Problématique : La satisfaction des patients et la qualité de vie reliée à la santé bucco-dentaire (OHRQoL) sont deux mesures de résultats fréquemment utilisées durant les études cliniques. Néanmoins, chez les patients totalement édentés, les évidences scientifiques relatives au niveau de relation entre ces deux mesures sont faibles. De plus, on ignore toujours quels éléments de la satisfaction des patients relativement à leurs prothèses partagent la meilleure relation avec la OHRQoL. Objectifs : Déterminer, chez les patients totalement édentés, s’il existe un lien entre leur satisfaction de leurs prothèses et leur OHRQoL et identifier les déterminants de satisfaction qui démontrent le meilleur niveau de relation avec la OHRQoL. Méthodologie : Les données provenant de 255 patients totalement édentés qui ont participé à une étude randomisée et contrôlée ont été utilisées. La OHRQoL a été évaluée à l’aide du questionnaire Oral Health Impact Profile (OHIP-20). Le McGill Denture Satisfaction Instrument a été utilisé pour estimer la satisfaction des patients. Ces mesures ont été prises au temps initial, à 6 mois et à 12 mois suivants la mise en bouche des prothèses. Des analyses statistiques de régression linéaire simples et multiples ont été utilisées afin d’évaluer la relation entre les deux mesures. Résultats : Une relation positive et considérable existe entre la satisfaction des patients totalement édentés et leur OHRQoL. La difficulté masticatoire (P = .005) et la condition buccale (P = .002) sont les éléments de la satisfaction qui possèdent le meilleur lien avec la OHRQoL. Ces deux facteurs expliquent 46.4% (P = .0001) de la variance dans l’amélioration d’OHIP suivant un traitement prosthodontique. La relation décrite est dépendante du temps, mais pas du type de traitement ni des variables sociodémographiques. Conclusions : Dans les limites de l’étude, il est conclu qu’une relation positive existe entre la satisfaction des patients et leur OHRQoL. La difficulté masticatoire et la condition buccale sont les deux éléments de la satisfaction les plus importants. / Statement of problem: Patients’ satisfaction and oral health-related quality of life (OHRQoL) are two commonly used patient-reported outcomes. Convincing evidence is lacking to demonstrate the relation between these two outcomes in completely edentate patients who receive prosthodontic treatments. In addition, it is still unclear which elements of denture satisfaction share the best association with OHRQoL. Objectives: To evaluate the level of association between patients’ denture satisfaction and OHRQoL in edentulous patients, and to identify the determinants of satisfaction that best predict OHRQoL. Methods: Data from 255 edentulous elders who participated in a randomized clinical trial were used to analyze the relationship between OHRQoL and denture satisfaction. OHRQoL was evaluated with the Oral Health Impact Profile (OHIP-20) questionnaire. The McGill Denture Satisfaction Instrument was used to assess patients’ satisfaction with treatment. Outcomes were measured prior to treatment and 6 and 12 months after delivery of new dentures. Simple and multiple linear regressions analyses were performed to statistically assess the relationship between the variables. Results: A highly positive association exists between oral health-related quality of life and denture satisfaction ratings. Chewing ability (P = .005) and oral condition (P = .002) are the aspects of satisfaction presenting the best association with OHRQoL. These two variables explained 46.4% (P = .0001) of the variance in OHIP’s change score following treatment. This association varied with time, but not with type of treatment or socio-demographic variables. Conclusions: Within the limitations of this study, a highly positive association exists between OHRQoL and denture satisfaction. Chewing ability and oral condition are the determinant of denture satisfaction best associated with OHRQoL, predicting 46.4% of its improvement following a treatment.

Le développement d’un médicament est non seulement complexe mais les retours sur investissment ne sont pas toujours ceux voulus ou anticipés. Plusieurs médicaments échouent encore en Phase III même avec les progrès technologiques réalisés au niveau de plusieurs aspects du développement du médicament. Ceci se traduit en un nombre décroissant de médicaments qui sont commercialisés. Il faut donc améliorer le processus traditionnel de développement des médicaments afin de faciliter la disponibilité de nouveaux produits aux patients qui en ont besoin. Le but de cette recherche était d’explorer et de proposer des changements au processus de développement du médicament en utilisant les principes de la modélisation avancée et des simulations d’essais cliniques. Dans le premier volet de cette recherche, de nouveaux algorithmes disponibles dans le logiciel ADAPT 5® ont été comparés avec d’autres algorithmes déjà disponibles afin de déterminer leurs avantages et leurs faiblesses. Les deux nouveaux algorithmes vérifiés sont l’itératif à deux étapes (ITS) et le maximum de vraisemblance avec maximisation de l’espérance (MLEM). Les résultats de nos recherche ont démontré que MLEM était supérieur à ITS. La méthode MLEM était comparable à l’algorithme d’estimation conditionnelle de premier ordre (FOCE) disponible dans le logiciel NONMEM® avec moins de problèmes de rétrécissement pour les estimés de variances. Donc, ces nouveaux algorithmes ont été utilisés pour la recherche présentée dans cette thèse. Durant le processus de développement d’un médicament, afin que les paramètres pharmacocinétiques calculés de façon noncompartimentale soient adéquats, il faut que la demi-vie terminale soit bien établie. Des études pharmacocinétiques bien conçues et bien analysées sont essentielles durant le développement des médicaments surtout pour les soumissions de produits génériques et supergénériques (une formulation dont l'ingrédient actif est le même que celui du médicament de marque, mais dont le profil de libération du médicament est différent de celui-ci) car elles sont souvent les seules études essentielles nécessaires afin de décider si un produit peut être commercialisé ou non. Donc, le deuxième volet de la recherche visait à évaluer si les paramètres calculer d’une demi-vie obtenue à partir d'une durée d'échantillonnage réputée trop courte pour un individu pouvaient avoir une incidence sur les conclusions d’une étude de bioéquivalence et s’ils devaient être soustraits d’analyses statistiques. Les résultats ont démontré que les paramètres calculer d’une demi-vie obtenue à partir d'une durée d'échantillonnage réputée trop courte influençaient de façon négative les résultats si ceux-ci étaient maintenus dans l’analyse de variance. Donc, le paramètre de surface sous la courbe à l’infini pour ces sujets devrait être enlevé de l’analyse statistique et des directives à cet effet sont nécessaires a priori. Les études finales de pharmacocinétique nécessaires dans le cadre du développement d’un médicament devraient donc suivre cette recommandation afin que les bonnes décisions soient prises sur un produit. Ces informations ont été utilisées dans le cadre des simulations d’essais cliniques qui ont été réalisées durant la recherche présentée dans cette thèse afin de s’assurer d’obtenir les conclusions les plus probables. Dans le dernier volet de cette thèse, des simulations d’essais cliniques ont amélioré le processus du développement clinique d’un médicament. Les résultats d’une étude clinique pilote pour un supergénérique en voie de développement semblaient très encourageants. Cependant, certaines questions ont été soulevées par rapport aux résultats et il fallait déterminer si le produit test et référence seraient équivalents lors des études finales entreprises à jeun et en mangeant, et ce, après une dose unique et des doses répétées. Des simulations d’essais cliniques ont été entreprises pour résoudre certaines questions soulevées par l’étude pilote et ces simulations suggéraient que la nouvelle formulation ne rencontrerait pas les critères d’équivalence lors des études finales. Ces simulations ont aussi aidé à déterminer quelles modifications à la nouvelle formulation étaient nécessaires afin d’améliorer les chances de rencontrer les critères d’équivalence. Cette recherche a apporté des solutions afin d’améliorer différents aspects du processus du développement d’un médicament. Particulièrement, les simulations d’essais cliniques ont réduit le nombre d’études nécessaires pour le développement du supergénérique, le nombre de sujets exposés inutilement au médicament, et les coûts de développement. Enfin, elles nous ont permis d’établir de nouveaux critères d’exclusion pour des analyses statistiques de bioéquivalence. La recherche présentée dans cette thèse est de suggérer des améliorations au processus du développement d’un médicament en évaluant de nouveaux algorithmes pour des analyses compartimentales, en établissant des critères d’exclusion de paramètres pharmacocinétiques (PK) pour certaines analyses et en démontrant comment les simulations d’essais cliniques sont utiles. / Drug development is complex with results often differing from those anticipated or sought after. Despite technological advances in the many fields which are a part of drug development, there are still many drugs that fail in the late stages of clinical development. Indeed, the success rate of drugs reaching commercialization is declining. Improvements to the conventional drug process are therefore required in order to facilitate development and allow new medications to be provided more rapidly to patients who require them. The aim of this Ph.D. project was to explore and propose ways to improve this inefficient drug development process with the use of advanced modeling and clinical trial simulations. For the first part of this research, new algorithms available in ADAPT 5® were tested against other available algorithms in order to determine their potential strengths and weaknesses. The two new algorithms tested were the iterative two-stage and the maximum likelihood expectation maximization (MLEM) methods. Our results demonstrated that the MLEM algorithm was consistently better than the iterative two-stage algorithm. It was also comparable with the first order conditional estimate method available in NONMEM®, with significantly fewer shrinkage issues in the estimation of the variances. Therefore, these new tools were used for the clinical trial simulations performed during the course of this Ph.D. research. In order to calculate appropriate noncompartmental pharmacokinetic parameter estimates during the drug development process, it is essential that the terminal elimination half-life be well characterized. Properly conducted and analyzed pharmacokinetic studies are essential to any drug development plan, and even more so for generic and supergeneric (a formulation similar to the reference product, containing the same active ingredient; however differing from the original reference product it its delivery process) submission where they often are the only pivotal studies that need to be done to decide if a drug product is good or not. Thus, the purpose of the second part of the research was to determine if the pharmacokinetic (PK) parameters obtained from a subject whose half-life is calculated from a sampling scheme duration that is considered too short could bias the bioequivalence conclusions of a study and if these parameters should be removed from statistical analyses. Results demonstrated that subjects with a long half-life relative to the duration of the sampling scheme negatively influenced results when these were maintained in the analysis of variance. Therefore, these subjects should be removed from the analyses and guidelines to this effect are required a priori. Pivotal pharmacokinetic studies done within the drug development process should therefore follow this recommendation to make sure that the right decision be taken on a drug product formulation. This information was utilized with the clinical trial simulations that were subsequently performed in this research in order to ensure the most accurate conclusions. Finally, clinical trial simulations were used to improve the development process of a nonsteroidal anti-inflammatory drug. A supergeneric was being developed and results from a pilot study were promising. However, some results from the pilot study required closer attention to determine if the test and reference compounds were indeed equivalent and if the test compound would meet the equivalence criteria of the different required pivotal studies. Clinical trial simulations were therefore undertaken to address the multiple questions left unanswered by the pilot study and these suggested that the test compound would probably not meet the equivalence criteria. In addition, these results helped determine what modifications to the test drug would be required to meet the equivalence criteria. This research brought forward solutions to improve different aspects of the drug development process. Notably, clinical trial simulations reduced the number of studies that would have been done for a supergeneric, decreased the number of subjects unnecessarily exposed to a drug, lowered costs and helped established new criteria for the exclusion of subjects from analyses. Research conducted during this Ph.D. provided concrete ways to improve the drug development process by evaluating some newly available tools for compartmental analyses, setting standards stipulating which estimated PK parameters should be excluded from certain PK analyses and illustrating how clinical trial simulations are useful to throughout the process.

Les gliomes sont les tumeurs cérébrales primaires les plus communes chez l’adulte. Parmi eux, le glioblastome (GBM) représente la tumeur cérébrale la plus fréquente avec le pronostic le plus sombre. Son incidence annuelle est d'environ 3 à 5 cas pour 100 000 personnes (environ 3000 nouvelles chaque année en France). La survie médiane varie entre 11 et 13 mois selon la qualité de la résection tumorale.Le standard de soins inclue une résection chirurgicale et est suivie d'une radiothérapie et d'une chimiothérapie. Une résection maximale est souhaitée afin de diminuer les risques de récidive. Bien que l’utilisation de la technique de diagnostic photodynamique peropératoire, appelée résection fluoroguidée (FGR), améliore la qualité de résection, une récidive survient dans ces berges de la cavité opératoire dans 85% des cas.Des thérapies alternatives doivent être développées pour améliorer la survie globale des patients. Dans ce contexte, la thérapie photodynamique (PDT) semble pertinente. La PDT est basée sur la synergie de trois paramètres : une molécule, la photosensibilisateur (PS) qui se concentre préférentiellement dans les cellules tumorales, la lumière laser et l'oxygène. La lumière laser induit une réaction entre le PS et l’oxygène de la cellule. Cette réaction produit des molécules cytotoxiques (dont l'oxygène singulet) et conduit à la mort de cellules tumorales. Deux modalités de traitement sont étudiées : la PDT interstitielle (iPDT) ou la PDT peropératoire.L'objectif principal de cette thèse est de fournir des outils technologiques afin développer la PDT pour le traitement du GBM. Ainsi, les deux modalités de traitement ont été étudiées.Lorsque la résection n'est pas réalisable (environ 20% à 30% des cas), l'iPDT peut être privilégiée. Cette modalité vise à insérer des fibres optiques dans la cible thérapeutique pour éclairer les tissus tumoraux. Ainsi, la simulation de la propagation de la lumière dans les tissus est nécessaire pour planifier la localisation des fibres optiques. Considérée comme méthode de référence, un modèle Monte-Carlo accéléré par processeurs graphiques a été développé. Ce modèle calcule la propagation de la lumière émise par un diffuseur cylindrique dans des milieux hétérogènes. La précision du modèle a été évaluée avec des mesures expérimentales. L'accélération fournie par la parallélisation permet son utilisation dans la routine clinique.L'iPDT doit être planifiée à l'aide d'un système de planification de traitement (TPS). Une preuve de concept d'un TPS dédié au traitement stéréotaxique iPDT du GBM a été développée. Ce logiciel fournit des outils de base pour planifier l'insertion stéréotaxique de diffuseurs cylindriques et calculer la dosimétrie associée. Le recalage stéréotaxique et la précision du calcul dosimétrique ont été évalués avec des méthodologies spécifiques.Lorsque la résection est réalisable, la PDT peropératoire peut être appliquée au début de la FGR. Celle-ci profite de la présence du PS (la protoporphyrine IX) utilisé pour la FGR et qui s’est déjà concentrée dans les cellules tumorales. Ainsi, la stratégie de traitement proposée peut s’inclure facilement au standard de soin. Un dispositif médical a été conçu pour s'adapter à la cavité et éclairer de façon homogène les berges de la cavité opératoire. Le dispositif est constitué de deux parties : un trocart couplé à un ballon gonflable et un guide de fibre optique développé au sein du laboratoire ONCO-THAI permettant d'insérer la source lumineuse. Des méthodologies spécifiques ont été développées pour étalonner et évaluer l'appareil en termes de contrainte mécanique et de dosimétrie. L'étalonnage a permis la création d’une fonction de transfert permettant une prescription de durée de traitement rapide, robuste et facile. De plus, de nombreux tests ont été réalisés en amont de l'essai clinique qui évalue la sécurité de la procédure. / Gliomas are the most common primary brain tumors in adults. Among them, glioblastoma (GBM) represents the most frequent primary brain tumor and have the most dismal prognosis. Its annual incidence is about 3 to 5 cases for 100,000 persons (about 3000 news cases each year in France). Median survival varies between 11 to 13 months according the extent of tumor resection.The standard of care includes surgery and is followed by radiation therapy and chemotherapy. Maximal resection is expected to delay recurrence. Despite of using intraoperative photodynamic diagnosis, or fluorescence guided resection (FGR), which improves the extent of resection, relapse still occurs in these resection margins in 85% of cases.Alternatives therapies have to be developed to enhance patients’ overall survival. In this context, Photodynamic Therapy (PDT) seems relevant. PDT is based on the synergy of three parameters: a photosensitizing molecule, the photosensitizer (PS) that concentrates preferentially into the tumor cells, laser light and oxygen. Laser light induces a reaction between the PS and the oxygen of the cell. This reaction produces highly cytotoxic molecules (including singlet oxygen) and leads to death of tumor cells. Two treatment modalities are investigated: interstitial PDT (iPDT) or intraoperative PDT.The main goal of this thesis is to provide technological tools to develop the PDT for GBM treatment. Thus, the two treatment modalities have been investigated.When tumor resection is non-achievable (about 20% to 30% of cases), iPDT may be preferred. This modality aims to insert optical fibers directly into the target to illuminate tumor tissues. Thus, simulation of light propagation in brain tissues is required to plan the location of optical fibers. Considered as reference method, a Monte-Carlo model accelerated by graphics processing unit was developed. This model computes the light propagation emitted by a cylindrical diffusor inside heterogeneous media. Accuracy of the model was evaluated with experimental measurements. The acceleration provided by the parallelization allows its use in clinical routine.The iPDT has to be planned using a Treatment Planning System (TPS). A proof of concept of a TPS dedicated to the stereotactic iPDT treatment of GBM was developed. This software provides basic tools to plan the stereotactic insertion of cylindrical diffusors in patient’s brain and to compute the associated dosimetry. The stereotactic registration and the dosimetry computation’s accuracy were evaluated with specific methodologies.When tumor resection is achievable, the intraoperative PDT may be applied early after the FGR. It takes advantage of the presence of the PS (the protoporphyrin IX) used for FGR purpose and that is already concentrates into the tumor cells. Thus, the proposed treatment strategy fits into the current standard of care. A medical device was designed to fit to the resection cavity and illuminate homogeneously the cavity’s margins. The device is constituted of two parts: a trocar coupled to an inflatable balloon and a fiber guide developed in the ONCO-THAI laboratory allowing to insert the light source. Specific methodologies were developed to calibrate and assess the device in terms of mechanical properties and dosimetry. The calibration process leaded to a transfer function that provides fast, robust and easy treatment duration prescription to induce a PDT response in cavity margins. Furthermore, a comprehensive experimental design has been worked out prior to the clinical trial that evaluate the safety of the procedure.

Introdução: A doença de Machado-Joseph (DMJ) ou ataxia espinocerebelar tipo 3 (SCA3) é causada por uma expansão de trinucleotídeos CAG no gene ATXN3, que leva à degeneração de múltiplos sistemas neurológicos. Seu curso é invariavelmente progressivo, não havendo tratamento específico. Objetivos: Descrever novos biomarcadores, aspectos não motores e definir quais escalas clínicas devem ser utilizadas como desfechos principais nos futuros ensaios clínicos randomizados (ECR) para a DMJ/SCA3. Além de avaliar se o tratamento com carbonato de lítio é seguro e efetivo em reduzir a progressão desta condição. Métodos: Em estudo caso-controle avaliamos: 1) a relação dos sintomas depressivos na DMJ/SCA3, pelo inventário de Beck (BDI), com aspectos de gravidade clínica e molecular; 2) alterações no índice de massa corporal (IMC) e sua correlação com aspectos clínico-moleculares e de neuroimagem; e 3) o Sistema Insulina/ IGF-1 (IIS) e o potencial de seus componentes como biomarcadores. Fizemos uma revisão sistemática sobre os aspectos psicométricos das escalas clínicas de SCAs já descritas, para em seguida iniciarmos um ECR, duplo-cego, paralelo, placebo-controlado de fase 2/3. Para este estudo foram randomizados 62 pacientes com diagnóstico molecular prévio de DMJ/SCA3 com marcha independente e ≤ 10 anos de doença (1:1) para tratamento com carbonato de lítio (0.5-0.8mEq/L) ou placebo. Resultados: Os escores do BDI foram mais elevados na DMJ/SCA3 (p= 0.012) e correlacionaram-se significativamente apenas com as escalas SARA (R=0.359, p=0.01) e NESSCA (R=0.412, p=0.003). Os pacientes com DMJ/SCA3 (N=46) apresentaram IMC menor (24.4 ± 4.1) do que os indivíduos controle (N=42, 27.1± 4.5, p=0.01), havendo correlação inversa (R=−0.396, p=0.015) entre o IMC e o tamanho da sequencia repetitiva CAG (CAGn). Encontramos uma maior sensibilidade periférica à insulina (HOMA2-%S, p=0.003, corrigido pelo IMC) e níveis séricos mais elevados da proteína ligante do IGF-1, IGFBP-1 (p=0.001) na DMJ/SCA3. A IGFBP1 correlacionou-se diretamente à CAGn (R=0.452; p = 0.006) e a sensibilidade à insulina inversamente à idade de início dos sintomas (R=-0.444; P = 0.003). Concluímos, na revisão sistemática, que as escalas semi-quantitativas SARA e NESSCA, e as quantitativas SCAFI e CCFS seriam os melhores desfechos para um ECR. O uso de lítio foi seguro após 24 semanas de tratamento, não havendo diferenças no número total de eventos adversos entre os grupos lítio (50,3%) e placebo (49,7%, p=1.00). O grupo placebo apresentou maior progressão (que não foi significativa) nos escores NESSCA (0.35 pontos, 95% IC -1.0 a 1.7, p=0.222, desfecho primário de efetividade) e SARA (0.96 pontos, 95% IC -0.46 a 2.38, p=0.329), após 48 semanas de tratamento. A gravidade da ataxia de marcha (p=0.008), as provas funcionais quantitativas: PATA rate (p=0.002) e Click Test ND (p=0.023), e os escores compostos SCAFI (p=0.015) e CCFS (p=0.029) apresentaram menor progressão no grupo tratado com lítio durante as 48 semanas. Conclusão: Os resultados destes estudos ajudam no entendimento da depressão e alterações nutricionais da DMJ/SCA3 e apontam a IGFBP-1 como biomarcador e a sensibilidade periférica insulínica como modificador do fenótipo. Houve efetividade do tratamento com carbonato de lítio nos desfechos secundários do ECR, sendo necessária confirmação por ensaios clínicos multicêntricos. / Background: Machado-Joseph disease (MJD) or spinocerebellar ataxia type 3 (SCA3) is caused by a CAG repeat expansion at ATXN3 gene, leading to progressive degeneration of multiple neurological systems. MJD/SCA3 is an invariably progressive disorder, with no current treatment. Objectives: To describe new disease biomarkers, non-motor aspects and to define the clinical SCA scales to be utilized as main outcomes in future randomized controlled trials (RCT) on MJD/SCA3. And further assess safety and effectiveness of lithium carbonate in reducing the progression of this condition. Methods: We performed a case-control study to evaluate: 1) the relation of MJD/SCA3 depressive symptoms, through Beck depression Inventory (BDI), with other clinical and molecular findings; 2) the Body Mass Index (BMI) of MJD/SCA3 patients and the correlation with other clinical, molecular and neuroimaging findings; and 3) the Insulin/IGF-1 system (IIS) in MJD/SCA3 and the possible biomarker properties of its components. We further performed a systematic review on the psychometric properties of the described SCAs scales in order to initiate the double-blind, parallel, placebo-controlled phase 2/3 clinical trial. 62 independently ambulatory MJD/SCA3 patients with ≤ 10 years of disease duration were randomly assigned in the RCT (1:1) to lithium (0.5-0.8mEq/L) or placebo. Results: BDI scores were higher in MJD/SCA3 patients (p= 0.012), with significant correlations only with the scales SARA (R=0.359, p=0.01) and NESSCA (R=0.412, p=0.003). MJD/SCA3 patients (N=46) presented lower BMI (24.4 ± 4.1) than control individuals (N=42, 27.1± 4.5, p=0.01). BMI correlated inversely with the length of the expanded CAG repeat (CAGn). We found higher peripheral sensitivity to insulin (HOMA2-%S, p=0.003, corrected for BMI) and serum levels of the IGF-1 binding protein, IGFBP-1 (p=0.001) in MJD/SCA3. IGFBP-1 correlated with CAGn (R=0.452; p = 0.006) and insulin sensitivity with the age of disease onset (R=-0.444; P = 0.003). In the systematic review we concluded that the semiquantitative SCA scales SARA and NESSCA and the quantitative instruments SCAFI and CCFS would be the most appropriate outcomes for the RCT. After 24 weeks, there were no differences in the number of adverse events in lithium (50.3%) and placebo (40.7%) groups (p=1.00) in the RCT. The placebo group presented a non-significant faster progression on NESSCA (0.35 points, 95% CI -1.0 to 1.7, p=0.612, primary effectiveness outcome) and SARA (0.96 points, 95% CI -0.46 to 2.38, p=0.186), after 48 weeks of treatment. Gait ataxia severity (p=0.008), the quantitative performance tasks: PATA rate (p=0.002) and Click Test ND (p=0.023), and the composite scores SCAFI (p=0.015) and CCFS (p=0.029) presented a slower progression under lithium therapy in the overall 48 weeks period. Conclusion: These studies added to the understanding of depressive and nutritional manifestations of MJD/SCA3 and points IGFBP-1 as a biomarker and peripheral insulin sensitivity as a disease phenotype modifier. The effectiveness of lithium carbonate treatment shown in secondary outcomes of the RCT opened a perspective for an effective therapy for this untreatable disorder that must be confirmed by large multicentric clinical trials.

Made available in DSpace on 2015-12-06T23:45:07Z (GMT). No. of bitstreams: 0 Previous issue date: 2010 / Objetivos: Realizar uma análise metodológica da área de odontologia quanto ao risco de viés de ensaios controlados randomizados (ECR) de acesso aberto, disponibilizados na base de dados Lilacs (Literatura Latino-Americana e do Caribe em Ciências da Saúde), avaliar a potencial contribuição da Lilacs como fonte de estudos primários para revisões sistemáticas da literatura e avaliar possível associação entre a base Qualis, tipo de estudo e risco de viés. Material e Métodos: Foram selecionados 40 periódicos de acesso aberto da base Lilacs. Uma busca manual página a página foi conduzida para identificar os artigos publicados, de acordo com o tipo de estudo, durante um período de seis anos. A classificação dos estudos foi realizada por revisores independentes com a confiabilidade avaliada por estatística Kappa. Os ECR identificados foram separados para a avaliação do risco de viés. Foram coletados dados sobre: geração da seqüência de alocação, sigilo da alocação, cegamento, dados de desfechos incompletos, número de dimensões de baixo risco de viés, país e Qualis. As associações foram avaliadas pelos testes de Kruskal-Wallis, Mann Withney e Kendal tau, correlação de Sperman e análise de regressão. Resultados: A pesquisa manual recuperou 4879 artigos com predominância de estudos com baixo nível de evidência (92%). Estudos com alto nível de evidência para avaliação de intervenções representavam apenas 1,94% dos artigos indexados. Estudos epidemiológicos como Caso-Controle e Coorte eram apenas 1,41%. O Brasil representou 72% do total de publicações, entretanto, 64,42% dos estudos utilizaram projetos de pesquisa com baixo nível de evidência. Dos 78 estudos classificados, somente 10 eram verdadeiros ECR e, destes, somente um único estudo era de baixo risco de viés. O item mais frequentemente nos ECR avaliados foi cegamento. A base Qualis não estava associada à hierarquia de evidência e nem às dimensões de risco de viés. Conclusão: O conjunto de estudos em odontologia indexados na base Lilacs se constitui em um corpo de evidência muito limitado para fornecer estudos primários elegíveis com alto nível de evidência para autores de revisões sistemáticas, para clínicos e gestores sobre intervenções, prognóstico ou etiologia em odontologia. / Objectives: To conduct a methodological analysis of the area of dentistry on the risk of bias in randomized controlled trials (RCT) of open access, available in the database Lilacs (Latin American and Caribbean Health Sciences), to assess the potential contribution Lilacs as the source of primary studies for systematic reviews and and evaluate possible association between the base and Qualis study type and risk of bias. Methods: We selected 40 open access journals of the Lilacs database. A handsearch page page has been conducted to identify published articles, according to the type of study, over a period of six years. The classification of studies was conducted by independent reviewers with reliability assessed by Kappa statistic. RCTs identified were separated to assess the risk of bias. We collected data on: generation of allocation sequence, allocation concealment, blinding, incomplete outcome data, number of dimensions of low risk of bias, country and Qualis. Associations were evaluated by Kruskal-Wallis, Mann Whitney and Kendal tau, Spearman correlations and regression analysis. Results: The handsearch retrieved 4879 articles with predominance of studies with a low level of evidence (92%). Studies with a high level of evidence for evaluation of interventions represented only 1.94% of the articles indexed. Epidemiological studies and case-control and cohort were only 1.41%. Brazil has accounted for 72% of all publications, however, 64.42% of the studies used research projects with low level of evidence. Of the 78 studies classified, only 10 were true RCT, and of these only one study was a low risk of bias. The item most often evaluated in the RCT was blinding. The base which was not associated with the hierarchy of evidence and not to the dimensions of risk of bias. Conclusion: The set of studies in dentistry indexed in Lilacs constitutes a very limited body of evidence to provide eligible primary studies with high evidence to authors of systematic reviews to clinicians and managers about operations, prognosis or etiology in dentistry. / BV UNIFESP: Teses e dissertações

Made available in DSpace on 2014-06-11T19:33:01Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-02-16Bitstream added on 2014-06-13T20:24:35Z : No. of bitstreams: 1 guimaraes_ms_dr_arafo.pdf: 1443329 bytes, checksum: 2d3d8b079af9426aadd16dd726576433 (MD5) / O objetivo deste trabalho, dividido em três estudos, foi investigar (1) a reparabilidade de um cimento de ionômero de vidro modificado por resina, (2) o efeito cariostático e (3) a retenção de selantes ionoméricos aderidos ao esmalte não desgastado com sistemas adesivos autocondicionantes simplificados. Materiais e Métodos: Para o estudo 1 foram confeccionados 60 espécimes de cada material, Vitremer (VT) e resina Z250 (RC). Após envelhecimento químico e térmico, eles foram divididos em 3 grupos de acordo com o tratamento mecânico da superfície: ponta diamantada em alta rotação, ponta em ultra-som e sem desgaste. Cada espécime foi reparado com o mesmo material utilizado inicialmente. Aplicou-se na superfície do VT o Vitremer Primer (VP), e para a resina, utilizou-se ácido fosfórico seguido de adesivo Single Bond. Os espécimes foram isolados deixando exposta a interface de união. Após novo envelhecimento, os mesmos foram impregnados por nitrato de prata, seccionados e avaliados quanto à infiltração e formação de fendas. Os dados foram analisados pelos testes de Kruskal-Wallis e Mann-Whitney (α=0,05). No segundo estudo 64 incisivos bovinos foram distribuídos em 4 grupos segundo o tratamento da superfície de esmalte: VP, Prompt L-Pop (Pr), Xeno III (Xe) ou sem tratamento. Um cilindro de VT foi construído em metade dos dentes, enquanto que a RC foi utilizada na outra metade. Os corpos de prova foram 19 submetidos a desafio cariogênico e seccionados, para realização de testes de dureza em três regiões: externa, união e interna, até a profundidade de 300 μm. Os dados transformados em porcentagem de perda mineral foram analisados pelo teste de ANOVA complementado pelo teste de Tukey ao nível de significância de 5%. No terceiro estudo, 20 pares de molares permanentes hígidos foram selecionados de crianças entre 6 e 10 anos. Em um dos dentes foi aplicado... / The purpose of this work, divided into three studies, was to investigate (1) the reparability of a resin-modified glass-ionomer cement, as well as (2) the cariostatic effect and (3) retention of glass-ionomer sealants bonded to enamel with one-step self-etching adhesive systems. Materials and Methods: For the first study, 60 specimens were prepared with Vitremer (VT) and Z250 resin. After chemical and thermal aging, the specimens were divided into 3 groups according to the mechanical treatment of the surface: diamond bur, ultrasound coupled bur or no treatment. Each specimen was repaired with the original restorative material. For VT repairs, Vitremer Primer (VP) was first applied while for composite resin the surface was phosphoric acid etched followed by the application of Single Bond. The specimens were coated with acid resistant varnish except for 1 mm around de interface. After additional aging, the specimens were impregnated by silver nitrate and sectioned medialy for the evaluation of silver infiltration and gap formation in SEM. Data were submitted to Kruskal-Wallis and Mann-Whitney tests (α=0.05). In the second study, 64 bovine teeth were randomly assigned to 4 groups according to the enamel surface treatment: VP, Prompt L-Pop (Pr), Xeno III (Xe) or no treatment. A cylinder of VT was built up in half of the teeth while a composite resin was used in the other half. The teeth were then submitted to a cariogenic challenge after which they 23 were medialy cut. Transversal hardeness evaluation was performed in three regions, external, interface and internal, up to the depth of 300μm. Hardness numbers were converted to percentage of mineral loss and the data were submitted to ANOVA and Tukey tests at the level of significance of 5%. For the third study, 20 pairs of sound permanent molars were selected from children between 6 and 10 years of age. One tooth of the pair received... (Complete abstract click electronic access below)

Orientador: Josimeri Hebling / Banca: Elisa Aparecida Maria Giro / Banca: Angela Cristina Cilense Zuanon / Banca: Célia Regina Moreira Lanza / Banca: Darlon Martins Lima / Resumo: O objetivo deste trabalho, dividido em três estudos, foi investigar (1) a reparabilidade de um cimento de ionômero de vidro modificado por resina, (2) o efeito cariostático e (3) a retenção de selantes ionoméricos aderidos ao esmalte não desgastado com sistemas adesivos autocondicionantes simplificados. Materiais e Métodos: Para o estudo 1 foram confeccionados 60 espécimes de cada material, Vitremer (VT) e resina Z250 (RC). Após envelhecimento químico e térmico, eles foram divididos em 3 grupos de acordo com o tratamento mecânico da superfície: ponta diamantada em alta rotação, ponta em ultra-som e sem desgaste. Cada espécime foi reparado com o mesmo material utilizado inicialmente. Aplicou-se na superfície do VT o Vitremer Primer (VP), e para a resina, utilizou-se ácido fosfórico seguido de adesivo Single Bond. Os espécimes foram isolados deixando exposta a interface de união. Após novo envelhecimento, os mesmos foram impregnados por nitrato de prata, seccionados e avaliados quanto à infiltração e formação de fendas. Os dados foram analisados pelos testes de Kruskal-Wallis e Mann-Whitney (α=0,05). No segundo estudo 64 incisivos bovinos foram distribuídos em 4 grupos segundo o tratamento da superfície de esmalte: VP, Prompt L-Pop (Pr), Xeno III (Xe) ou sem tratamento. Um cilindro de VT foi construído em metade dos dentes, enquanto que a RC foi utilizada na outra metade. Os corpos de prova foram 19 submetidos a desafio cariogênico e seccionados, para realização de testes de dureza em três regiões: externa, união e interna, até a profundidade de 300 μm. Os dados transformados em porcentagem de perda mineral foram analisados pelo teste de ANOVA complementado pelo teste de Tukey ao nível de significância de 5%. No terceiro estudo, 20 pares de molares permanentes hígidos foram selecionados de crianças entre 6 e 10 anos. Em um dos dentes foi aplicado... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The purpose of this work, divided into three studies, was to investigate (1) the reparability of a resin-modified glass-ionomer cement, as well as (2) the cariostatic effect and (3) retention of glass-ionomer sealants bonded to enamel with one-step self-etching adhesive systems. Materials and Methods: For the first study, 60 specimens were prepared with Vitremer (VT) and Z250 resin. After chemical and thermal aging, the specimens were divided into 3 groups according to the mechanical treatment of the surface: diamond bur, ultrasound coupled bur or no treatment. Each specimen was repaired with the original restorative material. For VT repairs, Vitremer Primer (VP) was first applied while for composite resin the surface was phosphoric acid etched followed by the application of Single Bond. The specimens were coated with acid resistant varnish except for 1 mm around de interface. After additional aging, the specimens were impregnated by silver nitrate and sectioned medialy for the evaluation of silver infiltration and gap formation in SEM. Data were submitted to Kruskal-Wallis and Mann-Whitney tests (α=0.05). In the second study, 64 bovine teeth were randomly assigned to 4 groups according to the enamel surface treatment: VP, Prompt L-Pop (Pr), Xeno III (Xe) or no treatment. A cylinder of VT was built up in half of the teeth while a composite resin was used in the other half. The teeth were then submitted to a cariogenic challenge after which they 23 were medialy cut. Transversal hardeness evaluation was performed in three regions, external, interface and internal, up to the depth of 300μm. Hardness numbers were converted to percentage of mineral loss and the data were submitted to ANOVA and Tukey tests at the level of significance of 5%. For the third study, 20 pairs of sound permanent molars were selected from children between 6 and 10 years of age. One tooth of the pair received... (Complete abstract click electronic access below) / Doutor

Made available in DSpace on 2014-12-17T15:16:17Z (GMT). No. of bitstreams: 1 IvaniziaSS_DISSERT.pdf: 831811 bytes, checksum: 8d5c9ce3de798ff5fead323295073f95 (MD5) Previous issue date: 2012-12-17 / In asthmatic, the lung hyperinflation leaves the inspiratory muscle at a suboptimal position in length-tension relationship, reducing the capacity of to generate tension. The increase in transversal section area of the inspiratory muscles could reverse or delay the deterioration of inspiratory muscle function. Objective: To evaluate the evidence for the efficacy of inspiratory muscle training (IMT) with an external resistive device in patients with asthma. Methods: A systematic review with meta-analysis was carried out. The sources researched were the Cochrane Airways Group Specialised Register of trials, Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 11 of 12, 2012), MEDLINE, EMBASE, PsycINFO, CINAHL, AMED, ClinicalTrials.gov and reference lists of articles. All databases were searched from their inception up to November 2012 and there was no restriction on the language of publication. Randomised controlled trials that involved the use of an external inspiratory muscle training device versus a control (sham or no inspiratory training device) were considered for inclusion. Two reviewers independently selected articles for inclusion, evaluated risk of bias in studies and extracted data. Results: A total of five studies involving 113 asthmatic patients were included. Three clinical trials were produced by the same group. The included studies showed a significant increase in maximal inspiratory pressure (MD 13.34 cmH2O, 95% CI 4.70 to 21.98), although the confidence intervals were wide. There was no statistically significant difference between the IMT group and the control group for maximal expiratory pressure, peak expiratory flow rate, forced expiratory volume in one second, forced vital capacity, sensation of dyspnea and use of beta2-agonist. There were no studies describing exacerbation events that required a course of oral and inhaled corticosteroids or emergency department visits, inspiratory muscle endurance, hospital admissions and days of work or school. Conclusions: There is no conclusive evidence in this review to support or refute inspiratory muscle training for asthma, once the evidence was limited by the small number of studies included, number of participants in them together with the risk of bias. More well conducted randomized controlled trials are needed, such trials should investigate respiratory muscle strength, exacerbation rate, lung function, symptoms, hospital admissions, use of medications and days off work or school. IMT should also be assessed in the context of more severe asthma / No paciente asm?tico, a hiperinsufla??o pulmonar coloca os m?sculos inspirat?rios em uma posi??o desfavor?vel na rela??o comprimento-tens?o, reduzindo a capacidade de gerar tens?o. O aumento na ?rea de sec??o transversa dos m?sculos inspirat?rios poderia reverter ou atrasar a deteriora??o da fun??o muscular inspirat?ria. Objetivo: Avaliar a evid?ncia da efic?cia do treinamento muscular inspirat?rio (TMI) com um dispositivo externo em pacientes com asma. M?todos: O tipo de estudo utilizado foi uma revis?o sistem?tica com metan?lise. As fontes pesquisadas foram o Cochrane Airways Group Specialised Register of trials, Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 11 of 12, 2012), MEDLINE, EMBASE, PsycINFO, CINAHL, AMED, ClinicalTrials.gov e lista de refer?ncias dos artigos. Todas as bases de dados foram pesquisadas desde seu in?cio at? novembro de 2012 e n?o houve restri??o de idioma. Foram considerados para inclus?o ensaios cl?nicos controlados e randomizados envolvendo o uso de um aparelho de treinamento muscular inspirat?rio externo versus um controle (placebo ou sem aparelho). Dois revisores independentemente selecionaram os artigos para inclus?o, avaliaram o risco de vi?s e extra?ram os dados dos estudos inclu?dos. Resultados: Um total de cinco estudos envolvendo 113 pacientes asm?ticos foram inclu?dos na revis?o, sendo 3 destes ensaios desenvolvidos pelo mesmo grupo. Os estudos inclu?dos mostraram que o TMI aumenta significativamente a press?o inspirat?ria m?xima (DM 13.34 cmH2O, 95% IC 4.70 ? 21.98), contudo existiu um largo intervalo de confian?a. N?o houve diferen?a significativa entre o grupo TMI e o grupo controle para press?o expirat?ria m?xima, taxa de pico de fluxo expirat?rio, volume expirat?rio for?ado no primeiro segundo, capacidade vital for?ada, sensa??o de dispneia e uso de beta2-agonista. Nenhum estudo investigou os seguintes desfechos: exacerba??es que requereram o uso de corticosteroides inalado ou oral ou visita ao servi?o de emerg?ncia m?dica, endurance dos m?sculos inspirat?rios, admiss?o no hospital e dias de falta ao trabalho ou escola. Conclus?es: N?o existe evid?ncia conclusiva para apoiar ou refutar o uso do TMI para a asma, uma vez que a evid?ncia foi limitada pelo pequeno n?mero de ensaios inclu?dos, reduzido n?mero de participantes e risco de vi?s. Mais estudos randomizados e controlados bem xiv conduzidos s?o necess?rios, tais ensaios devem investigar a for?a muscular respirat?ria, exacerba??es, fun??o pulmonar, sintomas, admiss?o no hospital, uso de medicamentos e dias de falta ao trabalho ou escola. O TMI deve tamb?m ser avaliado no contexto de asma mais grave

Introdução: A doença de Machado-Joseph (DMJ) ou ataxia espinocerebelar tipo 3 (SCA3) é causada por uma expansão de trinucleotídeos CAG no gene ATXN3, que leva à degeneração de múltiplos sistemas neurológicos. Seu curso é invariavelmente progressivo, não havendo tratamento específico. Objetivos: Descrever novos biomarcadores, aspectos não motores e definir quais escalas clínicas devem ser utilizadas como desfechos principais nos futuros ensaios clínicos randomizados (ECR) para a DMJ/SCA3. Além de avaliar se o tratamento com carbonato de lítio é seguro e efetivo em reduzir a progressão desta condição. Métodos: Em estudo caso-controle avaliamos: 1) a relação dos sintomas depressivos na DMJ/SCA3, pelo inventário de Beck (BDI), com aspectos de gravidade clínica e molecular; 2) alterações no índice de massa corporal (IMC) e sua correlação com aspectos clínico-moleculares e de neuroimagem; e 3) o Sistema Insulina/ IGF-1 (IIS) e o potencial de seus componentes como biomarcadores. Fizemos uma revisão sistemática sobre os aspectos psicométricos das escalas clínicas de SCAs já descritas, para em seguida iniciarmos um ECR, duplo-cego, paralelo, placebo-controlado de fase 2/3. Para este estudo foram randomizados 62 pacientes com diagnóstico molecular prévio de DMJ/SCA3 com marcha independente e ≤ 10 anos de doença (1:1) para tratamento com carbonato de lítio (0.5-0.8mEq/L) ou placebo. Resultados: Os escores do BDI foram mais elevados na DMJ/SCA3 (p= 0.012) e correlacionaram-se significativamente apenas com as escalas SARA (R=0.359, p=0.01) e NESSCA (R=0.412, p=0.003). Os pacientes com DMJ/SCA3 (N=46) apresentaram IMC menor (24.4 ± 4.1) do que os indivíduos controle (N=42, 27.1± 4.5, p=0.01), havendo correlação inversa (R=−0.396, p=0.015) entre o IMC e o tamanho da sequencia repetitiva CAG (CAGn). Encontramos uma maior sensibilidade periférica à insulina (HOMA2-%S, p=0.003, corrigido pelo IMC) e níveis séricos mais elevados da proteína ligante do IGF-1, IGFBP-1 (p=0.001) na DMJ/SCA3. A IGFBP1 correlacionou-se diretamente à CAGn (R=0.452; p = 0.006) e a sensibilidade à insulina inversamente à idade de início dos sintomas (R=-0.444; P = 0.003). Concluímos, na revisão sistemática, que as escalas semi-quantitativas SARA e NESSCA, e as quantitativas SCAFI e CCFS seriam os melhores desfechos para um ECR. O uso de lítio foi seguro após 24 semanas de tratamento, não havendo diferenças no número total de eventos adversos entre os grupos lítio (50,3%) e placebo (49,7%, p=1.00). O grupo placebo apresentou maior progressão (que não foi significativa) nos escores NESSCA (0.35 pontos, 95% IC -1.0 a 1.7, p=0.222, desfecho primário de efetividade) e SARA (0.96 pontos, 95% IC -0.46 a 2.38, p=0.329), após 48 semanas de tratamento. A gravidade da ataxia de marcha (p=0.008), as provas funcionais quantitativas: PATA rate (p=0.002) e Click Test ND (p=0.023), e os escores compostos SCAFI (p=0.015) e CCFS (p=0.029) apresentaram menor progressão no grupo tratado com lítio durante as 48 semanas. Conclusão: Os resultados destes estudos ajudam no entendimento da depressão e alterações nutricionais da DMJ/SCA3 e apontam a IGFBP-1 como biomarcador e a sensibilidade periférica insulínica como modificador do fenótipo. Houve efetividade do tratamento com carbonato de lítio nos desfechos secundários do ECR, sendo necessária confirmação por ensaios clínicos multicêntricos. / Background: Machado-Joseph disease (MJD) or spinocerebellar ataxia type 3 (SCA3) is caused by a CAG repeat expansion at ATXN3 gene, leading to progressive degeneration of multiple neurological systems. MJD/SCA3 is an invariably progressive disorder, with no current treatment. Objectives: To describe new disease biomarkers, non-motor aspects and to define the clinical SCA scales to be utilized as main outcomes in future randomized controlled trials (RCT) on MJD/SCA3. And further assess safety and effectiveness of lithium carbonate in reducing the progression of this condition. Methods: We performed a case-control study to evaluate: 1) the relation of MJD/SCA3 depressive symptoms, through Beck depression Inventory (BDI), with other clinical and molecular findings; 2) the Body Mass Index (BMI) of MJD/SCA3 patients and the correlation with other clinical, molecular and neuroimaging findings; and 3) the Insulin/IGF-1 system (IIS) in MJD/SCA3 and the possible biomarker properties of its components. We further performed a systematic review on the psychometric properties of the described SCAs scales in order to initiate the double-blind, parallel, placebo-controlled phase 2/3 clinical trial. 62 independently ambulatory MJD/SCA3 patients with ≤ 10 years of disease duration were randomly assigned in the RCT (1:1) to lithium (0.5-0.8mEq/L) or placebo. Results: BDI scores were higher in MJD/SCA3 patients (p= 0.012), with significant correlations only with the scales SARA (R=0.359, p=0.01) and NESSCA (R=0.412, p=0.003). MJD/SCA3 patients (N=46) presented lower BMI (24.4 ± 4.1) than control individuals (N=42, 27.1± 4.5, p=0.01). BMI correlated inversely with the length of the expanded CAG repeat (CAGn). We found higher peripheral sensitivity to insulin (HOMA2-%S, p=0.003, corrected for BMI) and serum levels of the IGF-1 binding protein, IGFBP-1 (p=0.001) in MJD/SCA3. IGFBP-1 correlated with CAGn (R=0.452; p = 0.006) and insulin sensitivity with the age of disease onset (R=-0.444; P = 0.003). In the systematic review we concluded that the semiquantitative SCA scales SARA and NESSCA and the quantitative instruments SCAFI and CCFS would be the most appropriate outcomes for the RCT. After 24 weeks, there were no differences in the number of adverse events in lithium (50.3%) and placebo (40.7%) groups (p=1.00) in the RCT. The placebo group presented a non-significant faster progression on NESSCA (0.35 points, 95% CI -1.0 to 1.7, p=0.612, primary effectiveness outcome) and SARA (0.96 points, 95% CI -0.46 to 2.38, p=0.186), after 48 weeks of treatment. Gait ataxia severity (p=0.008), the quantitative performance tasks: PATA rate (p=0.002) and Click Test ND (p=0.023), and the composite scores SCAFI (p=0.015) and CCFS (p=0.029) presented a slower progression under lithium therapy in the overall 48 weeks period. Conclusion: These studies added to the understanding of depressive and nutritional manifestations of MJD/SCA3 and points IGFBP-1 as a biomarker and peripheral insulin sensitivity as a disease phenotype modifier. The effectiveness of lithium carbonate treatment shown in secondary outcomes of the RCT opened a perspective for an effective therapy for this untreatable disorder that must be confirmed by large multicentric clinical trials.

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