Contexte: L’hémorragie intraventriculaire néonatale est associée à des séquelles neuro-développementales, mais le risque à long terme d'autres issues est inconnu. L'association entre l'hémorragie intraventriculaire néonatale et le risque de morbidité durant l’enfance a été évaluée. Méthodes: Une cohorte longitudinale de 794,384 bébés nés entre 2006 et 2016 au Québec, Canada a été analysé. Les nouveau-nés ont été suivis jusqu'à une période de 12 ans après leur naissance, pour identifier les hospitalisations subséquentes. Dans les modèles de régression de Cox, ajustés pour les caractéristiques maternelles et néonatales, les « hazard ratios » et intervalles de confiance (IC) à 95% ont été estimés pour l'association entre l'hémorragie intraventriculaire avec l’hospitalisation ultérieure. Résultats: Au total, 1,322 nourrissons (0,2%) ont développé une hémorragie intraventriculaire de grade I à IV. L'incidence de l'hospitalisation était plus élevée chez les bébés présentant une hémorragie intraventriculaire que chez les bébés sans hémorragie (23,8 vs 5,7 par 100 personnes-années). Comparés aux bébés sans hémorragie, les bébés affectés avaient un risque d'hospitalisation 1,56 fois plus élevé (IC à 95% 1,43-1,70). Le risque était 2,81 fois plus élevé pour les grades III/IV (IC à 95% 2,23 à 3,53) comparés à ceux nés sans hémorragie. Les hémorragies intraventriculaires pré-terme était associée à 1,82 fois le risque (IC 95% 1,66-2,00) comparés aux bébés nés termes sans hémorragie. Les hémorragies intraventriculaires à terme étaient associées à 3,19 fois le risque d'hospitalisation (IC 95% 2,55-4,00), comparativement à ceux nés termes sans hémorragie. Les raisons principales des hospitalisations comprenaient les maladies du système nerveux central, ophtalmologiques, musculo-squelettiques et cardiovasculaires. Conclusion: L'hémorragie intraventriculaire, notamment de grades sévères et parmi les bébés à terme, est un déterminant important du futur risque d’hospitalisation durant l’enfance. / Background: Neonatal intraventricular hemorrhage is associated with neurodevelopmental sequelae, but the long-term risk of other outcomes is unknown. The association between neonatal intraventricular hemorrhage and the risk of childhood morbidity was assessed. Methods: A longitudinal cohort of 794,384 infants born between 2006 and 2016 in Quebec, Canada was analyzed. Infants were tracked over time to identify later hospitalizations with follow-up extending up to 12 years after birth. In Cox regression models adjusted for maternal and infant characteristics, the hazard ratios and 95% confidence intervals (CI) were estimated for the association of intraventricular hemorrhage with future hospitalization. Results: A total of 1,322 (0.2%) infants developed grade I to IV intraventricular hemorrhage. The incidence of childhood hospitalization was higher in infants with intraventricular hemorrhage than in infants without hemorrhage (23.8 vs. 5.7 per 100 person-years). Compared with no hemorrhage, infants with intraventricular hemorrhage had 1.56 times the risk of hospitalization (95% CI 1.43-1.70). The risk was 2.81 times higher for grade III/IV hemorrhage (95% CI 2.23-3.53) compared to those born without hemorrhage. Preterm intraventricular hemorrhage was associated with 1.82 times the risk (95% CI 1.66-2.00) compared to term infants born without hemorrhage. Intraventricular hemorrhage at term was associated with 3.19 times the risk of hospitalization (95% CI 2.55-4.00) compared to those born term without hemorrhaging. Primary reasons for hospitalizations included central nervous system, ophthalmologic, musculoskeletal, and cardiovascular disorders. Conclusion: Intraventricular hemorrhage, especially of higher grades and in term neonates, is an important determinant of the future risk of child hospitalization.

Submitted by Claudio Meilman Ferreira (claudio.meilman@gmail.com) on 2017-01-05T15:53:53Z No. of bitstreams: 1 Claudio_Ferreira - Dissertação_Final.pdf: 1435979 bytes, checksum: f28673c2b369335f45c63beb6e43c635 (MD5) / Approved for entry into archive by ÁUREA CORRÊA DA FONSECA CORRÊA DA FONSECA (aurea.fonseca@fgv.br) on 2017-01-06T13:51:55Z (GMT) No. of bitstreams: 1 Claudio_Ferreira - Dissertação_Final.pdf: 1435979 bytes, checksum: f28673c2b369335f45c63beb6e43c635 (MD5) / Made available in DSpace on 2017-01-17T12:18:01Z (GMT). No. of bitstreams: 1 Claudio_Ferreira - Dissertação_Final.pdf: 1435979 bytes, checksum: f28673c2b369335f45c63beb6e43c635 (MD5) Previous issue date: 2016-12-06 / The impact of economic incentives on healthier eating is unclear, particularly in the long-term (i.e., after the intervention period). This research assessed the short- and long-term effectiveness of a private nutrition company’s promotion initiative in school cafeterias in Belo Horizonte, Brazil. Two hundred and eight children and adolescents from 3 schools participated in a short-lived, lottery-based incentives program contingent on the purchase of locally promoted healthy products. One hundred and forty-four children and adolescents from a fourth comparable school served as controls. A multilevel model compared the average number of promoted healthy products purchased daily per participant before (26 weekdays), during (9 weekdays), and after (28 weekdays) the intervention period. The results indicate a clear short-term effect. The incentives program significantly increased the purchase of promoted healthy products during (vs. before) the intervention period in the treated schools, specially among girls and younger children. On average, no long-term effect was observed. The purchase of the promoted healthy products returned to pre-intervention levels immediately after the removal of the incentives program. Interestingly, a detailed analysis revealed a rather heterogeneous long-term effect based on past consumption behavior. The incentive promoted a positive long-term effect on the children who had never consumed the incentivized healthier products prior to the intervention, whereas a negative long-term effect was noted for the already habitual consumers of the targeted healthier products. Past consumption behavior must be taken into consideration for a complete understanding of the long-term effects of incentives on healthier eating. / O impacto de incentivos econômicos sobre a alimentação saudável não é claro, particularmente no longo prazo (ou seja, após o período da intervenção). Esta pesquisa avaliou a eficácia de curto e longo prazo de uma iniciativa de promoção de uma empresa de nutrição privada em cantinas escolares em Belo Horizonte, Brasil. Duzentas e oito crianças e adolescentes de três escolas participaram de um programa de incentivos de curta duração baseado em um sorteio, condicionado à compra de produtos saudáveis promovidos localmente. Cento e quarenta e quatro crianças e adolescentes de uma quarta escola comparável serviram como controles. Um modelo multinível comparou o número médio de produtos saudáveis promovidos adquiridos diariamente por participante antes (26 dias úteis), durante (9 dias úteis) e após (28 dias úteis) o período da intervenção. Os resultados indicam um efeito claro de curto prazo. O programa de incentivos aumentou significativamente a compra de produtos saudáveis promovidos durante o período da intervenção (vs. antes) nas escolas tratadas, especialmente entre as meninas e crianças mais novas. Em média, nenhum efeito de longo prazo foi observado. A compra dos produtos saudáveis promovidos retornou aos níveis pré-intervenção imediatamente após a remoção do programa de incentivos. Curiosamente, uma análise detalhada revelou um efeito bastante heterogêneo de longo prazo baseado no comportamento prévio de consumo dos indivíduos. O incentivo promoveu um efeito positivo de longo prazo sobre as crianças que nunca haviam consumido os produtos promovidos e saudáveis antes da intervenção, ao passo que um efeito negativo de longo prazo foi observado para os consumidores já habituais dos produtos mais saudáveis visados. O comportamento do consumo passado deve ser levado em consideração para uma melhor compreensão dos efeitos de longo prazo de incentivos sobre uma alimentação mais saudável.

Les données de la littérature concernant la tolérance à long terme du traitement par hormone de croissance (GH) recombinante sont très réduites. L’objectif du travail rapporté dans cette thèse porte sur l’analyse de la morbidité chez 6874 patients de l’étude SAGhE traités en France dans le cadre d’un déficit idiopathique en GH ou d’une petite taille constitutionnelle, avec les 3 axes de travail suivants : Risque neurovasculaire : Utilisant des données de référence issues de 2 registres de population, nous avons montré une augmentation du risque d’accident vasculaire cérébral (SIR à 3.5 ou 4.4 selon le registre considéré), et plus particulièrement d’hémorragies sous-arachnoïdiennes (SIR 5.7 ou 6.3). Risque de diabète : Utilisant les prescriptions d’antidiabétiques fournies par le SNIIRAM au sein de notre cohorte, nous n’avons pas mis en évidence d’augmentation de la prévalence du diabète traité (SPR 1.0). Risque de cancer : En comparaison au registre de référence du réseau FRANCIM, il n’y a pas de différence significative dans le risque de survenue d’un cancer (SIR 0.7). En revanche, le risque de développer une tumeur osseuse est 3.5 fois plus élevé chez les sujets exposés à l’hormone de croissance dans l’enfance. Les évènements ont été identifiés à partir de trois sources : a) RNIPP et CépiDC pour la connaissance du statut vital et les causes de décès si le sujet est décédé, b) Questionnaire de santé envoyé aux sujets non décédés, c) Données SNIIRAM à partir d’une extraction spécifique basée sur les identifiants des sujets de notre cohorte, permettant d’obtenir les codes CIM-10 des déclarations d’Affection Longue Durée, les codages PMSI entre 2008 et 2010 correspondant aux hospitalisations, et les prescriptions d’antidiabétiques. / The literature is scarce regarding the long term effect of synthetic growth hormone (GH) treatment. The objective of this thesis was to analyse the morbidity of 6874 patients from the French SAGhE study treated by GH for short stature, focusing on three themes: Neurovascular risk: Using two population-based registries, we showed an increase in the risk of stroke (SIR 3.5 to 4.4 according the registry used), more specifically for the subarachnoid hemorrhage (SIR 5.7 or 6.3). Risk of diabetes : Using the antidiabetic drugs deliveries obtained from the French national health insurance database, no difference in the risk of treated diabetes was found (SPR 1.0). Risk of cancer : Compared with the French population-based registries of cancer, no significant difference in the risk of cancer was found (SIR 0.7), but the excess risk for bone tumor is 3.5 . Events were identified from three sources : a) Information on vital status collected from the Répertoire National d’Identification des Personnes Physiques and cause of death as indicated on death certificate, b) Health questionnaire sent to all living patients, c) Data extracted from the French national health insurance information, including the French hospital discharge database, also called Programme de Médicalisation des Systèmes d’Information from 2008 to December 2010, long-lasting affection statements, and antidiabetics drugs deliveries.

Pharmacometric modelling is widely used in many aspects related to type 2 diabetes mellitus (T2DM), for instance in the anti-diabetes drug development, and in quantifying the disease progression of T2DM. The aim of this thesis were to improve the design of early phase anti-diabetes drug development studies with the focus on the power to identify mechanism of drug action (MoA), and to characterize and quantify the progression from prediabetes to overt diabetes, both the natural progression and the progression with diet and exercise interventions, using pharmacometrics modelling. The appropriateness of a study design depends on the MoAs of the anti-hyperglycaemic drug. Depending on if the focus is power to identify drug effect or accuracy and precision of drug effect, the best design will be different. Using insulin measurements on top of glucose has increase the power to identify a correct drug effect, distinguish a correct MoA from the incorrect, and to identify a secondary MoA in most cases. The accuracy and precision of drug parameter estimates, however, was not affected by insulin. A natural diabetes disease progression model was successfully added in a previously developed model to describe parameter changes of glucose and insulin regulation among impaired glucose tolerance (IGT) subjects, with the quantification of the lifestyle intervention. In this model, the assessment of multiple short-term provocations was combined to predict the long-term disease progression, and offers apart from the assessment of the onset of T2DM also the framework for how to perform similar analysis. Another previously published model was further developed to characterize the weight change in driving the changes in glucose homeostasis in subjects with IGT. This model includes the complex relationship between dropout from study and weight and glucose changes. This thesis has provided a first written guidance in designing a study for pharmacometrics analysis when characterizing drug effects, for early phase anti-diabetes drug development. The characterisation of the progression from prediabetes to overt diabetes using pharmacometrics modelling was successfully performed. Both the natural progression and the progression with diet and exercise interventions were quantified in this thesis.