This thesis aimed to evaluate the feasibility and utility of a sickle cell disease registry for clinical patient management and research. Five hospitals out of nine in the North West London health region participated in the registry, with 78 percent coverage of the sickle cell disease population. There was 80% case ascertainment in participating hospitals. Aggregated anonymised demographic and diagnostic data was collected for all haemoglobinopathy patients. This provided the core dataset for quantifying prevalence of sickle cell and thalassaemia and mapping local hospital workloads and service requirements. Thirteen percent of HbSS adult patients were taking hydroxycarbamide. The cohort of patients treated with hydroxycarbamide was evaluated. Sixty two of the 80 patients started on treatment were included. Follow-up was censored after 9 years, totalling 249 person-years of data with a median follow-up of three years (IQR, 1-6). Results showed that haematological benefits were maintained in the long-term with treatment, but evidence of long-term clinical effectiveness was less strong. This appeared to be due to the patterns of clinical management in everyday practice. Patients tend to be treated with modest doses of hydroxycarbamide due to intolerance or inability to attain or maintain maximum tolerated dose. For example maximum tolerated dose was the aim of treatment for 91% of patients but it was achieved for 65% of participants. Non- compliance with treatment and monitoring schedule was the main reason for non- attainment. Results suggest that it is sensible to strive for maximum tolerated dose to ensure therapy remains effective, but with more realistic expectations of the dose patients can attain and maintain. Doses in adult patients average 20mg/kg/day and 25mg/kg/day in children. Adult patients may be able to achieve a higher dose, if there was more stringent monitoring and improved management of non-compliance. The North West London HU Sub-Registry proved useful for measuring long-term effectiveness and tolerability of hydroxycarbamide. Routinely collected data was utilized for both clinical management and research purposes. The novelty lay in examination of the nuances of routine clinical practice. An electronic patient record was developed as a clinical management tool. It is the first study reporting long-term outcomes for UK sickle cell disease patients on hydroxycarbamide. Findings should help clinicians devise effective treatment protocols and strategies for managing patients commenced on this therapy. Interventions need to be targeted at increasing utilisation, patient adherence and persistence with treatment. The electronic patient record could be used to maximise treatment benefit and improve adherence. More effective involvement of the multidisciplinary team and primary care colleagues in patient education and management should improve usage. Patients and carers need up to date and easy to assimilate information to make informed decisions about treatment options. Maintaining a SCD registry is challenging. Models which operate as clinical information systems provide an incentive for participation. These enable active involvement of local care providers in registry management and the ability to keep and utilize their own data. Clinicians require accurate and current data for patient management and to enable them to benchmark their local outcomes against national outcomes and care standards.

My PhD work aimed to assess intergenerational transmission and life-course change of attitudes towards authority. Intergenerational transmission is hypothesised as the mechanism through which parents' authoritarian attitudes affect their children's attitudes towards authority in adulthood. In the assessment of this transmission mechanism, this analysis accounts for individual-level theoretically relevant factors such as gender, education, social class, offspring's cognitive ability in childhood, as well as family background, in a longitudinal, single-cohort perspective. The research used the British Cohort Study 1970 (BCS70), which allows for the analysis of change at both the intra- and inter-individual levels. The sweeps analysed are those in years 1975 for the parents, and 1980, 1996, 2000 and 2012 for the cohort members. The analytical chapters of the thesis are made of three papers: The first assessed change (or stability) in attitudes to authority in the BCS70 from 1996 to 2012; the second looked at how parental authoritarian worldviews affect their children's attitudes towards authority when the children are adults; finally, the third paper aimed to evaluate the effect of parental attitudes on cohort members' attitudes towards authority in adulthood, after controlling for the latter's cognitive ability in childhood. I found that attitudes had a reasonably high level of stability across the life course. Despite moderately strong correlations across attitudes within waves, the different attitudes showed different patterns of longitudinal evolution, suggesting different causal influences. The evidence for direct transmission of attitudes from parents to children was surprisingly weak; the social statuses of the parents and cohort members, and especially the members' childhood cognitive ability, were the strongest predictors of authoritarian attitudes in adulthood.

We seek to observe the association between childhood obesity by different measures and adult obesity, metabolic syndrome (MetS), and diabetes. Thousand two hundred and nine subjects from “Beijing Blood Pressure Cohort Study” were followed 22.9 ± 0.5 years in average from childhood to adulthood. We defined childhood obesity using body mass index (BMI) or left subscapular skinfold (LSSF), and adult obesity as BMI ≥28 kg/m2. MetS was defined according to the joint statement of International Diabetes Federation and American Heart Association with modified waist circumference (≥90/85 cm for men/women). Diabetes was defined as fasting plasma glucose ≥7.0 mmol/L or blood glucose 2 h after oral glucose tolerance test ≥11.1 mmol/L or currently using blood glucose-lowering agents. Multiple linear and logistic regression models were used to assess the association. The incidence of adult obesity was 13.4, 60.0, 48.3, and 65.1 % for children without obesity, having obesity by BMI only, by LSSF only, and by both, respectively. Compared to children without obesity, children obese by LSSF only or by both had higher risk of diabetes. After controlling for adult obesity, childhood obesity predicted independently long-term risks of diabetes (odds ratio 2.8, 95 % confidence interval 1.2–6.3) or abdominal obesity (2.7, 1.6–4.7) other than MetS as a whole (1.2, 0.6–2.4). Childhood obesity predicts long-term risk of adult diabetes, and the effect is independent of adult obesity. LSSF is better than BMI in predicting adult diabetes.

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.

Yes / Despite a wealth of activity across the globe in the area of longitudinal population cohorts, surprisingly little information is available on the natural biomedical history of a number of age-related neurodegenerative diseases (ND), and the scope for intervention studies based on these cohorts is only just beginning to be explored. The Joint Programming Initiative on Neurodegenerative Disease Research (JPND) recently developed a novel funding mechanism to rapidly mobilise scientists to address these issues from a broad, international community perspective. Ten expert Working Groups, bringing together a diverse range of community members and covering a wide ND landscape (Alzheimer’s, Parkinson’s, frontotemporal degeneration, amyotrophic lateral sclerosis, Lewy-body and vascular dementia) were formed to discuss and propose potential approaches to better exploiting and coordinating cohort studies. The purpose of this work is to highlight the novel funding process along with a broad overview of the guidelines and recommendations generated by the ten groups, which include investigations into multiple methodologies such as cognition/functional assessment, biomarkers and biobanking, imaging, health and social outcomes, and pre-symptomatic ND. All of these were published in reports that are now publicly available online.

Yes / Introduction The Community Ageing Research 75+ Study (CARE75+) is a longitudinal cohort study collecting an extensive range of health, social and economic data, with a focus on frailty, independence and quality of life in older age. CARE75+ is the first international experimental frailty research cohort designed using Trial within Cohorts (TwiCs) methodology, to align applied epidemiological research with clinical trial evaluation of interventions to improve the health and well-being of older people living with frailty. Methods and analysis Prospective cohort study using a TwiCs design. One thousand community-dwelling older people (≥75 years) will be recruited from UK general practices. Nursing home residents, those with an estimated life expectancy of 3 months or less and people receiving palliative care will be excluded. Data collection assessments will be face to face in the person’s home at baseline, 6 months, 12 months, 24 months and 48 months, including assessments of frailty, cognition, mood, health-related quality of life, comorbidity, medications, resilience, loneliness, pain and self-efficacy. A modified protocol for follow-up by telephone or web based will be offered at 6 months. Consent will be sought for data linkage and invitations to additional studies, including intervention studies using the TwiCs design. A blood sample biobank will be established for future basic science studies. Ethics and dissemination CARE75+ was approved by the NRES Committee Yorkshire and the Humber—Bradford Leeds 10 October 2014 (14/YH/1120). Formal written consent is sought if an individual is willing to participate and has capacity to provide informed consent. Consultee assent is sought if an individual lacks capacity. Study results will be disseminated in peer-reviewed scientific journals and scientific conferences. Key study results will be summarised and disseminated to all study participants via newsletters, local older people’s publications and local engagement events. Results will be reported on a bespoke CARE75+ website. / NIHR CLAHRC Yorkshire and Humber - www.clahrc-yh.nihr.ac.uk (study funding number IS-CLA-0113-10020) and supported by the NIHR CLAHRC South West Peninsula and West Midlands CLAHRC.

Background/objectives There are few studies investigating the long-term association between childhood blood pressure (BP) and adult cardiovascular remodeling. We seek to examine the effect of elevated childhood BP on cardiovascular remodeling in early or middle adulthood.Methods We used the "Beijing BP Cohort Study", where 1259 subjects aged 6-18 years old were followed over 24 years from childhood (1987) to early or middle adulthood (2011). Anthropometric measures and BP were obtained at baseline and follow-up examinations. Carotid-femoral pulse wave velocity (cfPWV), carotid intima-media thickness (cIMT), and left ventricular mass index (LVMI) were measured to assess cardiovascular remodeling in early or middle adulthood. Multiple logistic regression models were used to assess the odds ratio (OR) and 95% confidence interval (CI) for cardiovascular remodeling.Results 82 out of 384 children with elevated BP (21.4%) had adult hypertension. Compared to those with normal BP, children with elevated BP were at 2.1 times (95% CI: 1.4-3.1) likely to develop hypertension in early or middle adulthood. Compared to those with normal BP, children with elevated BP were at higher OR of developing high cfPWV (OR = 1.8, 95% CI = 1.3-2.4), high cIMT (1.4, 1.0-1.9), or high LVMI (1.4, 1.0-1.9) in early or middle adulthood. The ORs for remodeling (for any measures) were 1.4 (0.9-2.0) in early adulthood for children age 6-11 years, and 1.6 (1.1-2.4) in middle adulthood for those aged 12-18 years.Conclusions Children with elevated BP from 6 years old have accelerated remodeling on both cardiac and arterial system in early or middle adulthood.

Les liens entre facteurs socio démographiques et trajectoires de consommation d’alcool chez les jeunes restent peu connus. De même, les études sur les liens entre trajectoire socio-économique et consommation d’alcool ont échoué à montrer un effet propre de la trajectoire socio-économique. Enfin, la littérature qui est disponible actuellement ne permet pas de dégager un consensus sur l'effet du sexe des enfants et des parents dans la transmission intergénérationnelle de la consommation d'alcool. L’objectif de cette thèse a été d’identifier les déterminants sociaux, économiques et démographiques des trajectoires de consommation d’alcool chez les jeunes. Il s’est agi d’une étude de cohorte prospective menée en population générale dans la cohorte TEMPO [(n=2.582, âgées de 4 à 16 ans en 1991), (n=1.333, âgés de 12 à 25 ans en 1999), (n=1.103, âgés de 22 à 35 ans en 2009)], et pour lesquels les données ont été recueillies par auto-questionnaire postal, incluant des jeunes dont un des parents participe à la cohorte GAZEL. Il est ressorti de nos analyses que la consommation excessive d’alcool qui s’installe au début de l’adolescence est un phénomène limité dans le temps chez la majorité des jeunes. Elle persiste dans des sous populations particulières comme les personnes issues de catégorie sociale défavorisée et les jeunes femmes. La situation sociale, mesurée par la trajectoire sociale de l’enfance au début de l’âge adulte, est un facteur prédictif de la consommation d’alcool au début de l’âge adulte. Les tendances de certains de nos résultats laissent penser que les mécanismes à l’œuvre dans un possible lien parents-descendance pour l'abus d'alcool pourraient être en lien avec le sexe des jeunes. Ces résultats suggèrent que la trajectoire de consommation d’alcool chez les jeunes est en partie déterminée par des facteurs sociodémographiques présents précocement, au cours de l’enfance et l’adolescence. Etant donné les risques de l’abus d'alcool chez les jeunes tant sur leur santé que sur leur devenir social et professionnel à long terme, les trajectoires d'abus d'alcool devraient faire l'objet d'une surveillance plus accrue. La prise en compte des mécanismes sociaux à l’œuvre dans les trajectoires d'abus d'alcool chez les jeunes pourrait être contributive. / Young adulthood is a critical period in terms of establishing lifelong health behaviors, including alcohol use. Yet, trajectories of alcohol abuse from adolescence onwards are not well known.Using data from a longitudinal cohort study set up in France [(n=2,582, age 4-16 years in 1991), (n=1,333, age 12-25 years in 1999), (n=1,103, age 22-35 years in 2009)], we examined the relationship between repeated alcohol intoxication in adolescence and later alcohol abuse, testing whether this association varies depending on individuals’ sociodemographic characteristics. We also studied the hypothesis that patterns of alcohol use in young adulthood are associated with lifecourse socioeconomic trajectory. In addition, we examined the relationship between parental history of alcohol use and offspring’s alcohol use in young adulthood, testing differences according to sex.In most adolescents, alcohol abuse is a time-limited behavior. Nonetheless, in adolescent participants from low income families, in girls, the likelihood of persistent alcohol abuse beyond adolescence may be increased. We also found that young adults who had a persistently low socioeconomic position from childhood to young adulthood were more likely to abstain from alcohol even after controlling for demographic, social, psychological and family characteristics. Additionally, participants with a downward social trajectory were disproportionately likely to abuse alcohol. In addition, parental history of alcohol use is especially predictive of offspring’s young adulthood alcohol misuse in men.Our findings suggest that alcohol use patterns in young adulthood may be influenced by early socioeconomic factors, which should be confirmed by additional studies in the future. Given young people alcohol abuse risks about their health and their future social and professional situation, alcohol use trajectories from adolescence onwards should be better monitored. Taking into account social mechanisms that influence trajectories of alcohol abuse among young people could be contributive, which should be brought to the attention of policymakers and mental health specialists.

People spend most of their time indoors and mostly in the dwelling. It is therefore important to investigate associations between indoor exposure in dwellings and health. Symptoms that may be related to the indoor environment are sometimes referred to as the "sick building syndrome" (SBS). SBS involves symptoms such as eye, skin and upper airway irritation, headache and fatigue. Three longitudinal studies and one prevalence study on personal and environmental risk factors for SBS in adults were performed. The prevalence study included measurements of indoor exposures in the dwellings. The longitudinal studies, with 8-10 years follow-up time, showed that smoking and indoor paint emissions were risk factors for SBS. Moreover, building dampness and moulds in dwellings were risk factors for onset (incidence) of general symptoms, skin symptoms and mucosal symptoms. In addition subjects living in damp dwellings have a lower remission of general symptoms and skin symptoms. Hay fever was a risk factor for onset of skin symptoms and mucosal symptoms, and asthma was a risk factor for onset of general and mucosal symptoms. Biomarkers of allergy and inflammation (bronchial reactivity, total IgE, ECP and eosinophil count) were predictors of onset of SBS symptoms, in particular mucosal symptoms. In the prevalence study, any SBS-symptom was associated with some individual volatile organic compounds of possible microbial origin (MVOC) e.g. 2-pentanol, 2-hexanon, 2-pentylfuran and 1-octen-3ol. Moreover, there were associations between indoor levels of formaldehyde and the plasticizer Texanol and any SBS. The result from the study indicates that individual MVOC are better indicators of SBS than the total value of MVOC. A final conclusion is that smoking, dampness and moulds and emissions from indoor painting may increase the onset of SBS. The indoor environment in dwellings over time has improved, but there is still a need for further improvements of the indoor environment in dwellings. More longitudinal SBS studies are needed.

Depressionen bei hochaltrigen Menschen sind weit verbreitet und folgenschwer, dennoch bleiben diese häufig unentdeckt und unbehandelt. Daher ist die Identifizierung von Risikofaktoren besonders wichtig, um Depressionen im Alter zu erkennen oder präventiv zu begegnen. Die Bedeutung von psychosozialen Faktoren, wie Verlusterfahrungen und das soziale Netzwerk, werden dabei häufig vernachlässigt. Dabei wird der Tod von nahestehenden Personen mit zunehmendem Alter häufiger und erfordert ein hohes Maß an psychologischer Anpassungsleistung der Hinterbliebenen. Die damit einhergehende Veränderung des sozialen Netzwerks birgt ein Risiko für soziale Isolation und damit auch für Depressionen. Das Ziel der Dissertation war es, Depressionen bei hochaltrigen Menschen in Deutschland in Abhängigkeit von sozialer Isolation und Verlusterfahrungen zu analysieren und dabei auf mögliche Geschlechtsunterschiede einzugehen. Datengrundlage der ersten Untersuchung war die „Leipziger Langzeitstudie in der Altenbevölkerung“ (LEILA 75+), eine prospektive, epidemiologische und bevölkerungs-repräsentative Kohortenstudie. Mit einer Stichprobe von 783 Personen (durchschnittliches Alter 80,78 (SD 4,52) Jahre) wurde zunächst mittels einer deskriptiven Analyse die Veränderung des sozialen Netzwerks (PANT) im Alter unter Berücksichtigung von Verlusterfahrungen analysiert. 57% der älteren Menschen lebte kontinuierlich in einem restriktiven sozialen Netzwerk. Bei 30,9% der Hochaltrigen konnte eine Änderung im sozialen Netzwerk während des Untersuchungszeitraums festgestellt werden, diese konnten allerdings in keinen Zusammenhang mit Verlusterfahrungen gebracht werden. Verlusterfahrungen (OR 7,56 (1,60–35,72)) und ein restriktives soziales Netzwerk (OR 4,08 (1,52–10,95)) stellten sich in den Hybridregressionen als signifikante Prädiktoren zur Entwicklung einer Depression (ADS-L) heraus. Protektive wirkte hingegen ein integriertes soziales Netzwerk. In der zweiten Studie wurden die AgeDifferent.de Daten, die aus drei gepoolten Alterskohortenstudien (LEILA 75+, AgeCoDe / AgeQualiDe und AgeMooDe) bestehen, ausgewertet. Das durchschnittliche Alter der 2.470 Befragten lag bei 79,2 (SD 3,64) Jahren. Bei Frauen konnte ein signifikant höherer Schweregrad der Depression festgestellt werden als bei Männern (β=0.16; 95%-CI=0.09; 0.23). Analysen zum Vergleich der Depressivität vor und nach der Verwitwung verdeutlichten, dass der Schweregrad der Depression nach der Verwitwung signifikant höher ist. In dieser Studie konnte zudem gezeigt werden, dass verwitwete Männer signifikant mehr depressive Symptome haben als nicht verwitwete Männer. Bei der Betrachtung von Frauen konnten jedoch keine Unterschiede festgestellt werden. Bei intraindividueller Betrachtung zeigte sich, dass sowohl verwitwete Männer als auch verwitwete Frauen signifikant mehr depressive Symptome haben als vor ihrer Verwitwung. In der letzten Untersuchung wurde mit Daten der AgeCoDe / AgeQualiDe Studie analysiert ob Unterschiede zwischen Verwitweten und Verheirateten in Alter, Geschlecht und Bildung auch eine mögliche Erklärung für die Unterschiede in der Depressivität zwischen diesen Gruppen sein könnten. Mit Daten von 679 Personen (456 verwitwet, 223 verheiratet), mit einem durchschnittlichem Alter von 86,5 (SD 2,9) Jahren konnte gezeigt werden, dass Verwitwete häufig älter, häufiger weiblich und eher niedriger gebildet sind. Mittels „Entropy Balancing“ wurden diese Eigenschaften von Verwitweten und Verheirateten vereinheitlicht. Das Ausmaß der depressiven Symptome bei verwitweten hochaltrigen Frauen und Männern war in dieser Untersuchung ähnlich. Bei der Berücksichtigung der sozialen Isolation stellte sich in dieser Untersuchung heraus, dass soziale Isolation vor allem in der Gruppe der Verwitweten zu mehr depressiven Symptomen führt. Verwitwete Männer und Frauen, die zudem sozial isoliert leben, weisen signifikant mehr depressive Symptome auf, als Verwitwete ohne soziale Isolation (β=0.83; 95%-CI=0.44; 1.23). Soziale Isolation hatte in der Gruppe der Verheirateten im Gegensatz zu den Verwitweten keinen Einfluss auf die Häufigkeit depressiver Symptome. Zusammenfassend zeigt sich, dass Verlusterfahrungen als ein Risikofaktor zur Entwicklung depressiver Symptome identifiziert werden konnte. Nicht eindeutig ist der Einfluss des Geschlechts. Mögliche Unterschiede zwischen Frauen und Männern im Zuge der Verwitwung könnte beispielsweise die Unterrepräsentation von verwitweten Männern sein. Wird dieser Faktor berücksichtigt, können Frauen und Männer als ähnlich vulnerabel zur Entwicklung einer Depression nach dem Verlust des Ehepartners gelten. Für Menschen die zusätzlich neben dem Verlust des Ehepartners ein sozial isoliertes soziales Netzwerk haben, ist das Risiko zur Entwicklung einer Depression noch größer. Ein gestärktes soziales Netzwerk kann hingegen bei beiden Geschlechtern als ein protektiver Faktor zum Erhalt der psychischen Gesundheit gesehen werden.:Abbildungsverzeichnis Tabellenverzeichnis Abkürzungsverzeichnis 1 Einleitung 1.1 Depressionen im Alter 1.2 Trauer- und Verlusterfahrungen im Alter 1.3 Bedeutung des sozialen Netzwerks im Alter 1.4 Geschlechtsunterschiede im Alter 2 Datengrundlage und Publikationen der vorliegenden Dissertation 2.1 Datengrundlage 2.1.1 LEILA 75+ 2.1.2 AgeCoDe / AgeQualiDe 2.1.3 AgeMooDe 2.1.4 AgeDifferent.de 2.2 Überblick über die Publikationen der vorliegenden Dissertation 3 Loss experiences in old age and their impact on the social network and depression– results of the Leipzig Longitudinal Study of the Aged (LEILA 75+) 4 Are older men more vulnerable to depression than women after losing their spouse? Evidence from three German old-age cohorts (AgeDifferent.de platform) 5 The role of social isolation and the development of depression. A comparison of the widowed and married oldest old in Germany 6 Diskussion 6.1 Allgemeine Diskussion 6.2 Implikationen für die Praxis und die Versorgungsforschung 6.3 Fazit Zusammenfassung der Arbeit Literaturverzeichnis Anhang A: Darstellung des eigenen Beitrags Anhang B: Erklärung über die eigenständige Abfassung der Arbeit Anhang C: Lebenslauf Anhang D: Wissenschaftliche Beiträge Anhang E: Danksagung