />- Pregnant women treated with NIV (group 1) have a longer duration of gestation compared to untreated (Group 2) with no statistically significant differences;<br />- Results Apgar-score values were also higher in group 1 compared to group 2 (without NIV) with no statistically significant differences;<br />- Not statistically significant difference in body weight between newborns Group 1 and Group 2, or in both groups compared to the control group (group 3);<br />- The emergence of hypertensive syndrome in groups 1 and 2 is no significant difference although less of pregnant women have this syndrome in group 1;<br />- The presence of SDB did not affect the ending of delivery in all groups, but risk pregnancies often ends with surgically.&nbsp;</p><p>Conclusion: For the first time in the region, non-invasive ventilation in patients with high-risk pregnancies is introduced, which will influence perinatal outcomes and improve health of pregnant women and their newborns. Since there is a negative trend of natural population increase in Serbia, new scientific developments in this field enable better medical care, as one of the priorities of scientific research.</p>

Particle-based films are today an important part of various designs and they are implemented in structures as conductive parts, i.e., conductive paste printing in the manufacture of Li-ion batteries, solar cells or resistive paste printing in IC. Recently, particle based films were also implemented in the 3D printing technique, and are particularly important for use in aircraft, wind power, and the automotive industry when incorporated onto the surface of composite structures for protection against damages caused by a lightning strike. A crucial issue for the lightning protection area is to realize films with high homogeneity of electrical resistance where an in-situ noninvasive method has to be elaborated for quality monitoring to avoid undesirable financial and time costs. In this work the drying process of particle based films was investigated by high-frequency eddy current (HFEC) spectroscopy in order to work out an automated in-situ quality monitoring method with a focus on the electrical resistance of the films. Different types of particle based films deposited on dielectric and carbon fiber reinforced plastic substrates were investigated in the present study and results show that the HFEC method offers a good opportunity to monitor the overall drying process of particle based films. Based on that, an algorithm was developed, allowing prediction of the final electrical resistance of the particle based films throughout the drying process, and was successfully implemented in a prototype system based on the EddyCus® HFEC device platform presented in this work. This prototype is the first solution for a portable system allowing HFEC measurement on huge and uneven surfaces.