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People with diabetes are at an increased risk of cardiovascular disease (CVD). Published data on risk of all-cause mortality, myocardial infarction (MI) and stroke in type 1 diabetes separately from risk in type 2 diabetes are scarce. Such data that do exist may be derived from studies limited to a specific geographical area with a high background risk of CVD. Cohorts and sample sizes are often small with limited data for the elderly or young. This thesis presents analyses of data taken from the General Practice Research Database (GPRD). This database provides longitudinal data from primary care representative of approximately 5% of the UK population in 1992. Cohorts of patients with type 1 (n 7,713) or type 2 (n 44,230) diabetes were identified and followed from baseline to 1999. Risk of all-cause mortality MI and stroke in type 1 diabetes and type 2 diabetes was compared with that risk in people without diabetes. Patients with type 1 diabetes were at three to four times the risk of death or CVD than their peers without diabetes. In people with type 2 diabetes the risks were generally twice those of people without diabetes. The relative risks stratified by age and sex in type 1 and type 2 diabetes revealed risk was highest in the younger age-groups, reduced with age and that the risk associated with having diabetes was greater for women than for men. Importantly, women with type 1 or type 2 diabetes in their late 50s or early 60s had a risk of CVD that was five times greater than that of women without diabetes. There was little difference between the relative risks associated with type 1 or type 2 diabetes. These data provide an important UK baseline against which the effectiveness of policies introduced after 1999 to reduce the relative risk associated with diabetes can be evaluated.

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This submission is a compilation of published work generated over a period of fifteen years on my research into the disease, multiple sclerosis. The first paper'is a historical work on the history of the first hundred years of the development of neurology in Belfast. Two distinguished predecessors were pioneers in the field. Studies of the epidemiology of multiple sclerosis have been performed, including analysis of sub-categories of the disease, in particular, benign and primary progressive multiple sclerosis. Studies on the genetic influences on susceptibility to the disease and genetic determinants of the course of the disease have been conducted. Current estimates of the life-time risk for developing multiple sclerosis for women in N. Ireland is 1:200. Two studies on patients in the community identified by their general practitioners have been carried out. These have been audits of the compliance with health monitoring by their general practitioners, and on needs assessments by patients livingin the community. A major component of the presentation is a series of studies of the immune response in multiple sclerosis patients, in the untreated state, early in the course of the disease. Particular interests have been in markers of activity if adhesion molecules and co-stimulatory molecules in the peripheral blood. Studies of adhesion molecule have also been per~ormed in cerebrospinal fluid obtained at diagnostic lumbar puncture, also the effects of treatment with corticosteroids and beta interferon on immune systems during the course of treatment.

The USSR came to an end in 1991, after almost 75 years ofexistence. Over the preceding • decade, it had become apparent that, in terms of health, the USSR had been a failure. Life expectancy was steadily declining, at a time when life expectancy in the west had been increasing rapidly. After the USSR broke apart, the decline in life expectancy accelerated rapidly. It continues to decline, except in the three Baltic republics that joined the European Union in 2004, where it is now improving. This thesis brings together a body ofwork that has sought to understand the low life expectancy in this region and the changes that have taken place since 1991. It begins by describing the evolving pattern ofmortality in this region, looking at changes over time. It continues by exploring how mortality is patterned by social factors, noting how those who are least advantaged have suffered most. The main part ofthe thesis examines some ofthe main risk factors: nutrition and physical activity; the environment; infectious disease; tobacco; and alcohol. The traditional Soviet diet is high in fat and low in micronutrients. The adoption ofhealthy diets is constrained by both prevalent beliefs about what a healthy diet is as well as high levels offood insecuri!y. Smoking rates among men are high and, unlike in the west, are not falling. Traditionally low rates among women are increasing rapidly in many countries, a change that has been accompanied by aggressive marketing by international tobacco companies. However alcohol emerges as the most important reason for the rapid decline in life expectancy in the 1990s, due largely to the pattern ofheavy episodic consumption, which drives deaths from injuries, cardiovascular disease, and alcohol poisoning. Finally, the legacy ofthe Soviet health system has prevented the delivery of health care that couId prevent many premature deaths.

BACKGROUND AND AIMS: Falls in old age can have serious consequences. The impact on health and social care is growing as the older population increases, but there are few data on falling amongst the “oldest old”. This study aimed to provide much needed information on this fastest growing section of the population: the epidemiology of falls and their consequences, the prevalence of potential risk factors and their predictive value in extreme old age. METHODS: This study added a special investigation of falling in advanced old age to the 2002–2003 interviews of 110 over-90-year-olds from the Cambridge City over-75s Cohort, a population-based longitudinal study of ageing. The survey (90 women, 20 men) comprised a standardised nurse-administered questionnaire with cognitive assessment, quantitative heel ultrasound scans and functional performance measures: Timed Unsupported Stand, Short Physical Performance Battery (standing balance tests, gait speed and chair rising),180° turn, functional reach and hand grip strength. Data collection also included a year’s prospective monitoring of falls using a combination of weekly calendars and telephone follow-up, with reports from participants themselves and proxy informants. KEY FINDINGS AND THEIR IMPLICATIONS: The study’s description of a representative population aged over 90 is valuable to service planners preparing for demographic change, revealing high levels of many fall risk factors. Detailed characterisation of functional status showed close agreement between reported disability levels and performance measures. This first population-based survey of skeletal fragility in the tenth decade found quantitative ultrasound measures markedly lower than in previous studies with younger old people. Skeletal fragility reflected weight-bearing functional test performance and reported current or past mobility. This first prospective study of falling amongst people aged over 90 in a representative population-based sample found falls are even more common than previously reported for very old people a decade younger: 60% fell at least once during follow-up, 45% more than once. Incidence was 277 falls/100 person-years. The extent to which falls in advanced old age lead to serious consequences – both immediate and longerterm – has not previously been reported. In one year’s follow-up 54% of fall reports described the participant as being found on the floor. 82% of falls occurred alone, 80% of those who fell were unable to get up after at least one fall, and 30% suffered long lies of an hour or more. Four out of five times when someone fell alone and could not get up they did not use available alarms to call help. More than half the falls reported to the study, and three in ten of the falls resulting in any injury, had not been reported to any health care professional. Findings also showed high levels of injuries (38% of falls but 68% of fallers) including fractures – one man and 1 in 8 of the women who fell. One in three people had at least one hospital admission, 2/3 of them at least partly due to falling, 2/3 of these directly prompted by a fall. Mean total length of stay of fallers was 6 times that of non-fallers. 1 in 7 of those not already living in long-term care had moved into homes within a year, 80% of these prompted at least in part by falling. Falls, adverse consequences and skeletal fragility shared a pattern of strong associations with several key risk factors, particularly impaired mobility and characteristics typical of frailty. Fracture risk factors were also associated with skeletal ultrasound measures. Functional tests added no predictive value to reported clinical risk factors. The implications of this research for policy and practice are fully discussed in relation to the current developing situation and future projections, setting these novel findings in the context of existing knowledge summarised in an extensive literature review.

This thesis aimed to investigate life coarse influences on cognitive ability and cerebrovascular disease (CVD) in older people. 110 community-dwelling subjects (70.0% female, mean age 78.2 (SD 1.4) years) born in Edinburgh hospitals between 1921 and 1926 had birth parameters (weight, length, placental weight) extracted from archives, underwent physical and neuropsychological tests, and imaging of brain volume, white matter lesions (WML) and diffusion tensor imaging (DTI). (1) Relationship between cognitive ability and structural brain indices. Cognitive ability (<i>g</i>) was associated with both whole brain volume (r = .24, P <.05) and intracranial area (r = .27, P <.01), suggesting the relationship between brain size and cognitive ability in old age is due to the persistence of this relationship from earlier life. (2) Relationships among early life factors (birth parameters, social class, the Apolipoprotein E (<i>APOE</i>) gene) and cognitive ability. There was an association between birth weight and cognitive ability in old age (Raven’s r = .20, P = .04; MMSE ρ = .23, P = .02), partly but not fully explained by this association in earlier life. Therefore, the prenatal environment may influence cognitive ability into old age. Social class correlated negatively with cognitive ability in childhood (ρ = .21, P = .02) but not later life (Raven’s ρ = -.09, P = .36): the influence of the shared environment decreases with time. <i>APOE</i>e4 was associated with worse performance on logical memory only. (3) Relationship among early life factors and CVD. Birth parameters, particularly placental weight, were associated with a history of CVD (t = -2.2, P = .04), WML load (ρ = -.23, P = .04), and DTI (<D> r ~ -.25, P = .03, FA frontal r = .36, P = .001), suggesting placental function may be important for the development and integrity of WM tracts. There was no association between either social class or <i>APOE</i>e4 and CVD.

This thesis uses causal diagrams to describe and quantify the associations between social conditions - such as wealth, education and occupation; proximal health risks - in particular indoor air pollution from solid fuel use; and acute lower respiratory infections (ALRI) among African children. The aim is to delineate different pathways that translate lower socio-economic status into poorer health outcomes. A conceptual causal diagram is used to organise a series of a priori hypotheses, which are operationalised and tested using Demographic and Health Survey data for Benin, Ethiopia, Kenya and Namibia and, for the solid fuel use pathway, a pooled set of World Health Survey data for sixteen African countries. In doing so, this thesis employs a variety of statistical techniques, including cluster analysis, logistic and ordered logistic regression, survival analysis and Bayesian multilevel and spatial modelling. The results suggest that solid fuel use across sub-Saharan Africa is particularly strongly structured by wealth, maternal education and, to a lesser extent, paternal education as partially independent determinants. Heterogeneity at community and district levels strongly influences fuel choice; in some countries this variation is spatially structured. With an adjusted hazard ratio of 2.35 (1.22; .4.52) cooking with solid fuels is confirmed as a major risk for ALRI mortality. However, socio-economic gradients in ALRI mortality are weak, and are not primarily mediated by smoke-producing cooking practices. Instead, across much of the social spectrum indoor air pollution appears to exert its effect on child health largely independently of p6~erty;~rlack of education. This thesis illustrates how the rigorous application of causal diagrams combined with standard statistical methods can characterise a complex web of interactions between distal and proximal causes of disease. The ALRI mortality risk associated with traditional fuel use points to a large potential for preventive interventions to reduce child. morbidity and mortality.

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