京都大学 / 0048 / 新制・論文博士 / 博士(社会健康医学) / 乙第13293号 / 論社医博第14号 / 新制||社医||10(附属図書館) / 京都大学大学院医学研究科社会健康医学系専攻 / (主査)教授 松田 秀一, 教授 今中 雄一, 教授 古川 壽亮 / 学位規則第4条第2項該当 / Doctor of Public Health / Kyoto University / DFAM

This thesis is divided in three chapters: (i) introduction to organ donation, (ii) rationale, implementation and design of a pilot observational study currently underway and (iii) justification for use of a waived consent model for observational research studies on organ donor care. Organ donation is a complex event that remains a mystery to most health care providers. The first chapter reports knowledge gaps in clinical management of deceased organ donors across Canada and summarizes ongoing trials in organ donor care. The persistent deficit in transplantable organs along with the limited scientific evidence to guide the clinical management of the organ donor justify the need for a national research program in organ donor care. There are logistical and methodological challenges unique to the design and conduct of research on deceased donors. To identify potential stakeholders involved in the process of organ donation and to provide an accurate description of usual management of deceased donor and assess its variability, we developed and initiated a prospective observational study called DONATE. The second chapter of this thesis described the pilot phase of this study. It contains the following sections: i) objectives of the study ii) the screening process, iii) data collection, iv) clinical outcomes, v) methods of measurement, vi) analysis plan and vii) strategies used to minimize the biases inherent to observational studies. The normative goal of obtaining informed consent from participants may not be appropriate for an observational study in organ donor care. The third chapter summarizes the justification for use of a waived consent model for observational studies of organ donation medicine. In this chapter, I discuss regulatory, ethical and logistical issues relevant to use of a waived consent model in organ donation research. / Thesis / Master of Science (MSc) / Organ donation saves lives and it is the most effective therapy available to treat end stage organ failure of a number of organs. Unfortunately, there is a growing gap between the number of donors and the number of patients waiting for transplantation. This thesis summarizes the foundational work of a national research program in deceased donor management. It describes the study design of a 4 centre prospective observational study in deceased donor management with outcome assessment on corresponding organ-recipients. This thesis also contains a justification for waiving the procurement of consent to research on organ donor management. Finally, it will inform investigators of future national multicentre observational studies on design and implementation issues related to donor management, in order to improve care provided to donors and outcomes of recipients while reducing the gap between transplant needs and organ supply.

Background and Objectives: Little is known about the impact of nicotine replacement therapy (NRT) use duration on smoking cessation in the general population. This study determines whether duration of NRT use is associated with smoking cessation. Methods: Data were from the Ontario Tobacco Survey longitudinal study of a population-based cohort of baseline smokers who made serious quit attempts during 18 months of follow-up. The association between NRT (any NRT, patches, or gum) use duration and smoking cessation outcomes (short-term abstinence ≥1 month and long-term abstinence ≥12 months) was estimated by Poisson regression, adjusting for all confounding variables. Results: Among the 1,590 eligible smokers, 933 (59%) did not use any NRT, 535 (34%) used NRT <8 weeks, and 112 (8%) used NRT ≥8 weeks at follow-up. The median duration of NRT use was 14 days. A consistent “J” shape of associations between quit aid use duration and smoking cessation outcomes (quit rates) was found. Using any NRT, patches, or gum <8 weeks was generally associated with a lower likelihood of quitting, but using them ≥8 weeks was generally associated with a higher likelihood of quitting, compared to not using them. Only using patches for the recommended duration (≥8 weeks) was associated with a higher likelihood of short-term (relative risk, RR 1.74, 95% confidence interval, CI 1.21-2.50) and long-term (RR 2.62, 95% CI 1.25-5.50) abstinence at the end of 18 months of follow-up, compared to not using patches. Using gum ≥8 weeks was not associated with short- or long-term abstinence at the end of 18 months of follow-up. Conclusions: Using nicotine patches for the recommended duration is associated with successful short- and long-term abstinence in the general population. More efforts are needed to encourage smokers to use nicotine patches for eight or more weeks when attempting to quit.

Background and Objectives: Little is known about the impact of nicotine replacement therapy (NRT) use duration on smoking cessation in the general population. This study determines whether duration of NRT use is associated with smoking cessation. Methods: Data were from the Ontario Tobacco Survey longitudinal study of a population-based cohort of baseline smokers who made serious quit attempts during 18 months of follow-up. The association between NRT (any NRT, patches, or gum) use duration and smoking cessation outcomes (short-term abstinence ≥1 month and long-term abstinence ≥12 months) was estimated by Poisson regression, adjusting for all confounding variables. Results: Among the 1,590 eligible smokers, 933 (59%) did not use any NRT, 535 (34%) used NRT <8 weeks, and 112 (8%) used NRT ≥8 weeks at follow-up. The median duration of NRT use was 14 days. A consistent “J” shape of associations between quit aid use duration and smoking cessation outcomes (quit rates) was found. Using any NRT, patches, or gum <8 weeks was generally associated with a lower likelihood of quitting, but using them ≥8 weeks was generally associated with a higher likelihood of quitting, compared to not using them. Only using patches for the recommended duration (≥8 weeks) was associated with a higher likelihood of short-term (relative risk, RR 1.74, 95% confidence interval, CI 1.21-2.50) and long-term (RR 2.62, 95% CI 1.25-5.50) abstinence at the end of 18 months of follow-up, compared to not using patches. Using gum ≥8 weeks was not associated with short- or long-term abstinence at the end of 18 months of follow-up. Conclusions: Using nicotine patches for the recommended duration is associated with successful short- and long-term abstinence in the general population. More efforts are needed to encourage smokers to use nicotine patches for eight or more weeks when attempting to quit.

BACKGROUND: Retaining participants in multi-year prospective cohort studies presents challenges, especially in urban settings. Early identification of participants at risk for attrition may enhance retention. We examine the validity of two risk for loss-to-follow-up assessments and early retention efforts in one Primary Sampling Unit during the National Children’s Study pilot. Our goal was to identify cases requiring additional attention. Retention challenges included high poverty, frequent moves, lack of spousal support, and mistrust of research. METHODS: Recruitment ended in 2012 and research activities shifted to retention. Data collectors (DC) completed subjective risk assignments (low, medium, high) based on knowledge of participants. Descriptive statistics compared risk assessments to socio-demographic characteristics, responses regarding participation, and missed appointments 11 months after risk assessment. RESULTS: We recruited approximately 100 participants. Higher perceived risk was associated with greater likelihood for mothers to be minorities, younger, and have lower education and income (X2=15.362, p<.01; X2=12.118, p<.05; X2=9.947. p<.01; and X2= 7.720, p<.05 respectively). Participants with income below federal poverty placed higher values on receiving incentives (X2= 6.011 p<.05). African American or “other” race participants placed a higher value on feeling comfortable with the interviewers than White respondents (X2=12.539 p<.01). Risk assignment and race were associated with number of missed appointments (X2=8.698 p<.01; X2 =4.307, p<.05). CONCLUSION: Results suggest DCs’ subjective assessment of risk predicts number of missed appointments. Future research might consider strategies to improve African American and “other” race participants’ comfort with interviewers. The ethics of dollar amounts for incentives among low-income participants remain a concern.

Depression is common in people with coronary heart disease (CHD) and is associated with worse physical outcomes. The nature of the causal association between CHD and depression, and the mechanism underpinning the association of depression with worse physical outcomes, remains unclear. Perseverative negative thinking may contribute to the development of depression in people with CHD. The aim of this thesis was to investigate the prospective association of perseverative negative thinking with depression, anxiety and worse physical outcomes in people with CHD, and to explore factors that may mediate this association. First, a systematic review identified 30 studies, of which the majority found an association between measures of perseverative negative thinking and subsequent depression, anxiety or emotional distress in people with long term conditions. Studies that controlled for covariates showed more mixed results, though the majority (15 / 25) still supported a significant association, with effects being small in magnitude. Findings were limited mainly to the association of rumination and/or catastrophizing with subsequent depression, and study quality was limited. Next, in an observational prospective cohort study 169 inpatients and outpatients with recent acute coronary syndrome (ACS) completed self-report assessments of rumination (Ruminative Responses Scale brooding subscale), worry (Penn State Worry Questionnaire), depression (Patient Health Questionnaire-8), anxiety (Beck Anxiety Inventory), and health-related quality of life (EuroQol-5D health-related quality of life, Seattle Angina Questionnaire) after hospitalisation, and at 2 month and 6 month follow-up. Additionally, assessments of potential mechanistic factors (social support, problem solving, instrumental behaviours and negative cognitive biases) were made. Baseline brooding was a significant independent predictor of depression at 6 months after controlling for the effects of important confounding variables, accounting for 2% of the variance. Findings suggested that the association of brooding with depression may be explained by deficits in problem solving ability. Rumination and problem solving may provide useful targets for the development of evidence-based interventions to improve depression among people with CHD, although the findings presented here fall short of proving a causal relationship. Future trials could be used to investigate the causal nature of the association of rumination and problem solving with depression in people with ACS.

Disertacijoje analizuojami pusantrų metų amžiaus kūdikių emocijų ir elgesio sunkumai bei juos prognozuojantys biomedicininiai, psichologiniai bei socialiniai veiksniai. Atliktas perspektyvusis kohortinis kūdikių, gimusių 2009 m. gegužės – rugsėjo mėnesiais LSMU ligoninėje Kauno klinikose, tyrimas. Duomenys surinkti vykdant tris tyrimo etapus: (1) ligoninėje surinkti biomedicininiai duomenys bei atlikta anketinė motinų apklausa, (2) atlikta anketinė motinų apklausa kūdikiams sulaukus trijų mėnesių amžiaus ir (3) anketinė motinų apklausa kūdikiams sulaukus pusantrų metų amžiaus. Pusantrų metų amžiaus kūdikių emocijų ir elgesio sunkumai buvo įvertinti naudojant Vaiko elgesio aprašo (CBCL/1½–5) (Achenbach, Rescorla, 2000) Lietuvoje adaptuotą ir standartizuotą versiją (Jusienė, Raižienė, 2006). Emocijų ir elgesio sunkumai buvo labiau išreikšti kūdikiams, kurie gimė atliekant cezario pjūvį bei kurių fiziologinė būklė po gimimo nebuvo optimali. Tyrimas atskleidė tokių psichologinių ir socialinių veiksnių svarbą prognozuojant emocijų ir elgesio sunkumus, kaip sudėtingas motinos emocinis nėštumo priėmimas, negatyviai motinos vertinami santykiai su vyru / partneriu nėštumo metu, dažnas motinos negatyvių emocijų patyrimas, dideliu nerimu dėl vaiko pasižymintis motinos pogimdyminis prieraišumas ir nelanksčios, į tėvus orientuotos motinos nuostatos kūdikio auginimo atžvilgiu. Disertacijoje taip pat analizuojamos ir aptariamos tirtų biomedicininių, psichologinių ir socialinių veiksnių... [toliau žr. visą tekstą] / The Dissertation analyses infants’ emotional and behavioral problems at the age of 1.5 years and their predictive biomedical and psychosocial factors. The Dissertation is based on data from prospective birth-cohort study. Study participants were infants born in the Hospital of Lithuanian University of Health Sciences (LUHS) Kauno Klinikos from May to September in 2009. The analysis included the data from three stages of the study: (1) biomedical data during and after childbirth and a questionnaire survey given to mothers 2 to 3 days after childbirth in hospital, (2) questionnaire survey of mothers three months postpartum, and (3) questionnaire survey of mothers 1.5 years postpartum. Emotional and behavioral problems were more expressed in infants born via caesarean section and whose physiological functioning after birth was not optimal. Study also revealed the importance of such psychosocial predictors of emotional and behavioral problems as complicated emotional acceptance of pregnancy, poor couple’s relationship during pregnancy, frequent negative maternal emotions, maternal postpartum attachment characterized by high anxiety regar¬ding child, and inflexible and parent-oriented attitudes toward infant-rearing. The associations between biomedical and psychosocial factors are also analyzed and discussed.

The prevalence of dementia is increasing globally and is linked to obesity and unfavorable dietary habits. The present study analyses the association of alcohol intake from wine and non wine alcoholic beverages (non-wine) in g/d, as well as coffee and tea in cups/d, with incident dementia. Over 4.2 million person-years, 4270 dementia cases occurred in 351,436 UK Biobank participants. Hazard ratios (HRs) for incident dementia were defined with Cox proportional hazard regression models in which beverage intake was fitted as penalized cubic splines. Wine intake showed a significant U-shaped association with the lowest risk for incident dementia (nadir) ranging from 21 to 23 g alcohol/d in all participants and in males. In contrast, non-wine consumption was significantly and dose-dependently associated with incident dementia, and the nadir was found at 0 g alcohol/d. Coffee consumption was not related to dementia risk, while moderate-to-high tea intake was negatively associated with incident dementia. Taken together, the current study shows on a population level that moderate consumption of wine and moderate-to-high tea intake is associated with a decreased risk of incident dementia. In contrast, non-wine is positively related to dementia risk in a linear fashion, and no clear association is found for coffee.

Background: Diabetes mellitus and vascular diseases have a significant impact on the eye. / Aim: To determine the prevalence, risk factors, and racial/ethnic differences of major eye conditions, particularly retinal conditions, associated with diabetes and vascular diseases. / Scope: To date, the majority of studies have examined the association of retinal vascular calibre and diabetes in predominantly white Caucasian populations. Further elucidation of ethnic differences in effects of hyperglycaemia on early microvascular disease is relevant, particularly amongst Asians where diabetes is likely to see the largest increase in prevalence over the next decade. We therefore examined these findings from three Asian population-based studies, the Singapore Malay Eye Study (n=3280), Singapore Prospective Cohort Study and Singapore Cardiovascular Cohort Study 2 (n=3748). / Results: The prevalence of diabetic retinopathy in the Singapore Malay Eye Study was 35%, and associated with longer duration of diabetes, poorer glycemic and blood pressure control. More importantly, 9.0% had vision-threatening retinopathy, and retinopathy was found in 6.0% of people without diabetes. Retinal vascular calibre changes were incriminated in diseases such as diabetes and hypertension, independent of traditional cardiovascular risk factors. Wider venular calibre was independently associated with early age-related macular degeneration. We also found a novel association between peripheral artery disease and glaucoma, stronger in persons with diabetes, independent of vascular risk factors, supporting the vascular theory of glaucoma. / Implications: Subtle changes in retina, including retinal vascular calibre may be early markers of widespread microvascular changes in diabetes, resulting from chronic hyperglycaemia and other pathogenic processes. These results will have broad implications for understanding the impact of both microvascular and macrovascular complications of diabetes in the Asia Pacific region and targeting relevant therapeutic interventions.

Les antidépresseurs figurent parmi les médicaments les plus prescrits dans les pays industrialisés, incluant la France. L’utilisation croissante de ces médicaments dans la population générale suscite de multiples préoccupations quant à leurs effets indésirables sur la santé des populations. Plusieurs travaux de recherche se sont récemment intéressés à l’impact de l’utilisation prolongée de ces médicaments sur le risque cardiométabolique. Toutefois, les résultats produits sont contradictoires, limitées et ne concernaient pas la population Française. L’objectif général de ce travail de thèse consiste donc à étudier, à partir des données de deux grandes cohortes françaises (E3N et D.E.S.I.R.), l’association entre l’utilisation de médicaments antidépresseurs et le risque cardiométabolique, en essayant d’en comprendre les mécanismes sous-jacents. La première étude a montré que l’utilisation d’antidépresseurs était associée à un risque accru de diabète de type II. Cependant, l’association était évidente uniquement chez les femmes qui avaient plus de consultations médicales au cours des douze derniers mois. Les résultats de la seconde étude n’ont montré aucune association entre l’utilisation d’antidépresseurs et les marqueurs physio-biologiques qui caractérisent le diabète tels que : la glycémie à jeun, l’hémoglobine glyquée, la fonction des cellules β et la sensibilité à l’insuline. Enfin la troisième étude de ce travail de thèse a mis en évidence un risque accru de syndrome métabolique chez les utilisateurs d’antidépresseurs même si l’effet semblait se potentialiser chez les hommes uniquement. Les résultats de ces études apportent des éléments en faveur de l’hypothèse d’un biais de détection pour expliquer l’association observée entre utilisation d’antidépresseurs et diabète. Ce travail de thèse a permis de clarifier l’association entre l’utilisation d’antidépresseurs chez l’adulte et le risque cardiométabolique. Les implications scientifiques, cliniques et de santé publique sont discutées. / Antidepressants are among the most frequently prescribed medications in industrialized countries, including France. The increasing use of antidepressants in the general population has led to concerns about their adverse effects on health. Recently, important research work has focused on the impact of the prolonged use of antidepressants on cardiometabolic risk. However, the results produced were conflicting, limited and were not based on French population. The general objective of this thesis is therefore to study, based on data from two large French cohorts (E3N and D.E.S.I.R.), the association between the use of antidepressant drugs and cardiometabolic risk, with the ambition to understand the underlying mechanisms. The first study showed antidepressant medication use to be associated with an increased risk of type II diabetes. However, this association was evident only in women with more medical visits in the last twelve months. The results of the second study shows no association between antidepressant medication use and physio-biological markers that characterize diabetes such as fasting plasma glucose, glycated haemoglobin, β-cell function and insulin sensitivity. Finally, the third study showed an increased risk of metabolic syndrome among users of antidepressants, although the effect was apparent in men only. The results of these studies provide evidence supporting the hypothesis of a detection bias to explain the observed association between antidepressants use and diabetes. This work has helped to clarify the association between the use of antidepressants in adults and cardiometabolic risk. The scientific, clinical and public health implications are discussed.