Contexte. Les études cas-témoins sont très fréquemment utilisées par les épidémiologistes pour évaluer l’impact de certaines expositions sur une maladie particulière. Ces expositions peuvent être représentées par plusieurs variables dépendant du temps, et de nouvelles méthodes sont nécessaires pour estimer de manière précise leurs effets. En effet, la régression logistique qui est la méthode conventionnelle pour analyser les données cas-témoins ne tient pas directement compte des changements de valeurs des covariables au cours du temps. Par opposition, les méthodes d’analyse des données de survie telles que le modèle de Cox à risques instantanés proportionnels peuvent directement incorporer des covariables dépendant du temps représentant les histoires individuelles d’exposition. Cependant, cela nécessite de manipuler les ensembles de sujets à risque avec précaution à cause du sur-échantillonnage des cas, en comparaison avec les témoins, dans les études cas-témoins. Comme montré dans une étude de simulation précédente, la définition optimale des ensembles de sujets à risque pour l’analyse des données cas-témoins reste encore à être élucidée, et à être étudiée dans le cas des variables dépendant du temps. Objectif: L’objectif général est de proposer et d’étudier de nouvelles versions du modèle de Cox pour estimer l’impact d’expositions variant dans le temps dans les études cas-témoins, et de les appliquer à des données réelles cas-témoins sur le cancer du poumon et le tabac. Méthodes. J’ai identifié de nouvelles définitions d’ensemble de sujets à risque, potentiellement optimales (le Weighted Cox model and le Simple weighted Cox model), dans lesquelles différentes pondérations ont été affectées aux cas et aux témoins, afin de refléter les proportions de cas et de non cas dans la population source. Les propriétés des estimateurs des effets d’exposition ont été étudiées par simulation. Différents aspects d’exposition ont été générés (intensité, durée, valeur cumulée d’exposition). Les données cas-témoins générées ont été ensuite analysées avec différentes versions du modèle de Cox, incluant les définitions anciennes et nouvelles des ensembles de sujets à risque, ainsi qu’avec la régression logistique conventionnelle, à des fins de comparaison. Les différents modèles de régression ont ensuite été appliqués sur des données réelles cas-témoins sur le cancer du poumon. Les estimations des effets de différentes variables de tabac, obtenues avec les différentes méthodes, ont été comparées entre elles, et comparées aux résultats des simulations. Résultats. Les résultats des simulations montrent que les estimations des nouveaux modèles de Cox pondérés proposés, surtout celles du Weighted Cox model, sont bien moins biaisées que les estimations des modèles de Cox existants qui incluent ou excluent simplement les futurs cas de chaque ensemble de sujets à risque. De plus, les estimations du Weighted Cox model étaient légèrement, mais systématiquement, moins biaisées que celles de la régression logistique. L’application aux données réelles montre de plus grandes différences entre les estimations de la régression logistique et des modèles de Cox pondérés, pour quelques variables de tabac dépendant du temps. Conclusions. Les résultats suggèrent que le nouveau modèle de Cox pondéré propose pourrait être une alternative intéressante au modèle de régression logistique, pour estimer les effets d’expositions dépendant du temps dans les études cas-témoins / Background: Case-control studies are very often used by epidemiologists to assess the impact of specific exposure(s) on a particular disease. These exposures may be represented by several time-dependent covariates and new methods are needed to accurately estimate their effects. Indeed, conventional logistic regression, which is the standard method to analyze case-control data, does not directly account for changes in covariate values over time. By contrast, survival analytic methods such as the Cox proportional hazards model can directly incorporate time-dependent covariates representing the individual entire exposure histories. However, it requires some careful manipulation of risk sets because of the over-sampling of cases, compared to controls, in case-control studies. As shown in a preliminary simulation study, the optimal definition of risk sets for the analysis of case-control data remains unclear and has to be investigated in the case of time-dependent variables. Objective: The overall objective is to propose and to investigate new versions of the Cox model for assessing the impact of time-dependent exposures in case-control studies, and to apply them to a real case-control dataset on lung cancer and smoking. Methods: I identified some potential new risk sets definitions (the weighted Cox model and the simple weighted Cox model), in which different weights were given to cases and controls, in order to reflect the proportions of cases and non cases in the source population. The properties of the estimates of the exposure effects that result from these new risk sets definitions were investigated through a simulation study. Various aspects of exposure were generated (intensity, duration, cumulative exposure value). The simulated case-control data were then analysed using different versions of Cox’s models corresponding to existing and new definitions of risk sets, as well as with standard logistic regression, for comparison purpose. The different regression models were then applied to real case-control data on lung cancer. The estimates of the effects of different smoking variables, obtained with the different methods, were compared to each other, as well as to simulation results. Results: The simulation results show that the estimates from the new proposed weighted Cox models, especially those from the weighted Cox model, are much less biased than the estimates from the existing Cox models that simply include or exclude future cases. In addition, the weighted Cox model was slightly, but systematically, less biased than logistic regression. The real life application shows some greater discrepancies between the estimates of the proposed Cox models and logistic regression, for some smoking time-dependent covariates. Conclusions: The results suggest that the new proposed weighted Cox models could be an interesting alternative to logistic regression for estimating the effects of time-dependent exposures in case-control studies.

Thèse numérisée par la Division de la gestion de documents et des archives de l'Université de Montréal.

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal.

Au cours des dernières années, le développement des connaissances au niveau de l’étiologie de la maladie ainsi que l’arrivée de nouveaux médicaments et de lignes directrices guidant la pratique clinique sont susceptibles d’avoir entraîné une meilleure gestion de la polyarthrite rhumatoïde (PAR) et de l’ostéoporose, une comorbidité fréquente chez ces patients. Dans cette thèse, trois questions de recherche sont étudiées à l’aide des banques de données administratives québécoises (RAMQ, MED-ÉCHO). Une première étude documente l’utilisation des médicaments pour la PAR au Québec. À ce jour, il s’agit de la seule étude canadienne à rapporter les tendances d’utilisation des DMARD (disease-modifying antirheumatic drug) biologiques depuis leur introduction dans la pratique clinique. Au cours de la période à l’étude (2002-2008), l’utilisation de DMARD (synthétiques et biologiques) a augmenté légèrement dans la population atteinte de PAR (1,9%, 95% CI : 1,1 - 2,8). Cependant, malgré la présence de recommandations cliniques soulignant l’importance de commencer un traitement rapidement, et la couverture de ces traitements par le régime général d’assurance médicaments, les résultats démontrent une initiation sous-optimale des DMARD chez les patients nouvellement diagnostiqués (probabilité d’initiation à 12 mois : 38,5%). L’initiation de DMARD était beaucoup plus fréquente lorsqu’un rhumatologue était impliqué dans la provision des soins (OR : 4,31, 95% CI : 3,73 - 4,97). Concernant les DMARD biologiques, le facteur le plus fortement associé avec leur initiation était l’année calendrier. Chez les sujets diagnostiqués en 2002, 1,2 sur 1 000 ont initié un DMARD biologique moins d’un an après leur diagnostic. Pour ceux qui ont été diagnostiqués en 2007, le taux était de 13 sur 1 000. Les résultats démontrent que si la gestion pharmacologique de la PAR s’est améliorée au cours de la période à l’étude, elle demeure tout de même sous-optimale. Assurer un meilleur accès aux rhumatologues pourrait, semble-t-il, être une stratégie efficace pour améliorer la qualité des soins chez les patients atteints de PAR. Dans une deuxième étude, l’association entre l’utilisation des DMARD biologiques et le risque de fractures ostéoporotiques non vertébrales chez des patients PAR âgés de 50 ans et plus a été rapportée. Puisque l’inflammation chronique résultant de la PAR interfère avec le remodelage osseux et que les DMARD biologiques, en plus de leur effet anti-inflammatoire et immunosuppresseur, sont des modulateurs de l’activité cellulaire des ostéoclastes et des ostéoblastes pouvant possiblement mener à la prévention des pertes de densité minérale osseuse (DMO), il était attendu que leur utilisation réduirait le risque de fracture. Une étude de cas-témoin intra-cohorte a été conduite. Bien qu’aucune réduction du risque de fracture suivant l’utilisation de DMARD biologiques n’ait pu être démontrée (OR : 1,03, 95% CI : 0,42 - 2,53), l’étude établit le taux d’incidence de fractures ostéoporotiques non vertébrales dans une population canadienne atteinte de PAR (11/1 000 personnes - années) et souligne le rôle d’importants facteurs de risque. La prévalence élevée de l’ostéoporose dans la population atteinte de PAR justifie que l’on accorde plus d’attention à la prévention des fractures. Finalement, une troisième étude explore l’impact de la dissémination massive, en 2002, des lignes directrices du traitement de l’ostéoporose au Canada sur la gestion pharmacologique de l’ostéoporose et sur les taux d’incidence de fractures ostéoporotiques non vertébrales chez une population de patients PAR âgés de 50 ans et plus entre 1998 et 2008. Étant donné la disponibilité des traitements efficaces pour l’ostéoporose depuis le milieu des années 1990 et l’évolution des lignes directrices de traitement, une réduction du taux de fractures était attendue. Quelques études canadiennes ont démontré une réduction des fractures suivant une utilisation étendue des médicaments contre l’ostéoporose et de l’ostéodensitométrie dans une population générale, mais aucune ne s’est attardée plus particulièrement sur une population adulte atteinte de PAR. Dans cette étude observationnelle utilisant une approche de série chronologique, aucune réduction du taux de fracture après 2002 (période suivant la dissémination des lignes directrices) n’a pu être démontrée. Cependant, l’utilisation des médicaments pour l’ostéoporose, le passage d’ostéodensitométrie, ainsi que la provision de soins pour l’ostéoporose en post-fracture ont augmenté. Cette étude démontre que malgré des années de disponibilité de traitements efficaces et d’investissement dans le développement et la promotion de lignes directrices de traitement, l’effet bénéfique au niveau de la réduction des fractures ne s’est toujours pas concrétisé dans la population atteinte de PAR, au cours de la période à l’étude. Ces travaux sont les premiers à examiner, à l’aide d’une banque de données administratives, des sujets atteints de PAR sur une période s’étalant sur 11 ans, permettant non seulement l’étude des changements de pratique clinique suivant l’apparition de nouveaux traitements ou bien de nouvelles lignes directrices, mais également de leur impact sur la santé. De plus, via l’étude des déterminants de traitement, les résultats offrent des pistes de solution afin de combler l’écart entre la pratique observée et les recommandations cliniques. Enfin, les résultats de ces études bonifient la littérature concernant la qualité des soins pharmacologiques chez les patients PAR et de la prévention des fractures. / Over the past two decades, progresses in the understanding of disease etiology, the arrival of new drugs, and the development of clinical practice guidelines may have led to a better pharmacological management of rheumatoid arthritis (RA) and osteoporosis, a common comorbidity. In this thesis, three research questions were investigated using well characterized administrative databases (RAMQ and MED-ECHO). A first study documented RA drug use in the province of Quebec. To this date, this is the only Canadian study to report on patterns of biologic DMARD use since their introduction in clinical practice. Over our study time horizon (2002-2008), the use of any DMARDs (synthetic and biologic) slightly increased in the overall RA population (1.9%, 95% CI: 1.1-2.8). However, despite clinical practice guidelines stressing the importance of early treatment, and the reimbursement of treatments by the Quebec drug plan, the results demonstrated suboptimal DMARD initiation in newly diagnosed RA (probability at 12 months: 38.5%), though DMARD initiation increased when rheumatologists were overseeing care (OR: 4.31, 95%CI: 3.73-4.97). For biologic DMARDs, the strongest predictor of initiation was the calendar year of study entry. Of subjects newly diagnosed in 2002, 1.2 in 1000 had a biologic initiated within one year, while for those newly diagnosed in 2007, it was 13.0 in 1000. The results showed that the pharmacological management of RA is improving over time, but remains below expectations. Ensuring better access to rheumatologists should be an area of focus in order to enhance the quality of RA care. A second study reported on biologic DMARD use and the risk of non-vertebral osteoporotic fractures in RA patients aged ≥50 years. Because chronic inflammation in RA interferes with bone remodeling and biologic DMARDs, in addition to their anti-inflammatory and immunosuppressive effects, are modulators of the cellular activity of osteoblasts and osteoclasts possibly leading to the preservation of bone mineral density (BMD), it was believed that their use may reduce the risk of fractures. A nested-case control study was conducted. Although a reduction in the risk of fractures subsequent to biologic DMARD use could not be demonstrated (OR: 1.03, 95% CI: 0.42-2.53), the study established the incidence rate of non-vertebral osteoporotic fractures in a Canadian RA population (11/1000 person-years) and highlighted some important risk factors. The high prevalence of osteoporosis in the RA population justifies that more attention be paid to preventing fractures. Finally, a third study investigated the impact of the 2002 Canadian osteoporosis guidelines on the pharmacological management of osteoporosis and on the rates of non-vertebral osteoporotic fractures in a RA population aged ≥50 years between 1998 and 2008. With the availability of effective osteoporosis treatments since the mid 90s, and the evolving clinical practice guidelines, a reduction in the rate of fractures was expected. Some Canadian studies have shown reductions in the rate of fractures following broader use of osteoporosis drugs and BMD testing in a general adult population, but none have specifically investigated the impact in RA. In this observational study using a time series approach, no reduction in the rate of fractures after 2002 (post guidelines dissemination) could be demonstrated. However, the use of osteoporosis drugs, BMD testing, and provision of post fracture osteoporosis care improved. This study demonstrated that years of availability of effective preventive measures and investments in the development and promotion of clinical practice guidelines have not yet translated into further reduction in the rate of fractures in our RA population over our study time horizon. This body of work is the first to examine, using healthcare administrative data, subjects with RA over a period of 11 years, allowing not only to study the changes in clinical practice following the introduction of new treatments and guidelines, but also to capture the impact on health. In addition, by studying predictors of treatment, the results provide good insights in terms of solutions to fill the gap between the observed clinical practice and guideline recommendations. Finally, the results of these studies substantiate the literature regarding the quality of RA care and the prevention of fractures.

Evidências de estudos genético-epidemiológicos têm demonstrado a existência de um fator de risco genético para o desenvolvimento da esquizofrenia. Na presente Tese, um total de 245 pacientes com esquizofrenia e 834 controles foi selecionado com o objetivo de investigar a diferença na distribuição de alelos e genótipos de seis polimorfismos de quatro diferentes genes do sistema dopaminérgico nesses dois grupos: 1. TaqI A1/A2 do DRD2 - rs1800497; 2. -141C (Ins/Del) do DRD2 - rs1799732; 3. Ser-9-Gly do DRD3 - rs6280; 4. VNTR da região 3´ não-codificadora do SLC6A3; 5. A1343G do SLC6A3 - rs6347; 6. A/G da região 3´ não-codificadora do COMT - rs165599. Os resultados mostraram associação dos polimorfismos -141C (Ins/Del) do DRD2 (rs1799732) e A1343G do SLC6A3 (rs6347) com esquizofrenia na amostra investigada. / Evidences from genetic epidemiological studies have demonstrated the existence of a genetic risk factor for schizophrenia. In the present work a total of 245 schizophrenic patients and 834 controls were selected to investigate differences in the allelic and genotypic distribution of six polymorphisms from four different genes of the dopaminergic system between the groups: 1. TaqI A1/A2 of the DRD2 - rs1800497; 2. -141C (Ins/Del) of the DRD2 - rs1799732; 3. Ser-9-Gly of the DRD3 - rs6280; 4. VNTR in the 3\'-untranslated region of the SLC6A3; 5. A1343G of the SLC6A3 - rs6347; 6. A/G in the 3\'-untranslated region of the COMT - rs165599. The results have found an association of the polymorphisms -141C (Ins/Del) of the DRD2 (rs1799732) and A1343G of the SLC6A3 (rs6347) with schizophrenia in the investigated sample.

Objetivo: Estudar as medidas de espessura da camada de fibras nervosas da retina(CFNR) peripapilar obtidas com as tomografias de coerência óptia (oCT) time domain (TD) e spectral domain (SD) em pacientes com perda assimétrica glaucomatosa de hemicampo visual, compará-las entre si e com aquelas de controles normais. Métodos: Trinta e seis pacientes com glaucoma primário de ângulo aberto e perda de campo visual em um hemicampo (afetado) e ausência de perda no hemicampo oposto (não afetado), e 36 controles pareados por idade tiveram o olho de estudo examinado com Stratus-OCT (Carl Zeiss Meditec Inc., Dublin, Califoprnia, USA) e o 3DOCT-1000 (Topcdon, Tokyo, Japan). As medidas de espessura da CFNR peripapilar e a classificação normativa fornecida pelos aparelhos foram registrados para análise. A média aritmética dos valores do mapa total deviation em cada hemicampo (mean deviation do hemicampo) foi calculada para cada indivíduo. \"Ìndices de assimetria\" para o campo visual e para a CFNR foram calculados como a razão entre o mean deviation dos hemicampos afetado e não-afetado, e como razão entre a espessura da CFNR das hemirretinas afetada e não-afetada, respectivamente. As variáveis contínuas foram comparadas usando os testes de Mann-Whitney, Kruskal-Wallis ou Wilcoxon, quando apropriados. As variáveis categóricas foram comparadas usando o teste qui-quadrado de Pearson. O coeficiente de correlação de Spearman foi usado para testar as correlações entre as medidas de espessura da CFNR fornecidas pelos OCTs. A presença de afinamento da CFNR foi estabelecida com base nos dados normativos fornecidos pelos softwares dos OCTs. As espessuras de CFNR fora do intervalo de previsão de 95% para a mesma faixa etária foram consideradas anormais. Resultados: As medidas de CFNR corespondentes a hemicampos não-afetados [média (DP) 87,0 (17,1) um e 84,3 (20,2) um, para TD e SD-OCT, respectivamente] foram menores do que as dos controles [média (DP) 119,0 (122,2)um e 117,0 (17,7) um, para TD e SD-OCT, respectivamente, P < 0,001, para ambos]. O banco de dados normativo classificou como alterado 42% e 67% das hemirretinas correspondentes a hemicampos não-acometidos com TD e SD-OCT, respectivamente (P = 0,01). As medidas da CFNR foram consistentemente mais espessas com TD comparadas com SD-OCT. Os índices de assimetria da CFNR em pacientes com glaucoma foram semelhantes entre TD [média (DP) 0,76 (0,17)] e SD-OCT [média (DP) 0,79 (0,12), P = 0,89] e significantemente maiores do que o índice de assimetria do campo visual [média (DP) 0,36 (0,20), P < 0,001]. Conclusões: Os hemicampos normais de pacientes com glaucoma apresentaram CFNR mais fina do que de olhos saudáveis. As medidas da CFNR foram mais espessas com TD do que com SD-OCT, o qual por sua vez detectou anormalidades na espessura da CFNR mais frequentemente do que o TD-OCT / Objective: To study the peripapillary retinal nerve fiber layer (RNFL) thickness measurements obtained with time domain (TD) and spectral domain (SD) optical coherence tomography (OCT) in glaucomatous patients with asymmetric visual hemifield loss, to compare themselves and with those obtained from normal controls. Methods : Thirty -six patients with primary open-angle glaucoma with visual primary open-angle glaucoma with visual field loss in one hemifield (affected ) and absence of loss in other (non-affected), and 36 age-matched healthy controls had the eye study imaged with Stratus-OCT (Carl Zeiss Meditec Inc., Dublin, Califoprnia, USA) and 3D OCT-1000 (Topcon , Tokyo, Japan). Peripapillary RNFL thickness measurements and normative classification were recorded for analysis. Total deviation values were averaged for each hemifield (hemifield mean deviation) for ecch subject. Visual field and RNFL \"asymmetry indexes\" were calculated as the ratio between the mean deviation of affected versus non-affected hemifields and RNFL thickness between as affected versus non-affected hemiretinas, respectively. Continuous variables were compared using the Mann-Whitney, Kruskal-Wallis or Wilcoxon tests, when appropriate. Categorical variables were compared using the Pearson\'s chi-square test. The Spearman\'s rank correlation coefficient was used to test correlations between RNFL thickness measurements provided by both OCTs . The presence of RNFL thinning was establised based on normative data provided by the OCT\'s software. The RNFL thicknesses outside the prediction interval of 95% for the same age group were considered abnormal. Results: The RNFL measurements in non-affected hemifields [mean (SD 87.0 (17.1) e 84.3(20.2) um, for TD and SD-OCT, respectively] were thinner than those of normal controls [mean (SD) 119.0 (12.2) um and 117.0 (17.7) um, for TD and SD-OCT, respectively, P < 0.001 for both ] . The OCT normative database classified 42 % and 67% of hemiretinas corresponding to non-affected hemifields as abnormal in TD and SD-OCT, respectively (P =0.01). The RNFL measurements were consistently thicker with TD compared with SD -OCT. The RNFL thickness asymetry index in patients with glaucoma was similar with TD [ mean (SD) 0.76 ( 0.17 ) ] and SD-OCT [ mean (SD)0.79(0.12), P = 0,89] and significantly greater than the visual field asymmetry index [ mean (SD ) 0.36 (0.20 ), P < 0.001]. Conclusions: Normal hemifields of glaucoma patients had thinner RNFL measurements than healthy eyes, as measured by TD and SD-OCT. The RNFL measurements were thicker with TD than SD-OCT, SD-OCT detected abnormal RNFL more often than TD-OCT

O diabetes melito gestacional (DMG) está relacionado ao crescimento fetal exagerado. Entender a influência de fatores relacionados ao crescimento fetal auxilia na identificação dos fetos com maior risco de desvios da normalidade. Objetivo: comparar fatores clínicos, laboratoriais e a expressão placentária de transportadores de glicose segundo o crescimento fetal em pacientes com DMG. Método: Para análise dos fatores clínicos e laboratoriais foi realizado um estudo retrospectivo com 425 gestantes com DMG do Setor de Endocrinopatias da Divisão de Clínica Obstétrica do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HC FM-USP) no período de janeiro de 2003 a novembro de 2009. Para a análise da expressão placentária dos transportadores de glicose dos tipos 1 (GLUT1), 3 (GLUT3) e 4 (GLUT4) foram selecionados todos os casos de recém-nascidos grandes para idade gestacional (RNGIG) pareados com um caso controle de recém-nascido adequado para idade gestacional (RNAIG). Foram incluídas apenas gestações únicas e com DMG diagnosticado pelo teste de tolerância à glicose oral de 100 gramas, sem malformações fetais e com idade gestacional definida e confiável. Todas as gestantes realizaram dieta para diabetes, controle glicêmico diário e uso de insulina quando necessário. Os critérios de seguimento e tratamento seguiram rigorosamente as normas do Protocolo de Condutas do Setor de Endocrinopatias da Divisão de Clínica Obstétrica do HC-FMUSP. As gestantes foram divididas para análise dos dados em dois grupos: Fatores clínicos e laboratoriais com: 376 RNAIG e 49 RNGIG num total de 425 DMG. Expressão Placentária dos Transportadores de Glicose: 50 RNAIG e 44 RNGIG. Foram realizados testes de associação e médias das variáveis e relacionadas com os grupos de RNAIG e RNGIG. Resultados: Na análise univariada, dos fatores clínicos e laboratoriais, não houve diferenças entre os grupos quanto a: idade materna, antecedente familiar de diabetes, antecedente pessoal de hipertensão arterial, número de gestações, valores de glicemia de jejum e 1 hora no TTGO-100g, idade gestacional no parto, sexo do RN, tipo de parto e índice de Apgar no 1º e 5º minutos. Houve diferenças estatisticamente significativas entre os grupos quanto a: índice de massa corpórea pré-gestacional (p < 0,02); uso de insulina (p < 0,041); macrossomia anterior (p < 0,001); idade gestacional do diagnóstico do DMG (p < 0,001); glicemias de duas e três horas no TTGO-100g respectivamente com (p < 0,003) e (p < 0,026). Na análise de regressão logística foram considerados preditores independentes da ocorrência de RNGIG: o índice de massa corpórea pré - gestacional, a macrossomia anterior, aidade gestacional do diagnóstico do DMG e a glicemia de duas horas após sobrecarga de 100 gramas. Em relação a expressão dos transportadores de glicose não diferiram entre os grupos em relação a expressão de GLUT1 na decídua, GLUT3 na decídua e vilosidades e GLUT4 na decídua e vilosidades. Houve diferença entre os grupos quanto à: a expressão do GLUT1 nas vilosidades. Conclusões: O índice de massa corpórea pré - gestacional, a macrossomia anterior, a idade gestacional do diagnóstico do DMG e a glicemia de duas horas após sobrecarga de 100 gramas foram preditores da ocorrência de RNGIG. A expressão de GLUT1 nas vilosidades coriônicas teve relação com a ocorrência de RNGIG / Gestational diabetes mellitus (GDM) is related to excessive fetal growth. Knowing the influence of factors related to fetal growth assists in the identification of fetuses at high risk of deviations from normality. Objective: To compare clinical and laboratory tests and the placental expression of glucose transporters according to fetal growth in patients with GDM. Method: A retrospective study of clinical and laboratory factors related with large for gestational age newborns, included 425 pregnant women with GDM was carried out at Sector Endocrine Clinic of Obstetrics Hospital of the School of Medicine, University of São Paulo (HC-FMUSP), between January 2003 to November 2009. For the analysis of placental expression of glucose transporters types 1 (GLUT1), 3 (GLUT3) and 4 (GLUT4) were selected all cases of newborns large for gestational age (LGA) paired with a case control newly born appropriate for gestational age (AGA). We included only patients with singleton pregnancies and GDM diagnosed by OGTT-100g, with newborns without malformations and birth weight classified as adequate or large for gestational age. All pregnant women received diet for diabetes, daily glycemic control and insulin when necessary. The criteria for monitoring and treatment followed strictly the standards of Conduct Protocol Endocrine Obstetric Clinic of the Clinic Hospital, School of Medicine, University of São Paulo. The pregnancies were divided for analysis into two groups: 376 cases of newborns AGA and 49 cases of newborns LGA. Data were analyzed and considered the probability value p <0.05. Results: In the univariate analysis of clinical and laboratory factors, there were no differences between the groups regarding maternal age, family history of diabetes, personal history of hypertension, number of pregnancies, blood fasting glucose and 1 hour in- OGTT 100g, gestational age at delivery, gender of the newborn, type of delivery, Apgar score at 1st and 5th minutes. There were statistically significant differences between the groups regarding: body mass index before pregnancy (p <0.02), insulin (p <0.041), previous macrosomia (p <0.001), gestational age at diagnosis of GDM (p <0.001), blood glucose levels two and three hours at 100 g OGTT, respectively, with (p <0.003) (p <0.026). In logistic regression analysis were considered independent predictors of the occurrence of LGA: body mass index before pregnancy, previous macrosomia gestational age at diagnosis of GDM and two hours after glucose overload 100 grams. Regarding the expression of glucose transporters, the groups did not differ regarding the expression of GLUT1 in the decidua, GLUT3 in the decidua and villi and GLUT4 in the decidua and villi. There were differences between the groups regarding the expression of GLUT1 in the villi. Conclusions: The body mass index before pregnancy, previous macrosomia, gestational age of diagnosis of GDM and two hours after glucose overload 100 grams were predictors of the occurrence of LGA. The expression of GLUT1 in chorionic villi was related to the occurrence of LGA newborn

Avaliamos as mudanças no padrão respiratório, movimento toracoabdominal e ventilação em portadores de DPOC e indivíduos sadios. Estudou-se 45 indivíduos entre 45 e 75 anos conforme o VEF1. Utilizou-se sistemas de pletismografia respiratória por indutância, análise metabólica de gases em posição semi-sentada ao repouso e radiografia de tórax para a mobilidade diafragmática. Os grupos DPOC apresentaram redução do TI, TTOT, aumento do VC/TI, f, VE, das relações VEM/VC, VE/VO2, VE/VCO2 e diminuição da SpO2. Redução da mobilidade do diafragma e aumento da VEM/VC associaram-se à ineficiência da ventilação e a alterações no modelo ventilatório utilizado, sem alterações no movimento toracoabdominal. / We assessed changes in breathing patterns, thoracoabdominal movement and ventilation in COPD sufferers and healthy individuals. Forty-five individuals between 45 and 75 were grouped by FEV1. Inductive plethysmographic equipment, respiratory metabolism measuring (with subject at rest in semi-recumbent position), and radiographic measurement of diaphragm mobility were used. The COPD groups presented reduction in TI and TTOT and increased VT/TI, f, VE, and VD/VT, VE/VO2, VE/VCO2 and decreased SpO2. Reduction in diaphragm mobility and increase of VEM/VC were associated with ventilatory inefficiency and alterations in the ventilatory model used. No alterations in thoracoabdominal movement

Introdução: A Neoplasia endócrina múltipla do tipo 2 (NEM-2) é uma síndrome tumoral de herança autossômica dominante, na qual os tumores associados são carcinoma medular de tireoide (CMT), feocromocitoma (FEO) e hiperparatireoidismo primário (HPT). Esta síndrome ocorre devido a mutações ativadoras no proto-oncogene RET que alteram a via do receptor tirosina quinase RET. Essas mutações levam à ativação constitutiva de vias de sinalização desregulando o ciclo celular. Segundo os Consensos Internacionais de 2001 e 2009 sobre CMT/NEM-2, portadores de mutações no gene RET, inclusive indivíduos assintomáticos, devem ser submetidos a tireoidectomia total (TT) preventiva, aumentando a chance de cura da doença. Não é recomendado rastreamento clínico em portadores que apresentem somente polimorfismos isolados (variante não patogênica). No entanto, existem indivíduos que carregam variantes genéticas de significado clínico desconhecido (VUS), gerando dúvida quanto à conduta clínica. Atualmente, não se tem conhecimento se essas variantes podem ou não estar envolvidas no aumento do risco ao desenvolvimento de CMT. Dessa forma, o presente projeto analisou diversos aspectos como frequência alélica, estudo in silico, dados na literatura e nos bancos genéticos com o intuito de abranger o entendimento dessas variantes e auxiliar na indicação de conduta clínica adequada aos portadores de RET VUS. Objetivo: Expandir o conhecimento do potencial patogênico das VUS do gene RET, focando na classificação controversa da variante p.Y791F. Métodos: Foi realizado o rastreamento dos exons hotspots do gene RET em indivíduos adultos/idosos-controle e em pacientes com CMT através da técnica de Sequenciamento de Nova Geração (NGS) e Sequenciamento de Sanger. Foi também analisada a predição computacional da patogenicidade dessas variantes em seis diferentes programas preditivos. Foi feito o levantamento de dados em diversos bancos genéticos. Resultados: As variantes p.Y791N, p.Y791F e p.E511K foram encontradas no rastreamento genético das amostras-controle sequenciadas. Além dessas variantes, foram identificadas e estudadas famílias de pacientes com CMT portadoras das variantes p.V648I e p.K666N. A variante p.Y791F foi identificada em um novo caso somente com FEO. A análise in silico demonstrou que 4/6 programas foram mais informativos, e que 25/48 VUS demonstram alterar a estrutura físico-química da proteína RET. A frequência alélica encontrada nos bancos de dados de indivíduos-controle e indivíduos com tumores foram bastante baixas. Apenas 15/48 VUS possuem dados sobre estudos in vitro. Conclusão: Nossos dados sugerem que a variante RET p.Y791F, quando isolada e sem coocorrência com mutações conhecidas RET, se comporta como um polimorfismo benigno raro, sem associação do aumento do risco ao CMT. Já a associação de p.Y791F com mutações conhecidas RET, como a C634Y, pode levar ao desenvolvimento de fenótipos atípicos, como maior risco ao feocromocitoma. A variante p.V648I é provavelmente um polimorfismo benigno raro, evidenciado pelo seguimento clínico de aproximadamente 15 anos de uma família portadora dessa variante, sem evidências de CMT, FEO ou HPT. Há necessidade de mais dados para classificar apropriadamente as demais VUS; no entanto, devido a possibilidade das variantes p.E511K, K666N e Y791N poderem ser patogênicas, portadores devem ser monitorados clinicamente / Introduction: Multiple endocrine neoplasia type 2 (MEN-2) is a tumor syndrome with autosomal dominant inheritance, in which tumors are associated with medullary thyroid carcinoma (MTC), pheochromocytoma (FEO) and primary hyperparathyroidism (HPT). This syndrome occurs due to activating mutations in the RET proto-oncogene, which lead to constitutive activation of tyrosine kinase signaling pathways that deregulate the cell cycle. According to the International Consensus on MTC/MEN-2 of 2001 and 2009 one should recommend that RET mutation carriers, including asymptomatic individuals, should undergo prophylactic total thyroidectomy (TT), increasing the chance of cure of the disease. It is not recommended clinical screening in patients that show only isolated polymorphisms (non-pathogenic variant). However, there are individuals who carry genetic variants of unknown clinical significance (VUS), generating doubt about the best clinical management. Currently, there is no consistent knowledge whether these variants may or may not be involved with the increased risk to MTC. The present project has approached the several aspects of these VUS, such as the allele frequency, in silico pathogenic prediction, published data and public databases, in order to increase our knowledge about VUS, in an attempt to contribute by offering appropriate clinical management to VUS carriers. Objective: To expand the knowledge of the pathogenic potential of some of the VUS of the RET gene, focusing especially on the controversial genetic variant p.Y791F. Methods: We performed the mutation screening of hotspots exons of the RET gene of DNA samples of 2061 adult/elderly healthy individuals and of patients with CMT by Sanger sequencing and Next Generation Sequencing (NGS) techniques. Pathogenic predictions of the studied variants were generated using six genetic softwares. Allelic frequency of RET VUS was assessed in different public databanks. Results: Genetic screening of control samples identified the presence of p.Y791N, p.Y791F and p.E511K germline variants. Patients with MTC carrying p.V648I and p.K666N germline variants were localized and family members were screened and clinically investigated. In addition, a new case with pheochromocytoma was found to carry the p.Y791F germline variant. The in silico analyses showed that 4 out of 6 packages were more informative, suggesting physico-chemical structure alteration caused by 25 out of 48 RET VUS. Very low allele frequencies were found in the public databases including healthy individuals and tumor samples. In vitro studies have been performed only for 15 out of 48 RET VUS. Conclusion: Our data strongly suggest that the p.Y791F variant, when occurring in an isolated form, is a benign polymorphism not associated with increased risk of MTC. Conversely, its co-occurrence with bona fide RET mutations as C634Y may lead to modulation of the phenotype, as increasing the frequencies of large and bilateral pheochromocytomas in MEN2A families. Family members carrying the p.V648I variant isolate have been followed clinically for approximately 15 years. As no indication of MCT, pheochromocytoma or hyperparathyroidism development has been documented, we conclude that this variant is a rare RET benign polymorphism. More information is needed to a better characterization of other VUS as E511K, K666N and Y791N. Thus, carriers with these variants should be necessarily examined through a periodic clinical follow up

Eventos adversos (EAs), definidos como complicações não intencionais decorrentes do cuidado prestado, são reconhecidos como um dos maiores problemas na área da saúde. Embora a maior parte dos eventos acarrete incapacitações leves, uma proporção considerável está relacionada à morte de pacientes. O atendimento de urgência é considerado importante fator de risco para o desencadeamento destas complicações. No Brasil, estudos relacionados a este tema não foram publicados até o momento. O presente estudo objetivou identificar a ocorrência de EAs em pacientes admitidos por acidente vascular cerebral (AVC) ao Pronto-Socorro de Clínica Médica (PSM) do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP) e determinar as categorias de EAs associadas a óbito. Este estudo caso-controle pareado envolveu 468 pacientes admitidos por AVC ao PSM-HCFMUSP no período de março de 1996 a setembro de 1999. O grupo-caso compreendeu 234 óbitos hospitalares consecutivos e o grupo-controle 234 pacientes que receberam alta, pareados pelo diagnóstico provisório e pela época de internação. Eventos adversos, detectados por revisão de prontuários, foram classificados segundo sua gravidade, causas imediatas, sistemas acometidos e categorias profissionais envolvidas no cuidado aos pacientes. A associação com óbito foi analisada por regressão logística multivariada condicional, incluindo variáveis relacionadas a aspectos demográficos, gravidade do quadro inicial e características da assistência. Nos 468 pacientes foram identificados 1.218 EAs: 932 EAs (76,5%) em 170 casos e 286 EAs (23,5%) em 125 controles. Eventos adversos major corresponderam a 54,1% do total de eventos, com 659 episódios: 538 eventos em 143 casos e 121 em 65 controles. Os procedimentos diagnósticos e terapêuticos e os cuidados de enfermagem foram responsáveis em conjunto por 55,2% do total de eventos. Em relação ao tipo de sistema afetado, 46,0% dos EAs identificados ocasionaram manifestações gerais. Eventos adversos relacionados à enfermagem e EAs médicos representaram as categorias profissionais de EAs mais freqüentes (38,4% e 31,0% do total de eventos). Uma associação significante com óbito foi encontrada em relação a EAs major, EAs médicos e infecções hospitalares, com valores de OR ajustado estimados em 3,72 (IC 95% = 1,63-8,48), 3,69 (IC 95% = 1,60-8,50) e 3,20 (IC 95% = 1,20-8,51), respectivamente. Em resumo, eventos adversos, na sua maioria graves, foram freqüentes em casos e controles, determinando predominantemente manifestações gerais. Os procedimentos diagnósticos e terapêuticos e os cuidados de enfermagem corresponderam às principais causas imediatas de EAs. Em relação à categoria profissional envolvida, os EAs relacionados à enfermagem e os eventos médicos predominaram. Eventos adversos major, EAs médicos e as infecções hospitalares associaram-se de maneira significante com óbito em pacientes com AVC admitidos ao Pronto-Socorro de Clínica Médica do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo / Adverse events (AEs), defined as unintended injuries caused by medical care, are recognized as a major health problem. Although most of them lead to minimal impairments, a considerable proportion is related to patients’ death. Urgent care is considered an important AE risk factor. No related Brazilian studies were published so far. The present study aimed to identify the occurrence of AEs in patients admitted for stroke to the medical emergency department of the Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP) and to determine the AEs’ categories associated to death. This paired case-control study enrolled 468 patients admitted for stroke to the HCFMUSP medical emergency department from March 1996 to September 1999. The cases comprised 234 consecutive deaths and the controls 234 discharged patients, matched for primary diagnosis and admission period. AEs, detected by retrospective chart review, were classified with regard to their severity, immediate causes, affected systems and professional involved in patient care. The association with death was analyzed by multivariate conditional regression including variables related to demographic aspects, clinical severity on admission and care characteristics. A total of 1,218 AEs were identified in 468 patients: 932 AEs (76.5%) in 170 cases and 286 AEs (23.5%) in 125 controls. Major AEs corresponded to 54.1% of all AEs, with 659 episodes: 538 events in 143 cases and 121 in 65 controls. Diagnostic and therapeutic procedures and nursing activities accounted together for 55.2% of all events. Concerning the affected system, 46.0% of the identified AEs lead to general manifestations. Nursing and medical AEs represented the most frequent professional categories involved (38.4% and 31.0% of all events). A significant association with death was found regarding major AEs, medical AEs and nosocomial infections, with adjusted OR estimates of 3.72 (95% IC = 1.63-8.48), 3.69 (95% IC = 1.60-8.50) and 3.20 (95% IC = 1.20-8.51), respectively. In summary, adverse events, most of them severe, were frequent in cases and controls, leading mainly to general manifestations. Diagnostic and therapeutic procedures and nursing activities corresponded to the main AEs’ immediate causes. Regarding the professional involved, AEs related to nurses and physicians predominated. Major AEs, medical AEs and nosocomial infectious were significantly associated to death in stroke patients admitted to the medical emergency department of the Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo