BACKGROUND Few high-quality observational studies have been conducted to examine clinically relevant features of emotional distress and Major Depressive Disorder (MDD) in adults with primary cerebral glioma. Our knowledge of these important complications of glioma is currently poor. AIMS This thesis aims to answer a series of relevant clinical questions. I have studied: [1] the frequency, independent clinical associations and course of general emotional distress measured using the NCCN Distress Thermometer (DT); [2] the utility of three depression screening tools for identifying MDD; [3] the frequency, independent clinical associations and course of MDD in glioma; [4] current patterns of practice, and the apparent tolerability of antidepressant treatment of depression in glioma; and [5] barriers to the effective management of MDD in glioma. METHODS I conducted a prospective, twin-centre, observational cohort study. Adults with a new histological diagnosis of primary supratentorial glioma were enrolled and interviewed three times: shortly after starting radiotherapy (T1), three months later (T2) and six months later (T3). At each time point participants completed the DT, the Hospital Anxiety and Depression Scale (Depression subscale, HAD-D), the Patient Health Questionnaire-9 (PHQ-9) and the Structured Clinical Interview for DSMIV MDD (SCID). Barriers to depression management were studied using questionnaires completed by the patient and their named GP. RESULTS During a two-year recruitment period, 223 patients were eligible and 155 provided useable data (57.4% male, mean age = 54.2 years, 85.8% high-grade glioma, 78.1% radical radiotherapy, 55.5% chemotherapy). [1] High distress (DT score ≥ 4/10) was consistently a frequent complication, occurring in between 36.4% ± 7.6% of patients at T1 to 33.7% ± 10.2% at T3. In a logistic regression analysis, high distress at T1 was independently associated with MDD, functional impairment and younger age (χ2 for model = 39.882, p < 0.001, R Square = 0.312). Patients who reported high distress at T1 (median DT score = 8; IQR 7 - 9) remained highly distressed on follow-up (T2 median score = 8, IQR 6 - 8; T3 median score = 7, IQR 5 - 8). [2] As screening tools, the HAD-D and PHQ-9 showed good internal consistency (α = 0.769 - 0.862 at any time point). The HAD-D displayed the best operating characteristics on ROC curve analysis. At a threshold of 7+, sensitivity = 0.933, specificity = 0.907 and Positive Predictive Value (PPV) = 0.56. A threshold of 8+ displayed similar PPV, however. [3] The cross-sectional prevalence of MDD was 13.5% ± 5.4% at T1, 14.8% ± 6.7% at T2 and 6.8% ± 5.8% at T3. Inter-rater diagnostic agreement was good (κ = 0.81, 95% CI 0.60 – 1.00). MDD was independently associated with a past history of depression (OR = 3.8, 95%CI 1.5 - 9.8), and with current functional impairment (OR = 3.6, 95%CI 1.4 - 9.4). MDD persisted for at least three months in 9/17 patients who could be followed up. [4] The frequency of antidepressant prescription was 8.4% ± 4.4% at T1, 7.4% ± 4.9% at T2 and 12.6% ± 6.9% at T3. Citalopram was the most frequent antidepressant choice. Antidepressant tolerability appeared to be good among patients who could be followed up. [5] Barriers to the management of depression included 78.4% of GPs regarding major depression as a normal reaction to having glioma, and 39.2% expressing a belief that major depression did not always require treatment. In addition, most patients expressed a degree of resistance to any kind of future depression treatment. DISCUSSION This is the largest cohort study of depression in consecutively presenting adults with glioma, and the first to utilise criterion standard structured interview diagnoses in a longitudinal design. There is a degree of theoretical uncertainty about the nosological validity of MDD in glioma, although the clinical relevance of this uncertainty can be debated. Methodological limitations to the presented study include an absence of alternative potential psychiatric diagnoses to MDD, the likelihood of selection bias in recruitment, and considerable attrition. Due to these and other limitations, findings from this study are tentative and should ideally be replicated. Clinicians should have a high index of suspicion for identifying low mood in glioma patients, particularly those with functional impairment or previous depressive episodes. The HAD-D (suggested threshold 8+) can reasonably be used to screen for depression, if desired. Caution is required when prescribing antidepressants. Clinicians should be educated about the frequency and consequences of MDD in glioma. Researchers interested in psychological neuro-oncology could convene a meeting to guide future projects, particularly since multi-centre studies may be necessary to recruit sufficient sample sizes in future.

T2DM continues to be a public health burden with its increasing incidence, prevalence, and mortality risks. The aim of this thesis was to examine a population-based cohort of 22,000 people with T2DM diagnosed between 1 January 2000 and 31 December 2010 within the Wirral Peninsula, UK with the aim of: Assessing factors relating to all-cause, cardivascular-, malignancy-, and non-cardiovascular mortality; evaluating the role of glycaemic control, socioeconomic status, smoking, dyslipidaemia, blood pressure, obesity, and nephropathy, as predicting risk factors for mortality; assessing the influence of age at diagnosis, duration of diabetes, year of diagnosis and gender on mortality; examining the life expectancy and mortality patterns and measuring the years of life lost as a result of a diagnosis of T2DM; applying Complexity Science to the dynamic interplay of the various factors in T2DM that lead to unpredictability in health outcomes.

We found no significant excess of fractures among Rochester, MN, residents with diabetes mellitus initially recognized in 1950-1969, but more recent studies elsewhere have documented an apparent increase in hip fracture risk. To explore potential explanations for any increase in fractures, we performed an historical cohort study among 1964 Rochester residents who first met glycemic criteria for diabetes in 1970-1994 (mean age, 61.7 ± 14.0 yr; 51% men). Fracture risk was estimated by standardized incidence ratios (SIRs), and risk factors were evaluated in Andersen-Gill time-to-fracture regression models. In 23,236 person-years of follow-up, 700 diabetic residents experienced 1369 fractures documented by medical record review. Overall fracture risk was elevated (SIR, 1.3; 95% CI, 1.2-1.4), but hip fractures were increased only in follow-up beyond 10 yr (SIR, 1.5; 95% CI, 1.1-1.9). As expected, fracture risk factors included age, prior fracture, secondary osteoporosis, and corticosteroid use, whereas higher physical activity and body mass index were protective. Additionally, fractures were increased among patients with neuropathy (hazard ratio [HR], 1.3; 95% CI, 1.1-1.6) and those on insulin (HR, 1.3; 95% CI, 1.1-1.5); risk was reduced among users of biquanides (HR, 0.7; 95% CI, 0.6-0.96), and no significant influence on fracture risk was seen with sulfonylurea or thiazolidinedione use. Thus, contrary to our earlier study, the risk of fractures overall (and hip fractures specifically) was increased among Rochester residents with diabetes, but there was no evidence that the rise was caused by greater levels of obesity or newer treatments for diabetes.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21251号 / 医博第4369号 / 新制||医||1029(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 佐藤 俊哉, 教授 川上 浩司, 教授 今中 雄一 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

MSc (Med), Epidemiology and Biostatistics, Faculty of Health Sciences, University of the Witwatersrand, 2009 / Introduction Malnutrition remains the major cause of child mortality and an essential component in child development and future productivity of the child in the world. With the increasing prevalence of undernutrition, micronutrient deficiencies, and over nutrition in South Africa, it calls for interventions which will help reduce malnutrition since child‟s growth is partly dependant on their diet. This study aimed at determining the association between post-weaning dietary patterns at age one and growth at age two among children from the Birth-To-Twenty cohort in Johannesburg, South Africa. Specific objectives: To describe dietary intake patterns (Diet Diversity Score and Food Variety Score) growth at age one and two among boys and girls in BT20, the prevalence of malnutrition (Stunting, wasting and underweight) among boys and girls in BT20, and to determine the association between dietary patterns at age one and growth at age two. Hypothesis There is no association between post-weaning dietary patterns at age one and growth at age two in the Birth-To-Twenty Cohort study. Study design: Prospective longitudinal study. Setting; Birth-To-Twenty Cohort study Johannesburg, South Africa. Inclusion criteria –Must have complete data on dietary questionnaires and growth data at age two. Data Collection data was collected on following variables; dietary patterns, socio-economic status, growth (height and weight), complimentary feeding, birthweight and gestational age. Anthropometric data (height and weight) was collected at age one and two. Food frequencies questionnaires were used for data collection. Data Analysis STATA 10 was used for data cleaning and analysis. Descriptive and inferential analysis was carried out. Multiple regression analysis was used to assess the association between outcome variable (growth at age 2) and dietary patterns at age 1(12months) and growth at age 2 (24months), and dietary patterns at age 1 controlling for confounders. P-values were calculated to test for v statistical significance at 5% significance level. Results: Ninety six percent of the infants were introduced to solid foods when they were less than 6 months. The Food Variety Score (FVS) was 32.4 and 32.6 for boys and girls respectively; Diet Diversity Score (DDS) was 9.7 and 9.8 for boys and girls respectively. A proportion of 20.5% (n=164) infants were underweight at birth, the prevalence of stunting among the boys rose from 8% at year one to 19% at year two, wasting demonstrated a slight increase from 5% to 8%, underweight too showed a sharp increase from 11% to 25%. Among the girls stunting prevalence increased from 6% at year one to 20% at year 2, wasting slightly rose from 3% to 4% and underweight from 6% to 11%. There was 7.7% (n=35) catch up growth and 20.7% (n=94) catch down with regard to stunting. A proportion of 3.3% (n=15) infants had catch up for weight-for-height and 5.5% (n=25) had a catch down growth. 3.7% (n=17) had catch up growth with regard to weight-for- age and 11.2% (n=51) had catch down growth. Birthweight, underweight and stunting at age one, gender and ethnicity were associated with growth at age two. There was no association between dietary patterns at age one and growth at age two. Conclusion: Diet diversity is good within Soweto and consequently food diversity is not associated with infant growth, however other factors such as macronutrient intake and morbidity maybe important in the Soweto context. Inappropriate feeding practices such as feeding the infant with high sugar diet, high fat and refined foods should be addressed so as to curb the increasing catch down growth at age two. Introduction of solid foods at less than 6 months of age should also be addressed; this can be done by emphasising that exclusive breastfeeding in community health programs for the first 6 months.

O impacto positivo do aleitamento materno (AM) na saúde de mulheres e crianças em curto e longo prazo, tanto em países de média e baixa renda como em países de alta renda, é amplamente reconhecido. Apesar disso, os índices de AM estão longe de ser considerados bons, tanto em nível mundial quanto no Brasil. Com base em alguns estudos, mães adolescentes são consideradas população de risco para não amamentação ou interrupção precoce dessa prática, configurando-se em um grupo prioritário para a promoção, proteção e apoio ao AM. Nesse sentido, estratégias devem levar em consideração as peculiaridades da amamentação em mães adolescentes, bem como os determinantes do abandono precoce ou da manutenção da amamentação por diferentes períodos nesse grupo. No entanto, faltam estudos abordando esse tema, o que justifica a realização do presente estudo, que teve como objetivo identificar os fatores associados à manutenção do AM por 6, 12 e 24 meses em uma coorte de mães adolescentes. Trata-se de um estudo de coorte aninhado em um ensaio clínico randomizado realizado com 323 mães adolescentes residentes no município de Porto Alegre (RS), que deram à luz no Hospital de Clínicas de Porto Alegre, e cujo recém-nascido era saudável, com peso superior a 2.500 g. Informações sobre vários aspectos da alimentação da criança foram obtidas mensalmente nos primeiros 6 meses e bimestralmente dos 6 aos 12 meses, por contato telefônico ou visita domiciliar. Quando as crianças tinham entre 4 e 7 anos de vida, as mães foram novamente entrevistadas. Os fatores associados com a manutenção do AM por 6, 12 e 24 meses foram avaliados por meio de regressão multivariável de Poisson com variância robusta, seguindo uma abordagem hierarquizada. A manutenção do AM por no mínimo 6, 12 ou 24 meses ocorreu em 68,4, 47,3 e 31,9% da amostra, respectivamente. Apenas um fator se associou à manutenção da amamentação nos três períodos estudados: o fato de a criança não usar chupeta aumentou a probabilidade de manutenção do AM por 6, 12 e 24 meses. Apoio da avó materna e duração do AME mostraram-se associados com a manutenção do AM por 6 e 12 meses. Os demais fatores se associaram à manutenção do AM por apenas um dos períodos: por 6 meses ou mais, cor da pele da mãe parda ou negra; por 12 meses ou mais, criança do sexo feminino e apoio do companheiro; e por 24 meses ou mais, maior idade paterna e multiparidade. Conclui-se que os fatores associados com a manutenção do AM podem variar dependendo da duração considerada, com destaque para não uso de chupeta, apoio da avó materna e duração do AME. Os achados deste estudo podem contribuir para o desafio de aumentar a duração do AM em mães adolescentes por meio de estratégias que contemplem os fatores aqui identificados. / The positive impact of breastfeeding (BF) on child and maternal health, in both the short and long terms, and in both developing and developed countries, is widely recognized. Nevertheless, BF practices in international and Brazilian settings are far from reaching optimal levels. Previous studies have demonstrated that adolescent mothers present a higher risk of not BF, or of interrupting BF early, and therefore these mothers should be prioritized in interventions aiming to promote, protect, and support BF. In this sense, interventions should take into consideration the peculiarities of BF among adolescent mothers and also the determining factors of early BF interruption or BF maintenance for different periods of time in this group. However, few studies have addressed this topic, thus justifying the conduction of the present study, whose aim was to identify factors associated with the maintenance of BF for 6, 12, and 24 months in a cohort of adolescent mothers. This cohort study is nested in a randomized clinical trial that involved 323 adolescent mothers residing in the city of Porto Alegre, state of Rio Grande do Sul. Mothers were recruited at the maternity ward of a teaching hospital (Hospital de Clínicas de Porto Alegre) and were included if they gave birth to a healthy infant weighing 2,500 g or more. Data on different aspects of infant feeding were collected monthly in the first 6 months via telephone interviews, and bimonthly between 6 and 12 months via either telephone interviews or home visits. When the children were 4-7 years old, the mothers were interviewed again in person. Factors associated with BF maintenance at 6, 12, and 24 months were assessed using multivariate Poisson regression analysis with a hierarchical approach. BF maintenance for at least 6, 12, and 24 months was observed in 68.4, 47.3, and 31.9% of the sample, respectively. Only one factor was associated with BF maintenance at all three time points assessed: infant not using a pacifier increased the chance of BF maintenance for 6, 12 and 24 months. Support from the infant’s maternal grandmother and exclusive BF duration were associated with maintenance of BF for 6 and 12 months. Other factors evaluated were associated with BF maintenance at only one of the time points assessed: at 6 months, non-white maternal skin color; at 12 months, female infant and partner’s support of BF; and at 24 months, older paternal age and multiparity. In conclusion, the factors associated with BF maintenance may vary according to the time period assessed, with emphasis on not using a pacifier, having the support of the infant’s maternal grandmother, and exclusive BF duration. The present findings can contribute to the challenge of increasing BF duration among adolescent mothers via the implementation of strategies that take into consideration the associated factors here identified.

This thesis describes a study undertaken between 1992 and 2001 to explore the possible health impacts of human exposure to pesticides. The study followed the health outcomes of approximately 4000 outdoor workers over a period of up to sixty-one years. These workers comprised two subcohorts of approximately even size, one composed of agricultural workers with high insecticide exposures, and the other made up of outdoor staff from local councils in the same area with little or no occupational exposure to insecticides. Mortality and morbidity were compared between the two groups, and with the general Australian community. The study identifies significantly increased mortality among both exposed and control subjects when compared to the Australian population. The major cause of this increase was mortality from smoking related diseases. The study also identifies significant increases in mortality among exposed subjects for a number of conditions that do not appear to be the result of smoking patterns, both when compared to the control group and the Australian population. These include pancreatic cancer in some DDT exposed subjects and asthma, diabetes, and leukaemia in subjects working with more modern chemicals. There was also an increase in self reported chronic illness and asthma, and lower neuropsychological functioning scores among surviving exposed subjects when compared to controls. Diabetes was also reported more commonly by subjects reporting occupational use of herbicides.

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This thesis describes a study undertaken between 1992 and 2001 to explore the possible health impacts of human exposure to pesticides. The study followed the health outcomes of approximately 4000 outdoor workers over a period of up to sixty-one years. These workers comprised two subcohorts of approximately even size, one composed of agricultural workers with high insecticide exposures, and the other made up of outdoor staff from local councils in the same area with little or no occupational exposure to insecticides. Mortality and morbidity were compared between the two groups, and with the general Australian community. The study identifies significantly increased mortality among both exposed and control subjects when compared to the Australian population. The major cause of this increase was mortality from smoking related diseases. The study also identifies significant increases in mortality among exposed subjects for a number of conditions that do not appear to be the result of smoking patterns, both when compared to the control group and the Australian population. These include pancreatic cancer in some DDT exposed subjects and asthma, diabetes, and leukaemia in subjects working with more modern chemicals. There was also an increase in self reported chronic illness and asthma, and lower neuropsychological functioning scores among surviving exposed subjects when compared to controls. Diabetes was also reported more commonly by subjects reporting occupational use of herbicides.