Dans un contexte où l'importance de la Responsabilité Sociale des Entreprises (RSE) va croissante, cette thèse explore la relation entre la RSE et plusieurs attributs financiers des entreprises comme l'information spécifique incorporée dans le prix des actions, le risque de détresse financière des entreprises et le niveau de crédit commercial. Les chercheurs en finance d'entreprise présentent deux points de vue opposés sur la RSE: "Faire le bien est bon pour les affaires" et "La RSE crée des problèmes d'agence". Le premier chapitre aborde brièvement les théories analysant les répercussions financière de la RSE et met en évidence les avantages financiers concomitants aux pratiques responsables. Les entreprises socialement responsables améliorent l'environnement informationnel ce qui complète l'information financière. Dans le deuxième chapitre, nous montrons que la RSE joue un rôle important dans l'amélioration de l'information incorporée dans les cours boursiers. Une meilleure performance RSE est appréciée par les investisseurs et les gestionnaires d'actifs et améliore la disponibilité des financements. Le troisième chapitre explique que les entreprises peuvent atténuer leur risque de détresse financière (Z-score) en améliorant leur performance en matière de RSE. Des entreprises plus responsables promeuvent de meilleures relations avec les parties prenantes grâce à un objectif de confiance et de maximisation de la valeur. Dans le quatrième chapitre, nous constatons que les entreprises socialement responsables ont un meilleur accès au financement (côté fournisseur du crédit commercial) et font plus confiance à leurs clients (côté acheteur du crédit commercial). Par conséquent, cette dissertation fournit un ensemble de résultats soulignant la pertinence et l'importance de "Faire le bien est bon pour les affaires". / In the context of the rapidly growing importance of Corporate Social Responsibility (CSR), this dissertation explores the relationship between CSR and firm financial attributes, like stock price informativeness, financial distress risk, and trade credit. First chapter briefly discusses the theories of CSR and highlights the financial advantages of favorable CSR practices. Corporate finance researchers present two opposite views on CSR, “Doing good is good for business” and “CSR creates agency problems”. In the second chapter, we testify this association and find that CSR plays an important role to improve the information impounding in stock prices. Socially responsible firms improve the financial information environment. Third chapter elaborates that firms can mitigate their financial distress risk (Z-score) through improved CSR performance. Firm better CSR performance is appreciated by the investors and asset managers and it improves the availability of finance. In fourth chapter, we find that socially responsible firms have better access to finance (supplier side of trade credit) and have more trust on their stakeholders (buyer side of trade credit). Better CSR firms promote the better relationship with stakeholders through trust and value maximization goal. Therefore, this dissertation provides evidence on the importance of “Doing good is good for business”.

Sabe-se que um bom fluxo sanguíneo colateral (FSC) leptomeníngeo está associado a melhor desfecho funcional em paciente com oclusão vascular da circulação anterior. Entretanto, poucos estudos avaliaram os preditores de FSC e seu impacto prognósticos em países em desenvolvimento. O objetivo deste trabalho é avaliar os preditores e o impacto prognóstico do FSC leptomeníngeo nas oclusões do primeiro segmento (M1) da Artéria Cerebral Média (ACM). Métodos: Foi avaliado de maneira retrospectiva, uma coorte prospectiva de pacientes com acidente vascular cerebral (AVC), admitidos em um centro terciário acadêmico de referência para o tratamento de AVC entre janeiro de 2014 e junho de 2017. Foram incluídos pacientes que apresentavam oclusão do segmento M1 da ACM e realizaram angiotomografia de crânio (AngioTC) até 12 horas após o ictus. O FSC foi analisado utilizando uma escala previamente validada na literatura, o rLMC score. Foi avaliado a relação do rLMC score com variáveis clínicas e com desfecho. Na análise univariada foi utilizado o teste de Fisher para variáveis categóricas e t de Student para variáveis quantitativas, também foi utilizado o teste de Spearman para correlação de variáveis contínuas. Características associadas com rLMC score e com desfecho funcional foram incluídas da regressão linear (rLMC não categorizado) e regressão logística binária (rLMC categorizado). Foi utilizado um valor de significância estatística convencional (p=0,05) Resultados: Dos 1559 pacientes com AVC isquêmico admitidos, foram analisados 121 pacientes que preencheram critérios de inclusão/exclusão do estudo. A idade média foi de 67.1±15 anos, NIHSS 13 [IQR 11-22]. Na regressão linear, menor idade (? = -0.2; p=0.005), Doença de14 Chagas (? = 0,22; p=0,008), Tabagismo (? = 0,22; p=0,009), menor NIHSS (? = - 0,25; p=0,002) e história de doença coronariana (? = 0,23; p=0,005) foram associados com melhor rLMC score. Menor idade (? = 0,29; p<0,001), menor NIHSS (? = 0,36; p<0,001) e rLMC>= 17 (? = -0,16; p=0,04) foram associados com melhor desfecho clínico. Conclusão: Pacientes com bom FSC leptomeníngeo apresentam menor NIHSS, menor idade, maior frequência de doença de Chagas, história de tabagismo e doença coronariana prévia. Um bom FSC leptomeníngeo está associado a melhor desfecho funcional entre paciente com AVC isquêmico por oclusão de artérias proximais da circulação anterior no Brasil. / A Good leptomeningeal collateral flow has been associated with better outcomes in patients with proximal occlusions of the anterior circulation. Nevertheless, only few studies have assessed the predictors of good leptomeningeal collateral flow and its impact on clinical outcome in developing countries. We aim to evaluate predictors and prognostic impact of leptomeningeal collateral flow among patients with proximal middle cerebral artery (MCA) occlusion. Method: We retrospectively analyzed a prospective stroke registry of AIS patients admitted to a tertiary Stroke Center in Brazil, with MCA-M1 occlusion within twelve hours of symptoms onset, admitted from January 2014-June 2017. Leptomeningeal score was evaluated using a previously validated Regional Leptomeningeal (rLMC) score. We evaluated association between rLMC score with clinical variables and outcomes. Univariate analysis was performed using Fisher exact test for categorical variables and t-Student for continuous variables. Spearman\'s correlation analysis was performed to find the relationship between continuous variables and rLMC. Variables were included in linear regression model (non categorized rLMC) or binary logistic regression model (categorized rLMC). Conventional levels of statistical significance were used (p=0.05). Results: From 1559 AIS patients, 121 were analyzed. Demographics: age 67.1±15 years, NIHSS 13 [IQR 11-22]. In linear regression, lower age (? = -0.2; p=0.021), Chagas Disease (? = 0.22; p=0.008), smoking (? = 0.22; p=0.009), lower NIHSS (? = -0.25; p=0.002) and history of coronary artery disease (? = 0.23; p=0,005) were associated with better rLMC score. Lower age (? = 0.29; p<0.001), lower NIHSS (? = 0.36; p<0.001) and rLMC>= 17 (? = -0.16; p=0.04) were associated with better functional outcomes. Conclusion: Patients with good leptomeningeal collateral flow had lower age, lower NIHSS, Chagas disease and history of smoking. Good leptomeningeal collaterals on CT angiography are associated to good outcome among AIS patients with proximal arterial occlusion of the anterior circulation in Brazil.

Este trabalho emprega métodos quantitativos a dados de Demonstrações Financeiras para avaliar a existência de relação de causalidade entre a Lei 12.249 de 11 de junho de 2010, que institui normas de subcapitalização no Brasil, e a estrutura de capital de empresas brasileiras que possuem partes vinculadas no exterior. Esta lei estabeleceu limites ao endividamento oriundo de tais partes vinculadas para que os respectivos juros pagos sejam considerados dedutíveis para fins da apuração de tributos sobre o lucro e foi usada como intervenção exógena na análise proposta. Os dados são oriundos de empresas fechadas e de empresas públicas, coletados manualmente, em jornais publicamente disponíveis, e na base de dados Economatica® e foi obtida uma amostra inicial de 2,070 observações. Após exclusão daquelas com Patrimônio Líquido negativo, restaram 1,816 observações em um painel não balanceado, subamostra usada para estimação com o método principal de investigação deste trabalho, que foi o de Diferenças-em-diferenças (DD). Neste, a variável dependente consistiu da razão entre dívida onerosa total e Ativo Total, observados anualmente no período compreendido entre o ano de 2006 e ano de 2014. Este método foi estimado por OLS seus resultados foram complementados com o pareamento de observações por meio de quatro procedimentos de propensity score matching (PSM), one-to-one, nearest neighbour, radius e kernel, em que a variável resposta consistiu da diferença, observada entre o ano de 2011 e o ano de 2009, dos valores da variável resposta descrita anteriormente. Para estimação por meio de matching, foram excluídas observações de empresas que variaram a composição societária ao longo do período de forma a possuir partes vinculadas estrangeiras em determinado momento e não possuí-las mais tarde e também foram excluídas aquelas empresas que não possuem observações durante todo o período avaliado, obtendo-se um painel balanceado com 114 empresas e 1,026 observações. O propensity score obtido foi ainda empregado para ponderar as observações no modelo previamente estimado com o método DD. As variáveis de controle empregadas tanto no DD quanto na estimação do propensity score consistiram dos valores de Ativo Imobilizado, Vendas Líquidas, Lucro Bruto e Patrimônio Líquido, obsevados anualmente e dividido pelo Ativo Total. Os resultados obtidos não foram significantes aos níveis convencionais de confiança, apontando para possível redução da relação entre dívida total e Ativo Total das empresas do grupo tratamento em valores que variaram entre 4.17% e 0.5% em termos de Ativo Total, dependendo do método e modelo estimados. Observa-se que tanto a variável resposta quanto o endividamento oneroso total das empresas de ambos os grupos parecem ter aumentado durante o período investigado, mas a variável resposta, aparentemente, já apresentava crescimento menos acentuado nas empresas do grupo tratamento antes do advento da lei, não sendo possível concluir que esta seja a causa da tendência de decréscimo da relação entre dívida e Ativo Total no grupo de empresas que possuem partes vinculadas estrangeiras. Ressalvadas as limitações do estudo, conclui-se que a lei não teve efeito sobre o endividamento total e, portanto, sem efeitos sobre a arrecadação de tributos sobre o lucro destas empresas. / This work applies quantitative methods to data from Financial Statements to assess the existence of a causal relationship between the Law 12,249 of June 11, 2010, which establishes thin capitalization rules in Brazil, and the capital structure of Brazilian companies that keep foreign related parties. This law established limits to the tax deductibility arising from interest payments to such related parties and was here employed as a source of exogenous variation to perform the proposed analysis. The data came from private and public companies, were manually collected, from publicly available newspapers, and obtained from the Economatica database. An initial sample of 2,070 observations was obtained. After the exclusion of those with negative Equity, there were 1,816 observations composing an unbalanced panel, sub-sample which was used for estimation with the main research method of this investigation, which was the Differences-in-differences (DD) method. A dependent variable consisted of the ratio between total costly debt and Total Asset, observed annually in the period between the years 2006 and 2014. This method has been estimated by OLS and its results were complemented with the pairing of companies by means of four matching methods: One-to-one, nearest neighbour, radius, and kernel, where the response variable consisted of the difference between the dependent variable\'s values observed in the years 2011 and 2009. To estimate the laws\' effects by means of matching procedures, data from companies that showed variation at the societal composition in such a way that led them to have foreign related parties in less than the whole period and from those companies that do not have data throughout the whole period evaluated were excluded, and a balanced panel with 114 companies and 1,026 observations remained. Yet again, the obtained propensity score was applied as weight for another OLS DD estimation. Control variables consisted of the values of Fixed Assets, Net Sales, Gross Profits and Shareholders\' Equity, reported annually and divided by Total Assets. The results obtained were not significant at any conventional confidence levels, nevertheless pointing to a reduction of the treatment group companies\' ratio between debt and Total Assets which varied between 4.17% and 0.5% of Total Assets, depending on the estimated method and model. It appears that the companies\' both response variable and total costly indebtedness increased during the period analysed, but the response variable seems to have already presented a less pronounced growth in the treatment group\'s companies before the existence of the law, therefore making it not possible to conclude that this legislation piece is the cause of the downward trend in the ratio between debt and Total Assets of companies that keep foreign related parties. Subject to this study\'s limitations, it is possible to conclude that the law had no effect on total indebtedness and, therefore, had no effect on profit taxes base erosion regarding this group of companies.

Submitted by JOSIANE SANTOS DE OLIVEIRA (josianeso) on 2017-08-01T16:51:38Z No. of bitstreams: 1 Tiago Henrique Lenhard_.pdf: 599231 bytes, checksum: 3887a7a17e0d823268ecff3b91709a7b (MD5) / Made available in DSpace on 2017-08-01T16:51:38Z (GMT). No. of bitstreams: 1 Tiago Henrique Lenhard_.pdf: 599231 bytes, checksum: 3887a7a17e0d823268ecff3b91709a7b (MD5) Previous issue date: 2017-05-15 / Nenhuma / O objetivo deste trabalho é verificar o efeito da aplicação de taxa de coparticipação como mecanismo de regulação da demanda por serviços de saúde, mais especificamente na frequência e nos custos de consultas médicas, em consultas de plantão hospitalar, em exames laboratoriais e de diagnóstico por imagem. Os dados utilizados para este trabalho são provenientes de uma operadora de planos de saúde (OPS) da modalidade de Cooperativa Médica A metodologia utilizada para avaliar os resultados da aplicação de taxa de coparticipação dos planos é o Propensity Score Matching (PSM) a partir de estimadores One to one Matching (OM), Nearest Neighbor Matching (NNM), Radius Matching (RM) e Kernel Matching (KM). Os resultados indicam a existência de risco moral em indivíduos que possuem plano sem taxa de coparticipação na demanda por consultas médicas e em plantão hospitalar. Para os custos gerados para a OPS por esses serviços o resultado é semelhante. Para os exames laboratoriais o risco moral não foi evidenciado pela ausência de coparticipação nos planos. Já para os exames de diagnóstico por imagem o risco moral foi evidenciado. Os custos para a OPS nesses exames apresentaram um aumento significativo para os indivíduos sem taxa nos dois grupos de exames. Os resultados obtidos por este trabalho indicam que o efeito causado pela taxa de coparticipação é positivo para a OPS, pois a aplicação desse mecanismo reduz significativamente a demanda e os custos para os serviços considerados nesta análise, evidenciando a ocorrência do risco moral em planos sem taxa de coparticipação. / The goal of our study is to investigate the role of copayment as a regulatory mechanism in health services demand. Specifically, we want to understand the effect of copayment on the number and costs related to appointments, emergency appointments, and laboratory and imaging tests. Our dataset was obtained from a health insurance cooperative company (HIC). To evaluate the effects of copayment application in the health care utilization we apply a Propensity Score Matching (PSM) method, using the following estimators: One to one Matching (OM), Nearest Neighbor Matching (NNM), Radius Matching (RM) and Kernel Matching (KM). The results indicate the evidence of moral hazard effects in appointments and emergency appointments demand for those individuals with health insurance without copayment. Similar results are obtained when we consider the costs incurred by the HIC when providing these services. As for laboratory tests, there was no evidence on moral hazard effects. However, when we consider imaging tests, moral hazard effects were evidenced. HIC provision costs of laboratory and imaging tests showed a significant increase for those individuals with health care plan without copayment. Our results indicate that charging a copayment reduces demand and costs of those health care services considered in out study, highlighting the incentives due to the moral hazard existence in the health care insurance market.

La Neurofibromatose 1 (NF1) est une maladie autosomique dominante dont l’évolutivité est inconnue. En effet, ni le type de mutation du gène, la gravité d’éventuels cas familiaux, ni une première complication ne permettent de prédire le pronostic de la maladie. L’objectif général de ce travail de thèse était de cibler les malades les plus à risque de morbi-mortalité au cours de la NF1. Méthode. Les différents travaux se sont appuyés sur les données phénotypiques de patients NF1 suivis dans le Réseau NF-France labellisé par le ministère de la Santé. Il s’agit d’une filière nationale monothématique ayant pour mission la prise en charge des malades atteints de NF1. Une cohorte d’environ 2500 malades est actuellement suivie dans ce réseau. Résultats. La mortalité des patients NF1 a tout d’abord été comparée à celle de la population générale française par l’estimation du rapport de mortalité standardisée (SMR). Entre 1980 et 2006, 1 895 patients NF1 ont été rétrospectivement inclus dans la cohorte. Un excès de mortalité était observé chez les [10-20[ ans (SMR=5.2, IC95% : 2.6 – 9.3, p<10-4) et les [20-40[ ans (SMR=4.1, IC95% : 2.8 – 5.8, p<10-4). Les principales causes de décès étaient la transformation de neurofibromes internes en tumeurs malignes des gaines nerveuses (TMGN). Une étude cas témoins portant sur 208 patients NF1 a permis d’expliquer le risque de mortalité accru chez les patients présentant des neurofibromes sous cutanés (SC-NF) en confirmant en IRM la présence chez ces patients de neurofibromes internes à fort risque de transformation en TMGN (OR=4.3, IC95% : 2.2 – 8.2). Cet effet était d’autant plus marqué que le nombre de SC-NF était important et notamment au-delà d’un seuil de 10 (OR=82, IC95% : 10.4 – 647.9) et que les neurofibromes internes étaient diffus (OR=14.7, IC95% : 3.8 – 57.3) et de taille ≥ 3 cm (OR=6.3, IC95% : 2.3 – 17.4). Les patients présentant des SC-NF représentent 20 à 30% de la population NF1. Afin d’identifier les patients à risque de développer une TMGN, nous avons élaboré un score prédictif de la présence des neurofibromes internes à partir des caractéristiques phénotypiques des patients. La présence de SC-NF (OR=4.7, IC95% : 2.1 – 10.5), l’absence de neurofibromes cutanés (OR=2.6, IC95% : 0.9 – 7.5), un âge inférieur ou égal à 30 ans (OR=3.1, IC95% : 1.4 – 6.8) et moins de 6 tâches café au lait (OR=2, IC95% : 0.9 – 4.6) étaient les variables qui constituaient le NF1Score. Le NF1Score = 10*(âge ≤ 30 ans) + 10*(absence de neurofibromes cutanés) + 5*(moins de 6 tâches café-au-lait) + 15*(plus de 2 neurofibrome sous cutanés) avait une excellente adéquation (test C de Hosmer-Lemeshow=4,53 avec 7ddl, p>0,50) et une capacité discriminante satisfaisante (aire sous la courbe ROC non paramétrique = 0,75 [0,68-0,82]). Enfin, l’expression phénotypique variant au cours du temps chez un même patient nous avons réalisé une étude spécifique chez l’enfant. Ainsi, l’âge (OR=1.1, IC95% : 1.0 – 1.2), la présence de xanthogranulomes (OR=4.5, IC95% : 0.9 – 21.7), celle de neurofibromes sous cutanés et plexiformes (OR=5.0, IC95% : 1.8 – 13.6) étaient indépendamment associés à celle des neurofibromes internes chez l’enfant NF1 de moins de 17 ans. Dans cette dernière étude, les neurofibromes internes se développaient de façon exponentielle pendant l’adolescence et plus précocement chez les femmes en accord avec les données de la littérature. Conclusion. La période à risque de développer des neurofibromes internes semblent donc sesituer entre l’adolescence et l’âge de 30 ans. Les recommandations de suivi pourraient prendre en compte le phénotype à risque, mais également la période de survenue de ces complications en réévaluant l’intérêt dans ce contexte d’investigations complémentaires / Neurofibromatosis-1 (NF1) is a common autosomal dominant condition which is a source of various multisystemic manifestations related either to the accumulation of neurofibromas or to specific developmental abnormalities. There are no obvious factors that predict disease progression. Thus, the aim of our project was to characterize the phenotype of NF1 patients with a severe prognosis. Patients were identified among adults with NF-1 followed up in the Réseau NF-France. The Réseau NF-France is a French medical network devoted to neurofibromatosis 1. It has elaborated recommendations for the management of the disease and recommended a coordinated follow-up in specialized multidisciplinary centres. About 2 500 patients were enrolled. We first evaluated the mortality in a large retrospective cohort of NF1 patients. The standardized mortality ratio (SMR) with its 95% confidence interval (CI) was calculated as the ratio of observed over expected numbers of deaths. Between 1980 and 2006, 1895 NF1 patients were seen. The excess mortality occurred among patients aged 10 to 20 years (SMR=5.2; CI, 2.6-9.3; P<10-4) and 20 to 40 years (SMR, 4.1; 2.8-5.8; P<10-4). The main cause of death was the malignant tumors of the nerve sheath (MPNSTs) developing from preexisting internal neurofibromas. Then, a case-control study including 208 patients with NF1 allowed us to explain the increased risk of mortality among NF1 patients harboring subcutaneous neurofibromas (SC-NF) by the presence of internal neurofibromas (NF) at risk of MPNSTs systematically investigated with imaging (MRI) (OR=4.3, IC95% : 2.2 – 8.2). The association with SC-NF was stronger for patients with ten or more SC-NFs (OR=82, IC95% : 10.4 – 647.9) and for diffuse (OR=14.7, IC95% : 3.8 – 57.3), and ≥ 3 cm (OR=6.3, IC95% : 2.3 – 17.4) internal neurofibromas. Patients with SC-NF constituted 20 to 30% of the NF1 population. So, to characterize patients at risk of developping MPNSTs, we developped and validated a clinical score for predicting internal neurofibromas in adults. Four variables were independently associated with internal neurofibromas: at least two subcutaneous neurofibromas (OR=4.7, IC95% : 2.1 – 10.5), age ≤30 years (OR=3.1, IC95% : 1.4 – 6.8), absence of cutaneous neurofibromas (OR=2.6, IC95% : 0.9 – 7.5), and fewer than six café-au-lait spots (OR=2, IC95% : 0.9 – 4.6). The NF1Score was computed as 10 . [age ≤30 years] + 10 • [absence of cutaneous neurofibromas] + 15 • [≥2 subcutaneous neurofibromas] + 5 • [<6 café-au-lait spots]). Calibration was excellent (Hosmer-Lemeshow statistic=4.53; degrees of freedom=7; P>0.5) and discrimination was good (AUC-ROC= 0.75; 95%CI, 0.7-0.8). Finally clinical expressivity is variable and manifestations of NF1 change at different times in an individual’s life. Consequently, a specific study was needed in pediatric patients. We identified easily recognizable clinical characteristics associated with internal neurofibromas in children with NF1. By multivariate analysis, age (OR=1.1, IC95% : 1.0 – 1.2), xanthogranulomas (OR=4.5, IC95% : 0.9 – 21.7), and presence of both subcutaneous and plexiform neurofibromas (OR=5.0, IC95% : 1.8 – 13.6) were independently associated with internal neurofibromas. Moreover internal neurofibromas increased during adolescence. Excess risk of developing internal neurofibromas seems to occur between the adolescence and the age of to 30 in NF1 patients. These clinical features in adults and children would define a new population at risk for complications that may need closer clinical and imaging follow-up

Le but principal d'un essai de phase I en oncologie est d'identifier, parmi un nombre fini de doses, la dose à recommander d'un nouveau traitement pour les évaluations ultérieures, sur un petit nombre de patients.Le critère de jugement principal est classiquement la toxicité. Bien que la toxicité soit mesurée pour différents organes sur une échelle gradée, elle est généralement réduite à un indicateur binaire appelé "toxicité dose-limitante" (DLT). Cette simplification très réductrice est problématiqu, en particulier pour les thérapies, dites "thérapies ciblées", associées à peu de DLTs.Dans ce travail, nous proposons un score de toxicité qui résume l'ensemble des toxicités observées chez un patient. Ce score, appelé TTP pour Total Toxicity Profile, est défini par la norme euclidienne des poids associés aux différents types et grades de toxicités possibles. Les poids reflètent l'importance clinique des différentes toxicités.\\ Ensuite, nous proposons la méthode de recherche de dose, QLCRM pour Quasi-Likelihood Continual Reassessment Method, modélisant la relation entre la dose et le score de toxicité TTP à l'aide d'une régression logistique dans un cadre fréquentiste.A l'aide d'une étude de simulation, nous comparons la performance de cette méthode à celle de trois autres approches utilisant un score de toxicité : i) la méthode de Yuan et al. (QCRM) basée sur un modèle empirique pour estimer, dans un cadre bayésien, la relation entre la dose et le score, ii) la méthode d'Ivanova et Kim (UA) dérivée des méthodes algorithmiques et utilisant une régression isotonique pour estimer la dose à recommander en fin d'essai, iii) la méthode de Chen et al. (EID) basée sur une régression isotonique pour l'escalade de dose et l'identification de la dose à recommander. Nous comparons ensuite ces quatre méthodes utilisant le score de toxicité aux méthodes CRM basées sur le critère binaire DLT. Nous étudions également l'impact de l'erreur de classement des grades pour les différentes méthodes, guidées par le score de toxicité ou par la DLT.Enfin, nous illustrons le processus de construction du score de toxicité ainsi que l'application de la méthode QLCRM dans un essai réel de phase I. Dans cette application, nous avons utilisé une approche Delphi pour déterminer avec les cliniciens la matrice des poids et le score de toxicité jugé acceptable.Les méthodes QLCRM, QCRM, UA et EID présentent une bonne performance en termes de capacité à identifier correctement la dose à recommander et de contrôle du surdosage. Dans un essai incluant 36 patients, le pourcentage de sélection correcte de la dose à recommander obtenu avec les méthodes QLCRM et QCRM varie de 80 à 90% en fonction des situations. Les méthodes basées sur le score TTP sont plus performantes et plus robustes aux erreurs de classement des grades que les méthodes CRM basées sur le critère binaire DLT.Dans l'application rétrospective, le processus de construction du score apparaît faisable facilement. Cette étude nous a conduits à proposer des recommandations pour guider les investigateurs et faciliter l'utilisation de cette approche dans la pratique.En conclusion, la méthode QLCRM prenant en compte l'ensemble des toxicités s'avère séduisante pour les essais de phase I évaluant des médicaments associés à peu de DLTs a priori, mais avec des toxicités multiples modérées probables. / The aim of a phase I oncology trial is to identify a dose with an acceptable safety level. Most phase I designs use the Dose-Limiting Toxicity (DLT), a binary endpoint, to assess the level of toxicity. DLT might be an incomplete endpoint for investigating molecularly targeted therapies as a lot of useful toxicity information is discarded.In this work, we propose a quasi-continuous toxicity score, the Total Toxicity Profile (TTP), to measure quantitatively and comprehensively the overall burden of multiple toxicities. The TTP is defined as the Euclidean norm of the weights of toxicities experienced by a patient, where the weights reflect the relative clinical importance of each type and grade of toxicity.We propose then a dose-finding design, the Quasi-Likelihood Continual Reassessment Method (QLCRM), incorporating the TTP-score into the CRM, with a logistic model for the dose-toxicity relationship in a frequentist framework. Using simulations, we compare our design to three existing designs for quasi-continuous toxicity scores: i) the QCRM design, proposed by Yuan et al., with an empiric model for the dose-toxicity relationship in a Bayesian framework, ii) the UA design of Ivanova and Kim derived from the "up-and-down" methods for the dose-escalation process and using an isotonic regression to estimate the recommended dose at the end of the trial, and iii) the EID design of Chen et al. using the isotonic regression for the dose-escalation process and for the identification of the recommended dose.We also perform a simulation study to evaluate the TTP-driven methods in comparison to the classical DLT-driven CRM. We then evaluate the robustness of these designs in a setting where grades can be misclassified.In the last part of this work, we illustrate the process of building the TTP-score and the application of the QLCRM method through the example of a paediatric trial. In this study, we have used the Delphi method to elicit the weights and the target toxicity-score considered as an acceptable toxicity measure.All designs using the TTP-score to identify the recommended dose had good performance characteristics for most scenarios, with good overdosing control. For a sample size of 36, the percentage of correct selection for the QLCRM ranged from 80 to 90%, with similar results for the QCRM design. Simulation study demonstrates also that score-driven designs present an improved performance and robustness compared to conventional DLT-driven designs. In the retrospective application of erlotinib trial, the consensus weights as well as the target-TTP were easily obtained, confirming the feasibility of the process. Some guidelines to facilitate the process in a real clinical trial for a better practice of this approach are suggested.The QLCRM method based on the TTP-endpoint combining multiple graded toxicities is an appealing alternative to the conventional dose-finding designs, especially in the context of molecularly targeted agents.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / O contingente de idosos iniciando tratamento de diálise vem aumentado de maneira importante desde o ano de 2000, conforme mostrado pelo United States Renal Data System. Dados nacionais demonstram que cerca de 31,5% dos pacientes em diálise tem idade acima de 65 anos, segundo o Censo Brasileiro de Diálise de 2011. Estes dados alertam para a importância no cuidado da saúde do idoso em diálise. O cuidado nutricional desse grupo merece especial atenção, uma vez que já foi demonstrado que a prevalência de desnutrição energético-proteica nos pacientes idosos em diálise é significantemente maior do que a de adultos jovens em diálise. Nesse sentido, faz-se importante desenvolver estudos com instrumentos que avaliem o estado nutricional desse grupo. Os questionários de avaliação subjetiva global de 7 pontos (ASG-7p) e o malnutrition inflammation score (MIS) têm sido bastante empregados em estudos incluindo pacientes em diálise. Contudo, estes instrumentos estão originalmente na língua Inglesa, e para o seu uso em nosso meio, é necessário a tradução por meio da adaptação transcultural. Porém, até o momento, não há estudos que tenham realizado a tradução transcultural desses questionários para a língua Portuguesa. Deste modo, o objetivo deste estudo foi realizar a adaptação transcultural para o português de dois instrumentos de avaliação do estado nutricional em pacientes idosos em tratamento crônico de hemodiálise (HD). O estudo é do tipo observacional e seccional. A adaptação transcultural consistiu na tradução para a língua Portuguesa da ASG-7p e MIS pelo método da retrotradução, avaliação da equivalência semântica, confiabilidade e validade de construto. Para tanto, 101 pacientes idosos em HD foram avaliados. Ambos questionários apresentaram alto grau de similaridade semântica. A consistência interna apresentou um valor de &#945; de Cronbach para a ASG-7p de 0,72 (satisfatório) e para o MIS de 0,53 (não satisfatório). A ASG-7p apresentou discreta reprodutibilidade intra-avaliador e moderada reprodutibilidade interavaliador; e para o MIS tanto a reprodutibilidade inter quanto intra-avaliador foi indicativo de forte reprodutibilidade. Referente à validade de construto, ao avaliar o estado nutricional pela ASG-7p notou-se que os pacientes classificados como bem nutridos apresentaram medidas de peso corporal, adequação da dobra cutânea tricipital, percentual de gordura corporal, circunferência da panturrilha e creatinina sérica significantemente maiores do que de pacientes desnutridos. Para o MIS, ao comparar os grupo de bem nutridos com o de desnutridos, a albumina sérica, ângulo de fase, percentual de gordura corporal, a adequação da força de preensão manual e da dobra cutânea tricipital e a circunferência da panturrilha apresentaram diferença significante entre os grupos. Em conclusão, os questionários ASG-7p e MIS traduzidos para o português podem ser utilizados na população de idosos em HD. / The contingency of elderly starting dialysis has substantially increased, according to the United States Renal Data System. Data from Brazil show about 31.5% of dialyzed patients are older than 65 years, according to the Brazilian Dialysis Census from 2011. These data show the importance of health care of elderly patients on dialysis. The nutritional status of this group requires attention, since it has been shown a high prevalence of protein-energy waisting in elderly patients on dialysis. Therefore, it is important to develop studies investigating instruments to assess the nutritional status of this group. The 7 point subjective global assessment (7p-SGA) and the malnutrition inflammation score (MIS) have been widely used in studies including patients on dialysis. However, these instruments are originally in English and the use of them in Brazil requires the translation to Portuguese through cross-cultural adaptation. Thus, the aim of this study is to performe the cross-cultural adaptation to Portuguese of 7p-SGA and MIS to assess the nutritional status of elderly patients on hemodialysis (HD). The study design is observational and cross-sectional. 7p-SGA and MIS were translated to Portuguese by back-translation methodology. In addition, the semantic equivalence, reliability and construct validity were performed. Therefore, 101 elderly patients on hemodialysis were evaluated. Both questionnaires showed a high degree of semantic similarity. The internal consistency showed a value of Cronbach's &#945; for the 7p-SGA of 0.72 (satisfactory) and for the MIS of 0.53 (unsatisfactory). The 7p-SGA showed mild intrarater reliability and moderate interrater reliability. For MIS a strong interrater and intrarater reliability was observed. Regarding the construct validity, for 7p-SGA, patients classified as well nourished had body weight, triceps skinfold thickness adequacy, body fat percentage, calf circumference and serum creatinine significantly higher than those classified as malnourished. For MIS, when comparing the group of well nourished with malnourished, serum albumin, phase angle, body fat percentage, handgrip and triceps skinfold thickness adequacy and calf circumference were significantly different between the groups. Conclusion: The questionnaires 7p-SGA and MIS translated to portuguese can be applied to asses the nutritional status of elderly patients on HD.

O câncer de próstata (CaP) é a segunda causa mais comum de câncer em homens. De acordo com o INCA, no Brasil, em 2016, estimam-se aproximadamente 61.200 novos casos de câncer de próstata. Objetivo: Identificar as características demográficas e epidemiológicas, bem como dados do estadiamento tumoral dos pacientes com CaP atendidos na Unidade de Oncologia do Hospital Marcio Cunha na cidade de Ipatinga-MG nos anos de 2012, 2013 e 2014. Metodologia: Trata-se de um estudo retrospectivo e descritivo onde foram analisados 668 prontuários de pacientes, com registro do diagnóstico anatomopatológico, atendidos nos anos de 2012, 2013 e 2014, conforme lista fornecida pela instituição, com diagnóstico de CaP cadastrados com CID-10 - C 61. As variáveis analisadas foram: procedência, ano do diagnóstico, faixa etária, raça autodeclarada, fatores de risco como tabagismo, etilismo, história familiar de CaP, PSA total ao diagnóstico, tipo histológico da biópsia, score de Gleason da biópsia, tipo histológico da peça cirúrgica, score de Gleason da peça cirúrgica. Os dados foram analisados empregando-se estatística descritiva e inferencial, utilizando o software SPSS, versão 19.0. Resultados: A maior incidência de casos de CaP foram provenientes das cidades mais populosas da microrregião de saúde analisada e faixa etária mais prevalente foi entre 61 e 80 anos com prevalência em pardos e brancos e com histórico familiar de 17,2% de parentes de primeiro grau; com o pai em 37,3%, o irmão em 60,8% e filho em 1,9%. Apenas 165 (25,9 %) eram fumantes e 20,8% etilistas. Os níveis de PSA ficaram entre 4,1ng/ e 10ng/ml (49,5%) e quanto maior a faixa etária maiores os valores do PSA. Pacientes pardos apresentaram PSA total mais elevado. Ao avaliarmos se existia relação entre os níveis de PSA total com fatores de risco como tabagismo, etilismo e histórico familiar, somente houve relação estatisticamente significativa com o etilismo. Houve concordância do score de Gleason entre biópsia e peça cirúrgica em 70%, subgraduação em 18,7% e supergraduação em 11,3%. Comparando a idade dos pacientes com Score de Gleason, quanto maior a idade do paciente maior foi o Score de Gleason do material obtido pela biópsia via transretal Pacientes tabagistas e etilistas apresentaram Score de Gleason da peça cirúrgica mais elevados. Conclusão: A concordância entre o Score de Gleason da biópsia e o Score de Gleason da peça cirúrgica foi de 70%; etilistas apresentaram PSA mais elevados; quanto maior foi a faixa etária, mais indiferenciado foi o tumor ( biópsia); pacientes tabagistas e etilistas apresentaram tumores mais indiferenciados na peça cirúrgica; este é o primeiro estudo epidemiológico de CaP desenvolvido na região do Vale do Aço, a caracterização sócio demográfica e as associações aqui encontradas podem contribuir com programas para desenvolver ações de controle do CaP nesta região. / Prostate cancer (PCa) is the second most common cause of cancer in men. According to INCA, in Brazil, in 2016, approximately 61,200 new cases of prostate cancer are estimated. Objective: To identify the demographic and epidemiological characteristics, as well as data on the tumor staging of patients with PCa treated at the Oncology Unit of Hospital Marcio Cunha in the city of Ipatinga-MG in the years of 2012, 2013 and 2014. Methodology: This is a retrospective and descriptive study where 668 patients\' records, with a diagnosis of pathological diagnosis, were analyzed in the years 2012, 2013 and 2014, according to the list provided by the institution, with a diagnosis of PCa registered with ICD-10-C 61. The analyzed variables were: origin, year of diagnosis, age group, self-reported race, risk factors such as smoking, alcoholism, family history of PCa, total PSA at diagnosis, histological type of biopsy, Gleason score of biopsy, histological type of the surgical specimen, Gleason score of the surgical specimen. Data were analyzed using descriptive and inferential statistics, using SPSS software, version 19.0. Results: The highest incidence of PCa cases came from the most populated cities of the analyzed health micro-region and the most prevalent age group was between 61 and 80 years old, with prevalence in brown and whites and with a family history of 17.2% of first-degree relatives degree; With father in 37.3%, brother in 60.8% and son in 1.9%. Only 165 (25.9%) were smokers and 20.8% were alcoholics. PSA levels ranged from 4.1ng / e to 10ng / ml (49.5%) and the higher the age group the higher the PSA values. Brown patients had higher total PSA. When we evaluated whether there was a relationship between total PSA levels and risk factors such as smoking, alcohol consumption and family history, there was only a statistically significant relationship with alcohol consumption. There was concordance of the Gleason score between biopsy and surgical specimen in 70%, subgrade in 18.7% and overdose in 11.3%. Comparing the age of patients with Gleason score, the greater the patient\'s age, the greater the Gleason score of the material obtained by the transrectal biopsy. Smokers and alcoholists presented the highest Gleason score of the surgical specimen. Conclusion: The agreement between the Gleason score of the biopsy and the Gleason score of the surgical specimen was 70%; Higher PSA levels; The longer the age group, the more undifferentiated was the tumor (biopsy); Smokers and alcoholics presented more undifferentiated tumors in the surgical specimen; This is the first epidemiological study of PCa developed in the Vale do Aço region, the socio-demographic characterization and the associations found here can contribute with programs to develop actions of control of PCa in this region.

Existem no mercado vários tipos de alimentos para cães, por isso a determinação de qual alimento fornecer e a quantidade deste que deve ser fornecida aos animais não uma tarefa das mais fáceis. Baseado nisto, o presente estudo visou determinar os efeitos de dois alimentos comerciais secos e dois tipos de fornecimento no consumo alimentar, peso vivo e metabólico, escore fecal e corporal e volume fecal. Para tanto foram utilizados quatro animais da raça Border Collie aos quais foram fornecidos dois alimentos, alimento A (“super premium") e alimento B (popular), distribuídos de duas formas “ad libitum" (AV) e controlada (C). Estes animais receberam os dois alimentos (A e B) fornecidos dos dois modos (AV e C) durante 4 períodos experimentais com 10 dias de duração cada (6 dias de adaptação e 4 de coleta). Os animais foram pesados e seu escore corporal foi observado nos dias coleta dos 4 períodos. Estes cães foram submetidos à atividade diária durante os 40 dias do experimento. Os alimentos eram fornecidos em dois horários 8:00h e 17:00h, sendo que as sobras da refeição anterior eram recolhidas e pesadas antes do fornecimento da próxima. Com isso foi possível a determinação do consumo diário dos animais. Nos dias de coleta foi realizada coleta total das fezes a fim de se determinar seu volume e escore. Os resultados foram analisados utilizando-se o programa SAS. Com a análise estatística pôde-se determinar que o alimento A é realmente de melhor qualidade que o alimento B, e que a quantidade de alimento fornecida foi suficiente para satisfazer as exigências diárias dos animais, mesmo tendo sido estipulada para animais em manutenção. / It is available in the market several types of foods for dogs, that the determination of which food to supply and the amount of this that should be supplied to the animals is not a simple task. Based on this, the aim of the present study was to determine the effects of two dry commercial foods and two supply types in the food consumption, in live and metabolic weights, fecal and corporal score and fecal volume. For so much four animals were used of the race Border Collie to which two foods were supplied, food A ("super premium") and food B (popular), distributed in two ways "ad libitum" (AV) and controlled (C). These animals received the two foods supplied of the two manners during 4 experimental periods with 10 days of duration each (6 days of adaptation and 4 of data collection). The animals were weighted and its corporal score was observed in data collection days of the 4 periods. These dogs were submitted to the daily activity during the all 40 days of the experiment. The foods were supplied in two schedules 8:00 AM and 5:00 PM, and the discard amount of the previous meal were picked up and weighed before the supply of the next. So it was possible the determination of the daily food consumption of the animals. In the days of collection, total collection of the feces was accomplished in order to determine its volume and score. The results were analyzed being used the SAS program. With the statistical analysis it could be determined that the food A is really of better quality than the food B, based mainly in the fecal volume and score, and that the amount of supplied food was enough to satisfy the daily demands of the active animals, even having been specified for animals in maintenance.

L’objectif de cette thèse est de conceptualiser, à partir de l’exploitation des données de remboursement de soins de l’Assurance Maladie, les différentes trajectoires de recours aux soins relatives à la prise en charge d’une pathologie chronique (asthme), et d’étudier les déterminants de ces trajectoires du point de vue du profil et du comportement subséquent du prescripteur de soins. L’étude de la relation entre le comportement prescriptif et la trajectoire de soins est appréhendée par des techniques de modélisation et d’analyses multivariées. L’objectif sous-jacent est d’évaluer, d’un point de vue médico-économique, l’impact de la typologie des prescripteurs (caractéristiques des offreurs de soins) sur les différentes trajectoires de soins suivies par les patients atteints de la pathologie définie supra. Les caractéristiques susceptibles d’identifier une typologie de prescripteur correspondent aux variables influant sur le comportement prescriptif, au sens large, du médecin (âge, sexe, durée d’exercice, type d’exercice, etc.). La question principale de la thèse est celle de l’effet régulateur de l’incitation économique, instaurée par le parcours de soins coordonnés (réforme de l’Assurance Maladie, août 2004), sur les trajectoires de soins, réellement observées, de patients atteints de pathologies chroniques. Les corollaires sont : Le déremboursement des actes hors parcours de soins coordonnés peut-il avoir un impact significatif sur la trajectoire empirique de prise en charge du patient ? Le profil du prescripteur d’actes médicaux a-t-il, toutes choses égales par ailleurs, un effet sur le respect ou non de la trajectoire de soins référentielle admise par le parcours de soins coordonnés ? Quels sont les déterminants principaux du non respect de cette trajectoire référentielle, du point de vue de l’analyse des caractéristiques des couples « médecin – patient» ? / The objective of this thesis is to conceptualize, starting from the exploitation of the refunding data of cares from the Sickness insurance, the various trajectories of cares recourses introduced by chronic diseases as asthma, and to study their determinants by analysing the profile and the subsequent behavior of the general practitioner. The study of the relation between the prescriptive behavior and the trajectory of cares is carried out by different multivariate analyses. The other objective is to evaluate, from a pharmacoeconomic point of view, the impact of the general practitioner characteristics on the various trajectories of cares followed by the patients with chronic diseases. The characteristics likely to identify a typology of practitioners correspond to the variables influencing the prescriptive behavior (age, sex, duration of exercise, type of exercise, etc). The principal question of the thesis is that of the regulating effect of the economic incentive, rested on the coordinated care pathway (reform of the Sickness insurance, August 2004), on the trajectories of cares, really observed by the chronic patients. The corollaries are: Does the no-reimbursement of some medical acts, not considered in the coordinated care pathway, have a significant impact on the empirical recourse of the patient? Does the profile of the general practitioner have an effect on the respect or not of the allowed trajectory of cares classified by the French reform? Which are the principal determinants of disregarding this referential trajectory, by notably analysing the “practitioner - patient” characteristics?