RESUMO
BACKGROUND: Asthma is a complex disease with worldwide public health relevance, is related to environmental causes and a genetic predisposition. The chromosomal 17q12-21 locus has been consistently demonstrated to be associated with asthma risk. The effects of variants in the 17q12-21 locus on childhood asthma were first identified in a genome wide- association study. Since that time, those findings have been replicated in different populations but not in South American populations. OBJECTIVE: This study aimed to investigate the role of variants in the 17q12-21 locus on asthma in a sample of Brazilian children. METHODS: This was a cross-sectional study conducted on a cohort of 1247 children. These analyses used 50 Single Nucleotide Variants (SNVs) in the 17q12-21 locus were genotyped as part of a genome wide association study (GWAS). RESULTS: Four SNVs (rs4065275, rs12603332, rs73985228 and rs77777702) were associated with childhood asthma. The rs73985228 exhibited the strongest association across the different genetic models (OR, 95%CI 2.8, 1.44-3.21, pâ¯<â¯0.01). In an analysis that was stratified by atopy, two SNVs (rs73985228 and rs2715555) were found to be associated with atopic and non-atopic asthma. For the first time, we observed a significant interaction with seropositivity for the Varicella zoster virus (for rs4065275, pâ¯=â¯0.02, and for rs12603332, pâ¯=â¯0.04); i.e., the association was found in those who were seropositive but not in those who were seronegative for this virus. CONCLUSIONS: We confirmed the associations of variants in the 17q12-21 locus with atopic and non-atopic asthma and identified an interaction with seropositivity for the Varicella zoster virus.
Assuntos
Asma/genética , Cromossomos Humanos Par 17/genética , Predisposição Genética para Doença , Herpesvirus Humano 3 , Polimorfismo de Nucleotídeo Único , Infecção pelo Vírus da Varicela-Zoster/genética , Asma/virologia , Criança , Pré-Escolar , Estudos Transversais , Feminino , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , MasculinoRESUMO
Antecedentes: La relación inversa entre el colesterol HDL y la mortalidad cardiovascular se debilita en presencia de enfermedad coronaria (EC). El objetivo de este trabajo fue investigar las asociaciones de las concentraciones de partículas de HDL con la mortalidad cardiovascular y el impacto de la EC en estas asociaciones. También se buscó evaluar comparativamente las concentraciones de colesterol HDL y partículas de HDL en la predicción de la mortalidad cardiovascular. Métodos: Las concentraciones totales de HDL y sus sub-clases se midieron mediante espectroscopía de resonancia magnética nuclear en 2.290 participantes del estudio LUdwigshafen RIsk and Cardiovascular Health remitidos para angiografía coronaria. Los participantes fueron seguidos prospectivamente durante una mediana (rango intercuartílico) con una duración de 10,0 (6,1-10,6) años. Resultados: La media de la edad (DE) de los participantes (1.575 hombres, 715 mujeres) fue de 62,9 (10,4) años, índice de masa corporal 27,6 (4,1) kg/m², colesterol-HDL 39 (11) mg/dL [1 (0,29) mmol/L], y la concentración total de partículas de HDL 24,1 (5,8) μmol/L. Cuatroscientos treinta y cuatro de los participantes murieron de enfermedad cardiovascular. En análisis multivariados, los tercilos de las concentraciones totales de partículas de HDL se relacionaron inversamente con la mortalidad cardiovascular (Hazard Ratio para 3° frente a 1° tercilo = 0,55; p<0,001). Esta asociación fue mediada principalmente por las partículas de HDL pequeñas (p<0,001). La adición a los modelos de predicción multivariada de las concentraciones de partículas HDL totales o pequeñas, en lugar de colesterol HDL, mejoró las métricas de rendimiento para predicción de mortalidad cardiovascular. La presencia de EC no tuvo impacto en las asociaciones entre las concentraciones de partículas de HDL y la mortalidad cardiovascular. Conclusiones: La alta concentración de partículas de HDL se encuentra asociada con una disminución de la mortalidad cardiovascular de manera consistente e independiente de la EC. Sin embargo, si esta relación inversa entre la concentración de partículas de HDL y la mortalidad cardiovascular se puede traducir en nuevas estrategias terapéuticas está aún bajo investigación.
Background: The inverse relationship between HDL cholesterol and cardiovascular mortality is weakened in coronary artery disease (CAD). We aimed to investigate the associations of HDL particle concentrations with cardiovascular mortality and the impact of CAD on these associations. We also sought to comparatively evaluate HDL cholesterol and HDL particle concentrations in predicting cardiovascular mortality. Methods: Total and subclass HDL particle concentrations were measured by nuclear magnetic resonance spectroscopy in 2,290 participants of the LUdwigshafen RIsk and Cardiovascular Health study referred for coronary angiography. The participants were prospectively followed over a median (interquartile range) duration of 10.0 (6.1-10.6) years. Results: The mean (SD) age of the participants (1,575 males, 715 females) was 62.9 (10.4) years, body mass index 27.6 (4.1) kg/m², HDL cholesterol 39 (11) mg/dL [1 (0.29) mmol/L], and total HDL particle concentration 24.1 (5.8) μmol/L. 434 persons died from cardiovascular diseases. In multivariate analyses, tertiles of total HDL particle concentrations were inversely related to cardiovascular mortality (HR for 3rd vs. 1st tertile = 0.55, P<0.001). This association was primarily mediated by small HDL particles (P<0.001). Adding total or small HDL particle concentrations rather than HDL cholesterol to multivariate prediction models improved performance metrics for cardiovascular mortality. The presence of CAD had no impact on the associations between HDL particle concentrations and cardiovascular mortality. Conclusions: High HDL particle concentration is consistently and independently of CAD associated with decreased cardiovascular mortality. Whether the inverse relationship between HDL particle concentration and cardiovascular mortality may be translated into novel therapies is under investigation.
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TraduçõesRESUMO
BACKGROUND: Immunologists often measure several correlated immunological markers, such as concentrations of different cytokines produced by different immune cells and/or measured under different conditions, to draw insights from complex immunological mechanisms. Although there have been recent methodological efforts to improve the statistical analysis of immunological data, a framework is still needed for the simultaneous analysis of multiple, often correlated, immune markers. This framework would allow the immunologists' hypotheses about the underlying biological mechanisms to be integrated. RESULTS: We present an analytical approach for statistical analysis of correlated immune markers, such as those commonly collected in modern immuno-epidemiological studies. We demonstrate i) how to deal with interdependencies among multiple measurements of the same immune marker, ii) how to analyse association patterns among different markers, iii) how to aggregate different measures and/or markers to immunological summary scores, iv) how to model the inter-relationships among these scores, and v) how to use these scores in epidemiological association analyses. We illustrate the application of our approach to multiple cytokine measurements from 818 children enrolled in a large immuno-epidemiological study (SCAALA Salvador), which aimed to quantify the major immunological mechanisms underlying atopic diseases or asthma. We demonstrate how to aggregate systematically the information captured in multiple cytokine measurements to immunological summary scores aimed at reflecting the presumed underlying immunological mechanisms (Th1/Th2 balance and immune regulatory network). We show how these aggregated immune scores can be used as predictors in regression models with outcomes of immunological studies (e.g. specific IgE) and compare the results to those obtained by a traditional multivariate regression approach. CONCLUSION: The proposed analytical approach may be especially useful to quantify complex immune responses in immuno-epidemiological studies, where investigators examine the relationship among epidemiological patterns, immune response, and disease outcomes.
Assuntos
Alergia e Imunologia , Asma/diagnóstico , Epidemiologia , Hipersensibilidade Imediata/diagnóstico , Biomarcadores/metabolismo , Pesquisa Biomédica , Brasil/epidemiologia , Criança , Simulação por Computador , Citocinas/metabolismo , Interpretação Estatística de Dados , Humanos , Imunoglobulina E/sangue , Sistemas Integrados e Avançados de Gestão da Informação , Avaliação de Resultados em Cuidados de Saúde/métodos , Valor Preditivo dos Testes , Prognóstico , Equilíbrio Th1-Th2RESUMO
BCG protection varies and in some places (nearest the equator) is low or absent. Understanding this variation can inform the efforts to develop new vaccines against tuberculosis. Two main hypotheses are used to explain this variation: under masking, new vaccines are unlikely to increase protection; under blocking new vaccines have a greater potential to be effective when BCG is not. We conducted a cluster randomized trial to explored the masking and blocking hypotheses by studying BCG vaccine efficacy of neonatal vaccination and when administered for the first or a second (revaccination) time at school age in two sites (Manaus close and Salvador further south from the equator). Seven hundred and sixty three state schools were matched on socio economic characteristics of the neighborhood and 239,934 children were randomized to vaccine (BCG vaccination at school age) or control group. Protection by first BCG vaccination at school age was high in Salvador (34%, 95% CI 7-53%, p=0.017) but low in Manaus (8%, 95% CI t0 39-40%, p=0.686). For revaccination at school age, protection was modest in Salvador (19%, 95% CI 3-33%, p=0.022) and absent in Manaus (1%, 95% CI to 27-23%, p=0.932). Vaccine efficacy for neonatal vaccination was similar in Salvador (40%, 95% CI 22-54%, p<0.001) and Manaus (36%, 95% CI 11-53%, p=0.008). Variation in BCG efficacy was marked when vaccine was given at school age but absent at birth, which points towards blocking as the dominant mechanism. New tuberculosis vaccines that overcome or by pass this blocking effect could confer protection in situations where BCG is not protective.
Assuntos
Vacina BCG/imunologia , Imunização Secundária , Tuberculose/prevenção & controle , Adolescente , Vacina BCG/uso terapêutico , Brasil/epidemiologia , Criança , Feminino , Geografia , Humanos , Recém-Nascido , Masculino , Classe Social , Tuberculose/epidemiologiaRESUMO
BACKGROUND: Neonatal BCG vaccination is part of routine vaccination schedules in many developing countries; vaccination at school age has not been assessed in trials in low-income and middle-income countries. Catch-up BCG vaccination of school-age children who missed neonatal BCG vaccination could be indicated if it confers protection and is cost-effective. We did a cluster-randomised trial (BCG REVAC) to estimate the effectiveness (efficacy given in routine settings) of school-age vaccination. METHODS: We assessed the effectiveness of BCG vaccination in school-age children (aged 7-14 years) with unknown tuberculin status who did not receive neonatal BCG vaccination (subpopulation of the BCG REVAC cluster-randomised trial), between July, 1997, and June, 2006, in Salvador, Brazil, and between January, 1999, and December, 2007, in Manaus, Brazil. 763 schools were randomly assigned into BCG vaccination group or a not-vaccinated control group. Neither allocation nor intervention was concealed. Incidence of tuberculosis was the primary outcome. Cases were identified via the Brazilian Tuberculosis Control Programme. Study staff were masked to vaccination status when identified cases were linked to the study population. We estimated cost-effectiveness in Salvador by comparison of the cost for vaccination to prevent one case of tuberculosis (censored at 9 years) with the average cost of treating one case of tuberculosis. Analysis of all included children was by intention to treat. For calculation of the incidence rate we used generalised estimating equations and correlated observations over time. FINDINGS: We randomly assigned 20,622 children from 385 schools to the BCG vaccination group and 18,507 children from 365 schools to the control group. The crude incidence of tuberculosis was 54·9 (95% CI 45·3-66·7) per 100,000 person-years in the BCG vaccination group and 72·7 (62·8-86·8) per 100,000 person-years in the control group. The overall vaccine effectiveness of a first BCG vaccination at school age was 25% (3-43%). In Salvador, where vaccine effectiveness was 34% (8-53%), vaccination of 381 children would prevent one case of tuberculosis and was cheaper than treatment. The frequency of adverse events was very low with only one axillary lymphadenitis and one ulcer greater than 1 cm in 11,980 BCG vaccinations. INTERPRETATION: Vaccination of school-age children without previous tuberculin testing can reduce the incidence of tuberculosis and could reduce the costs of tuberculosis control. Restriction of BCG vaccination to the first year of life is not in the best interests of the public nor of programmes for tuberculosis control. FUNDING: UK Department for International Development, National Health Foundation.
Assuntos
Vacina BCG/administração & dosagem , Mycobacterium tuberculosis/imunologia , Tuberculose/prevenção & controle , Vacinação/métodos , Adolescente , Vacina BCG/economia , Vacina BCG/imunologia , Criança , Análise por Conglomerados , Análise Custo-Benefício , Feminino , Humanos , Incidência , Masculino , Tuberculose/economia , Tuberculose/imunologia , Tuberculose/microbiologia , Vacinação/economiaRESUMO
BCG revaccination is still used in some tuberculosis endemic countries. Until now, the little evidence available suggested that BCG revaccination confers very limited additional protection, although there was no information on whether protection depends on the setting and age of revaccination, or if protection increases with time since vaccination. Here we report on an extended follow up of the BCG-REVAC trial, a cluster randomised trial conducted in the Brazilian cities Salvador and Manaus including over 200,000 children aged 7-14 years aimed to evaluate the efficacy of BCG revaccination in children who had received neonatal BCG vaccination. With the extended follow-up (9 years) and the additional cases accrued we now have enough power to report vaccine efficacy separately for the two cities (with different distances from Equator and presumably different prevalence of non-tuberculosis mycobacteria), and by age at vaccination and clinical form. The overall vaccine efficacy was 12% (-2 to 24%) as compared to 9% (-16 to 29%) for the 5-year follow up. Vaccine efficacy was higher in Salvador (19%, 3 to 33%) than in Manaus (1%, -27 to 27%) with the highest vaccine efficacy in children from Salvador aged <11 years at revaccination (33%, 3 to 54%). The findings are in line with the hypothesis that BCG vaccination offers higher efficacy in low NTMb prevalence, and show that revaccination with BCG can offer weak protection in selected subgroups.
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Vacina BCG/administração & dosagem , Vacina BCG/imunologia , Imunização Secundária/métodos , Tuberculose/epidemiologia , Tuberculose/prevenção & controle , Adolescente , Brasil/epidemiologia , Criança , Feminino , Seguimentos , Humanos , Incidência , Masculino , População UrbanaRESUMO
BACKGROUND: Sanitation affects health, especially that of young children. Residents of Salvador, in Northeast Brazil, have had a high prevalence of intestinal parasites. A citywide sanitation intervention started in 1996 aimed to raise the level of sewer coverage from 26% to 80% of households. OBJECTIVES: We evaluated the impact of this intervention on the prevalence of Ascaris lumbricoides, Trichuris trichuria, and Giardia duodenalis infections in preschool children. METHODS: The evaluation was composed of two cross-sectional studies (1998 and 2003-2004), each of a sample of 681 and 976 children 1-4 years of age, respectively. Children were sampled from 24 sentinel areas chosen to represent the range of environmental conditions in the study site. Data were collected using an individual/household questionnaire, and an environmental survey was conducted in each area before and after the intervention to assess basic household and neighborhood sanitation conditions. Stool samples were examined for the presence of intestinal parasites. The effect of the intervention was estimated by hierarchical modeling, fitting a sequence of multivariate regression models. FINDINGS: The prevalence ofA. lumbricoides infection was reduced from 24.4% to 12.0%, T. trichuria from 18.0% to 5.0%, and G. duodenalis from 14.1% to 5.3%. Most of this reduction appeared to be explained by the increased coverage in each neighborhood by the sewage system constructed during the intervention. The key explanatory variable was thus an ecological measure of exposure and not household-based, suggesting that the parasite transmission prevented by the program was mainly in the public (vs. the domestic) domain. CONCLUSION: This study, using advanced statistical modeling to control for individual and ecological potential confounders, demonstrates the impact on intestinal parasites of sanitation improvements implemented at the scale of a large population.
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Controle de Doenças Transmissíveis/métodos , Doenças Parasitárias/epidemiologia , Saneamento/métodos , Animais , Ascaríase/epidemiologia , Ascaríase/prevenção & controle , Ascaris lumbricoides/isolamento & purificação , Brasil , Pré-Escolar , Cidades , Estudos Transversais , Feminino , Água Doce/parasitologia , Giardia/isolamento & purificação , Giardíase/epidemiologia , Giardíase/prevenção & controle , Humanos , Lactente , Masculino , Doenças Parasitárias/prevenção & controle , Esgotos/parasitologia , Tricuríase/epidemiologia , Tricuríase/prevenção & controle , Trichuris/isolamento & purificaçãoRESUMO
BACKGROUND: The validity of unblinded randomised trials testing interventions against diarrhoea is severely compromised by the potential for bias. Objective proxy markers for diarrhoea not relying on self-report are needed to assess the effect of interventions that cannot be blinded. Short-term changes in weight-for-age z-score (WAZ) may (due to catch-up growth) not be a clinically important marker for nutritional status. However, even a transient decrease in WAZ could indicate recent diarrhoea, and be interpreted as the effect of an intervention. METHODS: Using data from two large vitamin A trials from Ghana and Brazil, the immediate effect of the cumulative diarrhoea occurrence over 14 and 28 day time windows on WAZ was explored. RESULTS: A very strong linear association was found between the number of days with diarrhoea over the last 14-28 days and WAZ. In both trials, differences in diarrhoea between the trial arms were associated with corresponding differences in WAZ. CONCLUSION: Repeated WAZ measures appear to be a suitable proxy marker for diarrhoea in children, but have disadvantages in terms of specificity and study power.
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Peso Corporal , Diarreia/diagnóstico , Vitamina A/uso terapêutico , Estatura , Brasil , Pré-Escolar , Diarreia/tratamento farmacológico , Diarreia/epidemiologia , Diarreia/etiologia , Suplementos Nutricionais , Estudos Epidemiológicos , Gana , Humanos , Lactente , Recém-Nascido , Estado Nutricional , Prevalência , Ensaios Clínicos Controlados Aleatórios como Assunto , Análise de Regressão , Deficiência de Vitamina ARESUMO
BACKGROUND: Environmental factors are likely to have profound effects on the development of host immune responses, with serious implications for infectious diseases and inflammatory disorders such as asthma. OBJECTIVE: This study was designed to investigate the effects of environmental exposures on the cytokine profile of children. METHODS: The study involved measurement of T helper (Th) 1 (interferon-gamma), 2 [interleukin (IL)-5 and IL-13], and the regulatory cytokine IL-10 in unstimulated peripheral blood leukocytes from 1,376 children 4-11 years of age living in a poor urban area of the tropics. We also assessed the impact of environmental exposures in addition to biological characteristics recorded at the time of blood collection and earlier in childhood (0-3 years before blood collection). RESULTS: The proportion of children producing IL-10 was greater among those without access to drinking water [p < 0.05, chi-square test, odds ratio (OR) = 1.67]. The proportion of children producing IL-5 and IL-10 (OR = 10.76) was significantly greater in households that had never had a sewage system (p < 0.05, trend test). CONCLUSIONS: These data provide evidence for the profound effects of environmental exposures in early life as well as immune homeostasis in later childhood. Decreased hygiene (lack of access to clean drinking water and sanitation) in the first 3 years of life is associated with higher spontaneous IL-10 production up to 8 years later in life.
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Exposição Ambiental , Poluentes Ambientais/toxicidade , Sistema Imunitário/efeitos dos fármacos , Interferon gama/sangue , Interleucina-10/sangue , Interleucina-13/sangue , Interleucina-5/sangue , Fatores Etários , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Esgotos/efeitos adversos , Abastecimento de Água/análiseRESUMO
BACKGROUND: Children in low-income settings suffering from frequent diarrhoea episodes are also at a high risk of acute lower respiratory infections (ALRI). We explored whether this is due to common risk factors for both conditions or whether diarrhoea can increase the risk of ALRI directly. METHODS: We used a dynamic time-to-event analysis of data from two large child studies in low-income settings in Ghana and Brazil, with the cumulative diarrhoea prevalence over 2 weeks as the exposure and severe ALRI as outcome. The analysis was adjusted for baseline risk of ALRI and diarrhoea, seasonality and age. RESULTS: The child population from Ghana had a much higher risk of diarrhoea, malnutrition and death than the children in Brazil. In the data from Ghana, every additional day of diarrhoea within 2 weeks increased the risk of ALRI by a factor of 1.08 (95% CI 1.00-1.15). In addition, we found a roughly linear relationship between the number of diarrhoea days over the last 28 days and the risk of ALRI. In the Ghana data, 26% of ALRI episodes may be due to recent exposure to diarrhoea. The Brazilian data gave no evidence for an association between diarrhoea and ALRI. CONCLUSION: Diarrhoea may contribute substantially to the burden of ALRI in malnourished child populations.