Growing up in an urban area has been shown to be associated with an increased risk of psychotic disorder in later life. While it is commonly held that a only a tiny fraction of exposed individuals will develop schizophrenia, recent evidence suggests that expression of psychosis in exposed individuals may be much more common, albeit at attenuated levels. Findings are based on a population sample of 2548 adolescents and young adults aged originally 14–24 years, and followed up over almost 5 years up to ages 17–28 years. Trained psychologists assessed all these subjects with the core psychosis sections on delusions and hallucinations of the Munich-Composite International Diagnostic Interview. Growing up in an urban area was associated with an increased risk of expression of psychosis in the adolescents and young adults (adjusted OR 1.31, 95% CI 1.03–1.66). The proxy environmental risk factor that urbanicity represents may shift a relatively large section of the adolescent population along a continuum of expression of psychosis. Other causal influences may be required to make the transition to schizophrenia in adult life.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18130号 / 医博第3850号 / 新制||医||1001(附属図書館) / 30988 / 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 横出 正之, 教授 中山 健夫 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第13220号 / 論医博第2167号 / 新制||医||1033(附属図書館) / (主査)教授 高橋 淳, 教授 宮本 享, 教授 伊佐 正 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

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.

Introduction: The placenta is essential for fetal development and pregnancy prolongation. Its dysfunction can lead to short and long-term health consequences for mother and child. A subset of diseases resulting from placental dysfunction have been collectively termed placental-mediated diseases (PMD) - which includes the common and serious hypertensive disorder of pregnancy preeclampsia (PE), among others. PMDs are independent risk factors for maternal cardiovascular disease (CVD) in later life. This thesis presents a multi-pronged body of work, which includes: 1) A systematic review, aimed at summarizing the current state of knowledge on the risk for future maternal CVD after PMDs; 2) A cohort study, aimed at assessing the utility of placenta pathology examination at delivery to identify women at high lifetime risk for CVD following PE; and 3) An assessment of an immunohistochemistry screening panel for 3 placenta protein markers of interest, aimed at determining if these markers can accurately identify women deemed to be at high-risk for future CVD following a PE pregnancy. Methods: 1) We searched 4 databases for observational studies evaluating clinical and biochemical markers of CVD risk and/or a subsequent calculated risk score based on these parameters in women with a history of PMD. We excluded interventional studies and studies measuring these outcomes during or prior to pregnancy. 2) A cohort study was established across two clinical sites (Kingston, Ottawa), in which patients with PE (N=85) underwent cardiovascular risk assessments at 6-months postpartum. The placentas from these pregnancies also underwent detailed placenta histopathology examination to determine the presence, absence, and severity of 35 distinct placental lesions. The associations between distinct placental lesions and estimated lifetime cardiovascular risk were evaluated by odds ratios (OR) and receiver operator curve analysis (ROC). 3) Immunohistochemistry (IHC) analysis was performed on placental samples from a subset of the previously described cohort (N=41; Ottawa site only). Protein expression for FLT-1, ENG, and CD68 was quantified. Using a multivariate logistic regression model, the association between placenta protein expression, with and without clinical and placenta pathology findings, and cardiovascular risk was assessed. Results: 1) The search yielded 11,039 articles of which 104 met our inclusion criteria. All PMD types demonstrated evidence of increased CVD risk markers at varying timepoints postpartum. At least one study per PMD type had non-optimal measures of systolic blood pressure, BMI, and total cholesterol. 2) In the analysis of placenta pathology lesions within the cohort of individuals with PE, lesions of maternal vascular malperfusion (MVM) were found to be associated with elevated life-time risk for maternal CVD at 6 months postpartum (OR: 3.10[1.20-7.92]). We also found that adding these lesions to a logistic regression model improved the predictive accuracy for elevated maternal lifetime CVD risk (AUC: 73.0, sensitivity: 78.4%, specificity: 51.6%). 3) Individually, no significant differences were found in FLT-1, ENG, and CD68 expression between the individuals deemed to be at high and low-risk for lifetime CVD. Although, when added to a model that included placenta pathology lesions and clinical data the predictive accuracy for elevated maternal lifetime CVD risk increased (AUC: 1.0, sensitivity: 100%, specificity: 100%). Conclusions: In conclusion, this thesis provides further evidence of the utility of assessing placenta features in the prediction of future maternal CVD. This is evidenced by the association between PMDs, placental pathology, and placental protein biomarkers with elevated risk profiles for lifetime CVD. Thus, specific placental phenotypes of PMDs may be at increased risk for CVD. The use of placental data should be further explored as a triage strategy to identify these high-priority of women following delivery.

Research on anxiety in oldest-old individuals is scarce. Specifically, incidence studies based on large community samples are lacking. The objective of this study is to assess age- and gender-specific incidence rates in a large sample of oldest-old individuals and to identify potential risk factors. The study included data from N = 702 adults aged 81 to 97 years. Anxiety symptoms were identified using the short form of the Geriatric Anxiety Inventory (GAI-SF). Associations of potential risk factors with anxiety incidence were analyzed using Cox proportional hazard models. Out of the N = 702 older adults, N = 77 individuals developed anxiety symptoms during the follow-up period. The incidence rate was 51.3 (95% CI: 41.2–64.1) per 1000 person-years in the overall sample, compared to 58.5 (95% CI: 43.2–72.4) in women and 37.3 (95% CI: 23.6–58.3) in men. Multivariable analysis showed an association of subjective memory complaints (HR: 2.03, 95% CI: 1.16–3.57) and depressive symptoms (HR: 3.20, 95% CI: 1.46–7.01) with incident anxiety in the follow-up. Incident anxiety is highly common in late life. Depressive symptoms and subjective memory complaints are major risk factors of new episodes. Incident anxiety appears to be a response to subjective memory complaints independent of depressive symptoms.

College students undergo stressors (e.g., potential financial strain, changes in workload or location), which may precipitate metabolic syndrome (MetS) risk associated with obesity and high blood pressure. Concerning rises in young adult obesity and type 2 diabetes, prompt study into MetS risk factor prevalence and awareness in youthful populations transitioning to new environments, such as college. This study assessed perceived stress, coping resources, and disease awareness differences in the first time on campus and final-year students associated with MetS risk factors (elevated body mass index (BMI) and blood pressure). We hypothesized lower stress perception, lower weight gain and blood pressure, higher MetS knowledge, and more positive coping strategies in final-year students. We conducted a longitudinal cohort study of 43 undergraduates with a baseline assessment in September (T0) and a follow-up in December (T1). BMI and blood pressure were measured at each visit and compared to baseline predictors of MetS knowledge, perceived stress, and coping resources. Though trends in MetS knowledge, perceived stress, and coping scores followed those in our hypothesis, only differences in weight and BMI change were statistically significant. The mixed-effects regression analysis did not find any statistically significant trends. First-time on-campus students gained an average of 1.736 kg, and their average BMI increased by 0.485 kg/m2. Conversely, final year students lost 0.313 kg, and their average BMI decreased by 0.210 kg/m2. Information on blood pressure was inconclusive. The average increase in weight/BMI in first-time on-campus students compared to final-year students highlights the need to provide education and resources to protect against metabolic syndrome risk in young adults. Trends in final year student clinical outcomes and their predictors illustrate how education may be a protective factor against MetS risk.

No / More than 1 billion people live in societies where consanguineous marriages are common. When children are born to consanguineous unions, there is an increased probability of the expression of single-gene disorders with a recessive mode of inheritance. There are presumptive social benefits of consanguineous marriages reported in the literature. METHODS: The UK's Born in Bradford birth cohort study recruited 12 453 women at 26-28 weeks' gestation between 2007 and 2010. In all, 11 396 completed a questionnaire, including questions about their relationship to their baby's father. We compared Pakistani and Other ethnic groups in consanguineous relationships and Pakistani, Other and White British groups not in consanguineous relationships, calculating percentages and age-adjusted prevalence ratios (95% confidence intervals). RESULTS: In the Pakistani group, 59.3% of women (n = 3038) were blood relatives of their baby's father. Consanguinity was uncommon in the Other ethnic group (7.3%, n = 127) and rare (n = 5) in the White British group. Compared with non-consanguineous counterparts, mothers in consanguineous relationships were socially and economically disadvantaged (e.g. never employed, less likely to have higher education). The Pakistani consanguineous group's social, economic and health lifestyle circumstances were equivalent to, in some cases better than, women in non-consanguineous relationships (e.g. up-to-date in paying bills, or in disagreeing that they wished for more warmth in their marital relationship). The consanguineous relationship group had less separation/divorce. Rates of cigarette smoking during pregnancy were lower in mothers in consanguineous relationships. CONCLUSION: Debate about consanguinity should balance the potential protective effect of consanguineous relationships with established genetic risk of congenital anomaly in children.

No / Congenital anomalies are a leading cause of infant death and disability and their incidence varies between ethnic groups in the UK. Rates of infant death are highest in children of Pakistani origin, and congenital anomalies are the most common cause of death in children younger than 12 in this ethnic group. We investigated the incidence of congenital anomalies in a large multiethnic birth cohort to identify the causes of the excess of congenital anomalies in this community. Methods: We obtained questionnaire data from the mothers of children with one or more anomalies from the Born in Bradford study, a prospective birth cohort study of 13 776 babies and their families in which recruitment was undertaken between 2007 and 2011. Details of anomalies were prospectively reported to the study and we cross checked these details against medical records. We linked data for anomalies to maternal questionnaire and clinical data gathered as part of the Born in Bradford study. We calculated univariate and multivariate risk ratios (RRs) with 95% CIs for various maternal risk factors. Findings: Of 11 396 babies for whom questionnaire data were available, 386 (3%) had a congenital anomaly. Rates for congenital anomaly were 305·74 per 10 000 livebirths, compared with a national rate of 165·90 per 10 000. The risk was greater for mothers of Pakistani origin than for those of white British origin (univariate RR 1·96, 95% CI 1·56–2·46). Overall, 2013 (18%) babies were the offspring of first-cousin unions. These babies were mainly of Pakistani origin—1922 (37%) of 5127 babies of Pakistani origin had parents in first-cousin unions. Consanguinity was associated with a doubling of risk for congenital anomaly (multivariate RR 2·19, 95% CI 1·67–2·85); we noted no association with increasing deprivation. 31% of all anomalies in children of Pakistani origin could be attributed to consanguinity. We noted a similar increase in risk for mothers of white British origin older than 34 years (multivariate RR 1·83, 95% CI 1·14–3·00). Maternal education to degree level was protective (0·53, 95% CI 0·38–0·75), irrespective of ethnic origin. Interpretation: Consanguinity is a major risk factor for congenital anomaly. The risk remains even after adjustment for deprivation, and accounts for almost a third of anomalies in babies of Pakistani origin. High levels of educational attainment are associated with reduced risk in all ethnic groups. Our findings will be valuable in health promotion and public health, and to those commissioning antenatal, paediatric, and clinical genetic services. Sensitive advice about the risks should be provided to communities at increased risk, and to couples in consanguineous unions, to assist in reproductive decision making. Funding: National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care programme.

No / The present study aimed to explore previously unreported ethnic differences in infant feeding practices during the introduction of solid foods, accounting for maternal and birth factors, and to determine whether these feeding patterns are associated with BMI at 3 years of age. An observational study using Poisson regression was carried out to investigate the relationship between ethnicity and infant feeding practices and linear regression was used to investigate the relationship between feeding practices and BMI at 3 years of age in a subsample of 1327 infants in Bradford. It was found that compared with White British mothers, mothers of Other ethnicities were less likely to replace breast milk with formula milk before introducing solid foods (adjusted relative risk (RR) – Pakistani: 0·76 (95 % CI 0·64, 0·91), Other South Asian: 0·58 (95 % CI 0·39, 0·86), and Other ethnicities: 0·50 (95 % CI 0·34, 0·73)). Pakistani and Other South Asian mothers were less likely to introduce solid foods early ( < 17 weeks) (adjusted RR – Pakistani: 0·92 (95 % CI 0·87, 0·96) and Other South Asian: 0·87 (95 % CI 0·81, 0·93)). Other South Asian mothers and mothers of Other ethnicities were more likely to continue breast-feeding after introducing solid foods (adjusted RR – 1·72 (95 % CI 1·29, 2·29) and 2·12 (95 % CI 1·60, 2·81), respectively). Pakistani and Other South Asian infants were more likely to be fed sweetened foods (adjusted RR – 1·18 (95 % CI 1·13, 1·23) and 1·19 (95 % CI 1·10, 1·28), respectively) and Pakistani infants were more likely to consume sweetened drinks (adjusted RR 1·72 (95 % CI 1·15, 2·57)). No association between infant feeding practices and BMI at 3 years was observed. Although ethnic differences in infant feeding practices were found, there was no association with BMI at 3 years of age. Interventions targeting infant feeding practices need to consider ethnicity to identify which populations are failing to follow recommendations.