In order for a medication treatment to be considered successful, several roles and functions along the pharmacological treatment chain must function and cooperate effectively. The chain can most easily be described as five transitions; diagnosis, prescription treatment, dispensing, drug use and finally results and follow-up. Unfortunately, there are many problems and inefficiencies in the pharmacological drug chain. Unfortunately, those who study medication errors and their solutions have focused on individual parts of the pharmacological treatment system. However, for this reason, this study aims to develop a general framework for system analysis of inefficiencies along the pharmacological treatment chain. Due to the size of the problem, this project focused on medication adherence. Adherence can be defined as to what extent the patient follows the medication treatment plan. Adherence has many known problems and difficulties, among other things, it has major financial consequences. It can also be difficult to measure compliance, and there is no recognized perfect method. A system dynamic model is a theoretical image of a real system or object, which is a model used to understand the nonlinear behavior of complex systems. These models are useful when considering interventions and their effects when there are complex relationships. The project started with a literature study, and then went into data collection. Here, a search design and refinements were designed to find relevant articles. Once the articles were selected, the data was compiled from the articles and the analysis began. Here, factors and effects on adherence were identified as well as other interesting information from the articles. When the information was compiled and analyzed, the system dynamic model was created. The model was then sent via email to experts in the field to validation and revise the model. During the data collection, 23 relevant articles were found, compiled into 38 factors associated with compliance. In addition to these factors, 8 were excluded because they were too disease-specific or too ambiguous in their effect of adherence. The various articles studied many different chronic diseases, but hypertension was the most common. How adherence was measured in the articles also varied greatly, however, some form of self-report or questionnaire was most common method used. Three out of seven experts responded to the sent-out model and provided valuable comments. Although these are not sufficient to validate the model, their views showed that a validation can be designed in this way. The model would have to be sent to a larger set of experts and stakeholders, but because these experts are recognized in their fields, it gave weight to the results even though they were few reviewers. With the support of the literature and the experts’ statement, it was concluded that this model provides a good foundation and structure to continue to build upon. In addition, the model has proven to have many key relationships and cornerstones with important and relevant factors. It is also concluded that it is possible to translate the model into quantitative patterns, which is based on the fact that the factor itself can be translated quantitatively. Overall, it is also finally concluded that the model created in this project could be of great use in future projects when working towards a framework for system analysis of inefficiencies along the pharmacological treatment chain.

Preoperativ ångest är en vanlig upplevelse hos patienter som ska genomgå kirurgiska ingrepp och kan orsaka patienten lidande och negativa konsekvenser på individ- och samhällsnivå. Anestesisjuksköterskan ska erbjuda en personcentrerad vård av hög kvalitet grundad i livsvärldsperspektivet och ge en stödjande individualiserad perioperativ omvårdnad till patienter som upplever de här känslorna, för att kunna lindra lidande och främja hälsa samt välbefinnande. Farmakologiska behandlingar kan medföra oönskade bieffekter, därför är det relevant att undersöka effektiviteten av icke farmakologiska omvårdnadsåtgärder för att lindra patienters preoperativa ångest. Metoden som har tillämpats är en systematisk litteraturöversikt med en narrativ dataanalys av 24 kvantitativa studier. Resultatet tyder på att icke farmakologiska strategier som musik, Virtual Reality (VR), aromaterapi, akupunktur och akupressur kan lindra patienters preoperativa ångest och vara värdefulla tilläggande verktyg i den perioperativa omvårdnaden, även om fler studier om olika typer av kirurgiska ingrepp med både kvinnor och män behövs för att stärka fynden. Slutsatserna indikerar att genomförandet av studier i nordiska länder kan bidra till ökad kunskap och förtroende för de här alternativen hos vårdpersonal. Användandet av de här omvårdnadsåtgärderna kan leda till en minskning av farmakologiska behandlingar för att hantera preoperativ ångest, vilket främjar god hälsa och välbefinnande samt gynnar hållbar utveckling. / Preoperative anxiety is a common experience among patients undergoing surgical procedures and can cause patient suffering and negative consequences at both individual and societal levels. The nurse anaesthetist must provide high quality person-centered care grounded in the lifeworld perspective and offer supportive, individualized perioperative nursing care to patients experiencing these feelings, aiming to alleviate suffering, promote health and enhance well-being. Pharmacological treatments may entail undesirable side effects, hence, it is relevant to examine the effectiveness of non-pharmacological nursing interventions in alleviating patients' preoperative anxiety. The method that has been applied is a systematic literature review with a narrative data analysis of 24 quantitative studies. The findings suggest that non-pharmacological strategies such as music, Virtual Reality (VR), aromatherapy, acupuncture, and acupressure can alleviate patients' preoperative anxiety and serve as valuable adjunctive tools in perioperative care, although further studies involving various types of surgical procedures with both genders are needed to substantiate the findings. The conclusions indicate that conducting studies in Nordic countries can contribute to increased knowledge and confidence in these alternatives among healthcare professionals. Implementing these nursing interventions may lead to a reduction in pharmacological treatments for managing preoperative anxiety, thereby promoting good health and well-being and fostering sustainable development.

Introduktion: Antalet personer med kognitiv sjukdom ökar och konsekvensen av detta är bland annat att fler personer drabbas av beteendemässiga och psykiska symtom. Detta ställer allt högre krav på hälso- och sjukvården. Distriktssköterskan har tillsammans med det interprofessionella teamet ansvar att tillämpa personcentrerade omvårdnadsåtgärder med syfte att lindra beteendemässiga och psykiska symtom hos personer med kognitiv sjukdom.  Syfte: Syftet var att beskriva omvårdnadsåtgärder som lindrar beteendemässiga och psykiska symtom hos personer med kognitiv sjukdom. Metod: En integrativ litteraturstudie med induktiv ansats baserat på Whittemore och Knafls integrativa metod. Vetenskapliga artiklar söktes fram i databaserna; CINAHL, PubMed och PsycINFO, 17 artiklar återstod efter urvalsprocessen och analyserades sedan i fem steg enligt Whittemore och Knafls analysmetod. Resultat: Utifrån artiklarnas resultat identifierades omvårdnadsåtgärder som lindrade beteendemässiga och psykiska symtom som presenteras under tre huvudkategorier: Stimulera sinnen, Främja emotionella funktioner och skapa en trygg miljö samt Stimulera till vardagliga aktiviteter. Konklusion: Distriktssköterskan kan med hjälp av individanpassade omvårdnadsåtgärder lindra beteendemässiga och psykiska symtom hos personer med kognitiv sjukdom. Omvårdnadsåtgärderna kan omfattas av massage, aromaterapi och musikterapi, som har en sinnesstimulerande effekt. Genom att initiera omvårdnadsåtgärder, som främjar emotionella funktioner, i form av aktivitet med docka eller stödja orienteringsförmågan genom miljöanpassning, kan BPSD lindras. Slutligen kan stimulering till vardagliga aktiviteter, som avser främja kroppsrörelse och koordinationsförmågan, stimulera språk- och räkneförmågan samt tillämpa identitetsfrämjande och kreativa aktiviteter, skapa förutsättningar för upplevelse av delaktighet och känsla av sammanhang. / Introduction: The number of people with cognitive illness is increasing and the consequence amongst others is that more people suffer from behavioral and psychological symptoms. This places increasingly high demands on health care. The district nurse, together with the interprofessional team, is responsible for applying person-centered nursing measures with the aim of alleviating behavioral and psychological symptoms in people with cognitive disorders. Purpose: The purpose was to describe nursing interventions that alleviate behavioural and psychological symptoms in people with cognitive disorders. Method: An integrative literature study with an inductive approach based on Whittemore and Knafl's integrative method. Scientific articles searched in the databases; CINAHL, PubMed and PsycINFO, 17 articles remained after the selection process and were then analysed in five steps according to Whittemore and Knafl's analysis method. Results: Based on the results of the articles, nursing interventions were identified that alleviated behavioural and psychological symptoms presented under three main categories: Stimulate the senses, Promote emotional functions and create a safe existence and Stimulate everyday activities. Conclusion: With the help of individually tailored nursing measures, the district nurse can relieve behavioral and psychological symptoms in people with cognitive disorders. Nursing measures may include massage, aromatherapy and music therapy, which have a mind-stimulating effect. By initiating nursing measures, which promote emotional functions, in the form of activity with a doll or supporting orientation skills through environmental adaptation, BPSD can be alleviated. Finally, stimulation for everyday activities, which aim to promote body movement and coordination skills, stimulate language and numeracy skills and apply identity-promoting and creative activities, can create the conditions for experiencing participation and a sense of context.

Problème. L'administration de médicaments aux propriétés sédatives pour la gestion des symptômes comportementaux, aussi appelée contention chimique, est une intervention complexe dont les finalités de contrôle, de protection, de traitement et d'alternative à d'autres coercitions entrent en conflit et sèment le désaccord chez les acteurs en établissements de santé. Tous s'entendent toutefois sur la nécessité d'en mesurer l'usage et d'évaluer la conformité des pratiques des soignants aux normes de qualité applicable. Or, à l'heure actuelle, aucune définition opérationnelle de la contention chimique, aucun outil ni indicateur de qualité des soins valide ne permet d'évaluer l'usage des contentions chimiques. But. Cette étude métrologique a pour but de développer et de valider un outil d'évaluation réflexive de la qualité des soins en matière de contention chimique de la perspective de l'infirmière. Méthodologie. Quatre questions de recherche rassemblées en deux grandes phases de l'étude ont permis de poursuivre ce but, lors desquelles des méthodes qualitatives et quantitatives ont été utilisées. La phase de développement de l'outil d'évaluation réflexive impliquait la conduite d'une revue réaliste pour rassembler, à l'intérieur d'un modèle théorique, un inventaire d'items potentiels. Cette méthode systématique de synthèse des connaissances suggère une étape préliminaire destinée à clarifier la nature et les contextes de déploiement de l'intervention d'intérêt, ici l'usage des contentions chimiques. Pour ce faire, un examen de la portée a été réalisé. Puis, une technique Delphi a permis la validation du contenu des items recensés, lesquels ont ensuite été intégrés dans une plateforme virtuelle d'évaluation réflexive qui permet de mesurer les perceptions des professionnelles en charge de la décision d'administrer la contention chimique, soit les infirmières. L'outil d'évaluation au format innovant, appelé E-value-action, a ensuite été pré-testé pour une appréciation de la validité apparente (face validity) auprès de futurs- utilisateurs d'un Centre intégré universitaire de santé et de services sociaux (CIUSSS) du Québec, Canada, lesquels ont offert une rétroaction qualitative suite à une simulation d'évaluation. Résultats. L'examen de la portée basé sur 33 articles de provenance internationale a fait ressortir la nécessité d'élargir le concept à définir et à mesurer pour aborder la contention chimique comme une notion synonyme à la sédation des symptômes comportementaux. Ensuite, par le biais de la revue réaliste, 28 normes de pratique répertoriées dans 45 articles scientifiques ou textes de lignes directrices ont pu être insérées au modèle théorique puis libellés sous forme d'items à intégrer à l'outil d'évaluation. Ces normes, appuyées d'exemples concrets, reflètent la qualité des soins infirmiers en trois contextes principaux : les soins en santé mentale, les soins aigus à l'adulte et les soins de longue durée à la clientèle âgée. Au niveau de la validité de contenu, les items de l'outil ont présenté un degré d'accord sur la clarté des items de 90% et de 95% sur la pertinence, témoignant d'un consensus (>70%) chez le panel d'experts chercheurs, gestionnaires et cliniciens (n = 20) de différentes régions administratives du Québec, Canada. L'adéquation de la plateforme virtuelle d'évaluation et l'intérêt pour son implantation en contextes cliniques ressortent de l'analyse des données de la validité apparente auprès d'infirmières en soins directs (n = 7) d'un CIUSSS québécois. Discussion. L'usage de cet outil d'évaluation réflexive devrait favoriser l'intégration des normes de pratique en soins infirmiers en plus de promouvoir une culture de réduction des mesures de contrôle favorable à des soins plus sécuritaires, efficaces et centrés sur la personne. Une validation ultérieure à plus grande échelle et la traduction du contenu d'E-value-action avec validations transculturelles sont recommandées pour soutenir les nombreux états/provinces et pays anglophones qui possèdent, comme le Québec, une règlementation sur la réduction ou l'usage d'exception des mesures de contrôle dont la substance chimique. / Background. The administration of sedative agents for the management of behavioral symptoms, also called chemical restraint, is a complex intervention of which the various goals of control, protection, treatment and alternative to other coercion inspire vigorous debate among professionals within the health care field. There is general consensus, however, on the necessity to reduce the application and to evaluate professional practices against relevant quality standards. Despite this clear recommendation, there is currently no operational definition of chemical restraint, and there is no valid measurement tool or indicator available for the evaluation of chemical restraint interventions in healthcare. Aim. This metrological study aims to develop and validate an instrument to assess the quality of chemical restraint practices from the perspective of nurses. Methods. This goal has been pursued through the formulation of four research questions organized into two large phases of study, involving both qualitative and quantitative methods. The development phase was based on a realist review of existing quality standards in order to gather, within a theoretical model, an inventory of potential items. This systematic method of knowledge synthesis requires, as a preliminary step, the clarification of the nature and various contexts of the intervention of interest, in this case, chemical restraint. This was accomplished through a scoping review. Following this, the Delphi method enabled the content validation of the identified items, which were then integrated into a virtual reflexive assessment tool within which the perceptions of the nurses in charge of administering chemical restraints could be measured. In order to gain an appreciation of the face validity of this innovative assessment tool, called E-value- action, it was then pre-tested among future users at one of Quebec's Integrated University Health and Social Services Centers (CIUSSS), Canada. After completing this simulated evaluation, participants were invited to provide a qualitative description of their experience. Results. The scoping review, based on 33 internationally sourced articles, highlighted the necessity to expand the concept being defined and measured to include chemical restraint or behavioral sedation. The realist review method was then used to identify 28 quality standards, inventoried within 45 scientific articles or practical guidelines, which were then integrated into the theoretical model and itemized to facilitate their inclusion within the quality assessment tool. These items, supported by concrete examples, reflect nursing practices in three principal contexts: mental health care, acute care for adults and long- term elder care. As concerns the content validity, the items within the theoretical model presented an agreement of 90% for the clarity, and of 95% for the relevance, demonstrating a consensus (>70%) among the panel of expert researchers, managers and clinicians (n = 20) from different administrative regions of Quebec, Canada. The alignment between the virtual self-evaluation platform and the interest for its implementation within clinical contexts is palpable from the analysis of the face validity data gathered from direct care nurses (n = 7) in the Quebec CIUSSS. Discussion. The application of this reflexive self-evaluation tool should engender a deeper integration of nursing standards in addition to promoting a diminished utilization of coercive measures leading to care that is more secure, effective and patient-centered. A subsequent large-scale pilot testing of the E-value-action platform is recommended, including the translation and adaptation for cross-cultural analysis, in order to support the numerous English-speaking jurisdictions which, like Quebec, have developed regulations concerning the reduction or exceptional application of coercive measures such as pharmacological agents.

No description available.

No description available.

Bakgrund: Oro är ett känslomässigt svar på stimuli som kan ge fysiologiska effekter. Att befinna sig i en operationssal är för många patienter en ny upplevelse där de överlämnar sin kropp till vårdpersonalen. Anestesisjuksköterskan kan hantera en patient i regional anestesi med olika omvårdnadsåtgärder. Syfte: Syftet med denna studie var att beskriva icke-farmakologiska omvårdnadsåtgärder som finns mot oro, pre och intraoperativt hos patienter som genomgår operationer i regional anestesi. Metod: Deskriptiv litteraturstudie där 17 artiklar granskades med SBU samt GRADE och analyserades deduktivt med Fundamentals of Care som teoretisk utgångspunkt. Resultat: Olika omvårdnadsåtgärder finns för att lindra oro icke-farmakologisk under regional anestesi. Majoriteten av resultaten visade tekniska åtgärder som video, musik, VR samt en minoritet om samtal och aromaterapi. Slutsats: Fler tekniska omvårdnadsåtgärder framkom vilket var oväntat. De hade effekt mot oro men på bekostnad av anestesisjuksköterskans relationella kontakt med patienten. Nyckelord: Regional anestesi, oro, icke farmakologisk, omvårdnadsåtgärder, Fundamentals of Care / Background: Anxiety is an emotional response to stimuli which can give physiological effects. To be in an operating theater is a new experience for many patients where they hand over their bodies to the healthcare staff. The nurse anesthetist can manage the patient during regional anesthesia with different nursing interventions.  Purpose: The aim of the study was to describe non-pharmacological nursing interventions that exist towards anxiety, pre and intraoperative in patients undergoing surgery under regional anesthesia.  Method: A descriptive literature review where 17 articles were reviewed with SBU and GRADE and analyzed deductively with Fundamentals of Care as a theoretical outset. Results: Various nursing interventions exist to alleviate anxiety non-pharmacologicaly under regional anesthesia. The majority of the results showed technical measures such as video, music, VR and a minority of conversation and aromatherapy.  Conclusion: Several technical nursing interventions emerged, which was unexpected. They had an effect on anxiety but at the expense of the nurse anesthetist´s relational contact with the patient.  Keywords: Regional anesthesia, anxiety, non pharmacological, nursing interventions, Fundamentals of Car

En todos los servicios de hospitalización neonatal, los neonatos se someten a diferentes tipos de procedimientos invasivos e intervenciones terapéuticas que generaran un evento doloroso (como, por ejemplo, una punción venosa, punción en el talón, inserción de un catéter periférico o venoso, o durante la toma de exámenes de laboratorio, entre otros). Mediante las investigaciones en salud se afirma que los recién nacidos son seres capaces de recibir el estímulo del doloroso y ello puede generarles efectos negativos en el desarrollo neurosensorial; por ello la importancia de la sensibilización al personal de enfermería sobre las diferentes técnicas que ayudaran a reducir y manejar el dolor neonatal a través de las intervenciones terapéuticas no farmacológicas. Por ello que profundizamos el análisis de la investigación secundaria titulada “Efectividad del uso de la sacarosa como analgesia durante la punción venosa en neonatos”; el cual tuvo como objetivo demostrar la efectividad del uso de la sacarosa al realizarse procedimientos invasivos que generen dolor. La metodología utilizada fue de “Enfermería Basada en la Evidencia” (EBE); en la cual se formuló la pregunta PICOT, Al administrar venopunción a recién nacidos, ¿el azúcar es un buen analgésico? Después de buscar en muchas bases de datos (incluidas VHL, Cyberindex, Scielo, Google Academic, Lilacs y Upto Date), pudimos localizar 396 artículos que eran relevantes para el tema. Después de aplicar nuestros criterios de selección, redujimos el campo a 10 artículos, Se seleccionó un artículo que cumplía los criterios de rigor científico (artículo 01) tras utilizar la Guía de Validez y Utilidad de Gálvez Toro. Para realizar el análisis del artículo elegido se utilizó la Guía Caspe. El Grupo de Trabajo Canadiense sobre Atención Médica Preventiva (CTFPHC) consideró que los hallazgos estaban en línea con sus expectativas, obteniendo un alto nivel de evidencia, la cual determinó que es efectivo el uso de la sacarosa como alternativa no farmacológica durante la punción venosa en neonatos para la disminución del dolor; proporcionando bienestar, evitando el estrés y daños neurosensoriales. / In all neonatal hospitalization services, neonates undergo different types of invasive procedures and therapeutic interventions that will generate a painful event (such as, for example, a venipuncture, heel stick, insertion of a peripheral or venous catheter, or during taking laboratory tests, among others). Through health research, it is affirmed that newborns are beings capable of receiving painful stimuli and this can generate negative effects on neurosensory development; Therefore, the importance of raising awareness among nursing staff about the different techniques that will help reduce and manage neonatal pain through non pharmacological therapeutic interventions. For this reason, we deepened the analysis of the secondary research titled “Results from the study "Efficacy of the use of sucrose as analgesia during venipuncture in neonates" were used to show that sucrose is helpful in reducing pain during invasive operations. The methodology used was “Evidence-Based Nursing” (EBE); in which the PICOT question was formulated: Is the use of sucrose as an analgesic during venipuncture in neonates effective? The necessary information search was carried out through a database of the Virtual Health Library (VHL), Cyber index, Scielo, Google Academic, Lilacs, Upto Date; finding 396 documents related to the topic; to which the selection criteria were applied, 10 articles were chosen, and; The Galvez Toro Validity and Usefulness Guide was applied, and one article was selected (01) complying with the established scientific rigor. For the selected article, the analysis was carried out with the Caspe Guide. The results met the objective, obtaining a High level of evidence, according to the Canadian Task Force on Preventive Health Care (CTFPHC), which determined that the use of sucrose as a non pharmacological alternative during venipuncture in neonates is effective to reduce the pain; providing well-being, avoiding stress and neurosensory damage.

[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

La douleur articulaire associée à l’arthrose est un problème clinique majeur, spécialement chez les personnes âgées. L’intensité de la douleur est souvent amplifiée lors de mouvement de l’articulation et principalement lors du soutien de la charge corporelle sur le membre lésé. Malheureusement, les traitements pharmacologiques proposés sont trop souvent associés à des effets secondaires néfastes et à une inefficacité pour le soulagement de la douleur à long terme. Divers modèles murins sont utilisés en laboratoire de recherche pour des études précliniques de molécules aux propriétés analgésiques. Une évaluation comparative de la réponse comportementale douloureuse des animaux d’un modèle d’instabilité articulaire induit par le sectionnement du ligament croisé antérieur accompagné d’une méniscectomie partielle (le modèle ACLT+pMMx) et d’un modèle de dégénérescence articulaire induite par le monoiodoacetate (le modèle MIA) a permis de sélectionner un modèle approprié pour la continuité du projet. Les deux modèles ont démontré des lésions tissulaires, mais le modèle MIA a démontré une réponse douloureuse plus prononcée que le modèle ACLT+pMMx. Par l’analyse de la démarche, le modèle MIA a démontré une boiterie claire dans le patron de la démarche des animaux qui est associée à une lésion unilatérale. Le modèle MIA a donc été choisi pour la suite du projet. La problématique principale dans la recherche sur la douleur associée à l’arthrose est une compréhension incomplète des mécanismes de douleur responsables de l’induction et du maintien de l’état de douleur. Il devient donc nécessaire d’améliorer nos connaissances de ces mécanismes en effectuant une caractérisation plus approfondie des modèles animaux employés pour l’évaluation de stratégies pharmacologiques analgésiantes. Afin de bien comprendre le modèle MIA, une caractérisation des événements moléculaires centraux lors de la progression du processus dégénératif des structures articulaires de ce modèle s’est effectuée aux jours 3, 7, 14, 21 et 28 post injection. Des mécanismes hétérogènes qui modulent l’information nociceptive en fonction de la progression temporelle de la pathologie ont été observés. Les changements du contenu i spinal des neuropeptides sélectionnés (substance P, CGRP, dynorphine A et Big dynorphine) ont débuté sept jours suivant l’injection de MIA. L’observation histologique a démontré que les dommages structuraux les plus importants surviennent entre les jours 14 et 21. C’est entre les jours 7 et 21 que les lésions démontrent le plus de similarités à la pathologie humaine. Cela suggère que lors d’une évaluation préclinique d’un traitement pharmacologique pour pallier la douleur articulaire utilisant le modèle MIA, l’étude doit tenir compte de ces événements afin de maximiser l’évaluation de son efficacité. Puisque les traitements pharmacologiques conventionnels proposés pour le soulagement de la douleur ne font pas l’unanimité en terme d’efficacité, d’effets non désirés et de coûts monétaires parfois onéreux, les molécules de dérivés de plante deviennent une alternative intéressante. L’eugénol, le principal constituant de l’huile de clou de girofle, a été administré oralement pour une période de 28 jours chez des rats ayant reçu l’injection intra-articulaire de MIA afin d’évaluer son efficacité pour le traitement de la douleur articulaire. L’eugénol à une dose de 40 mg/kg s’est révélé efficace pour l’amélioration du patron de la démarche des animaux ainsi que pour la diminution de l’allodynie mécanique secondaire. De plus, les concentrations spinales de neuropeptides pronocicepteurs ont diminué chez les animaux traités. Par une évaluation histopathologique, l’eugénol n’a démontré aucune évidence d’effets toxiques suite à une administration per os quotidienne pour une période prolongée. Ces résultats suggèrent le potentiel thérapeutique complémentaire de la molécule d’eugénol pour le traitement de la douleur articulaire. / Pain is the most predominant clinical symptom associated with osteoarthritis (OA), mostly among older people. Joint movement and weight bearing often increase the pain intensity. Unfortunately, the proposed pharmacological treatments are frequently associated with side effects and ineffective for pain alleviation for long time periods. Many murine models are used in laboratories for preclinical studies evaluating analgesic compounds. A comparative evaluation of the behavioral pain responses of animals with a joint instability model induced by the transection of the anterior cruciate ligament followed by a partial menisectomy (the ACLT+pMMx model) and of an articular degenerative model induced by an intra-articular injection of monoiodoacetate (the MIA model) was conducted to select an appropriate model for the continuation of the project. Both models demonstrated articular lésions, however the MIA model demonstrated a clearer behavioral pain response over the ACLT+pMMx model. The gait pattern of the MIA model revealed a clear limping gait similar to that observed with unilateral OA in humans. The MIA model was chosen for the subsequent studies. An unresolved issue in pain OA research is the lack of understanding of the pain mechanisms responsible for the induction and maintenance of the pain. Therefore, there is an urgent clinical need to improve the characterization of animal models to effectively discover novel pain relief pharmacological treatment stratégies for OA patients. A characterization of the spinal pain molecular events during the progression of the joint degenerative process in the MIA model was performed on days 3, 7, 14, 21 and 28 post injection. Heterogeneous nociceptive central molecular events were observed in respect to the time course of the pathology’s progression. Changes in selected spinal neuropeptide content (substance P, CGRP, dynorphin A, Big dynorphin) began 7 days following the MIA injection. Most severe joint structural damage on histology occured between days 14 and 21 post injection. These results suggest that preclinical drug evaluation employing this model should be conducted between 7 and 21 days post injection when the lesions resemble most those of human OA. iii As current pharmacological therapy for the alleviation of joint pain does not achieve the unanimity in respect to efficacy, side effects and cost, plant derivate compounds are now interesting alternatives to improve the situation. Eugenol, the main constituent of clove oil, was evaluated for its efficacy for alleviation of joint pain in rats who previously received an intra-articular injection of mono-iodoacetate to induce the MIA model. Eugenol, administered orally for 28 consecutive days at a dose of 40 mg/kg, improved gait pattern and reduced secondary mechanical allodynia. Furthermore, spinal concentrations of pronociceptive neuropeptides were also decreased in the treated animals. No toxic effects of the compoud were identified on histopathological assessment of the various tissues. These results suggest that eugenol could be a potential therapeutic option for alleviating OA joint pain.