Background: Variation in birth size has been linked to increased risk of a number of disorders later in life, including cardiovascular and metabolic disorders. However, less is known about other parameters of birth size, beyond birth weight, on later health. Moreover, the impact of the biological markers of stress, i.e. glucocorticoids, on various parameters of birth size remains understudied as well as their impact on later metabolic outcomes. Aims and objectives: The aim of this study was to examine the influence of the HPA axis on birth size (birth weight, ponderal index, birth length, head circumference) and subsequent metabolic health in adolescence. The main predictor being exposure to glucocorticoids either administered clinically or inferred as a result of maternal social stress. The genetic environment interplay of birth weight lowering alleles near LEKR and CCNL1 and in ADCY5 was also examined. Methods: Data came from the Northern Finland Birth Cohort (NFBC1986), and the National Finnish Medical Birth Registry (MBR) 2006-2010. Glucocorticoid treatment (sGC) to mature foetal lung in threatened preterm birth, social stress measures, and birth outcomes were obtained from medical records and via maternal report (in NFBC1986) during pregnancy. Data on NFBC1986 children at 16 years included anthropometry, blood pressure, blood sample for DNA, and metabolic outcomes. Results: The systematic literature review showed a dearth of information on the association of sGC on birth size, with the larger studies reporting smaller birth size in infants exposed to sGC. The NFBC1986 cohort showed only 17% (n=58) preterm infants had received sGC due to threatened preterm birth, with an association with smaller birth length of -0.18cm(95%CI -0.26, -0.10), but a larger birth weight of 116g(95%CI 98.9, 133.1) and head circumference of 0.75cm(95%CI 0.7, 0.81). In contrast, in the MBR (5090 exposed subjects) sGC treatment was consistently associated with lower birth weight of -207g(95%CI -220, -195), birth length of -1.26cm(95%CI -1.31, -1.20), head circumference of -0.94cm(95%CI -0.98, -0.90), and ponderal index of -0.91 (95%CI-1.02, -0.81). Maternal social stress during pregnancy and risk allele near LEKR and CCNL1 each was associated with smaller birth size. The association with stress was magnified with lower birth weight of -118g(95%CI -156, -79), birth length of -0.30cm(95%CI -0.46, -0.14), head circumference of -0.23cm(-0.35, -0.11), and ponderal index of -0.47(95%CI -0.67, -0.26) in the presence of risk allele. No robust association was found between maternal social stress during pregnancy and metabolic syndrome at 16 years. There was an association with more adverse lipid profile in particular with apolipoprotein B/A ratio (1.92% increase, 95%CI 0.34, 3.52, by maternal exposure to social stress). Conclusion: Stress and exposure to sGC during pregnancy in addition to genetic risk are related to smaller birth size. In the NFBC1986 there was no evidence of longer term impact of in utero stress exposure on metabolic syndrome in adolescence, though there was a poorer lipid profile noted. To better understand the degree to which the HPA axis plays in foetal programming, maternal and foetal cortisol levels during pregnancy would be beneficial.

The primary aim of this thesis was to study the population structure and epidemiology of the fungal pathogen of amphibians, Batrachochytrium dendrobatidis (Bd). I have addressed these questions by collecting and isolating Bd from multiple infected host species. I have then extracted and sequenced whole nuclear and mitochondrial genomes for 50 isolates of Bd using the ABI SOLiD 3 and Illumina HiSeq 2000 platforms. The first aspect of the analysis was to tailor a new method for identifying variant sites amongst the isolates, as well as verifying the accuracy of the alignment and SNP-calling methods. Next, using a number of phylogenetic methods, I identified a population split into at least three deeply divergent lineages. Two of these lineages were found in multiple continents and are associated with known introductions by anthropogenic means. Isolates belonging to one clade, which we named the Global Panzootic Lineage (BdGPL), have emerged across at least five continents and are associated with the onset of epizootics in all five continents we tested. Dating the divergence between BdGPL isolates suggested a recent common ancestor in the 20th Century, and that the widespread trade of amphibians is an important mechanism of transmission. In contrast, BdGPL diverged from the other two lineages approximately 1000 years ago, clearly refuting a single emergence hypothesis. The two newly identified divergent lineages were the Cape lineage (BdCAPE) that appeared to have originated from the Cape Province in South Africa and a Swiss lineage (BdCH) comprised of a single isolate from a pond in Gamlikon, Switzerland. The secondary aim of this thesis was to identify and compare virulence determinants and other genomic features responsible for known differences in phenotypes. Using a variety of statistical and computational methods, I identified compelling evidence for genetic recombination targeting virulence factors, selection of those and other virulence factors, and rapid changes in ploidy and aneuploidy amongst the isolates of all three lineages. These genomic features shed light on the emergence, patterns of global spread, and modes of evolution in the pathogen(s) responsible for contemporary disease-driven losses in amphibian biodiversity. Finally, I discuss how these findings update our understanding of Bd and the importance for tracking and understanding the dynamics of other current emerging pathogens in an increasingly globalised habitat.

No description available.

Cases of a novel form of liver disease, localised to a cluster of villages in the Tigray region of Northern Ethiopia, were first reported in 2001. Up to January 2010, 591 cases were recorded, including 228 deaths. Symptoms include epigastric and abdominal swelling. Children are particularly susceptible, with some children having died within three months of the onset of symptoms, whereas some adults report living with the disease for many years. The pattern of spread suggested an environmental toxin was the causative agent, with investigations implicating the plant toxins, pyrrolizidine alkaloids. The ultimate aim of the research presented in this thesis was to determine the aetiology of the disease and a multi-disciplinary approach, involving clinical research, ethnography, biochemical and metabonomic analysis and toxicology, has been employed to achieve this. The disease was first characterised clinically: The disease presents with epigastric pain, initial bloody diarrhoea and progressive ascites with either hepatomegaly or splenomegaly or both. Histology of liver biopsy specimens revealed centrilobular necrosis in acute cases and bile ductular proliferation and fibrosis in chronic cases. Biochemical analysis identified γ-glutamyl transferase as a sensitive indicator of the disease. Ethnographic investigation of the lifestyle of the residents of the affected villages revealed a monotonous diet, the presence of a similar disease among livestock and suggested millet and animal products as potential sources of exposure to the aetiological agent(s). The pesticide DDT was identified as a further potential risk factor for the disease. A global metabonomic analysis of patient urine samples using 1H NMR spectroscopy was conducted and several metabolites associated with the disease were identified. Targeted LC-MS assays were then developed to detect pyrrolizidine alkaloid exposure among patients, either through detection of the parent alkaloid, acetyllycopsamine (AL), in urine samples or extraction and detection of pyrrolic metabolite adducts from whole blood. Relative AL urinary concentrations were found to be significantly higher among cases. AL was shown to be hepatotoxic in the mouse model, and at high doses induced centrilobular hepatic necrosis and metabolic changes similar to that observed in the human disease. Finally, DDT was detected at high levels in patient urine and serum samples. DDT was shown to substantially enhance the toxic effects of AL in the mouse model, through induction of the CYP3A11 enzyme, and in combination with AL induced liver pathology closely resembling the human disease. In conclusion, the available evidence suggests that the disease arises from co-exposure to DDT and pyrrolizidine alkaloids, including AL.

The work is focussed on the HIV epidemic among key populations in Latin America, a region that has received limited international attention due to the concentrated nature of its epidemic. It faces important challenges in prevention and risks missing the opportunity to control the epidemic. Despite the evidence available showing the disproportionate burden of infection among key populations, principally men who have sex with men (MSM) and to a lesser extent injecting drug users (IDU) and female sex workers (FSW), a small percentage of countries’ HIV prevention spending is allocated towards prevention interventions among these groups. In this thesis, we first estimate the distribution of new infections by type of exposure in the Dominican Republic, Mexico and Peru and find that MSM account for a large share of new infections in the three countries (over 50% in Mexico and Peru and 30% in Dominican Republic). This highlights that this population should be prioritised in prevention programmes. We then turn to interventions for MSM, and investigate whether pre-exposure prophylaxis (PrEP) to prevent HIV acquisition among MSM in Lima, Peru represents a cost-effective intervention at the population level. We find PrEP to be a potentially cost-effective intervention although unaffordable at a large scale. We conclude it should be considered as an additional tool within a combination prevention approach among this population. Following these, we seek to understand the dynamics, causes and consequences of risk behaviours and HIV infection in another key population that has rarely been prioritised by public health programmes: prison inmates. We use data from the largest prison in Peru and find that HIV prevalence is 4 times higher than national prevalence and inmates engage in riskier sexual behaviours than in the general population. Nevertheless, there are indications of risk behaviours and HIV prevalence reducing in recent years. To help direct prevention efforts in this setting, we characterise the risk profile of inmates who engaged in sex with FSW, other men and in unprotected sex with casual partners and identify inmates who have sex with men as being at heightened risk of infection (due to higher levels of drug use and unprotected sex). We use those data to develop a mathematical model that represents the HIV epidemic in the prison. Contrary to expectations, we find that incidence is likely to be less than 1% per year within the prison and that the dynamics of HIV in prisons are principally driven by inmates infected before their incarceration. We further estimate that since the beginning of the epidemic, at least 5% of HIV cases identified in Lima have passed through the prison, suggesting that the routine screening system in place at prisons could make a substantial contribution to controlling the HIV epidemic across the city. Finally, we formulate a conceptual framework of HIV risk among prison inmates in Latin America focussing on the social and underlying determinants of risk and develop a structured questionnaire to test the hypotheses proposed through the framework and obtain information relevant to the design of interventions within prisons and at the community level. Together this work draws on social and quantitative science to provide new insights into key populations in Latin America that should contribute to stronger and responsive HIV prevention programmes, to the benefit of all those that remain at risk of HIV in the region.

HIV has disproportionately affected southern Africa. This region, which comprises 2% of the worlds population, is home to an estimated 34% of all people living with HIV, 29% of new HIV infections globally in 2010, and 30% of AIDS-related deaths. A strengthened response to the epidemic by countries in southern Africa in recent years has brought life-prolonging antiretroviral therapy to the majority of those in need of treatment, and declines from peak levels of HIV incidence over the past decade are a reason for optimism. But, in 2010, 770,000 new HIV infections occurred. A better understanding of why the epidemic has spread so severely in this region is required to inform strategies to reduce and eventually eliminate new HIV infections. This thesis uses data analysis and mathematical modelling to understand the interaction between behavioural and biological factors that may have contributed to the spread of HIV in southern Africa, and the implications of these for controlling the epidemic. It focuses specifically on two topics of recent attention for public health decision makers in southern Africa: concurrent sexual partnerships and HIV treatment as prevention. Chapters explore the interaction between high HIV infectiousness during primary HIV infection and concurrent sexual partnerships, describe and evaluate a consensus indicator for concurrency, develop a method to adjust for high levels of missing data in sexual behaviour surveys and examine trends in sexual behaviours in a high HIV prevalence population in South Africa, create a mathematical model to examine the potential impact of antiretroviral therapy on HIV incidence in hyperendemic settings, and systematically compare the predictions of twelve different mathematical models of the impact of HIV treatment as prevention in South Africa. Taken together, through these topics we come to understand more broadly the complexity of the epidemiological context in which HIV spreads in southern Africa.

Exposure models need to be developed which can be applied at the continental scale, while still reflecting local variations in exposure conditions. Land use regression (LUR) has been widely adopted to describe the spatial variations in air pollutants over the longer term but not for short-term time-variable exposures. This study, therefore, aimed to develop and validate a space-time O3 model applicable to epidemiological studies investigating the health effects of short-term (e.g. daily) O3 exposures at the small-area scale. A geographical information system (GIS) was developed, incorporating data from 1211 O3 monitoring sites across Western Europe and a range of predictors, stored as 100m grids, including land cover, roads, topography and meteorology. The spatial model consisted of a LUR model representing the long-term average for years 2001-2007. The monitoring sites were classified, using multivariate statistical techniques, into 13 site types based on a set of descriptive indicators, then 13 temporal models represented by time functions were produced – one for each site type. These were linked to the spatial model using probability of group membership as a weighting factor. Finally, local meteorological data were incorporated to produce the full space-time model to predict daily concentrations for point locations. The spatial and temporal models were individually evaluated based on agreement with measurement data from a reserved subset of 20% of the monitoring sites. The performance of the spatial model was similar to other continental LUR models (R2=0.67; RMSE=7.64 μg/m3), while performance of the temporal models ranged from 0.3 to 0.5 (R2). Including local meteorological data into the full spatial-temporal model improved correlation with the concentrations measured at 30 monitoring sites in the Netherlands (R2= 0.42 without; R2=0.53 with meteorology). Modelling daily O3 over large areas at a fine spatial scale is possible using this approach. Overall model performance was further improved as the temporal period was aggregated to weekly or monthly. The model was applied to mothers in two birth cohorts in the European Study of Cohorts for Air Pollution Effects (ESCAPE) to provide daily O3 exposure estimates, which can be aggregated as needed to provide individualised exposures based on date of birth.

This thesis was funded as part of the Chronic Health Effects of Smoke and SO2 in the UK (CHESS-UK) project and was aimed at deriving modelled concentration surfaces of historic black smoke and sulphur dioxide in Great Britain for 1955 onwards as a basis for exposure assessment in epidemiological investigations of chronic health effects. The UK’s National Smoke and Sulphur Dioxide Survey provides monitored concentration data from 1955 - 2005 with over 3,000 sites in existence over time. These measured concentrations of black smoke and sulphur dioxide served as a core set of data for the modelling of exposures at 1km scale. Additional data sourced and developed for input into modelling included modelled emission maps (generated with AEA Technology), emission proxies (including land cover and road networks), information on environmental factors (topography and meteorology), population distribution and some ancillary data (e.g. smoke control areas and the Douglas Waller Index based on domestic coal sales). An important product of this work are the data, aimed at modelling historical exposures to air pollution, fully geo-referenced and integrated into a geographic information system. This GIS was used as a platform to test and compare different appropriate methodologies for modelling and mapping air pollution concentrations. Methods evaluated include: ordinary kriging, emission based modelling (dispersion and focalsum); and land use regression models developed using emission proxies. Focus was placed on modelling one target year for each decade (1962, 1971, 1981 and 1991). Modelling methods were piloted for 1971, where ordinary kriging and land use regression outperformed other methods. These were developed further across the full study period with 90% data for model development and 10% reserved for evaluation. The LUR models were ultimately selected as the best consistent approach over the long time period, with model R2s ranging from 0.7 in early years to 0.3 in later years.

Background: The prevalence of diabetes, chiefly type 2 (T2DM), is particularly high in the United Arab Emirates (UAE). Effective management of the disorder and its co-morbidities is needed; however quality of T2DM care is variable and suboptimal worldwide. In the UAE, few studies have been undertaken to systematically review the prevalence of T2DM and its risk factors and any changes in these trends overtime. Also, studies on the quality of T2DM care and factors influencing it are lacking. Aim: To examine the quality of care provided to people with T2DM in Abu Dhabi, particularly Al-Ain, and identify factors influencing it. Methods: This was a multi-method study involving systematic reviews, and quantitative and qualitative approaches. Quantitative data were collected from a random sample of medical records of people with T2DM to assess the quality of T2DM care and improvement overtime and investigate any differences in the care provided to different age groups and genders. The qualitative method includes semi-structured interviews with healthcare professionals to investigate factors affecting the quality of T2DM care. Results: Findings from the quantitative study demonstrated that the care provided to people with T2DM is sub-optimal for glycaemic and blood pressure control. Better glycaemic control was more common among people aged 40 and above. However, encouraging progress with regard to intermediate outcomes of diabetes control including glycaemic and lipid between 2008 and 2010 was found among both genders. Four main themes emerged from the thematic analysis including motivation of healthcare professionals, training of healthcare professionals, team work and Emirate cultural impact on diabetes care.Conclusion: This study has provided a picture of T2DM prevalence and risk factors for its adverse outcomes in the UAE. Findings from this study can help policy makers, managers and healthcare professionals to plan and execute better quality culturally-appropriate interventions to improve diabetes care, and reduce its burden. Strengthening the collaboration and joint planning between different health authorities in the UAE through the development of a national planning framework is highly recommended to reduce the burden of T2DM epidemic and improve the quality of its care. Also, reinforcing the role of the primary care in providing T2DM care, and strengthening the collaboration and co-ordination between the primary and secondary care settings in the UAE is required to optimize the care provided to people with T2DM.

Background and Aim: Studies of the epidemiology of respiratory syncytial virus (RSV) bronchiolitis to date have been small; focused only on the hospital setting and selective groups of high-risk infants such as those born preterm; lacked long-term follow-up and few have been based on data from the United Kingdom (UK). Hence, the existing evidence base was likely to underestimate the scale and impact of RSV on health in UK infants. The aim of this thesis was to provide better estimates of the wider clinical burden of RSV bronchiolitis among infants presenting across primary and secondary care settings in the UK. Methods: The clinical spectrum of bronchiolitis illness across different healthcare settings was examined using routine data from electronic health records to develop longitudinal, population-based cohorts with follow-up from birth through early childhood. Databases examined in this thesis included Hospital Episodes Statistics (HES), the General Practice Research Database (GPRD) and the National Neonatal Research Database (NNRD). Results: The estimated bronchiolitis admission rate in NHS hospitals in England was 24.2 admissions per 1000 infants aged less than 1 year (95% CI 23.7 to 24.8) with a median length of stay of 1 day (IQR 0 to 3 days) at a median age of 120 days (IQR 61 to 209 days). 15% of infants admitted with bronchiolitis were born preterm (47.3 per 1000 infants) and 24% had at least one known clinical risk factor for severe RSV infection. Cystic fibrosis, cerebral palsy and Down‟s syndrome also increase an infant‟s risk of bronchiolitis admission. The bronchiolitis consultation rate in UK general practice was 58.1 per 1000 infants (95% CI 56.5 to 59.8) at a mean age of 5.5 months (SD=3.2). Using a broader bronchiolitis case definition the estimated consultation rate was 206.7 per 1000 infants (95% CI 204.0 to 209.6). 36% of bronchiolitis consultations resulted in a prescription, of which 28% were for antibiotics and 27% for beta agonists, despite no evidence to support their use. Bronchiolitis in infancy is a predictor of subsequent hospital admissions and general practice consultations for asthma and wheezing in early childhood. Conclusions: The clinical burden of RSV bronchiolitis across healthcare settings in the UK is greater than previously estimated. Between 4% and 21% of infants have a bronchiolitis GP consultation in their first year. 2.4% of the national birth cohort are admitted to hospital with bronchiolitis in the first year of life, most of whom are born at term with no known clinical risk factors for severe RSV infection. This thesis has identified new groups of infants who may be at increased risk of severe RSV disease including those with cystic fibrosis, cerebral palsy and Down‟s syndrome. These findings highlight the need to prioritise development of new approaches for the prevention and treatment of RSV infection and have important implications for clinical training and management of bronchiolitis across healthcare settings.