DM is a serious and complex public health problem in the U.S. The CDC (2013) estimated that 25.8 million people, or 8.3% of the U.S. population, were suffering from DM in 2011. DM can significantly affect patient’s quality of life. Additionally, DM places a significant economic burden on the U.S. healthcare system. Over the past two decades, DMPs have emerged as a promising intervention to improve health outcomes for patients suffering from chronic conditions, such as DM, and to bend the cost curve. DMP’s aim is to improve communication and follow-up so that patients can better manage their chronic condition(s) to avoid costly hospital stays and emergency room visits (Fireman, Bartlett, & Selby, 2004). The Georgia region of Kaiser Permanente (KPGA) is a fully integrated health system that serves 260,000 members at 28 medical offices along with two specialty offices in the metropolitan Atlanta area. The Center for Care Partnership, the population care division of KPGA, administers a chronic disease management program (DMP), Healthy Solutions (HS). HS exists to improve and maintain the health of chronically ill KPGA members, including patients diagnosed with diabetes mellitus (DM), by providing health coaches via telephone who counsel members on their specific chronic disease and aid members in starting or maintaining a physician approved self-care management plan. In order to determine the impact HS has on KPGA members with DM, an evaluation plan was created to evaluate the impact HS has on members’ glycated hemoglobin (A1C), blood pressure, and emergency department (ED) utilization. This capstone thoroughly details the proposed evaluation plan created for HS by using Robert Milstein and Scott Wetterhall’s six-step framework for program evaluation. Additionally, further evaluation questions are suggested and discussed in order to provide a more complete picture of program performance to stakeholders.

Parkinson’s disease (PD) is a progressive, degenerative, neurological disease. The progressive disability associated with PD results in substantial burdens for those with the condition, their families and society in terms of increased health resource use, earnings loss of affected individuals and family caregivers, poorer quality of life, caregiver burden, disrupted family relationships, decreased social and leisure activities, and deteriorating emotional well-being. Currently, no cure is available and the efficacy of available treatments, such as medication and surgical interventions, decreases with longer duration of the disease. Whilst the cause of PD is unknown, genetic and environmental factors are believed to contribute to its aetiology. Descriptive and analytical epidemiological studies have been conducted in a number of countries in an effort to elucidate the cause, or causes, of PD. Rural residency, farming, well water consumption, pesticide exposure, metals and solvents have been implicated as potential risk factors for PD in some previous epidemiological studies. However, there is substantial disagreement between the results of existing studies. Therefore, the role of environmental exposures in the aetiology of PD remains unclear. The main component of this thesis consists of a case-control study that assessed the contribution of environmental exposures to the risk of developing PD. An existing, previously unanalysed, dataset from a local case-control study was analysed to inform the design of the new case-control study. The analysis results suggested that regular exposure to pesticides and head injury were important risk factors for PD. However, due to the substantial limitations of this existing study, further confirmation of these results was desirable with a more robustly designed epidemiological study. A new exposure measurement instrument (a structured interviewer-delivered questionnaire) was developed for the new case-control study to obtain data on demographic, lifestyle, environmental and medical factors. Prior to its use in the case-control study, the questionnaire was assessed for test-retest repeatability in a series of 32 PD cases and 29 healthy sex-, age- and residential suburb-matched electoral roll controls. High repeatability was demonstrated for lifestyle exposures, such as smoking and coffee/tea consumption (kappas 0.70-1.00). The majority of environmental exposures, including use of pesticides, solvents and exposure to metal dusts and fumes, also showed high repeatability (kappas >0.78). A consecutive series of 163 PD case participants was recruited from a neurology clinic in Brisbane. One hundred and fifty-one (151) control participants were randomly selected from the Australian Commonwealth Electoral Roll and individually matched to the PD cases on age (± 2 years), sex and current residential suburb. Participants ranged in age from 40-89 years (mean age 67 years). Exposure data were collected in face-to-face interviews. Odds ratios and 95% confidence intervals were calculated using conditional logistic regression for matched sets in SAS version 9.1. Consistent with previous studies, ever having been a regular smoker or coffee drinker was inversely associated with PD with dose-response relationships evident for packyears smoked and number of cups of coffee drunk per day. Passive smoking from ever having lived with a smoker or worked in a smoky workplace was also inversely related to PD. Ever having been a regular tea drinker was associated with decreased odds of PD. Hobby gardening was inversely associated with PD. However, use of fungicides in the home garden or occupationally was associated with increased odds of PD. Exposure to welding fumes, cleaning solvents, or thinners occupationally was associated with increased odds of PD. Ever having resided in a rural or remote area was inversely associated with PD. Ever having resided on a farm was only associated with moderately increased odds of PD. Whilst the current study’s results suggest that environmental exposures on their own are only modest contributors to overall PD risk, the possibility that interaction with genetic factors may additively or synergistically increase risk should be considered. The results of this research support the theory that PD has a multifactorial aetiology and that environmental exposures are some of a number of factors to contribute to PD risk. There was also evidence of interaction between some factors (eg smoking and welding) to moderate PD risk.

Parkinson’s disease (PD) is a progressive, degenerative, neurological disease. The progressive disability associated with PD results in substantial burdens for those with the condition, their families and society in terms of increased health resource use, earnings loss of affected individuals and family caregivers, poorer quality of life, caregiver burden, disrupted family relationships, decreased social and leisure activities, and deteriorating emotional well-being. Currently, no cure is available and the efficacy of available treatments, such as medication and surgical interventions, decreases with longer duration of the disease. Whilst the cause of PD is unknown, genetic and environmental factors are believed to contribute to its aetiology. Descriptive and analytical epidemiological studies have been conducted in a number of countries in an effort to elucidate the cause, or causes, of PD. Rural residency, farming, well water consumption, pesticide exposure, metals and solvents have been implicated as potential risk factors for PD in some previous epidemiological studies. However, there is substantial disagreement between the results of existing studies. Therefore, the role of environmental exposures in the aetiology of PD remains unclear. The main component of this thesis consists of a case-control study that assessed the contribution of environmental exposures to the risk of developing PD. An existing, previously unanalysed, dataset from a local case-control study was analysed to inform the design of the new case-control study. The analysis results suggested that regular exposure to pesticides and head injury were important risk factors for PD. However, due to the substantial limitations of this existing study, further confirmation of these results was desirable with a more robustly designed epidemiological study. A new exposure measurement instrument (a structured interviewer-delivered questionnaire) was developed for the new case-control study to obtain data on demographic, lifestyle, environmental and medical factors. Prior to its use in the case-control study, the questionnaire was assessed for test-retest repeatability in a series of 32 PD cases and 29 healthy sex-, age- and residential suburb-matched electoral roll controls. High repeatability was demonstrated for lifestyle exposures, such as smoking and coffee/tea consumption (kappas 0.70-1.00). The majority of environmental exposures, including use of pesticides, solvents and exposure to metal dusts and fumes, also showed high repeatability (kappas >0.78). A consecutive series of 163 PD case participants was recruited from a neurology clinic in Brisbane. One hundred and fifty-one (151) control participants were randomly selected from the Australian Commonwealth Electoral Roll and individually matched to the PD cases on age (± 2 years), sex and current residential suburb. Participants ranged in age from 40-89 years (mean age 67 years). Exposure data were collected in face-to-face interviews. Odds ratios and 95% confidence intervals were calculated using conditional logistic regression for matched sets in SAS version 9.1. Consistent with previous studies, ever having been a regular smoker or coffee drinker was inversely associated with PD with dose-response relationships evident for packyears smoked and number of cups of coffee drunk per day. Passive smoking from ever having lived with a smoker or worked in a smoky workplace was also inversely related to PD. Ever having been a regular tea drinker was associated with decreased odds of PD. Hobby gardening was inversely associated with PD. However, use of fungicides in the home garden or occupationally was associated with increased odds of PD. Exposure to welding fumes, cleaning solvents, or thinners occupationally was associated with increased odds of PD. Ever having resided in a rural or remote area was inversely associated with PD. Ever having resided on a farm was only associated with moderately increased odds of PD. Whilst the current study’s results suggest that environmental exposures on their own are only modest contributors to overall PD risk, the possibility that interaction with genetic factors may additively or synergistically increase risk should be considered. The results of this research support the theory that PD has a multifactorial aetiology and that environmental exposures are some of a number of factors to contribute to PD risk. There was also evidence of interaction between some factors (eg smoking and welding) to moderate PD risk.

Background: Parkinson’s disease (PD) is a complex disease with a multi-factorial aetiology, comprising both genetic and environmental risk factors. The disease pathology is progressive and neurodegenerative where dopaminergic nerve cell death occurs predominantly in the substantia nigra pars compacta (SNpc) with the subsequent loss of the dopamine neurotransmitter in the basal ganglia. The most significant risk factors for PD include an advancing age and a family history of the disease, while environmental and lifestyle risk factors such as pesticide exposure and smoking are widely accepted as risk altering exposures. Currently up to 10% of PD is attributed to Mendelian inherited PD at one of 13 PARK loci in 9 genes. The pursuit of common susceptibility alleles for idiopathic PD has proven challenging with only a few loci reproducibility associated with an altered risk. The aim of this thesis is to study, using a candidate gene case-control design, the potential role of genetic variants in PD. The APOE candidate gene was hypothesized to modify the risk of PD as it is a proven modifier of Alzheimer’s disease (AD). The common pathological finding in PD of elevated levels of iron within the SNpc is proposed to increase the oxidative state of the nerve cells and predispose the dopaminergic neurons to apoptosis. Therefore, susceptibility alleles within the candidate genes that regulate iron metabolism and homeostasis are hypothesized to alter iron metabolism and predispose to iron-induced neurodegeneration in PD. Missense variants and common “tagging” SNPs with the HFE, Transferrin and Transferrin Receptor genes are investigated extensively in this thesis. Finally, autosomal recessively inherited PD can result from mutations in the parkin gene at the PARK2 locus. The final hypothesis explored in this thesis suggests that non-deleterious missense variants in the parkin gene modify the risk for developing sporadic PD. Further genetic variation in the parkin gene such as exon rearrangements is a frequently reported mutation where heterozygosity for these rearrangements may increase the risk of PD. Heterozygous deletions or duplications of exons in the parkin gene provide technical challenges for their detection. In this thesis a novel assay for the detection of these mutations is investigated. Methods: Genotyping was performed using PCR-RFLP for genetic variants in the APOE (E2 and E4 alleles), HFE (C282Y, H63D and S65C), Transferrin receptor (TfR; S142G), Transferrin (Tfn; P570S and G258S), IREB2 genes (L159V) and the parkin gene (S167N, R366W and V380L) in a cohort of 425 PD cases and 387 controls recruited from throughout Queensland, Australia. A tagged SNP high-throughput genotyping approach was then employed to try to replicate single SNP associations in 6 iron-related genes using a cohort of 1034 PD cases and 774 controls. These genetic variants were analysed for direct association with PD risk, age of onset effects as well as potential gene x gene (GxG) and gene x environment (GxE) interactions. Additionally, a quantitative PCR assay was developed to detect heterozygous deletions and duplications within the parkin gene and utilised to screen 43 YOPD cases for these mutations. Results: The initial study of the HFE C282Y variant revealed a significant protective association with PD in the two independent cohorts studied. Further study did not reveal significant associations with PD for the other HFE variants or missense variants within the Tfn and TfR genes. When analysed for GxE interactions, the C282Y, P589S and G277S variants showed evidence for an increased risk of PD in synergy with pesticide and herbicide exposure. Carriers of the risk variant and with toxin exposure were at two-fold increased risk of PD, although the number of individuals in this category was small. A further investigation of the role of common genetic polymorphisms in iron genes revealed only one of the 20 SNPs genotyped using high-throughput multiplex methods, remained significantly associated with PD after correction for age and sex. The rs198855 SNP is downstream of the HFE gene and further implicates a role for HFE in PD. The APOE E4 allele demonstrated modifying effects for the age of PD onset, restricted to the female cases. Analysis of the parkin missense variants also demonstrated a modifying effect on the age of PD onset in carriers of the S167N variant, with putative interactions between the APOE E4 allele, a family history of PD and toxin exposure that further reduced the age of onset. Twenty individuals of the 43 YOPD cases screened demonstrated heterozygous parkin exon rearrangements using the novel qPCR method. Conclusions: Non-synonymous variants within iron-related genes or the parkin gene putatively interact with herbicide and pesticide exposure to increase the risk of PD or modify the phenotype, highlighting the need for future studies to address the multi-factorial aetiology of PD in their study design and analysis. This thesis provides evidence for the association between genetic variation within the HFE locus and PD and for the APOE E4 allele as a modifier of PD.

Klebsiella pneumoniae carbapenemase producing Klebsiella pneumoniae (KPC-Kp) is an emerging pathogen with acquired resistance to several antimicrobial classes and produces infections associated with considerable mortality. This study aims to identify risk factors for acquisition of hospital infections caused by KPC-Kp and to identify the clinical outcomes of these patients. This is a case-control study performed at a tertiary teaching hospital with 365 beds. The cases with hospital infection caused by KPC-Kp were compared with controls admitted to the same hospital paired by gender, age group and admission entry in a proportion of 2:1. During the period from February 2013 to August 2014, 22 patients were included in the study as cases and 44 as controls. The following independent risk factors for acquisition of hospital infections caused by KPC-Kp were identified: presence of a central venous catheter (OR 21.89; 95% CI 3.7 129.0); admission in an intensive care unit (OR 8.05; 95% CI 1.5 43.2); use of beta-lactams associated with or without beta-lactamase inhibitors (OR 6.02; 95% CI 1.1 32.6); use of carbapenems (OR 11.01; 95% CI 2.1 58.0) and the use of polymyxin B (OR 15.74; 95% CI 1.3 194.2). The crude case mortality rate was 36.8% (P=0.004). Infections caused by KPC-Kp are severe with an elevated mortality. To avoid unnecessary usage of antimicrobials, mainly beta-lactams, carbapenems and polymyxin B appear to be an essential way to control these infections. / Klebsiella pneumoniae produtora de klebsiella pneumoniae carbapenemase (KPC-Kp) é um patógeno emergente, com resistência a várias classes de antibióticos, sendo que suas infecções são associadas a considerável mortalidade. Este estudo tem como objetivo identificar fatores de risco para aquisição de infecções hospitalares causadas por KPC-Kp e identificar o desfecho clínico dos pacientes que adquirem essas infecções. Este é um estudo de caso-controle realizado em um hospital-escola terciário de 365 leitos. Os casos com infecção hospitalar por KPC-Kp foram comparados com controles internados no mesmo hospital, pareados por sexo, faixa etária e data de internação, na proporção de 2:1. Durante o período de fevereiro de 2013 a agosto de 2014, 22 pacientes foram incluídos no estudo como casos e 44 como controles. Foram identificados, como fatores de risco independentes para infecções hospitalares causadas por KPC-Kp, o uso de cateter venoso central (OR 21.89; 95% CI 3.7 129.0); a internação em unidade de tratamento intensivo (OR 8.05; 95% CI 1.5 43.2); o uso de b-lactâmicos associados ou não a inibidores de b-lactamase (OR 6.02; 95% CI 1.1 32.6); o uso de carbapenêmicos (OR 11.01; 95% CI 2.1 58.0); e o uso de polimixina B (OR 15.74; 95% CI 1.3 194.2). A mortalidade por qualquer causa nos casos considerados foi de 36,8% (p=0,004). Infecções por KPC-Kp são infecções graves com elevada mortalidade. Evitar o uso desnecessário de antibióticos, principalmente de b-lactâmicos, carbapenêmicos e polimixina B, parece ser caminho essencial para que se atinja o controle dessas infecções.

Objetivos: Investigar os fatores associados à hospitalização por pneumonia, em crianças menores de cinco anos de idade, no município de Ribeirão Preto - SP. Métodos: Estudo epidemiológico com delineamento do tipo caso-controle de base hospitalar, com alocação de 345 casos e 345 controles. Fatores socioeconômicos, reprodutivos, ambientais, perinatais, nutricionais, relativos ao cuidado à criança e à morbidade prévia foram considerados variáveis explanatórias. Os dados foram coletados por meio da aplicação de um questionário pré-codificado que contemplou o elenco de variáveis do estudo, incluindo-se o Instrumento de Avaliação da APS - PCATool. Odds ratios (OR) brutos e ajustados, com respectivos intervalos de confiança (95%) foram calculados, aplicando-se a regressão logística multivariada e seguindo-se os pressupostos da abordagem hierarquizada, buscando-se um modelo explicativo que contemplasse as relações hierárquicas existentes entre as exposições e o desfecho, sendo as análises desenvolvidas no software STATA, versão 12.0. Resultados: Renda familiar superior a R$700,00 foi responsável por uma redução de 32% na chance de hospitalização das crianças por pneumonia (OR=0,68; IC95%=0,47-0,98). Paridade >=2 representou um expressivo aumento na chance de hospitalização (categoria 2 partos: OR=4,60, IC95%=2,18-9,72; categoria >=3 partos: OR=3,25, IC95%=1,55-6,81), enquanto o intervalo interpartal >=48 meses e o ganho de peso na gestação de 10 Kg ou mais apresentaram efeito protetor para o desfecho (OR=0,28, IC95%=0,14-0,56 e OR=0,68, IC95%=0,47-0,97, respectivamente). Frequência à creche foi responsável por um aumento de 67% na chance de hospitalização por pneumonia (OR=1,67, IC95%=1,16-2,41). As crianças desnutridas apresentam uma chance duas vezes maior de serem hospitalizadas pela doença (OR=2,53; IC=1,06-6,05) enquanto aquelas com excesso de peso apresentam uma redução de 63% nessa chance (OR=0,37; IC=0,14-0,99); no entanto, questiona-se a plausibilidade biológica desse efeito protetor. A situação vacinal não atualizada foi responsável por um aumento de quase 3 vezes na chance de hospitalização por pneumonia (OR=2,81; IC=1,76-4,49). As crianças que fizeram uso pregresso de medicamentos apresentaram uma chance 67% maior de serem hospitalizadas por pneumonia (OR=1,67; IC=1,00-2,78; p=0,049). Crianças com sibilância prévia apresentaram o dobro de chance de serem hospitalizadas pela doença (OR categoria 1 episódio = 2,13; IC95%=1,31-3,47; OR categoria >=3 episódios = 2,37; IC95%=1,35-4,15). A exclusão de pneumonias aspirativas dentre os casos pode ter contribuído para uma maior proporção de crianças com refluxo referido entre os controles, levando a uma associação inversa à esperada (efeito de proteção) entre refluxo gastroesofágico e hospitalização por pneumonia (OR=0,55; IC=0,31-0,99). Escores Essenciais da APS acima de 3,17 foram responsáveis por um efeito protetor em relação à hospitalização por pneumonia, reduzindo as chances de hospitalização em 43% (OR para a categoria >3,41 = 0,57; IC=0,32-0,99) a 50% (OR para a categoria >3,17 e <=3,41 = 0,50; IC=0,28-0,88). Conclusões: O modelo explicativo obtido pelo presente estudo é composto, em grande parte, por variáveis relacionadas ao cuidado à criança ou às características da mãe e da família. Considerando-se os procedimentos referentes ao planejamento do estudo, à execução da coleta de dados e às análises estatísticas empregadas, reitera-se a consecução de validade interna para o estudo, sendo possível afirmar que o modelo obtido é explicativo do fenômeno da hospitalização por pneumonia, na população estudada. / Objectives: To investigate the factors associated with hospitalization due to pneumonia in children under five years of age in the city of Ribeirão Preto - SP, Brazil. Methods: Epidemiological study with a hospital-based case-control design, including 345 cases and 345 controls. Socioeconomic, reproductive, environmental, perinatal, nutritional, childcare and previous morbidity factors were considered as explanatory variables. The data were collected through the application of a pre-coded questionnaire that addressed the study variables and included the Primary Care Assessment Tool - PCATool. Gross and adjusted odds ratios (OR) were calculated with their respective confidence intervals (95%), applying multivariate logistic regression in accordance with the premises of the hierarchized approach, looking for an explanatory model that considered the existing hierarchical relations between the exposures and the outcome. The analyses were developed in STATA software, version 12.0. Results: A family income superior to R$700 was responsible for a 32% reduction in children\'s chance of hospitalization due to pneumonia (OR=0.68; 95%CI=0.47-0.98). Parity>=2 represented a considerable increase in the chance of hospitalization (category 2 births: OR=4.60, 95%CI=2.18-9.72; category >=3 births: OR=3.25, 95%CI=1.55-6.81), while the inter-birth interval >=48 months and the weight gain of 10 Kg or more during pregnancy represented a protective effect against the outcome (OR=0.28, 95%CI=0.14-0.56 and OR=0.68, 95%CI=0.47-0.97, respectively). Attending kindergarten was responsible for a 67% increase in the chance of hospitalization due to pneumonia (OR=1.67, 95%CI=1.16-2.41). Malnourished children present twice as many chances of being hospitalized due to the disease (OR=2.53; CI=1.06-6.05), while children with overweight present a 63% reduction in that chance (OR=0.37; CI=0.14-0.99); the biological plausibility of this protective effect is questioned though. An outdated vaccine situation was responsible for almost three times as many chances of hospitalization due to pneumonia (OR=2.81; CI=1.76-4.49). Children with earlier medication use revealed a 67% higher chance of being hospitalized due to pneumonia (OR=1.67; CI=1.00-2.78; p=0.049). Children with earlier wheezing presented twice as many chances of being hospitalized due to the disease (OR category 1 episode = 2.13; 95%CI=1.31-3.47; OR category >=3 episodes = 2.37; 95%CI=1.35-4.15). The exclusion of aspiration pneumonias from the cases may have contributed to a greater proportion of children with reflux among the control, leading to an inverse association (protective effect) between gastroesophageal reflux and hospitalization due to pneumonia (OR=0.55; CI=0.31-0.99). Essencial Scores of PHC superior to 3.17 were responsible for a protective effect with regard to hospitalization due to pneumonia, reducing the chances of hospitalization by 43% (OR for the category >3.41 = 0.57; CI=0.32-0.99) to 50% (OR for the category >3.17 and <=3.41 = 0.50; CI=0.28-0.88). Conclusions: The explanatory model obtained in this study largely includes variables related to childcare or the mother\'s and family\'s characteristics. In view of the study planning and data collection procedures and the statistical analyses applied, the internal validity of the study is highlighted, based on which it can be affirmed that the obtained model explains the phenomenon of hospitalization due to pneumonia in the study population.

Introdução. A etiologia da leucemia linfocítica aguda (LLA), câncer mais comum na infância, não é completamente conhecida. Objetivo. Examinar a associação de infecções na infância e características maternas com a LLA em crianças residentes no Estado de São Paulo. Métodos. Estudo caso-controle com 241 casos recrutados em oito hospitais do Estado de São Paulo e diagnosticados com LLA de janeiro de 2003 a fevereiro de 2009. Os 598 controles foram selecionados na base de Declarações de Nascidos Vivos da Fundação Sistema Estadual de Análise de Dados. Entrevistas com a mãe ou responsável pela criança foram realizadas no hospital para os casos e no domicílio para os controles utilizando-se questionário semelhante. A análise dos dados foi conduzida com três grupos distintos: Grupo 1 - todos os subtipos de LLA, entrevistas com as mães ou outros responsáveis pelas crianças; Grupo 2 - todos os subtipos de LLA, entrevistas com as mães; Grupo 3 - LLA de precursores B, entrevistas com as mães. Para estimar o risco de LLA associado com as variáveis relacionadas a infecções e características maternas odds ratios (OR) e intervalos com 95 por cento de confiança (IC 95 por cento ) foram calculados por meio de análise de regressão logística multivariada não condicional. Três modelos de regressão logística foram conduzidos: a) com ajuste por sexo e idade da criança; b) com ajuste por sexo, idade da criança e escolaridade materna; c) com ajuste por todas potenciais variáveis de confusão via stepwise forward selection. Resultados. Os resultados correspondentes ao Grupo 3 e Modelo 3 de análise revelaram proteção para LLA em crianças com histórico de episódios de gripe (categoria frequentemente versus não OR = 0,27; IC 95 por cento 0,15-0,48), episódios de dor no ouvido (categoria raramente versus não OR = 0,48; IC 95 por cento 0,25-0,90), frequência à creche (categoria mais de 24 meses versus nunca OR = 0,37; IC 95 por cento 0,17-0,77), e contato com cães no primeiro ano de vida (categoria sim versus não OR = 0,76; IC 95 por cento 0,45-1,27). Foi observado tênue aumento do risco de LLA em crianças com mães que referiram consumo de álcool no passado (OR = 1,29; IC 95 por cento 0,62-2,68) e ainda bebe (OR = 1,53; IC 95 por cento 0,97-2,41) em comparação àquelas cujas mães referiram nunca ter consumido álcool. Baixo nível educacional das mães foi associado com aumento do risco de LLA em crianças (categoria 0 a 4 anos versus 12 e mais OR = 2,71; IC 95 por cento 1,26-5,81). Conclusões. Os resultados mostraram que exposição a infecções na infância, frequência à creche e contato com cães no primeiro ano de vida exercem papel protetor para LLA, por outro lado, o consumo de álcool e o baixo nível educacional das mães aumentaram o risco de LLA em crianças / Introduction. The etiology of acute lymphoblastic leukemia (ALL), the most common cancer in childhood, is not completely known. Objective. To examine the association of childhood infections and mother characteristics with ALL in children living in São Paulo. Methods. Case-control study with 241 cases recruited in eight hospitals in the state of São Paulo and diagnosed with ALL from January 2003 to February 2009. The 598 controls were selected from the São Paulo Birth Registry. Interviews with the mother or guardian were conducted in the hospital for cases and at home for controls through a similar questionnaire. Data analysis was performed in three distinct groups: Group 1 - all subtypes of ALL, interviews conducted with the mother or other childs guardian; Group 2 - all subtypes of ALL, interviews conducted with the mother; Group 3 - precursor B ALL, interviews conducted with the mother. In order to estimate the risk of ALL associated with variables related to infections and mother characteristics odds ratios (OR) and 95 per cent confidence interval (95 per cent CI) were calculated by unconditional multivariate logistic regression. Three logistic regression models were conducted: a) with adjustment for sex and age of child; b) with adjustment for sex, age of child and maternal education; c) adjusted for all potential confounders through stepwise forward selection. Results. The results corresponding to Group 3 and Model 3 revealed protection for ALL in children with episodes of influenza (category often versus no OR = 0.27; 95 per cent CI 0.15-0.48), episodes of earache (category rarely versus no OR = 0.48; 95 per cent CI 0.25-0.90), daycare attendance (category over 24 months versus never OR = 0.37; 95 per cent CI 0.17-0.77), and contact with dogs in the first year of life (category yes versus no OR = 0.76; 95 per cent CI 0,45-1.27). Slight increase was observed in the risk of ALL in children with mothers who reported alcohol consumption in the past (OR = 1.29; 95 per cent CI 0.62-2.68) and still drink (OR = 1.53; 95 per cent CI 0.97-2.41) compared to those whose mothers reported never having consumed alcohol. Low educational level of the mothers was associated with increased risk of ALL in children (category 0-4 years versus 12 and over OR = 2.71; 95 per cent CI 1.26-5.81). Conclusions. The results provided evidences that exposure to infections in the childhood, daycare attendance and contact with dogs in the first year of life have a protective role in ALL, on the other hand, alcohol consumption and low education level of mothers increase the risk of ALL in children

A dengue é um importante problema de saúde pública, responsável por cerca de 25.000 mortes anuais em áreas subtropicais do mundo. Desde 2001, há uma tendência de aumento da incidência de formas fatais de febre hemorrágica da dengue (FHD) no Brasil, com aumento dramático de casos graves em menores de 15 anos de idade a partir de 2007, especialmente na região nordeste do país. O objetivo deste estudo caso-controle foi avaliar fatores de risco associados a óbito em crianças com dengue grave. Avaliamos a condição clínica de pacientes internados que morreram de dengue (n=18) e comparamos com pacientes internados com dengue grave que sobreviveram (controles, n=77). Os pacientes incluídos no estudo foram menores de 13 anos de idade internados em hospitais de São Luís, nordeste do Brasil, com diagnóstico laboratorial confirmado de dengue. O diagnóstico de infecção aguda de dengue foi confirmado pela detecção de anticorpos IgM específicos de dengue através do MAC-ELISA (IgM Antibody Capture Enzyme-Linked Immunosorbent Assay) ou pela detecção do DENV em soro, sangue ou víscera pela técnica de Transcrição Reversa - Reação em Cadeia de Polimerase (RT-PCR). Sinais de choque descompensado (extremidades frias, cianose e letargia) e hemoptise foram fortemente associados a óbito, o que está de acordo com a mais recente classificação da Organização Mundial de Saúde (OMS) para dengue grave. Epistaxe e vômitos persistentes também foram fortemente associados a óbito. Embora incluídos na mais recente classificação de dengue da OMS como sinais de alarme, epistaxe e vômitos incoercíveis não estão incluídos na definição da OMS para dengue grave. Estes achados necessitam ser explorados em estudos posteriores. Como unidades de terapia intensiva são frequentemente limitadas em cenários com poucos recursos, qualquer informação que possa distinguir, dentre os pacientes com dengue grave, aqueles com maior risco de evolução a óbito, pode ser crucial. / Dengue is a major public health problem, responsible for about 25,000 deaths in subtropical areas every year. In Brazil, the incidence of fatal forms of dengue hemorrhagic fever has increased since 2001. In particular, there has been a dramatic increase in severe cases in patients younger than 15 years of age since 2007, especially in the Northeastern region of the country. The purpose of this case-control study was to evaluate risk factors associated with death in children with severe dengue. The clinical condition of hospitalized patients with severe dengue who died (cases, n=18) was compared with that of hospitalized patients with severe dengue who survived (controls, n=77). Inclusion criteria for this study were: age under 13 years; hospital admission in São Luis, Northeastern Brazil; and laboratory-confirmed diagnosis of dengue. The diagnosis of acute dengue infection was confirmed by detection of dengue-specific IgM antibodies using an IgM Antibody Capture Enzyme-Linked Immunosorbent Assay (MAC-ELISA) or by DENV detection in serum, blood, or viscera by a Reverse Transcription - Polymerase Chain Reaction (RT-PCR). Death was strongly associated with signals of hypotensive shock (cold extremities, cyanosis and lethargy) and hemoptysis. These associations are in accordance with the most recent World Health Organization (WHO) case classification for severe dengue. We also found that epistaxis and persistent vomiting were strongly associated with death, both are included as warning signs in the WHO classification of dengue, but they are not included in the most recent WHO definition of severe dengue. These findings should be explored in further studies. Because intensive care units are often limited in resource-poor settings, any information that can help to distinguish patients with severe dengue with higher risk to progress to death may be crucial.

O diabetes mellitus (DM) está associado com alguns tipos de câncer. No entanto, estudos realizados sobre a associação entre DM e câncer de cabeça e pescoço (CCP) apresentaram resultados controversos. Na avaliação da associação entre DM e câncer, destaque deve ser dado à metformina, medicamento utilizado no DM tipo 2, que se mostra inversamente associado a alguns tumores. O objetivo deste estudo foi avaliar a associação entre DM e CCP, bem como o impacto do uso de metformina no risco de CCP. Este estudo caso-controle incluiu 1021 casos de CCP com confirmação histológica de carcinoma espino celular selecionados em cinco hospitais de grande porte no estado de São Paulo entre 2011 e 2014. Os 1063 controles foram recrutados nos mesmos hospitais, pareados por frequência com os casos por sexo e idade (em grupos de 5 anos). Para avaliar o risco de CCP associado ao DM, odds ratios (OR) e intervalos com 95 por cento de confiança (IC 95 por cento ) foram estimados por meio de regressão logística não condicional. Os participantes diabéticos tiveram associação inversa com o CCP (OR = 0,68; IC 95 por cento : 0,49-0,95), e a proteção foi maior entre diabéticos usuários metformina (OR = 0,54; IC 95 por cento : 0,29-0,99). Diabéticos usuários de metformina que eram fumantes (OR = 0,13; IC 95 por cento : 0,04-0,44), ou consumidores de álcool acima de 40 g/ dia (OR = 0,31; IC 95 por cento : 0,11-0,88) apresentaram proteção ainda maior com relação ao CCP, comparado aos não diabéticos. Em conclusão, os indivíduos diabéticos apresentaram risco inverso de CCP e o uso de metformina pode explicar, ao menos parcialmente, esta associação. / Diabetes mellitus (DM) is directly associated with some cancers. However, studies on the association between DM and head and neck cancer (HNC) have rendered controversial results. Assessing DM and cancer, emphasis should be given to metformin, a medication used for DM type 2, which is shown to be inversely associated with some cancers. The objective of this study was to evaluate the association between DM and HNC, as well as the impact of metformin use on the risk of HNC. This case-control study included 1021 HNC cases with squamous cell carcinoma, histologically confirmed, and admitted in five large hospitals in the state of São Paulo, from 2011 to 2014. A total of 1063 controls were selected in the same hospitals and were frequency-matched to cases by sex and age (in 5-year groups). In order to assess the risk of CCP associated with DM, odds ratios (OR) and 95 per cent confidence intervals (CI 95 per cent ) were estimated using unconditional logistic regression. Diabetic participants had an inverse risk of HNC (OR=0.68; 95 per cent CI: 0.49 0.95), and this inverse association was more intense among diabetic metformin users (OR=0.54; 95 per cent CI: 0.29-0.99). Diabetic metformin users that were current smokers (OR=0.13; 95 per cent CI: 0.04-0.44) or had an alcohol consumption of >40 g/day (OR=0.31; 95 per cent CI: 0.11-0.88) had lower risk of HNC than non-diabetic participants. In conclusion, DM patients have um inverse risk of HNC and the use of metformin may at least partially explain this association.

INTRODUÇÃO: Os pacientes submetidos a transplante renal estão sujeitos a um risco muito aumentado para câncer, porém inexistem dados concretos quanto a maior chance de tumor de próstata nesses pacientes. Neste estudo, avaliou-se a freqüência de câncer de próstata em transplantados renais comparada à de pacientes-controle, bem como a sua relação com etnia, antecedentes familiares, toque prostático, níveis de PSA e aos esquemas de imunossupressão nos pacientes transplantados renais. MÉTODOS: Neste estudo caso-controle realizado entre agosto de 2004 e junho de 2006 comparou-se a freqüência de câncer de próstata entre pacientes transplantados renais (n=119) há mais de um ano e pacientes do grupo-controle (n=184), bem como as variáveis: etnia, idade, presença de antecedentes familiares, escore internacional de sintomas prostáticos, toque retal, níveis de PSA e índice de massa corpórea (IMC). Os pacientes com PSA e/ou toque retal alterado foram submetidos à biópsias prostáticas guiadas por ultra-som transretal. As comparações das freqüências entre os dois grupos deram-se através das variáveis: idade, etnia, presença de antecedentes familiares, toque suspeito e valores de PSA>2,5ng/mL e >4,0ng/mL. Avaliou-se também a relação entre os tipos e doses de imunossupressor e presença de câncer. RESULTADOS: Não houve maior freqüência de tumor de próstata em transplantados (6,7%) em relação ao grupo-controle (7,6%). A mediana de idade dos transplantados com câncer foi menor em relação aos controles (p=0,012). Os dois grupos não variaram quanto à etnia (p=0,675), ao peso (p=0,202), ao IMC (p=0,637) e à presença de antecedentes familiares (p=0,515) para detecção de tumor. O toque alterado não foi determinante para detectar tumor em ambos (p=0,659). Os pacientes transplantados apresentaram mediana de PSA menor que os controles (p=0,029). Com exceção da rapamicina, não houve associação entre o uso de imunossupressores e câncer (p>0,05) e as doses médias utilizadas em transplantados com e sem tumor não variaram de maneira estatisticamente significante (p>0,05). CONCLUSÕES: A freqüência de câncer de próstata em transplantados renais há mais de um ano assemelhase a da população de homens normais, é significativa quando se consideram valores de PSA entre 2,5ng/mL e 4,0ng/mL e não se relaciona com a dose e o tipo de droga imunossupressora / INTRODUCTION: Patients submitted to renal transplantation are at a greater risk to develop cancer, but there is no valuable data about prostate cancer in these patients. In this research we compared the frequencies of prostate cancer between renal transplanted recipients and control patients, as well as its relations with race, family history, digital rectal examination, PSA levels and the immunosupressive protocols applied to renal transplanted recipients. METHODS: In this case-control study performed between August 2004 and June 2006, we compared the frequency of prostate cancer between patients submitted to renal transplantation more than a year before the beginning of our study (n=119) and control patients (n=184), as well as its relations with race, age, international prostate symptoms score, digital rectal examination, PSA levels and body mass index (BMI). The patients who had high PSA levels and/or altered digital rectal examination were submitted to transrectal ultrasound guided biopsy of the prostate. The frequencies of cancer in both groups were compared by age, race, family history, altered digital rectal examination and PSA levels higher than 2,5ng/mL and 4,0ng/mL. The relationship between types and dosis of immunosupressive drugs and cancer were also analysed. RESULTS: The frequency of prostate cancer in renal transplanted patients (6,7%) was not higher than the frequency in control patients (7,6%). The median age of renal transplanted patients with cancer were lower when compared to control group with cancer (p=0,012). Race (p=0,657), body weight (p=0,202), BMI (p=0,637) and family history (p=0515) weren´t statistically different between both groups to detect cancer. Altered digital rectal examination wasn´t statistically significant to detect cancer in both groups (p=0,659). The median of PSA levels in renal transplanted recipients with cancer was lower when compared to control patients with cancer (p=0,029). There was no correlation between the use of immunosupressive drugs and occurrence of cancer (p>0,05), with exception of rapamycin. The median dosis of these drugs used in the group with cancer wasn´t statistically different from that used in transplanted patients without cancer (p > 0,05). Conclusions: The frequency of prostate cancer in patients submitted to renal transplantation more than a year before the study was the same as in control patients, it was significant when the PSA values were between 2,5ng/mL and 4,0ng/mL and it was not related to the type and dosis of immunosupressive drugs