Utilizou-se um modelo de escolha discreta (MED) para avaliar as preferências e disposição-a-pagar (DAP) dos pacientes por diferentes atributos de risco-benefício do tratamento insulínico, entre eles a via de administração da insulina. Através de uma revisão da literatura, consulta com especialistas, e do desenvolvimento de um estudo qualitativo utilizando as técnicas de entrevistas individuais e grupos focais, os atributos (e níveis) mais importantes do tratamento insulínico foram identificados, sob o ponto de vista dos pacientes. Os atributos incluídos no MED foram: controle da glicemia de jejum, número de episódios de hipoglicemia, ganho de peso, via de administração para as insulinas de ação longa e rápida, e custo do tratamento. Pares de opções de tratamentos insulínicos hipotéticos contendo diferentes níveis dos atributos foram apresentados aos pacientes com DM1 ou DM2, e lhes foi solicitado que, para cada cenário, eles escolhessem a alternativa de sua preferência. Dados demográficos, nível sócio-econômico (NSE) e informações relacionadas ao diabetes também foram coletados. Para a análise dos dados utilizou-se um modelo logit condicional de regressão e modelos segmentados foram posteriormente utilizados para a análise das sub-populações. Um total de 274 questionários foram incluídos na análise final dos dados. A idade média (± DP) dos participantes foi de 56.7 ± 12.98 anos, e 53% eram homens. Quarenta e nove por cento dos participantes eram usuários de insulina e 47 eram portadores de DM1. O tratamento insulínico ideal, sob o ponto de vista dos pacientes, resultaria em um melhor controle glicêmico, menos reações adversas, menor custo, e seria administrado por via oral. Houve uma forte preferência e uma DAP mais elevada por um melhor controle glicêmico, seguido pelos atributos de risco ganho de peso e episódios de hipoglicemia. Surpreendentemente, a via de administração da insulina foi o atributo menos valorizado. A estratificação social revelou que pacientes com alta renda anual familiar apresentaram uma DAP mais elevada por um melhor controle glicêmico e por menos reações adversas em relação aos grupos com rendas inferiores. Ainda, quanto mais alto o nível de renda, maior o desejo por uma insulina oral, enquanto a via inalada torna-se menos importante para os pacientes. A estratificação da amostra pelo uso de insulina e tipo de diabetes revelaram uma forte aversão pela via subcutânea pelos não-usuários de insulina e pacientes com DM2. Tais resultados sugerem a existência de uma importante barreira psicológica em se iniciar uso da insulina; no entanto, os resultados também revelam que os pacientes tendem a se acomodar com a via subcutânea uma vez iniciado o tratamento insulínico. Este estudo demonstra a importância que os pacientes com DM atribuem ao atributo controle glicêmico, e como suas preferências e DAP pelo tratamento insulínico variam entre as sub-populações. Especificamente, esforços devem ser realizados no sentido de vencer a barreira psicológica em se iniciar o uso da insulina, o que contribuirá para que se alcance um melhor controle glicêmico, através da melhor aderência do paciente ao tratamento, resultando em uma redução dos custos do DM e melhora na qualidade de vida dos pacientes. / We used a discrete choice experiment (DCE) to evaluate patients preferences for various attributes of insulin treatment, including route of insulin delivery. Through a review of the literature, expert consultation, and a qualitative descriptive study using individual interviews and focus group techniques, the attributes (and levels) of diabetes treatment most important to patients were identified. The attributes included in the DCE were: glucose control, frequency of hypoglycaemic events, weight gain, route of administration for the long-acting and the short-acting insulin, and out-of-pocket cost. Patients with type 1 or type 2 diabetes were presented with pairs of hypothetical insulin therapy profiles (i.e. choice sets) with different levels of the attributes and were asked to choose the treatment option they preferred. Sociodemographic data and diabetes medication were also collected. Data were analysed using conditional logit regression and segmented models were also developed for the analysis of subgroups. A Two hundred and seventy four questionnaires were completed. The mean age (±SD) of participants was 56.7 ± 12.98 years, and 53% were men. Forty-nine percent of participants were insulin users, and 47 had type 1 diabetes. Overall, patients ideal insulin treatment would provide better glucose control, result in fewer adverse reactions, have the lowest cost, and be administered orally. There was a strong preference and highest mean WTP for glucose control followed by the risk attributes weight gain and hypoglycaemic events. Surprisingly, route of insulin administration was the least valued attribute. Stratification of the sample revealed that patients with higher incomes had a significant higher WTP for better glucose control and less adverse reactions compared to lower income groups. Moreover, the highest the income, the stronger the preference for an oral insulin, while inhaled insulin becomes less important for patients. Segmented models by insulin use and type of diabetes indicated that insulin naïve and type 2 diabetics had a greater aversion to the subcutaneous route. These findings suggest that there may be an important mental barrier to initiating insulin therapy; however, patients tend to accommodate to subcutaneous administration once they initiate therapy. This study illustrates the importance that patients with diabetes place on glucose control and how preferences for insulin therapy vary between subgroups. Specifically, efforts need to be made to overcome the mental barrier to initiating insulin therapy, which may lead to improved control, through improved compliance and ultimately reduce the financial burden of the disease and improve patients quality of life.

La séquence d’IRM de perfusion pondérée T1 après injection de Gadolinium (Gd), appelée dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) fait partie du protocole d’IRM multiparamétrique (IRM-mp) réalisée pour le bilan d’extension du cancer prostatique (CaP). Le rationnel pour l’utilisation de cette séquence est d’une part le rôle capital de la néoangiogénèse dans le développement et la dissémination du CaP et d’autre part la possibilité d’imager l’angiogénèse in vivo et de façon non invasive. L’analyse quantitative nécessite un post-traitement multi-étapes complexe, dont le principe repose sur la modélisation pharmacocinétique (PC) de la biodistrubtion du Gd. Elle permet de calculer des paramètres PC reflétant la perméabilité capillaire et/ou la perfusion. Dans le CaP, ces paramètres PC ont montré leur potentiel pour évaluer l’agressivité tumorale, le pronostic, l’efficacité d’un traitement et/ou pour déterminer la dose efficace d’une nouvelle molécule anti-angiogéniques ou antivasculaires en cours de développement. Néanmoins, ils manquent de reproductibilité, notamment du fait des différentes techniques de quantifications utilisées par les logiciels de post-traitement.Nous avons développé au sein du laboratoire un outil de quantification capable de calculer une cartographie T1(0) à partir de la méthode des angles de bascule variables, nécessaire pour convertir les courbes du signal en courbe de concentration du Gd (Ct); de déterminer la fonction d’entrée artérielle (AIF – arterial input function) dans l’artère fémorale (Indivuduelle – Ind) ou lorsque cela n’était pas possible, d’utiliser une AIF issue de la littérature, telle que celle de Weinmann (W) ou de Fritz-Hansen (FH) ; et d’utiliser deux modèles PC, celui de Tofts et celui de Tofts modifié. Le logiciel a été validé sur des données simulées et sur une petite série clinique.Nous avons ensuite étudié l’impact du choix de la fonction d’entrée artériel sur les paramètres PC et notamment sur leur capacité à distinguer le CaP du tissu sain. 38 patients avec un CaP (>0,5cc) de la zone périphérique (ZP) ont été rétrospectivement inclus. Chaque patient avait bénéficié d’une IRM-mp sur laquelle deux régions d’intérêt (RI) : une tumorale et une bénigne ont été sélectionnées en utilisant une corrélation avec des cartes histo-morphométriques obtenues après prostatectomie radicale. En utilisant trois logiciels d’analyse quantitative différents, les valeurs moyennes de Ktrans (constante de transfert), ve (fraction du volume interstitiel) and vp (fraction du volume plasmatique) dans les RI ont été calculées avec trois AIF différentes (AIF Ind, AIF de W et AIF de FH). Ktrans était le paramètre PC qui permettait de mieux distinguer le CaP du tissu sain et ses valeurs étaient significativement supérieures dans le CaP, quelque soit l’AIF ou le logiciel. L’AIF de W donnait des aires sous les courbes ROC (Receiver Operating Characteristic) significativement plus grandes que l’AIF de FH (0.002≤p≤0.045) et plus grandes ou égales à l’AIF Ind (0.014≤p≤0.9). L’AIF Ind et de FH avaient des aires sous les courbes ROC comparables (0.34≤p≤0.81). Nous avons donc montré que les valeurs de Ktrans et sa capacité à distinguer CaP du tissu sain variaient significativement avec le choix de l’AIF et que les meilleures performances étaient obtenues avec l’AIF de W. / Dynamic contrast enhanced (DCE)-MRI is a T1 weighted sequence performed before, during and after a bolus injection of a contrast agent (CA). It is included in the multi-parametric prostate MRI (mp-MRI) protocol using to assess the extent of prostate cancer (PCa). The rationale for using DCE-MRI in PCa is that on one hand angiogenesis has been shown to play a central role in the PCa development and metastasis and on the other hand that DCE-MRI is a non invasive method able to depict this angiogenesis in vivo. The quantitative analysis of DCE-MRI data is a complex and multi-step process. The principle is to use a pharmacokinetic (PK) model reflecting the theoretical distribution of the CA in a tissue to extract PK parameters that describe the perfusion and capillary permeability. These parameters are of growing interest, especially in the field of oncology, for their use in assessing the aggressiveness, the prognosis and the efficacy of anti-angiogenic or anti-vascular treatments. The potential utility of these parameters is significant; however, the parameters often lack reproducibility, particularly between different quantitative analysis software programs.Firstly, we developed a quantitative analysis software solution using the variable flip angle method to estimate the T1 mapping which is needed to convert the signal-time curves to CA concentration-time curves; using three different arterial input functions (AIF): an individual AIF (Ind) measured manually in a large artery, and two literature population average AIFs of Weinmann (W) and of Fritz-Hansen (FH); and using two PK models (Tofts and modified Tofts). The robustness of the software programs was assessed on synthetic DCE-MRI data set and on a clinical DCE-MRI data set. Secondly, we assessed the impact of the AIF selection on the PK parameters to distinguish PCa from benign tissue. 38 patients with clinically important peripheral PCa (≥0.5cc) were retrospectively included. These patients underwent 1.5T multiparametric prostate MR with PCa and benign regions of interest (ROI) selected using a visual registration with morphometric reconstruction obtained from radical prostatectomy. Using three pharmacokinetic (PK) analysis software programs, the mean Ktrans, ve and vp of ROIs were computed using three AIFs: Ind-AIF, W-AIF and FH-AIF. The Ktrans provided higher area under the receiver operating characteristic curves (AUROCC) than ve and vp. The Ktrans was significantly higher in the PCa ROIs than in the benign ROIs. AUROCCs obtained with W-AIF were significantly higher than FH-AIF (0.002≤p≤0.045) and similar to or higher than Ind-AIF (0.014≤p≤0.9). Ind-AIF and FH-AIF provided similar AUROCC (0.34≤p≤0.81).We have then demonstrated that the selection of AIF can modify the capacity of the PK parameter Ktrans to distinguish PCa from benign tissue and that W-AIF yielded a similar or higher performance than Ind-AIF and a higher performance than FH-AIF.

<p>Soil bottles and soil slurry experiments were conducted to investigate the effect of some additives on the aerobic and anaerobic biodegradation of chlorinated aliphatic hydrocarbons; tetrachloroethylene (PCE), trichloroethylene (TCE) and dichloroethylene (DCE) in a contaminated soil from Startvätten AB Linköping Sweden. For the aerobic degradation study the soil sample was divided into two groups, one was fertilised. The two groups of soil in the experimental bottles were treated to varying amount of methane in pairs. DCE and TCE were added to all samples while PCE was found in the contaminated soil. Both aerobic and anaerobic experiments were conducted. For aerobic study air was added to all bottles to serve as electron acceptor (oxygen). It was observed that all the samples showed a very small amount of methane consumption while the fertilised soil samples showed more oxygen consumption. For the chlorinated compounds the expected degradation could not be ascertained since the control and experimental set up were more or less the same.</p><p>For the anaerobic biodegradation study soil slurry was made with different media i.e. basic mineral medium (BM), BM and an organic compound (lactate), water and sulphide, phosphate buffer and sulphide and phosphate buffer, sulphide and ammonia. To assure anaerobic conditions, the headspace in the experimental bottles was changed to N2/CO2. As for the aerobic study all the samples were added DCE and TCE while PCE was found in the contaminated soil. The sample without the soil i.e. the control was also given PCE. It was observed that there was no clear decrease in the GC peak area of the pollutants in the different media. The decrease in GC peak area of the pollutants could not be seen, this may be so because more susceptible microorganisms are required, stringent addition of nutrients and to lower the risk of the high concentration of PCE and petroleum products in the soil from Startvätten AB.</p>

Soil bottles and soil slurry experiments were conducted to investigate the effect of some additives on the aerobic and anaerobic biodegradation of chlorinated aliphatic hydrocarbons; tetrachloroethylene (PCE), trichloroethylene (TCE) and dichloroethylene (DCE) in a contaminated soil from Startvätten AB Linköping Sweden. For the aerobic degradation study the soil sample was divided into two groups, one was fertilised. The two groups of soil in the experimental bottles were treated to varying amount of methane in pairs. DCE and TCE were added to all samples while PCE was found in the contaminated soil. Both aerobic and anaerobic experiments were conducted. For aerobic study air was added to all bottles to serve as electron acceptor (oxygen). It was observed that all the samples showed a very small amount of methane consumption while the fertilised soil samples showed more oxygen consumption. For the chlorinated compounds the expected degradation could not be ascertained since the control and experimental set up were more or less the same. For the anaerobic biodegradation study soil slurry was made with different media i.e. basic mineral medium (BM), BM and an organic compound (lactate), water and sulphide, phosphate buffer and sulphide and phosphate buffer, sulphide and ammonia. To assure anaerobic conditions, the headspace in the experimental bottles was changed to N2/CO2. As for the aerobic study all the samples were added DCE and TCE while PCE was found in the contaminated soil. The sample without the soil i.e. the control was also given PCE. It was observed that there was no clear decrease in the GC peak area of the pollutants in the different media. The decrease in GC peak area of the pollutants could not be seen, this may be so because more susceptible microorganisms are required, stringent addition of nutrients and to lower the risk of the high concentration of PCE and petroleum products in the soil from Startvätten AB.

Utilizou-se um modelo de escolha discreta (MED) para avaliar as preferências e disposição-a-pagar (DAP) dos pacientes por diferentes atributos de risco-benefício do tratamento insulínico, entre eles a via de administração da insulina. Através de uma revisão da literatura, consulta com especialistas, e do desenvolvimento de um estudo qualitativo utilizando as técnicas de entrevistas individuais e grupos focais, os atributos (e níveis) mais importantes do tratamento insulínico foram identificados, sob o ponto de vista dos pacientes. Os atributos incluídos no MED foram: controle da glicemia de jejum, número de episódios de hipoglicemia, ganho de peso, via de administração para as insulinas de ação longa e rápida, e custo do tratamento. Pares de opções de tratamentos insulínicos hipotéticos contendo diferentes níveis dos atributos foram apresentados aos pacientes com DM1 ou DM2, e lhes foi solicitado que, para cada cenário, eles escolhessem a alternativa de sua preferência. Dados demográficos, nível sócio-econômico (NSE) e informações relacionadas ao diabetes também foram coletados. Para a análise dos dados utilizou-se um modelo logit condicional de regressão e modelos segmentados foram posteriormente utilizados para a análise das sub-populações. Um total de 274 questionários foram incluídos na análise final dos dados. A idade média (± DP) dos participantes foi de 56.7 ± 12.98 anos, e 53% eram homens. Quarenta e nove por cento dos participantes eram usuários de insulina e 47 eram portadores de DM1. O tratamento insulínico ideal, sob o ponto de vista dos pacientes, resultaria em um melhor controle glicêmico, menos reações adversas, menor custo, e seria administrado por via oral. Houve uma forte preferência e uma DAP mais elevada por um melhor controle glicêmico, seguido pelos atributos de risco ganho de peso e episódios de hipoglicemia. Surpreendentemente, a via de administração da insulina foi o atributo menos valorizado. A estratificação social revelou que pacientes com alta renda anual familiar apresentaram uma DAP mais elevada por um melhor controle glicêmico e por menos reações adversas em relação aos grupos com rendas inferiores. Ainda, quanto mais alto o nível de renda, maior o desejo por uma insulina oral, enquanto a via inalada torna-se menos importante para os pacientes. A estratificação da amostra pelo uso de insulina e tipo de diabetes revelaram uma forte aversão pela via subcutânea pelos não-usuários de insulina e pacientes com DM2. Tais resultados sugerem a existência de uma importante barreira psicológica em se iniciar uso da insulina; no entanto, os resultados também revelam que os pacientes tendem a se acomodar com a via subcutânea uma vez iniciado o tratamento insulínico. Este estudo demonstra a importância que os pacientes com DM atribuem ao atributo controle glicêmico, e como suas preferências e DAP pelo tratamento insulínico variam entre as sub-populações. Especificamente, esforços devem ser realizados no sentido de vencer a barreira psicológica em se iniciar o uso da insulina, o que contribuirá para que se alcance um melhor controle glicêmico, através da melhor aderência do paciente ao tratamento, resultando em uma redução dos custos do DM e melhora na qualidade de vida dos pacientes. / We used a discrete choice experiment (DCE) to evaluate patients preferences for various attributes of insulin treatment, including route of insulin delivery. Through a review of the literature, expert consultation, and a qualitative descriptive study using individual interviews and focus group techniques, the attributes (and levels) of diabetes treatment most important to patients were identified. The attributes included in the DCE were: glucose control, frequency of hypoglycaemic events, weight gain, route of administration for the long-acting and the short-acting insulin, and out-of-pocket cost. Patients with type 1 or type 2 diabetes were presented with pairs of hypothetical insulin therapy profiles (i.e. choice sets) with different levels of the attributes and were asked to choose the treatment option they preferred. Sociodemographic data and diabetes medication were also collected. Data were analysed using conditional logit regression and segmented models were also developed for the analysis of subgroups. A Two hundred and seventy four questionnaires were completed. The mean age (±SD) of participants was 56.7 ± 12.98 years, and 53% were men. Forty-nine percent of participants were insulin users, and 47 had type 1 diabetes. Overall, patients ideal insulin treatment would provide better glucose control, result in fewer adverse reactions, have the lowest cost, and be administered orally. There was a strong preference and highest mean WTP for glucose control followed by the risk attributes weight gain and hypoglycaemic events. Surprisingly, route of insulin administration was the least valued attribute. Stratification of the sample revealed that patients with higher incomes had a significant higher WTP for better glucose control and less adverse reactions compared to lower income groups. Moreover, the highest the income, the stronger the preference for an oral insulin, while inhaled insulin becomes less important for patients. Segmented models by insulin use and type of diabetes indicated that insulin naïve and type 2 diabetics had a greater aversion to the subcutaneous route. These findings suggest that there may be an important mental barrier to initiating insulin therapy; however, patients tend to accommodate to subcutaneous administration once they initiate therapy. This study illustrates the importance that patients with diabetes place on glucose control and how preferences for insulin therapy vary between subgroups. Specifically, efforts need to be made to overcome the mental barrier to initiating insulin therapy, which may lead to improved control, through improved compliance and ultimately reduce the financial burden of the disease and improve patients quality of life.

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Cette étude cherche à évaluer le Débit de la Filtration Glomérulaire (DFG) dans le rein humain par IRM. L'estimation de ce paramètre quantitatif nécessite le suivi de la cinétique intrarénale de Gd après son injection en bolus. Pour atteindre cet objectif, nous avons développé sous IDEA Siemens une séquence SR-FLASH strictement pondérée en T1 capable de suivre en dynamique l'évolution du signal RMN après l'injection d'un bolus de produit de contraste. Cette séquence possède un codage de phase centré permettant de déterminer le contraste au début de la période d'acquisition de l'image. Nous avons également mis en oeuvre une séquence d'inversion IR-FLASH (avec codage de phase centré) permettant la mesure de la relaxation longitudinale en l'absence de produit de contraste, ce paramètre étant indispensable à la conversion de l'intensité du signal en concentration. Sachant que la relation entre l'intensité du signal RMN et la concentration de Gd n'est pas linéaire, nous avons proposé deux méthodes originales et malgré tout rapides et robustes pour convertir le signal RMN en concentration locale de Gd. Ceci nous a permis d'évaluer l'évolution de la concentration dans les deux reins et dans l'aorte au cours des premiers passages du produit. L'ajustement des ces mesures de concentration sur les équations décrivant une modélisation bicompartimentale de la fonction rénale a permis de calculer le DFG de chaque rein dans une population de cinq sujets possédant un fonctionnement rénal normal. / This study seeks to assess the Glomerular Filtration Rate (GFR) in the human kidney by MRI. To quantitatively estimate this parameter requires monitoring of the intrarenal kinetics of Gd after its bolus injection. To achieve this goal, we have developed under IDEA Siemens a SR-FLASH T1-weighted MRI sequence which can follow dynamic NMR signal changes after a bolus injection of Gd. This sequence has a centric phase-encoding scheme, and thus the image contrast was determined at the beginning of the acquisition period. Subsequently, we have implemented an IR-FLASH (with centric phase-encoding scheme) sequence to measure the longitudinal relaxation time in the absence of any injection of Gd ; this parameter is required to convert NMR signal intensities into Gd concentrations. knowing that the relation between the NMR signal intensities and the Gd concentrations is not linear, we have proposed two novel methods and yet fast and robust for conversion of the NMR signal intensities into local Gd concentration. This allowed us to estimate the temporal evolution of Gd concentrations in both kidneys and aorta. The fit of these concentrations measurements by a two-compartments model describing the function of the kidney allowed us to calculate the GFR of each kidney in a population of five subjects with normal renal function.

This thesis deals with perfusion analysis using DCE-MRI (Dynamic contrast-enhanced magnetic resonance imaging). DCE-MRI is commonly used for microcirculation evaluation mainly in oncology and in recent years also in cardiology. The theoretical overview focuses on the issue of pharmacokinetic modeling and the estimation of perfusion parameters using selected models. The experimental part describes research software PerfLab and then it is aimed at the proposed program for synthetic data generation. Simulated data obtained under ideal conditions and in the presence of noise were used to compare models for the accuracy and reliability of DCE-MRI analysis.

This diploma thesis deals with DCE-MRI (Dynamic Contrast-Enhanced Magnetic Resonance Imaging) thus one of the contrast magnetic resonance imaging methods. It describes the principle of conventional continuous DCE-MRI, which uses single bolus of contrast agent and further it focuses on the dual bolus contrast agent techniques, especially the interleaved acquisition. The graphical interface for processing Bruker systems data was made. Synthetic data were used to evaluate the influence of this method on the perfusion parameters estimation. Simulations proved that the further the second bolus is from the first one, the better results are. Simulations of acquisition interruption did not lead to the clear result. However, two statements, which are expected to lead to as good estimation of perfusion parameters as possible, were formulated

Im Rahmen des Modellierungsseminars wurde die Kopplung einer Strömung mit der Ausbreitung einer reaktiven Substanz im Strömungsgebiet untersucht. Die Strömung wurde dabei durch die inkompressiblen Navier-Stokes-Gleichungen beschrieben. Zusätzlich wurde ein mathematisches Modell für die Ausbreitung der Substanz durch eine Diffusions-Konvektions-Gleichung bestimmt. Beide wurden durch die FEM- Sofware NAVIER berechnet und simuliert.:0 Notation 3 1 Aufgabenstellung 4 1.1 Projekt 4 1.2 Navier-Stokes-Strömung gekoppelt mit (passivem) Transport einiger (reaktiver) Substanzen 4 2 Einleitung 6 2.1 Strömungslehre 6 2.2 Regelungstheorie 7 3 Mathematische Modellierung 8 3.1 Strömungsmodellierung 8 3.2 Modell zur Ausbreitung des gelösten Stoffes 8 3.3 Gekoppeltes Modell und Randbedingungen 12 3.4 Grenzschichten 13 3.5 Feedback-Steuerung 15 4 Numerische Simulation 19 4.1 Umsetzung des Modells in NAVIER 19 4.1.1 Mathematische Grundlagen für NAVIER 20 4.1.2 Problemimplementation 21 4.2 Beispielsimulation 24 4.2.1 Gebietstriangulation 24 4.2.2 Konfigurationsdaten sowie Anfangs- und Randbedingungen 25 4.2.3 Ergebnisauswertung 28 4.3 Zusatzfunktionen für die Regelung 34 4.3.1 outflow-Funktion 34 4.3.2 Systemmatrizen 34 4.3.3 Feedback-Funktion 34 5 Zusammenfassung/Ausblick 35 5.1 Zusammenfassung 35 5.2 Ausblick 36 6 Schlusswort 37 7 Quellenverzeichnis 38 8 Verzeichnisse 39