[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. / [CAT] 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 no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/62166 / TESIS

La pandémie de l'obésité entraine une augmentation de la prévalence des maladies chroniques du foie ou stéatopathies métaboliques (NAFLD). Le spectre des NAFLD va de la stéatose caractérisée par une accumulation de lipides dans le foie à la stéatohépatite (NASH) associant une inflammation, de la mort hépatocytaire et de la fibrose. Lors de l'obésité, l'élévation de signaux de dangers métaboliques perturbe les fonctions du réticulum endoplasmique (RE) essentielles pour l’homéostasie cellulaire. Les perturbations sont transmises par 3 senseurs : IRE1α, ATF6 et PERK pour activer une réponse adaptative. Si ce stress est sévère ou devient chronique, la cellule enclenchera une réponse terminale apoptotique. La protéine Bax Inhibitor-1 (BI-1) pourrait jouer un rôle hépatoprotecteur en inhibant l’hyperactivation de la voie de signalisation IRE1α.En combinant des études chez l’homme et dans des modèles animaux, l’objectif de cette étude était de mieux caractériser l'activation chronique du stress du RE dans les NAFLD. Ce travail a émis l’hypothèse qu’une déficience en BI-1 entrainerait l’activation soutenue de la voie IRE1α qui serait responsable de la transition de la stéatose à la NASH. Cette étude s'intéresse au dialogue potentiel entre le stress du RE et l’activation de l'inflammasome NLRP3, qui induit la sécrétion des cytokines pro-inflammatoires (IL-1β, IL-18) grâce aux caspases pro-inflammatoires (caspase-1, caspase-4/11). L’utilisation d’un inhibiteur global du stress du RE ou des inhibiteurs pharmacologiques spécifiques à la voie IRE1α améliorerait les caractéristiques pathophysiologiques de la NASH et pourrait ouvrir de nouvelles perspectives thérapeutiques. / Due to the obesity pandemic, the last decades have been marked by a constantly increasing prevalence of Non-Alcoholic Fatty Liver Disease (NAFLD). NAFLD covers a spectrum of hepatic disorders ranging from steatosis, characterized by the ectopic accumulation of lipids in the liver, to steatohepatitis (NASH), featuring inflammation, hepatocellular death and fibrosis. During obesity, an increase in metabolic danger signals leads to disrupted endoplasmic reticulum (ER) function, essential for cellular homeostasis. The resulting ER stress activates a signaling network involving three sensors: IRE1α, ATF6 and PERK to enforce adaptive programs. If this stress is severe or becomes chronic, the cell will trigger a terminal apoptotic response. The protein Bax Inhibitor-1 (BI-1), as a negative endogenous regulator of the IRE1α signaling pathway in the liver, may play a hepatoprotective role.By combining data from obese patients with liver complications and experimental approaches in mice, this thesis aimed to better characterize the chronic activation of ER stress in NAFLD pathogenesis. This work also emitted the hypothesis that a deficiency in BI-1 leads to unrestrained IRE1α signaling that may be responsible for the steatosis to NASH transition. This study further investigated the potential dialogue between ER stress and the activation the NLRP3 inflammasome, which induces the secretion of pro-inflammatory cytokines (IL-1β, IL-18) by activating pro-inflammatory caspases (caspase-1, caspase-4/11). The administration of a broad spectrum ER stress inhibitor or specific inhibitors of IRE1α improved the pathophysiological features of NASH and may open novel therapeutic perspectives.

Bakgrund: Sömnstörningar är ett vanligt fenomen hos personer med demenssjukdom. Störningarna yttrar sig ofta genom upplevd trötthet under dagtid och osammanhängande sömn under natten. Sömnen är betydelsefull för återhämtningen och bidrar till en ökad livskvalitet.  Problem: Personer med demenssjukdom lider ofta av flera symtom som kan förvärras vid sömnbrist. Omvårdnadsåtgärder som sjuksköterskan kan använda för att främja sömnen för personer med demenssjukdom är bristande och behöver tydliggöras samt lyftas fram. Syfte: Syftet är att skapa en översikt av omvårdnadsåtgärder för att främja sömnen hos personer med demenssjukdom. Metod: En litteraturöversikt med kvalitativa-, mixade- samt kvantitativa artiklar. Resultat: Resultatet visade flera olika omvårdnadsåtgärder som kan tillämpas vid sömnstörningar för att främja sömnen hos personer med demenssjukdom. De olika kategorierna som presenteras under resultatet är: Miljöns betydelse, kvalitetssäkra rutiner för sömn och vikten av beröring. Slutsats: Några generella slutsatser kunde inte dras då evidensen för omvårdnadsåtgärderna är låg och kräver mer forskning. Sömnen kunde dock främjas genom de omvårdnadsåtgärder som presenteras i resultatet. / Background: Sleep disorders are a common phenomenon in people with dementia. The disorders are often manifested by perceived fatigue during the day and incoherent sleep during the night. Sleep is important for recovery and contributes to an increased quality of life. Problem: People with dementia can suffer from several symptoms that can be worsened by a lack of sleep. Nursing interventions that can be used to promote sleep in people with dementia are deficient therefore, they need to be clarified and highlighted. Aim: The aim is to create an overview of nursing measures to promote sleep in people with dementia. Method: A literature review with qualitative-, mixed-and quantitative articles. Results: The results showed several different nursing interventions that can be applied in sleep disorders to promote sleep in people with dementia. The importance of the environment, quality-assured routines for sleep and the importance of touch. Conclusion: No general conclusions could be drawn as the evidence for nursing measures is low and needs more research. However, sleep could be promoted through the nursing measures presented in the development.

Bakgrund: Fysisk aktivitet har flera positiva effekter på hälsan. Fysisk aktivitet på recept är en behandlingsmetod mot olika ohälsotillstånd, samt i preventivt syfte. Fysisk aktivitet på recept kan förskrivas av legitimerad vårdpersonal, exempelvis sjuksköterskor.  Syfte: Att beskriva patienters upplevelser av följsamhet till fysisk aktivitet på recept. Metod: Kvalitativ litteraturöversikt med induktiv ansats där tio vetenskapliga artiklar sammanställdes efter analys av materialet enligt Fribergs femstegsanalys.  Resultat: Tre kategorier formades: individuella påverkansfaktorer, sociala påverkansfaktorer och yttre påverkansfaktorer. Individuella påverkansfaktorer berörde exempelvis symtom och tidigare erfarenheter. Sociala faktorer var till exempel stöd från familj och närstående samt vårdpersonal. Yttre påverkansfaktorer handlade bland annat om tid och ekonomi. Slutsats: Både yttre och inre faktorer påverkade följsamheten till receptet. Orsakerna till följsamhet/icke följsamhet var ofta multifaktoriella och komplexa. Vårdpersonalen som förskriver receptet behöver vara lyhörda för patientens behov och förutsättningar. Som förskrivande vårdpersonal är det även viktigt att erbjuda stöd och uppföljningar. / Background: Physical activity (PA) has several beneficial effects on health. Physical activity on prescription (PAP) is a non-medical treatment method and is also used to prevent future illness. Health care practioners with a legitimation – e.g. nurses - can prescribe PAP. Aim: To describe patients experiences of compliance to physical activity on prescription.  Method: A qualitative literature review with inductive approach. Ten articles with qualitative design were analyzed and compiled through Friberg’s analyze in five steps.  Results: The result was organized in three main categories: individual factors, social influential factors and external factors. Individual factors was for example symptoms and previous experience. Social factors was for example support from family, friends and healthcare staff. External factors was for example time and economy. Conclusion: Both external and internal factors had impact on the participants adherence to PAP. The reasons explained by the participants were multifactorial and complex. Health care professionals who prescribe physical activity need to be responsive to the patients` needs and prerequisites. It is also important to offer support and follow-ups.

Title: Physical education of individuals with type 2 diabetes mellitus Objectives: The aim of this thesis is to evaluate the effect of physical education of individuals with type 2 diabetes mellitus cured in diabetologic outpatient clinic of Genereal University Hospital in Prague. The physical education was focused on nordic walking. Methods: Eight patients of diabetological outpatient clinic were chosen by the doctor for this survey. The physical examination was carried out with seven patients. It involved anthropometrical measurements (weight, waist circumference) and blood collection for biochemical parameters assessment (glycemia, glycated hemoglobin). Two-minute step test was chosen for assessment of subject's physical fitness. Results: The physical activity education of individuals with type 2 diabetes mellitus doesn't increase the amount of their physical activity. The physical activity of type 2 diabetes mellitus individuals is rather low as well as their exercise adherence. Nordic walking exercise program can improve anthropometrical parametres (weight, waist circumference) and can reduce HbA1c levels. Lower health-related quality of life in physical and physological aspects wasn't proved in type 2 diabetes patients. Key words: nordic walking, physical activity, type 2 diabetes management,...

Bakgrund Demenssjukdom utgör ett stort hälsoproblem med både emotionella och fysiska konsekvenser. Många av de personer som lever med demenssjukdom flyttar till särskilda boenden när de inte längre klarar sig på egen hand. Beteendemässiga och psykiska symtom vid demens (BPSD) innefattar olika vanligt förekommande symtom vid demenssjukdom. Symtombehandling med läkemedel medför risker i form av förvirring, olyckor och fall. Syfte Syftet med denna litteraturöversikt är att beskriva effekter och användande av icke-farmakologiska metoder för att lindra symtom vid demens. Metod Litteraturöversikten baserades på 13 vetenskapliga artiklar, varav 11 kvantitativa och 2 kvalitativa, publicerade mellan 2012 och 2021. Artiklarna inhämtades från databaserna CINAHL, PubMed och PsycInfo. Studierna granskades enligt Örebros universitets mallar och därefter analyserades innehållet. Resultat Resultatet utgjordes av två huvudkategorier; Interventioners effekter med underkategorierna BPSD, Kognition, ADL, Livskvalitet och Vårdgivarbörda samt Användande av icke-farmakologiska metoder, med underkategorierna Tillfällen för icke-farmakologiska metoder, Kunskap och Hindrande faktorer. Resultatet visade att icke-farmakologiska metoder hade god effekt vid lindring av symtom vid demens. Effekten på olika symtom och grad av demens varierade beroende på metod. Slutsats Eftersom effekterna av de icke-farmakologiska metoderna varierade, krävdes en personcentrerad inställning där interventionerna individanpassades. Vid sidan av symtomlindring sågs effekter i form av ökad ADL-förmåga, ökad livskvalitet och minskad vårdgivarbörda. / Background Dementia constitutes a large threat on health and has both emotional and physical consequences. Many people that live with dementia move into care facilities when they can no longer cope on their own. Behavioural and psychological symptoms of dementia(BPSD) include different symptoms that are common in dementia. To treat these symptoms with drugs entails risks, such as confusion, accidents and falls. Aim The aim of this study is to describe effects, and use of, non-pharmacological methods to alleviate symptoms of dementia. Method This literature rewiev is based on 13 scientific articles; 11 quantitative and 2 qualitative, published between 2012 and 2021. The articles were obtained from the databases CINAHL, PubMed and PsycInfo. The studies were reviewed according to templates by Örebro University and thereafter the content was analysed. Results The result was divided into two main categories; The effects of interventions, with the subcategories BPSD, Cognition, ADL, Quality of life and Caregiver burden and The use of non-pharmacological methods, with the subcategories Opportunities for non-pharmacological methods, Knowledge and Hindering factors. The result indicated that non-pharmacological methods were effective for alleviation of symptoms of dementia.The effect on different symptoms and degree of dementia varied depending on method. Conclusions Since the effects of the non-pharmacological methods varied, a person-centred approach with individualized interventions was necessary. In addition, there were positive effects in form om increased capability to perform ADL, increased quality of life and reduced caregiver burden.

This doctoral thesis aims to demonstrate the relevance of resting-state functional connectivity (RSFC) for the study of brain function. RSFC refers to the spontaneous brain activity structured in intrinsic connectivity networks. These networks mirror task-based activations and show significant variations across several behavioral domains and phenotypical traits. Furthermore, changes in these networks after, for instance, pharmacological manipulations, may disentangle the specific role of several neurotransmitters systems in normal and pathological functional connectivity. While various neuroimaging techniques enable the detection of intrinsic connectivity networks, data-driven methods, such as independent component analysis, provide a robust spatial representation of brain networks that are distinguishable from physiological signals and scanner noise. Within the above-mentioned framework, this thesis presents data from two studies designed to better understand 1) individual differences in decision making reflected in intrinsic network connectivity and 2) variations in intrinsic network connectivity following serotonergic manipulations. The first part is the general introduction where I present the theoretical background, the methodology used in both experiments and an overview of the current research related to the studies of this thesis. The second chapter presents the first study, which examined the relationship between a set of value-based decision-making parameters with large-scale intrinsic connectivity networks. Findings of this study revealed that individuals who prefer to gamble in order to avoid a sure loss, exhibit stronger connectivity between the default mode and left frontoparietal systems to their adjacent brain regions, especially to those involved in prospective thinking, affective decision making and visual processing. The third chapter presents the second experimental study, which examined changes in default mode network connectivity after two tryptophan interventions to increase and decrease brain serotonin synthesis, and a control condition. Results of this study showed decreased functional connectivity between the default mode network and emotion-related regions associated with higher serotonin brain levels. Finally, the fourth chapter includes a general discussion that integrates the significance of the findings from both studies. In this section, limitations and recommendations for future research are also considered before presenting the conclusion that highlights the contribution of this work for unraveling the continuous activity of the resting brain.:1.CONTENTS 1 LIST OF FIGURES 3 LIST OF TABLES 4 ABBREVIATIONS 5 ABSTRACT 7 GENERAL INTRODUCTION 9 1.1. Resting-state functional connectivity: the silent work of the resting brain 9 1.2. Intrinsic connectivity networks 12 1.3. Independent Component Analysis 17 1.4. Summary: research objectives and study hypotheses 20 STUDY I: Risk seeking for losses modulates the functional connectivity of the default 2.mode and left frontoparietal networks in young males 22 2.1. Abstract 23 2.2. Introduction 24 2.3. Materials and Methods 26 2.4. Results 33 2.5. Discussion 41 2.6. Notes 44 2.7. Supplemental Material Study I 45 3. STUDY II: Acute Tryptophan Loading Decreases Functional Connectivity between the Default Mode Network and Emotion-Related Brain Regions 49 3.1. Abstract 50 3.2. Introduction 51 3.3. Materials and Methods 53 3.4. Results 61 3.5. Discussion 67 3.6. Acknowledgments 71 3.7. Supplemental Material Study II 72 4. GENERAL DISCUSSION 78 4.1. Research objectives and summary of results 78 4.2. Risk seeking for losses is associated with changes in default mode and frontoparietal systems 79 4.3. Higher serotonin brain synthesis decreases DMN connectivity 80 4.4. Integration of findings 81 4.5. Limitations and future directions 83 4.6. General conclusion 85 5. ZUSAMMENFASSUNG 86 Hintergrund 86 Fragestellung 86 Material und Methoden 87 Ergebnisse 88 Schlussfolgerungen 89 6. SUMMARY 90 Background 90 Research question 90 Material and Methods 91 Results 92 Conclusion 92 7.REFERENCES 93 8.ANNEX 113 8.1. Publikationsverzeichnis 113 8.3.Danksagung 115 8.4. Erklärungen zur Eröffnung des Promotionsverfahrens 116 8.5. Erklärung zur Einhaltung gesetzlicher Vorgaben118 8.6. Erklärungen zur Publikation 119

Indiana University-Purdue University Indianapolis (IUPUI) / The present study sought to identify the effects of chronic lithium administration on ethanol intakes in high alcohol-preferring (HAP) mice. Lithium is a well-established treatment for bipolar disorder and has demonstrated efficacy in reducing impulsivity, an endophenotype of the disease. Impulsivity is also a prominent trait of alcoholism. HAP mice display a preference for consuming substantial amounts of ethanol and exhibit abnormally high levels of impulsivity. Previous work has determined that chronic lithium exposure in HAP mice reduces their levels of impulsivity. The present study analyzed fluctuations in established intake patterns after lithium exposure and how pre-exposure to lithium would affect ethanol intake acquisition. The results showed an increase in ethanol intake and no change in preference for ethanol over water in lithium treated mice. There was an increase in overall total fluid consumption in these mice, likely resulting from polydipsic effects. There also appeared to be a potentiated lithium toxicity effect found in those mice pre-exposed to lithium. The conclusion was that lithium therapy does not decrease ethanol consumption in HAP mice.

L’insuffisance cardiaque (IC) est associée à une mortalité élevée et de récurrentes hospitalisations. Sa détection précoce et sa prise en charge sont alors considérées fondamentales à une amélioration de la survie et de la qualité de vie des patients qui en souffrent. Pourtant, bien que des lignes directrices synthétisant les évidences des essais cliniques phares soient périodiquement publiées pour guider les cliniciens dans la prise en charge de l’IC, l’adhésion des professionnels de la santé à celles-ci semble être insatisfaisante. En effet, alors que les taux de prescription de certaines thérapies soient élevés, les doses prescrites n’atteignent pas toujours les cibles recommandées et d’autres thérapies sont moins utilisées. Ainsi, bien que l’inertie clinique puisse justifier une partie de ces lacunes, une caractérisation plus élaborée de cette adhésion aux lignes directrices en milieu clinique est nécessaire à une meilleure compréhension de ces écarts et par le fait même, à une meilleure prise en charge de l’IC. L’objectif de ce projet est alors de dresser, dans un premier temps, un portrait détaillé de la prise en charge des patients atteints d’IC avec une fraction d’éjection réduite suivis par une équipe interdisciplinaire dans une clinique ambulatoire spécialisée au Québec puis, dans un second temps, d’évaluer l’impact de cette adhésion sur le pronostic de ces patients. Le premier papier présenté dans ce travail démontre non seulement des taux de prescriptions élevés, mais également des taux d’optimisation des thérapies recommandées supérieurs à ce qui est rapporté dans la littérature, lorsque les paramètres physiologiques et biologiques propres à chaque patient sont considérés. Il reste néanmoins une proportion considérable de patients qui nécessitent une titration plus lente au-delà des 6 mois recommandés tandis que d’autres demeurent indéfiniment à des doses inappropriées. Le second papier présenté approfondit cette analyse et démontre que les patients recevant un traitement pharmacologique aux doses optimales sont ceux qui présentent le meilleur pronostic dans l’année suivant la période d’optimisation allouée, suivis de ceux nécessitant une titration prolongée puis, ceux demeurant à des doses sous-optimales. Or, les patients à plus haut risque de morbidité ou de mortalité sont ceux présentant une intolérance ou une contre-indication aux thérapies recommandées, une population de patients fragiles nécessitant une attention particulière lors de la prise en charge de leur IC. / Heart failure (HF) is associated with high mortality rates and recurrent hospitalizations. Hence, its early detection and optimal management are essential to improve the survival and quality of life of patients who suffer from it. Yet, although guidelines synthesizing evidence from landmark clinical trials are periodically published to guide clinicians regarding the management of HF, healthcare providers’ adherence to these recommendations appears to be unsatisfactory. Indeed, while the prescription rates for some therapies are high, doses prescribed do not always reach recommended targets, let alone other therapies that are less often used. Although clinical inertia has been suggested to potentially justify some of these care gaps, a more elaborate characterization of this adherence to guidelines in the real-world clinical setting is necessary for a better understanding of these deviations and ultimately, for a better management of HF. The objective of this project is therefore to, firstly, draw-up a detailed portrait of the management of patients with HF and reduced ejection fraction (HFrEF) followed by a multidisciplinary team in a specialized outpatient clinic in Quebec and then, to assess the impact of the different level of adherence to guidelines on the prognosis of these patients. The first paper presented in this work demonstrates not only high prescription rates, but also rates of optimization of recommended therapies higher than what was previously reported in the literature, when physiological and biological parameters specific to each patient are considered. However, there remains a considerable proportion of patients who require slower titration beyond the recommended 6 months while others remain indefinitely on inappropriately low doses. The second paper presented deepens this analysis and demonstrates that patients receiving pharmacological treatment at optimal doses are those with the best prognosis in the year following the allocated optimization period, followed by those requiring prolonged titration and then those remaining at suboptimal doses. However, the patients at the highest risk of morbidity or mortality are those presenting an intolerance or a contraindication to the recommended therapies, a population of fragile patients requiring special attention during the management of their HF.

Cystic fibrosis (CF) is a rare genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), an epithelial anion channel expressed in several vital organs. Absence of functional CFTR results in imbalanced osmotic equilibrium and subsequent mucus build up in the lungs-which increases the risk of infection and eventually causes death. CFTR is an ATP-binding cassette (ABC) transporter family protein composed of two transmembrane domains (TMDs), two nucleotide binding domains (NBDs), and an unstructured regulatory domain. The most prevalent patient mutation is the deletion of F508 (F508del), making F508del CFTR the primary target for current FDA approved CF therapies. However, no experimental multi-domain F508del CFTR structure has been determined and few studies have modeled F508del using multi-domain WT CFTR structures. Here, we used cryo-EM density data and Rosetta comparative modeling (RosettaCM) to compare a F508del model with published experimental data on CFTR NBD1 thermodynamics. We then apply this modeling method to generate multi-domain WT and F508del CFTR structural models. These models demonstrate the destabilizing effects of F508del on NBD1 and the NBD1/TMD interface in both the inactive and active conformation of CFTR. Furthermore, we modeled F508del/R1070W and F508del bound to the CFTR corrector VX-809. Our models reveal the stabilizing effects of VX-809 on multi-domain models of F508del CFTR and pave the way for rational design of additional drugs that target F508del CFTR for treatment of CF.