The Born in Bradford cohort study was established in 2007 to examine how genetic, nutritional, environmental, behavioural and social factors impact on health and development during childhood, and subsequently adult life in a deprived multi-ethnic population. Between 2007 and 2011, detailed information on socio-economic characteristics, ethnicity and family trees, lifestyle factors, environmental risk factors and physical and mental health has been collected from 12 453 women with 13 776 pregnancies (recruited at ∼28 weeks) and 3448 of their partners. Mothers were weighed and measured at recruitment, and infants have had detailed anthropometric assessment at birth and post-natally up to 2 years of age. Results of an oral glucose tolerance test and lipid profiles were obtained on the mothers during pregnancy at ∼28 weeks gestation, and pregnancy serum, plasma and urine samples have been stored. Cord blood samples have been obtained and stored and Deoxyribonucleic acid (DNA) extraction on 10 000 mother–offspring pairs is nearly completed. The study has a biobank of over 250 000 samples of maternal blood, DNA and urine, cord blood and DNA and paternal saliva. Details of how scientists can access these data are provided in this cohort profile.

Yes / Heterozygous germline mutations of BMPR2 contribute to familial clustering of pulmonary arterial hypertension (PAH). To further explore the genetic basis of PAH in isolated cases, we undertook a candidate gene analysis to identify potentially deleterious variation. Members of the bone morphogenetic protein (BMP) pathway, namely SMAD1, SMAD4, SMAD5, and SMAD9, were screened by direct sequencing for gene defects. Four variants were identified in SMADs 1, 4, and 9 among a cohort of 324 PAH cases, each not detected in a substantial control population. Of three amino acid substitutions identified, two demonstrated reduced signaling activity in vitro. A putative splice site mutation in SMAD4 resulted in moderate transcript loss due to compromised splicing efficiency. These results demonstrate the role of BMPR2 mutation in the pathogenesis of PAH and indicate that variation within the SMAD family represents an infrequent cause of the disease.

O presente estudo é um subprojeto do Instituto de Psiquiatria do Desenvolvimento intitulado \"Novas Ferramentas na Compreensão do Desenvolvimento Infantil: a Interação Gene-Ambiente e Conectividade Neuronal\", financiado pela FAPESP e aprovado pela CAPPESQ com o número de protocolo 0054/09. Os primeiros anos são particularmente importantes no ciclo vital, é rápido o crescimento e desenvolvimento do cérebro, tornando-se vulnerável à exposição a diferentes fatores de risco biológicos e psicossociais. Os fatores biológicos, em geral, são acompanhados por fatores psicossociais e ambientais que potencializam o seu efeito. Essas condições adversas são fatores de risco e ameaça ao desenvolvimento infantil. Devido à importância e ao impacto dos atrasos no desenvolvimento sobre o futuro da criança, quanto mais precocemente forem identificadas as crianças de maior risco, menor o agravamento futuro. O objetivo dessa dissertação foi caracterizar o desenvolvimento neuropsicomotor de crianças de 6 a 9 meses através da Escala Bayley de Desenvolvimento, em uma amostra de base populacional. Estimou-se a prevalência de atraso e a identificou os fatores de risco psicossociais e ambientais associados. É um estudo epidemiológico de coorte de nascimento longitudinal, com três seguimentos. A primeira entrevista com a gestante, para coleta de dados socioeconômicos e a entrevista para diagnósticos psiquiátricos, o segundo encontro para verificar diagnósticos psiquiátricos no puerpério, dados de nascimento e alimentação do lactente e por último aos 6 meses a aplicação da Escala Bayley. Avaliados 368 lactentes, encontramos 15,4% das crianças classificadas com atraso significativo em pelo menos um dos domínios, entre eles 10,87% tiveram atraso no desenvolvimento motor, com déficit de linguagem o total de 8,15% e 3,01% dos lactentes apresentaram atraso no desenvolvimento cognitivo aos 6 meses. Em analises constatou que o desenvolvimento cognitivo foi o fator com maior associação a fatores de estresse materno. Os transtornos, de humor durante a gestação, transtorno psicótico e transtorno de ansiedade no puerpério, a classe econômica, escolaridade materno, mãe adolescente e fumo durante a gestação, foram associados ao atraso no desenvolvimento mesmo após ajustes para fatores confundidores. Conclui-se que os transtornos psiquiátricos são preditores de atraso no desenvolvimento neuropsicomotor aos 6 meses de idade. Esse estudo mostra a importância da triagem para identificação de possíveis atrasos no desenvolvimento, para consequentes programas de intervenção a fim de evitar ou minimizar agravos futuros e possibilitar a criança desenvolver-se com todo seu potencial / This study is a subproject of Developmental Psychiatry Institute entitled \"New Tools in Child Development Understanding: Gene-Environment Interaction and Connectivity Neuronal\", funded by FAPESP and approved by CAPPESQ with protocol number 0054/09. It aims to characterize the neurological development of children aged 6 to 8 months by the Bayley scale in a population-based sample. It is expected, therefore, to estimate the prevalence of delay and the identification of psychosocial and environmental risk factors. The first years are particularly important in the life cycle, when is the rapid growth and development of the brain, making it vulnerable to exposure to different biological and psychosocial risk factors. Biological factors generally are accompanied by psychosocial and environmental factors that increase its effect. These adverse conditions are a risk factor and threat to child development. The importance and the impact of delays in the development of the child\'s future, the earlier identified the delay development, the risk could be smaller. The purpose of this thesis was to characterize the neurological development of children 6-9 months ago through the Bayley scale in a population-based sample, then estimate the prevalence of delay and identifying psychosocial and environmental risk factors. A longitudinal epidemiological study of birth cohort with three segments, the first interview with the pregnant woman, to collect socioeconomic data and the psychiatric diagnoses interview, the second meeting to check psychiatric diagnoses in the postpartum period, data of birth and infant feeding. At last, on six months, implementation the Bayley Scale of Development. Evaluated 368 infants, 15.4% children were classified as significant delay in at least one of the areas, among them 10.87% had delayed motor development, language delay total of 8.15% and 3.01 % of infants were delayed cognitive. In analysis, found that cognitive development was the factor with the largest association of maternal stress factors. Disorders, mood during pregnancy, psychotic disorder and anxiety disorder in the postpartum period, economic class, maternal education, teenage mother and smoking during pregnancy were associated with delayed development even after adjusting for confounding factors. It is concluded that, psychiatric disorders are predictors of delay in psychomotor development at 6 months of age. This study shows the importance of screening to identify possible developmental delays, for subsequent intervention programs to prevent or minimize future hazards and allow the child to develop to their full potential. Keywords: development; risk factors; infants

O momento ideal para a extubação de crianças graves é ainda difícil de ser avaliado. A razão entre espaço morto e volume corrente (Vd/Vt), como valor preditiva de extubação bem sucedida, já foi testada em adultos e crianças. O objetivo deste trabalho foi avaliar a eficácia do Vd/Vt, como preditivo do sucesso da extubação, em crianças de uma UTI pediátrica geral. Após aplicação dos critérios de inclusão e exclusão, testou-se o Vd/Vt em 86 pacientes extubados num período de 16 meses. Nos estudos estatísticos o índice Vd/Vt médio não discriminou os grupos de falha e sucesso na extubação nas análises uni e multivariada. O valor do índice, com corte em 0,65, foi limitado na sensibilidade e especificidade e mediano na razão de verossimilhança. O estudo sugere que o índice Vd/Vt, pode ser considerado como complementar aos dados de avaliação clínica no momento da extubação. / The ideal moment for extubation of critically ill children is still difficult to determine. The dead-space : tidal volume ratio (Vd/Vt) has been tested as predictor of extubation failure in adults and children. The purpose of this study was to evaluate the efficacy of the Vd/Vt as a predictor of the success of extubation in children admitted to a pediatric intensive care unit. After the inclusion and exclusion criteria, 86 patients were studied during 16 months. The statistical study revealed that the mean Vd/Vt was not able to discriminate between failure and success of extubation in the multivariate analysis. The utility of the Vd/Vt was limited, in terms of sensibility and specificity, using a cutoff of 0,65, but was medially satisfactory in the likelihood ratio. This study suggests that the Vd/Vt can only be considered as complementary to the routine clinical evaluation prior to extubation.

O presente estudo é um subprojeto do Instituto de Psiquiatria do Desenvolvimento intitulado \"Novas Ferramentas na Compreensão do Desenvolvimento Infantil: a Interação Gene-Ambiente e Conectividade Neuronal\", financiado pela FAPESP e aprovado pela CAPPESQ com o número de protocolo 0054/09. Os primeiros anos são particularmente importantes no ciclo vital, é rápido o crescimento e desenvolvimento do cérebro, tornando-se vulnerável à exposição a diferentes fatores de risco biológicos e psicossociais. Os fatores biológicos, em geral, são acompanhados por fatores psicossociais e ambientais que potencializam o seu efeito. Essas condições adversas são fatores de risco e ameaça ao desenvolvimento infantil. Devido à importância e ao impacto dos atrasos no desenvolvimento sobre o futuro da criança, quanto mais precocemente forem identificadas as crianças de maior risco, menor o agravamento futuro. O objetivo dessa dissertação foi caracterizar o desenvolvimento neuropsicomotor de crianças de 6 a 9 meses através da Escala Bayley de Desenvolvimento, em uma amostra de base populacional. Estimou-se a prevalência de atraso e a identificou os fatores de risco psicossociais e ambientais associados. É um estudo epidemiológico de coorte de nascimento longitudinal, com três seguimentos. A primeira entrevista com a gestante, para coleta de dados socioeconômicos e a entrevista para diagnósticos psiquiátricos, o segundo encontro para verificar diagnósticos psiquiátricos no puerpério, dados de nascimento e alimentação do lactente e por último aos 6 meses a aplicação da Escala Bayley. Avaliados 368 lactentes, encontramos 15,4% das crianças classificadas com atraso significativo em pelo menos um dos domínios, entre eles 10,87% tiveram atraso no desenvolvimento motor, com déficit de linguagem o total de 8,15% e 3,01% dos lactentes apresentaram atraso no desenvolvimento cognitivo aos 6 meses. Em analises constatou que o desenvolvimento cognitivo foi o fator com maior associação a fatores de estresse materno. Os transtornos, de humor durante a gestação, transtorno psicótico e transtorno de ansiedade no puerpério, a classe econômica, escolaridade materno, mãe adolescente e fumo durante a gestação, foram associados ao atraso no desenvolvimento mesmo após ajustes para fatores confundidores. Conclui-se que os transtornos psiquiátricos são preditores de atraso no desenvolvimento neuropsicomotor aos 6 meses de idade. Esse estudo mostra a importância da triagem para identificação de possíveis atrasos no desenvolvimento, para consequentes programas de intervenção a fim de evitar ou minimizar agravos futuros e possibilitar a criança desenvolver-se com todo seu potencial / This study is a subproject of Developmental Psychiatry Institute entitled \"New Tools in Child Development Understanding: Gene-Environment Interaction and Connectivity Neuronal\", funded by FAPESP and approved by CAPPESQ with protocol number 0054/09. It aims to characterize the neurological development of children aged 6 to 8 months by the Bayley scale in a population-based sample. It is expected, therefore, to estimate the prevalence of delay and the identification of psychosocial and environmental risk factors. The first years are particularly important in the life cycle, when is the rapid growth and development of the brain, making it vulnerable to exposure to different biological and psychosocial risk factors. Biological factors generally are accompanied by psychosocial and environmental factors that increase its effect. These adverse conditions are a risk factor and threat to child development. The importance and the impact of delays in the development of the child\'s future, the earlier identified the delay development, the risk could be smaller. The purpose of this thesis was to characterize the neurological development of children 6-9 months ago through the Bayley scale in a population-based sample, then estimate the prevalence of delay and identifying psychosocial and environmental risk factors. A longitudinal epidemiological study of birth cohort with three segments, the first interview with the pregnant woman, to collect socioeconomic data and the psychiatric diagnoses interview, the second meeting to check psychiatric diagnoses in the postpartum period, data of birth and infant feeding. At last, on six months, implementation the Bayley Scale of Development. Evaluated 368 infants, 15.4% children were classified as significant delay in at least one of the areas, among them 10.87% had delayed motor development, language delay total of 8.15% and 3.01 % of infants were delayed cognitive. In analysis, found that cognitive development was the factor with the largest association of maternal stress factors. Disorders, mood during pregnancy, psychotic disorder and anxiety disorder in the postpartum period, economic class, maternal education, teenage mother and smoking during pregnancy were associated with delayed development even after adjusting for confounding factors. It is concluded that, psychiatric disorders are predictors of delay in psychomotor development at 6 months of age. This study shows the importance of screening to identify possible developmental delays, for subsequent intervention programs to prevent or minimize future hazards and allow the child to develop to their full potential. Keywords: development; risk factors; infants

O momento ideal para a extubação de crianças graves é ainda difícil de ser avaliado. A razão entre espaço morto e volume corrente (Vd/Vt), como valor preditiva de extubação bem sucedida, já foi testada em adultos e crianças. O objetivo deste trabalho foi avaliar a eficácia do Vd/Vt, como preditivo do sucesso da extubação, em crianças de uma UTI pediátrica geral. Após aplicação dos critérios de inclusão e exclusão, testou-se o Vd/Vt em 86 pacientes extubados num período de 16 meses. Nos estudos estatísticos o índice Vd/Vt médio não discriminou os grupos de falha e sucesso na extubação nas análises uni e multivariada. O valor do índice, com corte em 0,65, foi limitado na sensibilidade e especificidade e mediano na razão de verossimilhança. O estudo sugere que o índice Vd/Vt, pode ser considerado como complementar aos dados de avaliação clínica no momento da extubação. / The ideal moment for extubation of critically ill children is still difficult to determine. The dead-space : tidal volume ratio (Vd/Vt) has been tested as predictor of extubation failure in adults and children. The purpose of this study was to evaluate the efficacy of the Vd/Vt as a predictor of the success of extubation in children admitted to a pediatric intensive care unit. After the inclusion and exclusion criteria, 86 patients were studied during 16 months. The statistical study revealed that the mean Vd/Vt was not able to discriminate between failure and success of extubation in the multivariate analysis. The utility of the Vd/Vt was limited, in terms of sensibility and specificity, using a cutoff of 0,65, but was medially satisfactory in the likelihood ratio. This study suggests that the Vd/Vt can only be considered as complementary to the routine clinical evaluation prior to extubation.

Le risque attribuable (RA) mesure la proportion de cas de maladie qui peuvent être attribués à une exposition au niveau de la population. Plusieurs définitions et méthodes d'estimation du RA ont été proposées pour des données de survie. En utilisant des simulations, nous comparons quatre méthodes d'estimation du RA dans le contexte de l'analyse de survie : deux méthodes non paramétriques basées sur l'estimateur de Kaplan-Meier, une méthode semi-paramétrique basée sur le modèle de Cox à risques proportionnels et une méthode paramétrique basée sur un modèle à risques proportionnels avec un risque de base constant par morceaux. Nos travaux suggèrent d'utiliser les approches semi-paramétrique et paramétrique pour l'estimation du RA lorsque l'hypothèse des risques proportionnels est vérifiée. Nous appliquons nos méthodes aux données de la cohorte E3N pour estimer la proportion de cas de cancer du sein invasif attribuables à l'utilisation de traitements hormonaux de la ménopause (THM). Nous estimons qu'environ 9 % des cas de cancer du sein sont attribuables à l'utilisation des THM à l'inclusion. Dans le cas d'une exposition protectrice, une alternative au RA est la fraction préventive (FP) qui mesure la proportion de cas de maladie évités. Cette mesure n'a pas été considérée dans le contexte de l'analyse de survie. Nous proposons une définition de la FP dans ce contexte et des méthodes d'estimation en utilisant des approches semi-paramétrique et paramétrique avec une extension permettant de prendre en compte les risques concurrents. L'application aux données de la cohorte des Trois Cités (3C) estime qu'environ 9 % de cas d'accident vasculaire cérébral peuvent être évités chez les personnes âgées par l'utilisation des hypolipémiants. Notre étude montre que la FP peut être utilisée pour évaluer l'impact des médicaments bénéfiques dans les études de cohorte tout en tenant compte des facteurs de confusion potentiels et des risques concurrents. / The attributable risk (AR) measures the proportion of disease cases that can be attributed to an exposure in the population. Several definitions and estimation methods have been proposed for survival data. Using simulations, we compared four methods for estimating AR defined in terms of survival functions: two nonparametric methods based on Kaplan-Meier's estimator, one semiparametric based on Cox's model, and one parametric based on the piecewise constant hazards model. Our results suggest to use the semiparametric or parametric approaches to estimate AR if the proportional hazards assumption appears appropriate. These methods were applied to the E3N women cohort data to estimate the AR of breast cancer due to menopausal hormone therapy (MHT). We showed that about 9% of cases of breast cancer were attributable to MHT use at baseline. In case of a protective exposure, an alternative to the AR is the prevented fraction (PF) which measures the proportion of disease cases that could be avoided in the presence of a protective exposure in the population. The definition and estimation of PF have never been considered for cohort studies in the survival analysis context. We defined the PF in cohort studies with survival data and proposed two estimation methods: a semiparametric method based on Cox’s proportional hazards model and a parametric method based on a piecewise constant hazards model with an extension to competing risks. Using data of the Three-City (3C) cohort study, we found that approximately 9% of cases of stroke could be avoided using lipid-lowering drugs (statins or fibrates) in the elderly population. Our study shows that the PF can be estimated to evaluate the impact of beneficial drugs in observational cohort studies while taking potential confounding factors and competing risks into account.

Acrylamide is a common dietary exposure that crosses the human placenta. It is classified as a probable human carcinogen, and developmental toxicity has been observed in rodents. OBJECTIVES: We examined the associations between prenatal exposure to acrylamide and birth outcomes in a prospective European mother-child study. METHODS: Hemoglobin (Hb) adducts of acrylamide and its metabolite glycidamide were measured in cord blood (reflecting cumulated exposure in the last months of pregnancy) from 1,101 singleton pregnant women recruited in Denmark, England, Greece, Norway, and Spain during 2006-2010. Maternal diet was estimated through food-frequency questionnaires. RESULTS: Both acrylamide and glycidamide Hb adducts were associated with a statistically significant reduction in birth weight and head circumference. The estimated difference in birth weight for infants in the highest versus lowest quartile of acrylamide Hb adduct levels after adjusting for gestational age and country was -132 g (95% CI: -207, -56); the corresponding difference for head circumference was -0.33 cm (95% CI: -0.61, -0.06). Findings were similar in infants of nonsmokers, were consistent across countries, and remained after adjustment for factors associated with reduced birth weight. Maternal consumption of foods rich in acrylamide, such as fried potatoes, was associated with cord blood acrylamide adduct levels and with reduced birth weight. CONCLUSIONS: Dietary exposure to acrylamide was associated with reduced birth weight and head circumference. Consumption of specific foods during pregnancy was associated with higher acrylamide exposure in utero. If confirmed, these findings suggest that dietary intake of acrylamide should be reduced among pregnant women.

To enable improved interpretation of the total score and faster scoring of the Rivermead Mobility Index (RMI) by studying item ordering or hierarchy and formulating start-and-stop rules in patients after stroke. DESIGN: Cohort study. SETTING: Rehabilitation center in the Netherlands; stroke rehabilitation units and the community in the United Kingdom. PARTICIPANTS: Item hierarchy of the RMI was studied in an initial group of patients (n=620; mean age +/- SD, 69.2+/-12.5y; 297 [48%] men; 304 [49%] left hemisphere lesion, and 269 [43%] right hemisphere lesion), and the adequacy of the item hierarchy-based start-and-stop rules was checked in a second group of patients (n=237; mean age +/- SD, 60.0+/-11.3y; 139 [59%] men; 103 [44%] left hemisphere lesion, and 93 [39%] right hemisphere lesion) undergoing rehabilitation after stroke. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Mokken scale analysis was used to investigate the fit of the double monotonicity model, indicating hierarchical item ordering. The percentages of patients with a difference between the RMI total score and the scores based on the start-and-stop rules were calculated to check the adequacy of these rules. RESULTS: The RMI had good fit of the double monotonicity model (coefficient H(T)=.87). The interpretation of the total score improved. Item hierarchy-based start-and-stop rules were formulated. The percentages of patients with a difference between the RMI total score and the score based on the recommended start-and-stop rules were 3% and 5%, respectively. Ten of the original 15 items had to be scored after applying the start-and-stop rules. CONCLUSIONS: Item hierarchy was established, enabling improved interpretation and faster scoring of the RMI.

Chemerin is a chemoattractant adipokine that regulates adipogenesis and may induce insulin resistance. Chemerin serum concentrations are elevated in obese, insulin-resistant, and inflammatory states in vivo. Here we investigate the role of omental (OM) and subcutaneous (SC) adipose tissue chemerin and CMKLR1 messenger RNA (mRNA) expression in human obesity. In addition, we test the hypothesis that changes in chemerin serum concentrations are primarily associated with reduced body fat mass in the context of 3 weight loss intervention studies. Chemerin serum concentration was measured in 740 individuals in a cross-sectional (n = 629) study including a subgroup (n = 161) for which OM and SC chemerin mRNA expression has been analyzed as well as in 3 interventions including 12 weeks of exercise (n = 60), 6 months of calorie-restricted diet (n = 19) studies, and 12 months after bariatric surgery (n = 32). Chemerin mRNA is significantly higher expressed in adipose tissue of patients with type 2 diabetes mellitus and correlates with circulating chemerin, body mass index (BMI), percentage body fat, C-reactive protein, homeostasis model assessment of insulin resistance, and glucose infusion rate in euglycemic-hyperinsulinemic clamps. CMKLR1 mRNA expression was not significantly different between the 2 fat depots. Obesity surgery–induced weight loss causes a significant reduction on both OM and SC chemerin expression. All interventions led to significantly reduced chemerin serum concentrations. Decreased chemerin serum concentrations significantly correlate with improved glucose infusion rate and reduced C-reactive protein levels independently of changes in BMI. Insulin resistance and inflammation are BMI-independent predictors of elevated chemerin serum concentrations. Reduced chemerin expression and serum concentration may contribute to improved insulin sensitivity and subclinical inflammation beyond significant weight loss.