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Antibiotic resistance (ABR) is a global problem impacting humans, animals, and environmental health, causing great economic loss and threatening food security. Whole genome sequencing (WGS) is a valuable tool when characterizing ABR bacteria from a one-health perspective, however, few studied have investigated evidence for direct sharing between one-health compartments. Studies by the OH-STAR project have used WGS to characterize Escherichia coli resistant to two critically important antibacterials (CIAs); third-generation cephalosporins (3GCs) and fluoroquinolones (FQs) from humans and cattle within a 50 x 50 km study area. Here we investigated 600 dogs in the same study region using WGS and phylogenetic analysis to characterize ABR E. coli in dogs and to identify evidence of sharing between dogs, humans and/or cattle. We also carried out risk factor analysis for excretion of CIA resistant E. coli in dogs. In addition, we characterized CIA resistant E. coli from zoo mammals in the study region. Faecal samples from 600 dogs and 167 samples from zoo mammals were processed to select ABR E. coli which were then subjected to WGS. We found evidence for sharing of CIA resistant E. coli between humans, cattle, and dogs in our study region, and identified "geographical associations", where dogs living in rural areas carried E. coli more similar to cattle than those living in urban areas. Risk factor analysis demonstrated a strong association between feeding raw meat and excretion of 3GC-R and FQ-R E. coli by dogs, confirming farm animal to dog transmission of these bacteria. We also found evidence for farm animal to human transmission of phylogroup A/B1 E. coli, accounting for 11% of human BSI within our study region in 2020, identified due to their carriage of farm animal specific ABR genes. Furthermore, we demonstrated the carriage of nitrofurantoin resistant E. coli by dogs, which may also be due to raw feeding, suggesting an unexpected farm animal reservoir for such E. coli. The zoo environment was a hotspot for evolution and circulation of CIA resistant E. coli, but there was no evidence of escape into the local community. These studies highlight the importance of ABR surveillance from a one-health perspective, which can be beneficial for the control of ABR bacterial prevalence.

Introduction: Cerebral small vessel disease (SVD) is increasingly recognised as a key factor in dementia and cognitive impairment, although its role in the pathogenesis of Alzheimer's disease (AD) remains poorly understood. Through the investigation of how SVD relates and interacts with (1) molecular AD pathologies and (2) early midlife risk factors of dementia, this body of work aims to advance our understanding of SVD in relation to AD. Methods: In two separate cohorts, SVD was quantified on 3T MRI through the assessment of white matter hyperintensities (WMH), enlarged perivascular spaces (EPVS), cerebral microbleeds (CMB), and lacunes. Regional data on SVD location was used to derive composite scores for global SVD burden, and the SVD subtypes of hypertensive arteriopathy and cerebral amyloid angiopathy. The first objective was investigated in the Neuroimaging of Inflammation in Memory and Other Disorders (NIMROD) study, which consisted of multimodal PET imaging of older adults with varying degrees of clinical severity. Here, we investigated whether SVD was associated and interacted with the hallmark AD pathologies of amyloid, tau, and neuroinflammation (microglial activation) - these were quantified with PET imaging of [11C]PiB, [18F]AV-1451, and [11C]PK11195, respectively. For insights into the pre-clinical stages of AD pathogenesis, we examined cognitively healthy midlife adults from the PREVENT-Dementia study. We investigated whether well-established risk factors of late-life dementia were related to SVD burden much earlier on, at midlife. Results: SVD was associated with PET markers of neuroinflammation and tau, and plasma Aβ. Notably, associations with amyloid and tau markers were largely limited to WMH. In healthy middle-aged adults, inherited predisposition to dementia (APOE4, parental family history of dementia) was related to longitudinal SVD progression, but not baseline SVD severity. On the other hand, modifiable risk factors of late-life dementia were associated with midlife SVD burden. The two SVD subtypes were differentially related to AD pathologies and risk factors - neuroinflammation and modifiable risk factors were more closely associated with hypertensive arteriopathy, while amyloid and tau related more closely to cerebral amyloid angiopathy. Conclusions: Together, our findings implicate SVD in the early pathogenesis of AD and suggest that lifestyle modifications as early as midlife may reduce the vascular-driven component of AD. Findings highlight the need to further inspect the biological underpinnings of WMH and fluid markers of AD pathology.

Objective: The paper aims to explore the factors that cause the software failure of on-board PISs in China's rail transit and to determine how these factors affect the software outcome to construct a mechanism of influencing factors on software failure based on which empirical improvement solutions can be recommended. Method: The study carries out mixed-method research by combining quantitative analysis and qualitative analysis. First the semi-structured interview contents are inductively processed with the aid of Nvivo to code the information and to identify the factors influencing software failure. The literature review and an industry expert questionnaire help to construct the influencing factor system, and then the DEMATEL method is used for quantitative analysis of the causal relationships between different factors. Finally, the questionnaire survey and structural equation analysis quantitatively define the action path of the factors that influence PIS software failure. Result: The factors that influence, and the mechanism of, PIS software failure are studied from the perspective of external market factors and internal organizational factors. The results show that an uncertain external environment, inadequate project management and insufficient software testing are the direct factors affecting the failure of PIS software; customer requirement defects indirectly affect the failure of PIS software through employees' negative characteristics, inadequate project management and insufficient software testing; and employees' negative characteristic affects the failure of PIS software through inadequate project management and insufficient software testing. Contributions: This research makes a threefold contribution. First, the study identifies the mechanism and action pathways that influence software failure. Second, this thesis puts forward a research model/framework based on the existing literature review and semi-structured interviews. Third, the process of the scale development, the design and selection of variables in the research also provide a good reference for future studies.

Background: Myopia prevalence is rising around the world at a rate that cannot be explained by genetics alone therefore, environmental risk factors must have an influence. Accurate measurements of refractive error and potential risk factors are required to better understand the relationship between environment and refractive development such that evidence-based advice can be provided to patients and parents by eye care professionals. This thesis was designed to investigate some potentially modifiable risk factors for myopia in young UK children. Methods: One hundred children (aged 6-9) participated in cross-sectional evaluation of previously proposed environmental risk factors for myopia. Spherical equivalent refraction (SER) and axial length (AL) were determined by cycloplegic autorefraction and ocular biometry. Potential risk factors for myopia were measured using Actiwatch 2 and Clouclip devices. Screen time, sleep, physical activity, and parental myopia data were collected using questionnaires. 42 children were followed up 12-months after baseline and change in SER and AL measures examined. Correlations were explored between change in SER and AL and baseline environmental exposure profiles. Results and Conclusions: The data demonstrated that: • Compared with children classed as non-myopic (≥+0.75 D), pre-myopes/myopes (< +0.75) go to bed later and fall asleep faster (increasing their sleep efficiency), are exposed to higher illumination during sleep, and have poorer subjective sleep quality. Over 12-months, higher sleep efficiency and less wake after sleep onset were associated with faster axial elongation, whereas less time spent in mesopic light was associated with faster myopic progression. • Compared with children classed as non-myopic, pre-myopes/myopes spent significantly more time undertaking moderate-vigorous physical activity later in the day, potentially disrupting circadian rhythms. • More myopic SER's were significantly associated with increased time spent viewing at near on weekday mornings and increased time spent on intermediate viewing was significantly related to greater myopic shift over 12-months.• Using a phone/tablet for 1-2 hours/day, watching TV/video games 1-3 hours/day and a higher duration of near work all increased the likelihood of children demonstrating accelerated eye growth over a 12-month period. • Parents wishing to mitigate against myopia-promoting eye growth should encourage; less near work, less time on phones/tablets or watching TV/video games, less bright light and less physical activity in the evenings, earlier bedtimes and sleeping in darkness.

Mathematical modelling and machine learning algorithms have been successfully applied to the healthcare domain and epidemiological chronic disease including diabetes mellitus, which is classified as an epidemic due to its high rates of prevalence around the world. Machine learning and statistical techniques are useful for the processes of description, prediction, and evaluation of various diseases, including diabetes. These techniques can be efficient tool in modelling diabetes and the most related risk factors. Although, Machine learning methods have been utilised in different aspects of diabetes research, but most of them were based on diagnosing or detecting the disease, and little research attention has explored the adoption of machine learning methods to study the trends in the prevalence of diabetes and forecast its future in specific populations. Thus, this thesis attempts to apply various machine learning and combination methods for studying diabetes and make future predictions. This thesis has investigated the application of machine learning and statistical techniques for developing prediction models for diabetes and the relevant risk factors (smoking, obesity, and physical inactivity) in the Kingdom of Saudi Arabia that can be used to support health policy planning and diabetes controlling. Regression, classification, and time series modelling approaches were used for diabetes modelling. Several models were developed namely, Multiple Linear Regression, Adaptive Neuro-Fuzzy Interference System ANFIS, Artificial Neural Network ANN, Support Vector Regression, Bayesian Linear Regression, Support Vector Machine, K-Nearest Neighbour KNN, Linear Discriminant, Neural Network Pattern Recognition, and Neural Network Time Series NARX-NN models. These models integrate historical data on diabetes, smoking, obesity, and inactivity prevalence to achieve its aim for examining the trends in prevalence of diabetes mellitus in the Kingdom of Saudi Arabia, to predict the future level of the disease. A combination of regression models is performed to improve the prediction accuracy using combination methods (Average, Weighted Average, Majority Voting, Weighted Majority, Minimum, and Maximum, and a new combination method consensus model). Several statistical evaluation metrics were applied to evaluate the performance of regression and time series models: mean squared error, root mean squared error, mean absolute percentage error, and the coefficient of determination R-squared. Classification models' accuracy performance was evaluated. Results from the regression and combined models were validated by comparison with some observed data from existing studies by the World Health Organization, International Diabetes Federation, and Family Health Survey from the Saudi General Authority for Statistics, revealing that improved accuracy was achieved with ANFIS model and the combined weighted average model in comparison to previous studies. The experimental results demonstrate the effectiveness of regression and combined models compared to classification and time series models. The ANFIS and WAVR models were found to be suitable for diabetes prediction due to their flexibility and high accuracy.

BACKGROUND: The effects of maternal exposure to adverse childhood experiences (ACEs) may be transmitted to the subsequent generation through various biopsychosocial mechanisms. Previous studies have found an association between maternal ACEs and poor infant outcomes (i.e., preterm birth and low birthweight). Further, evidence suggest that one intermediary mechanism is through a behavioural pathway, specifically, through the use of substances (i.e., tobacco, alcohol, illicit drugs) during pregnancy. This doctoral thesis aimed to explore the associations between maternal ACEs, prenatal substance use, and poor infant outcomes. METHODS: To address this overarching research question, a systematic review and meta-analysis was conducted. Additionally, various statistical analyses (i.e., multilevel logistic regression with marginal effects, mediation analyses, and latent class analyses) were performed using the Evidence for Better Lives Study (EBLS) dataset (n = 1189). Moreover, the research focus was expanded by exploring the interrelationships of maternal ACEs, a wide array of biopsychosocial and environmental risks during pregnancy, and the adverse infant outcomes of interest by conducting network analysis using the Avon Longitudinal Study of Parents and Children (ALSPAC) dataset (n = 8379). RESULTS: Results from the review and the multilevel models indicate a positive association between threshold ≥ 4 threshold ACEs and prenatal substance use but not with poor infant outcomes. Additionally, results from the mediation analyses found no evidence to suggest that prenatal substance use played a mediating role between the former and the latter. The marginal effects analyses identified childhood physical abuse and parental incarceration, respectively, as individual risks with the highest predictive probabilities for prenatal smoking. Domestic violence exposure and neglect were the individual risk factors for prenatal alcohol use, having a household member with mental illness was the individual risk factor with the highest predictive probability for prenatal illicit drug use and childhood sexual abuse in relation to adverse infant outcomes. The LCA identified three high-risk classes and one low-risk class, namely: (1) highly maltreated (7%), (2) emotionally and physically abused with domestic violence exposure (13%), (3), emotionally abused (40%), and (4) low household dysfunction and abuse (40%). Pairwise comparisons between classes indicate that class 1 and 3 had higher probabilities of prenatal illicit drug use compared to class 4. Additionally, class 2 had higher probability of low birthweight compared to the three remaining classes. Finally, results from the network analyses indicate that childhood and prenatal risk factors were highly interrelated. Childhood physical abuse, but not ≥ 4 threshold ACEs, was directly associated with low birthweight. In addition, childhood sexual abuse played a central role in bridging ACEs to other risks and to the outcomes of interest. Overall, prenatal smoking was determined as the most influential prenatal risk factor. This thesis has implications for research, policy, and practice. The results illuminated the dynamic and multifaceted nature of ACEs and their deleterious impact on maternal behavioural outcomes during pregnancy. Despite of this, it was also evident that greater specificity is warranted, by paying further attention to various parameters of risk exposure and risk and protective factors at different levels of the individual's social ecology in order to gather a more accurate representation of its impact on adult and infant health. Also, consensus is needed in research in how ACEs are constructed, measured, coded, and analysed before we can start teasing out similarities and differences across cultures. Smoking cessation during pregnancy should be a key target to improve lifelong health and promote healthy child development. Policymakers should consider investing in cessation services that are integrated in antenatal health services where trauma-informed principles are embedded in practice; where social, cultural, and organisational stigma are addressed; and the focus lie in enhancing support rather than directing blame.

Previous investigations into human infectious diseases have revealed RNA viruses as major etiological agents. Given the recent rate of newly detected human-infective RNA viruses such as severe acute respiratory syndrome coronavirus (SARS-CoV), SARS-CoV-2, Middle East respiratory syndrome coronavirus, and Bundibugyo ebolavirus, targeting virus discovery in high-risk regions, characterizing viruses with the greatest likelihood of spreading and establishing sustained infection in humans would benefit better preparedness for future outbreaks. There is a lack of evidence on determinants of spatio-temporal patterns in the discovery of human-infective RNA viruses, though previous studies have attempted to identify hotspots of emerging infectious diseases caused by various pathogens. There are also no quantitative studies exploring predictors of geographical extent and the disappearance for all currently known human-infective RNA viruses. This thesis aimed to address the following gaps. 1. Identifying predictors discriminating between areas with and without discovery of human-infective RNA viruses and predicting discovery hotspots, at both global and regional scales. Predictors identified include socio-economic, climatic, land use, and biodiversity variables. 2. Prediction of the geographical extent and the disappearance of human-infective RNA viruses, using features such as taxonomy, virus structure, transmission mode, host range, origin, and clinical presentation. 3. Taking SARS-CoV-2 as an example, investigating how predictors related to demographics, socioeconomics, travel, healthcare, co-morbidities, readiness, geography, COVID-19 testing, and interventions have affected the epidemic of the disease it caused-coronavirus disease 2019 (COVID-19)-between countries in the WHO African Region. In order to address the gaps outlined above, I firstly geocoded the first reports of 223 human-infective RNA viruses at the global scale. Using a Poisson boosted regression tree (BRT) model, I identified GDP growth, GDP, and urbanization as top predictors of virus discovery, and predicted discovery hotspots including both historical hotspots-eastern North America, Europe, central Africa, eastern Australia, and north-eastern South America, and new hotspots-East and Southeast Asia, India, and Central America. Stratified analyses suggested discovery of vector-borne viruses and strictly zoonotic viruses was more correlated with climatic variables and biodiversity, whereas the discovery of non-vector-borne viruses and human-transmissible viruses was more strongly correlated with GDP and urbanization. Next, I focused on comparisons of the specific predictors of RNA virus discovery in three different regions with different GDP-United States, China, and Africa. A similar methodology as the global analysis was used on each region separately, the results showed that predictors such as GDP and land use continued to be top predictors in three regions, but climate and biodiversity variables were consistently less important predictors than at a global scale. To identify predictors of the geographical extent and the disappearance (no record of infection in the literature for the past ten years or more), I collated information for 223 human-infective RNA viruses on their geographical extents and persistence in causing human infections from peer-reviewed literature. By fitting Bernoulli BRT models, I observed that viral features that predicted wide geographic extent included transmissibility between humans, a +ssRNA genome, narrow host range [i.e. infecting humans only or humans and other non-human primates (NHP) only], and having a reservoir host in a NHP. Viruses were more likely to disappear if they were incapable of transmission between humans, have had a localised geographic extent, a dsRNA genome, were non-pathogenic and non-fatal, were firstly discovered through active discovery programmes rather than passive investigation of the aetiology, and were transmitted by vectors and direct contact. Results for both geographical extent and virus disappearance did not change after factoring out reporting effort. I concluded that multiple characteristics determined the geographical extent and disappearance of human-infective RNA viruses; however, transmission mode and structure were consistently the most important predictors of the geographical extent and disappearance of human-infective RNA viruses. Host range was an important predictor of geographical extent, though less important for disappearance. Geographical extent, clinical presentation and discovery process all contributed to the probability of a virus disappearing. To understand the differences between epidemics of COVID-19 between countries of the WHO African Region, I selected the timing of the first case and the mortality rate in the first and second waves as the three outcomes. By applying a series of statistical models including Cox proportional hazards regression models, generalized linear mixed models and multinomial logistic regression models, I found that COVID-19 in Africa arrived earlier and caused greater mortality in countries with more pre-pandemic international connectivity and a more urban population. Mortality was exacerbated by high HIV prevalence. The stringency and timing of government restrictions on behaviour were not associated with a lower per capita mortality rate. A more urban population and a higher infectious disease resilience score were associated with more stringent restrictions and/or a higher per capita mortality rate. The predictor set for the first and second waves were similar, and first wave per capita mortality was a significant predictor of second wave per capita mortality. In summary, studies in this thesis showed that there were variations in predictors of discovery both between virus types and geographical regions, and identified high-risk regions for virus discovery beyond their historical extent. The studies also provided proof-of-principle for the prediction of attributes such as mortality, geographical extent, and disappearance for new human-infective RNA viruses. These results help identify priority regions for investment in surveillance systems for new human-infective viruses, and to make risk assessments once they have emerged.

Identification of cows at increased disease risk during the transition period is necessary to reduce the negative economic impact of disease and to improve animal welfare. Although timely identification of at-risk cows is a vital component of health management, it is challenging in modern dairy herds, where staff manage an increasing number of cattle. The consequent reduction in time available for individual animal observation has created a need for the development of decision support tools which facilitate individual cow monitoring. However, uncertainty exists as to which measurable traits best reflect cow health status, especially in the dry and transition periods where little monitoring of individual cows is performed. Therefore, the objectives of this project were 1) to quantify the effect of early lactation disease on productivity 2) to identify variables of routinely recorded herd data which could be used for disease prediction or as risk factors for disease and 3) to assess the feasibility of using such indicators in predictive disease modelling. Retrospective analyses were performed on 482 cow-lactations from the Langhill herd of Holstein cattle. Cow-lactations were assigned to 1 of 4 health groups based on disease incidence in the first 30 days of lactation. These groups were no clinical disease (NCD; n = 335, reproductive (REP; n = 77) (which included cases of retained placenta and metritis), subclinical mastitis (SCM; n = 53) (determined by somatic cell counts) and metabolic (MET; n = 17) (which included cases of displaced abomasum, ketosis, hypomagnesaemia and hypocalcaemia). The data were analysed using descriptive statistics, mixed models, and generalised linear mixed models, with a logit link, in SAS 9.3 and GenStat 16. There were significant differences in average milk yield between health groups throughout lactation. In the first 30 days of lactation, NCD cows had significantly higher (p<0.01) daily milk yield than either REP, SCM or MET cows. Days to first observed heat and first service were significantly higher in MET cows than all other groups (p<0.01) and was extended by 27 days compared to NCD cows. No difference existed between services per conception or calving interval across all groups however the 100 day in-calf rate was reduced amongst cows with disease compared to cows without disease. Preceding disease, milk yield at dry-off and the ratio of energy corrected milk to body energy content were found to be significantly different between health groups; both measures were significantly higher in SCM cows compared to REP and MET cows. Additionally, in the first 15 days of the dry period preceding disease diagnoses, REP cows had a significantly (p=0.02) greater rate of change in body energy content than NCD cows; -18.3±7.44 MJ per day vs. 0.6±5.11 MJ per day, respectively. Overall change in body energy content between dry off and calving was significantly greater (p<0.001) in REP cows than both NCD and SCM cows. The predictive ability of candidate indicators identified as being significantly different between health groups was assessed using further statistical analysis. The distribution of each candidate indicator was investigated before Pearson and Spearman correlation tests were used to quantify the relationships between indicators. Single candidate models, employing generalised linear mixed modelling with random effect for cow, were used to test the effect of each candidate indicator on each response measure (health group). Dry period length, change in live weight and body energy content across the dry period, condition score and body energy content at dry off and the rate of change in body energy content in the first 15 days of lactation were significant predictors (p<0.05) of reproductive disorders while the year of calving and live weight at calving were significant predictors (p<0.05) of subclinical mastitis when included in single candidate models. Multivariate models for each of the disease response measures (REP, SCM and MET) were developed using combinations of the candidate indicators as explanatory variables. Despite some highly significant relationships between the candidate indicator variables and response measures, the multivariate models developed do not currently have potential to predict risk of disease at an acceptable level of accuracy, as very few significant effects were found. This can be explained by the large individual cow variance components and a low incidence of disease in the current data set. Future research should focus on tracking candidate indicator data in individual cows with a view to establishing a baseline for each cow. This would allow each cow to be used as its own control, with deviations from the normal indicating potential disease challenge. This study has demonstrated that early lactation disease has both short- and long-term effects on productivity. Further, routine measures of herd data including body weight and body condition score, recorded in the dry period have been shown to be significantly different between cows of different disease status in the subsequent lactation. This study has shown that disease in early lactation has serious consequences for the productivity of dairy cattle and has shown the potential for predicting the risk of disease in the transition period in dairy cows. However, further work is needed with larger datasets and in different herds to develop greater accuracy in prediction.

Both depression and cardiovascular disease (CVD) affect millions of people worldwide and account for considerable mortality. In adults, comorbidity between these conditions is common, suggesting that shared pathophysiological mechanisms, such as systemic inflammation, may be involved. However, the direction of association between depression and CVD risk in young people remains unclear. Gaps also remain in our understanding of the role of different immune components in these relationships across the lifespan. The purpose of this thesis was two-fold. First, to investigate the association between CVD risk (as defined by systolic blood pressure, total cholesterol, low-density lipoprotein, high-density lipoprotein, high body mass index, and smoking status) and depressive symptoms in young people. Second, to test the convergence of evidence for systemic inflammation as a shared mechanism for depression and CVD across the lifespan. I conducted a systematic review and meta-analysis of longitudinal studies of CVD risk factors and subsequent depressive symptoms in young people. Then I used data from two contrasting observational studies: the Avon Longitudinal Study of Parents and Children (ALSPAC) and the United Kingdom (UK) Biobank to study associations between inflammation, depression, and CVD risk in different age groups. ALSPAC is a prospective birth cohort of 15,000 individuals born in and around Bristol in 1990/91. In contrast, UK Biobank is a long-term UK-based study of over 500,000 individuals aged 40 years old and over. I used several measures of systemic inflammation including interleukin-6 (IL-6), C-reactive protein (CRP), white blood cell count (WCC), and number of childhood infections. Through the systematic review and meta-analysis, I highlighted that obesity and cigarette smoking are strongly associated with depressive symptoms in individuals up to age 24 years. Few longitudinal studies of young people have considered the effect of other CVD risk factors such as systolic blood pressure, total cholesterol, low-density lipoprotein, or high-density lipoprotein. I followed PRISMA guidelines when reporting these findings. Using ALSPAC data, I revealed that CVD risk is associated with subsequent depressive symptoms but not the other way around. Obesity and cigarette smoking in particular appear to drive this association. These findings suggest that targeting smoking and obesity in young people may be important for the prevention of both depression and CVD in adults. I also used ALSPAC to study the effects of inflammatory markers on health outcomes in young people. Specifically, I investigated the associations of childhood infections, IL-6, and CRP with depressive symptoms and psychotic experiences. I showed that a higher burden of common childhood infections is associated with depressive symptoms and psychotic experiences in early and mid-adolescence. In contrast, I discovered that childhood IL-6 and CRP were more strongly associated with subsequent CVD risk than depressive symptoms. CVD risk in adolescence appeared to mediate the relationship between childhood IL-6 or CRP and depressive symptoms in late-adolescence. These results suggest that markers of systemic inflammation in early life have differing associations with depression and CVD risk in young people. I used the UK Biobank to investigate the potential effects of inflammatory markers on comorbid and monomorbid depression and CVD outcomes in middle-aged and older adults. I used both CRP concentration and WCC as exposures. I discovered that CRP and WCC are both associated with depression and ischaemic heart disease (IHD), as well as comorbid depression and IHD. I also showed evidence of specific association between WCC and IHD. These findings suggest that systemic inflammation is likely to be a shared mechanism for depression and IHD, but the risk of each outcome may be underpinned by distinct inflammatory pathways. Taken together, these results indicate that the bidirectional association between CVD and depression is not present until adulthood. While the association between systemic inflammation and depression/CVD appears to be robust, pathophysiological mechanisms for depression and CVD may differ across the lifespan.

Background: Mental health services have undergone a paradigm shift in recognition of the widespread and long-lasting impact of trauma; changing the central question from "what is wrong with you?" to "what happened to you?" Though it has been shown that forensic mental health populations have high levels of trauma, it is a relatively under-researched population in comparison with other groups. This thesis portfolio therefore sought to add to the knowledge base considering forensic mental health populations experiences of trauma. This thesis portfolio consists of two chapters. The first is a systematic review of research exploring the association between childhood abuse and adult psychopathology in forensic psychiatric inpatients. The second presents an empirical project which aimed to explore incidents of victimization experienced by individuals whilst detained within a high secure forensic hospital, and identify potential risk factors for victimization within this environment based on existing victimization literature. Methods: The systematic review involved a comprehensive search of online databases of published research, to identify relevant papers against predefined inclusion criteria. The resulting 13 included papers were assessed for using two quality assessment tools, and their relevant findings extracted and synthesised. The empirical project consisted of a retrospective examination of a 5-year period, including all patients (n=278), and all incidents of peer-victimization recorded within this period. The victimized and non-victimized sub-samples were compared on demographic and clinical characteristics. Each individual's history of childhood abuse, and current mental health diagnoses were extracted from their case files, and analysed to explore any association with victimization as an inpatient. Results: The systematic review found that the included studies were as generally acceptable quality, though some methodological weaknesses were identified. Prevalence of childhood abuse was found to be above that of the general population. Evidence was found of an association between childhood abuse and a range of mental health disorders; namely PTSD, personality disorders, psychopathy, suicidality and self-harming, and global psychological distress. The empirical project found that total days spent in the hospital by the end of the study period was associated with being victimized, as were diagnoses of a psychotic disorder, schizoaffective disorder, personality disorder, and intellectual impairment. Only days within the study and a diagnosis of intellectual impairment were found to be significantly associated with the number of victimizations experienced. The prevalence of PTSD within the sample was lower than expected, highlighting an ongoing under-recognition of trauma in this setting. Discussion: Both the systematic review and the empirical project highlight that this population is victimized at high levels in their childhood, and through into forensic inpatient care. Both chapters agree that screening for childhood abuse is essential within the forensic mental health population, and the empirical project highlights the need to recognise and respond to forensic inpatients as victims in the present. Those with an intellectual impairment were found to have an increased risk of victimization; this should be recognised and integrated into care planning. Limitations of both the review and empirical project are acknowledged, and recommendations for future research are provided.

This thesis aimed to review abuse across the lifespan of an individual, from childhood to older age and how frailty may be both a consequence and a predictor of abuse. The thesis is split into two chapters. The first chapter is a systematic literature review assessing whether frailty is associated with an increased incidence of elder abuse and neglect (EAN). The review included nine studies which provide evidence that frailty may lead to an increased incidence of elder abuse and neglect. Furthermore, it reviews other factors and perpetrator characteristics that may also lead to elder abuse and neglect. Recommendations comprise using longitudinal studies to establish internationally recognised definitions and measures for both frailty and EAN, and the development of evidence-based interventions for people who are older. The second chapter is an empirical study exploring the potential link between adverse childhood experiences (ACEs) and an increased level of frailty in people who are older. A cross-sectional questionnaire design was completed in an NHS setting. Correlation and multiple hierarchical regression analyses were performed. Although there was no association reported between ACEs and frailty, both an increased number of social connections and a positive perception of self were negatively correlated with frailty. Recommendations suggest creation of preventative measures for frailty that incorporate both physical and social interventions, within the context of recent social distancing measures imposed by COVID-19.

Objective. The relationship between crime and mental disorders has long been a topic of debate. While in public perception these two phenomena are often seen as inextricably linked, research has painted a more complex picture, with only little consensus about the precise nature of the association. The aim of this thesis is to further unravel the interrelations between offending and mental disorders and to contribute to a more comprehensive understanding of their association over the life-course. Methods. First, a broader view is adopted as a strategy to assess the current understanding of the relationship. Then, a more specific stance is taken within the theoretical framework of developmental and life-course criminology in order (1) to link research into offending pathways with the study of longitudinal effects and intergenerational transmission of mental health problems and (2) to investigate the link between family socio-psychological factors, violence, and personality disorders over the life-course by using different quantitative methods and drawing on data from the Cambridge Study in Delinquent Development. Results. Having drawn attention to the importance of studying different offending pathways in the development of mental health problems, the considerable heterogeneity of mental disorder symptoms, and the role of early-life family context, findings demonstrate (1) that those with more severe offending pathways have an overall greater vulnerability to developing internalising problems in middle adulthood, (2) that certain personality disorder symptoms, specifically cluster A and cluster B disorders, are associated with lifetime violent behaviour, and (3) that early life paternal offending is associated with adult children's internalising and externalising problems. Conclusions. It is suggested that early-life interventions targeting families as part of their work can play an important role in preventing the development of both later-life internalising and externalising problems. Further, results highlight the importance of recognising the heterogeneity of people with internalising and externalising problems in order to offer responses that are effectively tailored to an individual's needs. Finally, the thesis supports further efforts to improve mental health awareness and knowledge to reduce stigma.

Each year 100,000's of people are booked into police custody, where they can be detained without charge for up to 24 hours. Whilst in custody, the police have a duty of care and statutory obligation to ensure their safe detention. To aid them in this, national guidance provides a set of core questions around health and wellbeing that the Custody Officer should ask the detainee as part of the booking-in process, as well as recording their own observations. Part of then managing the identified risk is to place the detainee on a particular observation level which relates to how often the detainee is visited in cell. Although some research has been conducted into whether this assessment identifies risk effectively, there has been little research into how Custody Officers then analyse and evaluate the identified risk in order to apply the most appropriate observation level. Using a mixed methods approach, this thesis investigates this initial risk assessment of detainees to better understand the Custody Officer's decision-making process. Three studies have been conducted to examine the robustness of the current process and enhance understanding around influences and significant factors that affect the analysis and evaluation of risk. The first study examines the risk assessment process as set out in national guidance, investigating the extent to which the content varies between police forces. Information from each force was collated and combined with police custody inspection reports, produced from visits conducted by HM Inspectorate of Constabulary and Fire and Rescue Services, to provide an overview of the process. The findings from this study demonstrate that the risk assessment of detainees is not consistent across police forces in England and Wales. Not only does the content differ from the national guidance, but the content and delivery differ considerably between police forces. This highlights a practical problem for police forces in ensuring that this risk assessment process is conducted to a consistent standard and ensuring the robustness of decision-making. The research then focuses on how risk is assessed and evaluated at two police forces within England using a novel approach to the research of policing practices by incorporating quantitative and qualitative research methods. In Study 2, custody record data has been statistically modelled to identify the risk factors that have the greatest influence on observation level using logistic regression, decision trees and discriminant analysis. This robust approach enables the results from these multivariate methods to be compared to determine if a core set of influencing variables can be identified. The findings from this analysis suggests that, quantitatively, there are key driving variables that Custody Officers consider in PAGE ii their decision-making around risk and observation level such as self-harm, alcohol use/intoxication, physical injuries, the demeanour and compliance of the detainee and if the detainee needs to see a healthcare practitioner. However, these variables did not account for all the variation in observation level. This study also provided new and previously untested knowledge to suggest that known risks related to deaths in custody are significant in the decision-making process around observation level. A qualitative approach was used in Study 3 with observations of the process and interviews with Custody Officers conducted to identify influencing factors on their judgment and decision-making that could not be identified quantitively. Thematic analysis was used to analyse and group the information which identified a number of previously unrecorded factors and influences. These ranged from the busyness of the suite and staffing capacity to the Custody Officer's risk appetite and gut instinct. These factors were considered against a risk assessment framework providing novel insight as to how they influence the identification, analysis and evaluation of risk and provide an in-depth understanding of how Custody Officer's risk assess detainees and the influences on their subjective decision-making. The findings from these three studies have then been triangulated to provide an enhanced understanding of the process and a greater knowledge of the subjectivity that is involved in the risk assessment of detainees. The thesis found that although there are key risk factors which are taken into consideration, the lack of decision-making framework specific to assessing risk of harm to detainees leads to subjective decision-making based on a number of non-tangible factors, especially gut instinct. Using a potential model of a fast and frugal tree, a number of recommendations are provided to explore further how a decision-making framework can be developed that would incorporate the most significant risk factors as well as the judgement of the Custody Officer.

Introduction: Colorectal cancer (CRC) is the third most common cancer by incidence and second by mortality worldwide in 2018. Variation in individual genetic susceptibility and environmental exposures both contribute to the aetiology of CRC. Gene-environment (G×E) interaction, which is known as the interplay of genetic variants and environmental exposures, should also contribute to the aetiology of CRC. Although genome-wide association studies (GWAS) have identified a number of common genetic variants associated with CRC susceptibility, the role of G×E interactions involving these GWAS-identified common genetic variants underlying CRC susceptibility remains unclear. Consequently, investigation of G×E interactions between known CRC-associated SNPs and established environmental risk factors for CRC should be of value to inform the development of CRC disease prevention strategies and risk assessment strategies. Vitamin D deficiency is highly prevalent worldwide, especially in populations living at high latitude areas or in individuals leading indoor-oriented lifestyles. Vitamin D deficiency has been implicated as a possible risk factor in the aetiology of several diseases of public health importance, including cancer. There is available evidence from observational studies suggesting inverse associations between vitamin D levels and CRC risk. However, these associations could be biased by reverse causality or confounding factors. Although several randomized controlled trials of vitamin D and CRC have so far been conducted, findings from these studies are inadequate to resolve the question definitively. In addition, genetic variants that modify the association between vitamin D status and CRC risk have not yet been completely identified. Taken together, a causal relationship between vitamin D status and CRC risk remains to be conclusively established, and investigation of genetic modifiers of CRC risk associated with vitamin D should provide clues to both personalized medicine and public health. Aims and objectives: The main aims of this thesis were: 1) to provide an overview on associations between G×E interaction and CRC risk by performing an umbrella review of existing literature; 2) to examine the presence of G×E interactions between published CRC-associated SNPs and established environmental risk factors for CRC by using study samples from population-based studies and 3) to identify genetic modifiers of CRC risk associated with circulating vitamin D by searching for gene-vitamin D interactions at a genome-wide scale. Methods: First, an umbrella review was performed to provide an overview on associations between G×E interactions and CRC risk. This umbrella review collected and evaluated cumulative evidence across existing systematic reviews, meta-analyses of observational studies and genome-wide G×E analyses that have investigated G×E interactions in CRC risk. This umbrella review also identified associations with robust evidence by assessing the cumulative evidence for the G×E interactions using an extension of the Human Genome Epidemiology Network's (HuGENet's) Venice criteria. Next, I searched for interaction effects between well-established environmental CRC risk factors and 100 published common genetic variants exerting main effects on CRC risk by using study samples from the UK Biobank cohort and the Study of Colorectal Cancer in Scotland (SOCCS). The 100 independent CRC-associated single-nucleotide polymorphisms (SNPs) [linkage disequilibrium (LD) r2 < 0.2] were detected in two published GWAS studies. The environmental CRC risk factors [standing height, body mass index (BMI), smoking, alcohol intake, physical activity, nonsteroidal anti-inflammatory drug (aspirin and others) use, hormonal replacement therapy (HRT) use, and dietary intakes of fruit, vegetables, red meat, processed meat, fibre, calcium and vitamin D] were selected according to the World Cancer Research Fund International (WCRF)/American Institute for Cancer Research (AICR) 2017 Continuous Update Project (CUP) Colorectal Cancer Report. To test for the interactions, I applied a two-phase approach: i) a discovery phase (2,652 incident CRC cases and 10,608 controls from the UK Biobank cohort) and ii) a validation phase (1,656 cases and 2,497 controls from the SOCCS study). Interactions with nominal p<0.05 in the discovery phase were taken forward for validation. Case-control logistic regression models were used to test for multiplicative interactions in both phases. A method based on False Discovery Rate (FDR) controlling procedures was applied to account for multiple testing in the validation phase. Fixed-effect meta-analysis methods were applied to combine results from both phases. Stratified analyses were performed for G×E interactions identified from the analysis in order to estimate combined associations in strata defined by both the SNP and the environmental risk factor. Lastly, I searched for G×E interactions between genetic variants and circulating vitamin D for CRC risk at a genome-wide scale. To test for the interactions, I applied a two-step approach: i) a case-only screening step (3,139 CRC cases from the Scottish case-control CRC series) and ii) a case-control validation step (2,652 incident CRC cases and 10,608 control individuals from the UK Biobank cohort). Circulating 25-hydroxyvitamin D (25-OHD) was used as a measure of vitamin D status in the analysis. SNPs of a minor allele frequency (MAF) <0.05 or a low imputation score (r2 <0.8) were excluded, leaving 6,420,434 SNPs for the analysis in the screening step. For the examination of associations between 25-OHD and the SNPs in the case-only screening step, I fitted conventional logistic regression models by treating each SNP genotype/dosage as the independent variable and the 25-OHD concentration as the dependent variable while simultaneously adjusting for age and gender. Season-standardised values of 25-OHD concentrations were used in the analyses in order to account for the effect of different seasons when blood samples were taken. Associations that were found with nominal p<0.0001 in the screening step were taken forward for validation. For the examination of interactions in the case-control validation step, I fitted each conventional logistic regression model by treating CRC status as the dependent variable, and both 25-OHD concentration (5 nmol/L) and the genotype/dosage of each SNP as the independent variables while simultaneously including a G×E interaction term. The FDR correction method was used to adjust for multiple testing in the validation step. Results: The umbrella review comprised of 15 articles reporting systematic reviews of observational studies on 89 G×E interactions, eight articles reporting 33 genome-wide interaction analyses, and 20 articles reporting meta-analyses of candidate gene-based studies on 521 G×E interactions. After evaluating the strength of the evidence, no interaction was observed to have highly convincing evidence. Only the interaction between aspirin use and rs6983267 (8q24) was observed to have a moderate overall credibility score and a main genetic effect (p=7.45×10-13). In addition, five other interactions were observed to have moderate strength of evidence; however, the interaction effects were considered to be tenuous due to the lack of main environmental and/or genetic effects. The analysis, examining the presence of G×E interactions between the 100 published independent CRC-associated SNPs and the well-established environmental risk factors for CRC, identified 73 nominally significant G×E interactions in the discovery phase. After testing these 73 interactions in the validation phase, none of the interactions reached statistical significance after adjustment of multiple testing. Two interactions were found to be nominally significant: the interactions between rs11903757 (2q32.3/NABP1) and BMI (nominal p=0.02), and rs2735940 (5p15.33/TERT) and smoking status (nominal p=0.04). In particular, the rs11903757*BMI interaction was found with the same direction of effects. After performing fixed-effect meta-analyses, the rs11903757*BMI interaction was found to be statistically significant (ORinteraction = 1.26; 95% CI, 1.10 to 1.44; p-value for interaction: 6.03×10-4; p-value for heterogeneity: 0.63). When stratified by genotypes of rs11903757, above median BMI significantly increased CRC risk in individuals with TC genotype (OR=1.27; 95% CI, 1.07 to 1.50; p=5.69×10-3) in the UK Biobank dataset. The effect of BMI on CRC risk stratified by genotypes of rs11903757 was also limited to men in the UK Biobank dataset. In the genome-wide search of G×E interaction with circulating vitamin D for CRC risk, associations between 25-OHD and 606 SNPs showed nominal p < 0.0001 in the screening step and should to be taken forward for validation. In particular, three SNPs (rs1193692, rs962638 and rs496388) at chromosome 11 (11q13.4 and 15p14) were observed to be involved in genome-wide significant associations with 25-OHD (nominal p < 5×10-8). Of the 606 SNPs that needed to be tested in the validation step, 490 SNPs were genotyped or imputed in UK Biobank and were successfully validated among the UK Biobank study samples.

Liver cancer is one of the leading causes of deaths in many countries around the world therefore identifying new risk factors for liver cancer is a priority. The aim of this thesis was to investigate new risk factors for liver cancer and add new insights to previously identified liver cancer risk factors. Excessive iron levels due to hemochromatosis have been shown to increase liver cancer risk. However, the association between elevated iron levels and liver cancer risk in people not predisposed to hemochromatosis has not been well studied. We conducted a systematic review and meta-analysis to synthesize evidence from previous cohort and nested-case control studies. We found some evidence of an increased risk of primary liver cancer with high iron levels as measured by serum ferritin or serum iron. Proton pump inhibitors and histamine-2 receptor antagonists are commonly used. Proton pump inhibitors have been shown to promote liver cancer in rats; however, only one study has examined the association in humans. We conducted the first study on the use of proton pump inhibitors and histamine-2 receptor antagonist in relation to liver cancer risk. We conducted a nested case-control study using Primary Care Clinical Informatics Unit (PCCIU) and a cohort study using UK Biobank. We found an increased risk of liver cancer, especially of intrahepatic bile duct carcinoma in proton pump inhibitors users but not in histamine-2 receptor antagonists users. This novel association requires further research to determine whether it is causal or reflects confounding. Using these study designs in PCCIU and UK Biobank, we also explored the relationship between statin use and liver cancer risk. We found a consistent decreased risk of liver cancer in statin users, specifically for hepatocellular carcinoma, even after adjusting for high cholesterol and chronic liver disease. Previous studies have shown an inverse association between coffee consumption and liver cancer, but have not investigated coffee by type. We examined the role of different types of coffee on liver cancer risk using the UK Biobank. Findings showed that any type of coffee (caffeinated, decaffeinated, or instant coffee) was similarly associated with a reduced risk of liver cancer, specifically for hepatocellular carcinoma. Future studies should further investigate which components of coffee may have anti-carcinogenetic properties. Another cohort study based on China Kadoorie Biobank investigated the relationship between household air pollution, from cooking and heating, and the risk of liver cancer mortality. We found use of coal and smoke in the household were associated with an increased risk of liver cancer mortality. Consistent reports of a lower risk of liver cancer in women compared to men suggest female sex hormones may be protective. We conducted a cohort study in the China Kadoorie Biobank exploring a range of reproductive factors in relation to liver cancer mortality. Among reproductive factors, only menopausal status was found to increase the risk of liver cancer mortality. We also investigated circulating sex hormones and liver cancer risk in men and women from UK Biobank cohort. Our findings showed that men who had higher levels of testosterone and SHBG had higher risk of liver cancer, specifically of HCC, but this association was not found in women. In summary, the current thesis has contributed to the literature by identifying new risk factors for liver cancer and clarifying previously identified associations. Future studies are required to replicate the novel associations observed in this thesis.

Introduction: The older adult population is rapidly increasing, and overweight and obesity prevalence is fast rising in older people globally. It is unclear whether excess body weight in older age reduces or increases the risk of incident dementia and whether it prolongs survival. Evidence of the risk factors for overweight and obesity in older age is scarce. This thesis investigated the risk factors and health effects of overweight and obesity in older age, with a focus on their impacts on incident dementia and all-cause mortality. Methodology: This study employed a mixed method of quantitative and qualitative approaches that are based on a large cohort study dataset from China and two focus group discussions from the United Kingdom. The cohort consisted of 3,336 participants in total: 1,736 aged >= 65 years recruited from urban areas in 2001 and 1,600 aged>=60 years from rural areas in 2003 in Anhui province, China. In the standard methods of interview, they were documented for sociodemographic, lifestyle, social network, disease, and other risk factors at the baseline survey. Body Mass Index (BMI) and waist circumference (WC) were measured, and dementia was diagnosed by the GMS-AGECAT for each of the participants. The cohort members were followed up for 10 years to monitor mortality and examine the cause of death. There were three waves of interview for surviving cohort members during the follow up to document incident dementia apart from the causes of mortality. The data of the Anhui cohort study were analysed in multivariate Logistic and Cox regression models. Two focus groups research were conducted in Wolverhampton UK. It included 12 twelve older adults who were recruited from the community through their place of worship. The focus group data were collected in a digital audiotape. They were transcribed verbatim and analysed thematically. Findings: The data from the cohort wave three surveys showed that the risk factors for overweight and obesity in older people included female gender, low education, low income, residing in urban areas, being married, watching TV/reading newspapers, and hypertension at baseline. Over the 10-year follow-up, 271 participants were diagnosed as having incident dementia. The continuous BMI at baseline increased the risk of incident dementia (multivariate-adjusted odds ratio (OR) 1.06, 95%CI 1.00-1.11). There was no significant increase in OR in participants who were overweight (1.34, 0.91-1.98) and obese (1.52, 0.86-2.70) when compared to normal weight, but separate data by gender showed that dementia risk was significantly increased in men with overweight (3.09, 1.65-5.77) and obesity (4.19, 1.75-10.03) and not in women (0.74, 0.43-1.27; 0.72, 0.32-1.64). The prediction was similar regardless of different adiposity measures used; the risk of dementia was elevated in non-smokers with obesity measured by BMI (4.28, 1.46-12.53) and in non-smokers with waist circumference classed as action level two (3.19, 1.04-9.77). The Anhui cohort data did not show significantly reduced mortality in older people with overweight (HR 0.78, 95%CI 0.56-1.08) and obese BMI (0.79, 0.47-1.33) when compared to normal BMI. There were no gender differences. But the risk of all-cause mortality was significantly increased in older people with underweight (2.04, 1.25-3.33), and the sex-stratified data analysis showed a stronger effect in men (2.31, 1.21-4.42) and not in women (1.59, 0.73-3.44). The focus group data also supported such findings of deleterious effects of overweight and obesity by major themes including theme-harm, impairment, and mortality. Conclusions: Overweight and obesity in older age increased the risk of incident dementia. They were not significantly associated with reduced risk of mortality although underweight increased the risk. Curtailing overweight and obesity and maintaining normal weight in older age could help reduce the risk of developing dementia and extend survival.

Intimate partner violence and abuse (IPVA) is a global phenomenon that impacts individuals, families and societies in a myriad of ways. Since the work of feminist activists in the 1970s bought this subject to the forefront of public and policy debate, IPVA has largely been regarded as a set of behaviours perpetrated by men against women. There has recently been growing interest in examining less traditional narratives of the topic and one such area is that of women who perpetrate IPVA. In England and Wales, there has been an increase in the number of women convicted of IPVA-related offences and more women than ever are therefore entering criminal justice settings related to this crime. When men are convicted of IPVA-related offences, typically, they can access interventions specifically designed to address these behaviours. However, there are no equivalent programmes for women. It is unclear whether women who perpetrate IPVA have the same treatment needs as male perpetrators and what interventions would benefit them. The first aim of this thesis was to identify the state of knowledge regarding the risk factors for women who perpetrate IPVA and are situated in criminal justice settings. A systematic review revealed a paucity of research conducted in the UK and identified that although some factors are associated with IPVA perpetration (experiencing child abuse, experiencing trauma, substance use, borderline personality traits and attachment issues), methodological shortcomings of the studies reviewed meant it was impossible to say if these were causal risk factors. The second aim of the thesis was to critically examine the dominant theories of IPVA perpetration in relation to both male- and female-perpetrated IPVA in order to uncover any substantive theory of female IPVA perpetration. Although the review found that no single theory could adequately explain female-perpetrated IPVA, two had potential explanatory power (Background Situational model and Contextual Framework). The findings from the reviews informed the third aim of the thesis – to explore the pathways to IPVA perpetration in both women and men through primary qualitative research. In-depth qualitative interviews with 15 women and 14 men currently in prison were undertaken. Thematic Analysis was used to characterise and compare developmental pathways, the function of IPVA and the offence process of IPVA perpetration between women and men. Results of this study suggest that there are more similarities than differences across women and men in prison who have perpetrated IPVA, with both following similar trajectories to IPVA perpetration. Women discussed the impact of their trauma experiences more than men, some displayed a different pattern of insecure attachment and although women tended to report being diagnosed with borderline personality disorder more so than men, both genders displayed trauma symptomology that has been labelled differently throughout their lives. Functions of IPVA perpetration were similar across both women and men (expression of negative emotion, revenge, actions of partners, substance use and self-defence), although women reported unique functions related to a need to take back control in their relationships, an anticipation of violence and problems with managing conflict. The developmental pathway to IPVA perpetration in women is unlikely to be explained by single factor theories. Thus, a ‘contextual maintenance’ theory of IPVA perpetration is proposed to explain IPVA perpetration in both women and men. This has incorporated the impact of trauma and mental health issues as factors that perpetuate IPVA perpetration that has been missing from previous theoretical explanations. An approach to intervention for those who perpetrate IPVA and are situated within criminal justice settings is also proposed, containing eight key components. It is suggested that the key driver in intervention development is not the gender of the person perpetrating IPVA, but individual need and risk factors.

The emergence and spread of carbapenem-resistant organisms (CRO) is a global public health threat in healthcare settings, resulting in high mortality, prolonged healthcare and increased costs. In the last two decades, many papers aiming to identify individuals at high risk of acquiring CRO have been published. However, the results reported across these studies are inconsistent and there are no studies systematically summarising those findings. Carbapenem resistance is mediated by multiple mechanisms. Carbapenemase production is the most concerning as the encoding genes of carbapenemases are located on mobile genetic elements, facilitating horizontal genetic exchange and therefore promoting the acquisition and spread of resistance genes. Examination of the epidemiology of carbapenemase-producing organisms (CPO) will inform local infection prevention and control strategies. This thesis has two main parts. The aim of the first part is to systematically summarise risk factors for CRO infection and colonisation in healthcare facilities worldwide and identify study characteristics contributing most to the heterogeneity across studies. In the second part I focused on CPO in Scotland to investigate the incidence, microbiological characteristics and outcomes of CPO and determine risk factors associated with CPO among hospitalised patients. In the first part, I conducted a systematic review and meta-analysis to evaluate risk factors associated with infection and/or colonisation of CRO in healthcare facilities. In total, 227 papers published between 1986 and 2016 were identified. Using pooled odds ratio estimates and the likelihood of statistical significance as criteria, prior carriage of multidrug-resistant organisms, prior antibiotics usage (carbapenem or oxazolidinone), prior provision of medical devices (mechanical ventilation or nasogastric tube) and prior healthcare exposure (intensive care unit ICU stay, and longer hospital stay) were most consistently found to be leading risk factors for CRO infection and/or colonisation. Additionally, decubitus ulcer was a specific leading risk factor for CRO infection, and prior antibiotics usage (polymyxin or cefepime) and steroid treatment were specific for hospital acquired CRO infection. However, prior provision of some medical devices (parenteral nutrition or gastrostomy or urinary catheter) were only leading risk factors for CRO colonisation. Study organism, case-control selection, study population, sample size, study setting and specialty (ICU or non-ICU) were the characteristics accounting for most heterogeneity across the published studies examined. In the second part of this thesis, I focused on CPO in Scotland using data extracted from several national datasets. I performed a retrospective analysis on all CPO from clinical and screening cultures in 2003-2016 using generalised linear models and survival analyses, and then conducted a matched casecontrol study to determine risk factors for CPO infection and colonisation among hospitalised patients using conditional logistic regression models. In total, 243 CPO isolates were identified in 214 individuals from 13 of 14 NHS Boards. The overall incidence of CPO cases increased significantly (P < 0.001), from 0.02 to 1.38 per 100,000 population. The case fatality rate was 5.6%. Enterobacteriaceae isolates predominated (84.8%) and increased significantly faster than non-fermenters. Community-associated CPO were more likely to be colonisations while healthcare-associated CPO were more likely to be infections. The ‘big 5’ carbapenemases (VIM, NDM, KPC, OXA-48 and IMP) predominated (96.7%). Awareness is required that older patients, with systemic infection or organ failure or presenting non-fermenters are at higher 30-day mortality risk from CPO. Patients with CPO infection had higher hospital mortality and longer hospital stay. A history of prolonged hospitalisation, prolonged ICU or high dependency unit (HDU) stay and being immunocompromised all independently increased the risk of CPO infection, while a history of HDU stay and ‘endocrine, nutritional and metabolic diseases’ were independent risk factors for CPO colonisation. In conclusion, this thesis sheds light on patients at high risk of being infected or colonised by CRO including CPO in healthcare facilities. Pre-emptive management should be prioritised for these patients. The findings also demonstrate the necessity of continuing the existing acute hospital admission screening programme for carbapenemase-producing Enterobacteriaceae in Scotland. Future efforts are required to understand underlying factors accounted for mortality, evolution and transmission of carbapenem resistance in Scotland.

This PhD research focuses on understanding a maternal pregnancy condition known as pre-eclampsia. This condition contributes to around 14 % of the global burden of maternal mortality and fivefold of perinatal mortality in developing countries. Genetic, environmental, nutritional and socioeconomic factors are thought to disproportionately affect the burden of pre-eclampsia in low and middle-income countries (LMIC). The first chapter gives an overview; it introduces pre-eclampsia and outlines its contribution to the burden of maternal and infant mortality and morbidity. It summarises all chapters in this thesis. The second chapter gives the background of the literature review. This chapter describes pre-eclampsia in the context of hypertensive disorders of pregnancy. It then explains some of the risk factors of pre-eclampsia, the natural history of the disease and the health system response: current modalities in screening, the evolution of the definition pre-eclampsia, diagnosis, prevention and management. The third chapter describes the scoping study, which aims at summarising explored risk factors in Africa, to identify potential gaps and the feasibility of conducting a systematic review. Its results showed that there were twenty studies done in Africa that had explored relatively few risk factors. These studies had methodological limitations of size and rigour, hence produced conflicting and inconclusive associations between pre-eclampsia outcome and most explored risk factors, including malaria infection. They also showed a gap in the literature regarding models built by risk factors that attempted to classify pre-eclampsia outcome in African populations. The fourth chapter describes the systematic review that explores the relationship between malaria infection and gestational hypertension (GH) with proteinuria (pre-eclampsia) or without. It considers two pathways that malaria possibly exert its effect on causing gestational hypertension. One pathway being through a dysfunctional placenta and the other pathway is by endothelial inflammation of blood vessels from malaria toxins. The result of the meta-analysis was a pooled odds ratio (OR) of 2.6, 95 % confidence interval (CI) 1.5 to 4.5. The odds of pre-eclampsia among pregnant women with malaria infection were 2.6 times than pregnant women without malaria infection. The fifth chapter describes the analysis of secondary data from Tanzania. This data analysis has four objectives. The sixth chapter describes the results of the four objectives, while chapter Seven presents the discussions of the four objectives. This data analysis used data from two sources: a hospital maternity register from northern Tanzania and a clinical trial in Dar es Salaam, Tanzania. The data analysis had four objectives; objective one determined the incidence pre-eclampsia to be 1.9 %, 95 % CI 1.3 % to 2.2 % in Dar es Salaam city, Tanzania. Objective two describes the sociodemographic characteristics of women with pre-eclampsia compared with those without pre-eclampsia in northern Tanzania population. Preeclampsia was more frequent among women with age above 35 years, single and tertiary level education. Objective three aimed to identify biomedical risk factors for pre-eclampsia among women in northern Tanzania. Then, I used these identified risk factors to build prediction models for pre-eclampsia. I later assessed the ability of these models to classify women with and without pre-eclampsia. Maternal age, weight before pregnancy, contraceptive intrauterine device (IUD) use, a diagnosis of malaria, diagnosis of infections, history of hypertension and HIV treatment were statistically significant predictors in some of my models. My final models in predicting pre-eclampsia in all deliveries, term and preterm delivery subgroups produced an area under the curve of 69.4 %, 71.2 % and 66.9 % respectively. The points of maximum sensitivity and specificity produced sensitivity values of 65 %, 65 % and 59 % respectively, while also producing specificity values of 63 %, 65 % and 66 % respectively. The risk factors and the prediction models were developed on a hospital-based register where the incidence of pre-eclampsia was 3.5%. Since hospital estimates tend to overestimate the incidence compared to population survey, the results of my prediction models will differ in women populations with a high risk of pre-eclampsia. The fourth objective describes the pregnancy outcome of women with preeclampsia compared to women without pre-eclampsia. The results showed there were more stillbirths among women with pre-eclampsia. The odds of stillbirth were 4.8 (95 % CI 3.7 – 6.3) times among women with preeclampsia than women without pre-eclampsia in all deliveries. Upon stratifying by term and preterm deliveries the odds were 2.6 (95 % CI 1.6 – 4.3) and 2.9 (95 % CI 2.0 – 4.1) respectively. The surviving offspring have worse developmental indicators compared to their counterparts in terms of low a Apgar score at 1-minute, low birth weight, small head circumference and short birth length. The odds of a low Apgar score (0 – 3) baby was 4.3 times (95 % CI 3.4 - 5.4) among pre-eclampsia women in all deliveries compared to normal Apgar score (4 – 10) babies. The association was maintained in the subgroups of term and preterm delivery (OR = 2.3, 95 % CI 1.5 – 3.5 and 2.8, 95 % CI 2.0 - 3.9 respectively). Chapter Eight covers the conclusion and recommendations of this thesis, which are: (i) Few studies that explored risk factors in Africa, more studies are needed to resolve conflicting and inconclusive findings from these studies. (ii) Malaria infection is associated with pre-eclampsia and gestational hypertension in malaria endemic regions. Malaria control should be intensified among pregnant women and further studies should explore the causal mechanisms. (iii) The incidence of pre-eclampsia should be tracked to observe changes in its trends in the evolving urban populations of LMIC. (iv) Affordable and feasible prediction models for pre-eclampsia should be developed and assessed for performance to enable identification and provision of prevention services on women with a high risk of developing preeclampsia. (v) Women with pre-eclampsia should receive appropriate treatment to mitigate the negative impact on their pregnancy outcome.

Background People with diabetes are at an increased risk of developing vascular disease, which is the leading cause of morbidity and mortality in this population. The retina is one of the few places in the body that offers noninvasive visualisation of the vascular system and thus provides a rich platform to evaluate local and systemic vascular disease. Recent advancements in retinal image analysis tools allow us to evaluate the retinal microvasculature in a more efficient and unbiased way compared to manual methods. Local retinal changes may provide insight into vascular disease prior to overt pathological changes. Aim The aim of this thesis was to explore and evaluate retinal vessel traits in relation to various manifestations of vascular disease, specifically diabetic retinopathy and cognitive decline, using prospectively collected data. In addition to undertaking this research, this PhD project also aimed to contribute to the collection of primary data from in ongoing longitudinal cohort in order to provide data not only for this project, but for many other future and ongoing projects. Methods Edinburgh Type 2 Diabetes Study is a cohort of 1,066 adults aged 60-75 years with type 2 diabetes living in the Lothian region of Scotland. Data were collected through research clinics as well as record linkage. Diabetic retinopathy status was obtained from the national screening programme and to evaluate cognitive decline, dementia diagnosis was obtained from a combination of medical records, death records and self-report. Cognitive decline was also evaluated using cognitive status derived from a battery of cognitive tests administered at baseline and then again after 10 years. Retinal images were analysed using VAMPIRE software for central retinal arteriolar equivalent (CRAE), central retinal venular equivalent (CRVE), arteriolar and venular tortuosity, fractal dimension and density. Results A total of 83 participants (11.6%) developed retinopathy over 10 years. After controlling for a wide number of cardiometabolic, diabetic and vascular risk factors, there was evidence of an association between increased venular tortuosity and incident retinopathy (odds ratio (OR) 1.51, 95% confidence interval (CI) 1.15 to 1.98, p = 0.003), as well as decreased standardised fractal dimension and incident retinopathy (OR 0.75, 0.58 to 0.96, p = 0.025). Of the total 1066, 106 (9.9%) were determined to have a dementia diagnosis after 10 years of follow-up. Cognitive decline, as measured by cognitive testing after 10 years, controlling for baseline cognitive status, was measured in the 581 returning participants. There were no independent associations between the retinal vessel traits and cognitive decline, using either dementia or the general intelligence factor, after controlling for various covariates. There was, however, evidence of age-related decreases in fractal dimension and density over the course of the study. Conclusions This thesis has provided evidence from the ET2DS that venular tortuosity and fractal dimension are independently associated with diabetic retinopathy. The independent associations were modest and need to be contextualised within the heterogeneity that exists within the supporting literature as well as replicated in other studies, but they provide exciting support for the use of the retinal vessel traits in future risk prediction modelling for diabetic retinopathy. There was no evidence of an association between the reported retinal vessel traits and cognitive decline. Novel findings regarding age-related decreases in fractal dimension and density are important as more information is coming to light regarding the vessel traits and their associations with vascular disease.

In most cases, spontaneous intracerebral haemorrhage (ICH) is thought to result from cerebral small vessel diseases (SVDs). Cerebral amyloid angiopathy (CAA) and arteriolosclerosis (non-CAA SVD) are the two main types of SVD associated with ICH. The risk of recurrent ICH and post-stroke dementia may be higher with CAA-associated ICH compared with non-CAA SVD-associated ICH. It is, therefore, important to identify the type of SVD associated with ICH. Commonly, ICH in the cerebral lobes (lobar ICH) is thought to be associated with CAA, whereas non-lobar ICH is associated with non-CAA SVD. However, this generalisation is not accurate. The aims of my thesis were to (a) histopathologically assess the types and severity of SVDs associated with lobar and non-lobar ICH using brain autopsy tissue, (b) explore whether brain imaging (magnetic resonance imaging (MRI), positron emission tomography (PET) and computed tomography (CT)) biomarkers can be used in living patients to identify the type of SVDs associated with ICH and (c) determine whether CT biomarkers can predict outcome after ICH. Throughout my thesis, I use data from two overlapping studies of ICH. The Lothian Audit of the Treatment of Cerebral Haemorrhage (LATCH) is a prospective community-based audit of all residents in the Lothian Health board region of Scotland who were aged 16 years or above and had an incident ICH between 1st June 2010 and 31st May 2013 inclusive. During LATCH and until 31st May 2016, consecutive adults with SVD-associated ICH were able to consent to have apolipoprotein E genotyping, brain MRI and brain autopsy as part of the prospective Lothian INtraCerebral Haemorrhage Pathology, Imaging and Neurological outcome (LINCHPIN) study. In an autopsy study of 126 LINCHPIN participants with first-ever SVDassociated ICH, I found that 98% of participants with a non-lobar ICH had moderate or severe non-CAA SVD. In contrast, 60% of participants with a lobar ICH had moderate or severe CAA, while many had moderate or severe non-CAA SVD, either with or without CAA. The most common approach used in clinical practice to identify CAAassociated ICH is the MRI-based modified Boston criteria for CAA. However, I found that only about one-third of ICH patients during LATCH were able to undergo MRI. Also, in 16 LINCHPIN participants with research MRI, the modified Boston criteria showed limited accuracy against the histopathological assessment of CAA on subsequent research autopsy. Molecular imaging using tracers designed to detect parenchymal β-amyloid in Alzheimer’s disease, such as flutemetamol, may also identify the perivascular β-amyloid found in CAA. I found that in LINCHPIN brain tissue samples, the amyloid tracer flutemetamol labelled both parenchymal and perivascular β amyloid. Among 20 participants with first-ever ICH, flutemetamol PET scans were 86% sensitive and 77% specific for CAA-associated ICH based on the modified Boston criteria. Brain CT is the test that usually diagnoses ICH. I found in 62 LINCHPIN participants with first-ever lobar ICH that subarachnoid haemorrhage and finger-like projections on CT, and APOE ε4 allele possession were independently associated with CAA-associated lobar ICH defined on subsequent autopsy. I developed diagnostic models and criteria (“Edinburgh criteria”) based on these predictors that could accurately rule in or exclude CAA-associated lobar ICH. I performed a multicentre external validation study of the Edinburgh criteria. In a preliminary analysis, the CT-only diagnostic criteria (subarachnoid haemorrhage and finger-like projections) had high sensitivity (88%) and good specificity (84%) for CAA-associated lobar ICH. The risk of recurrent ICH is a key outcome for ICH survivors. I found that the risk of recurrent ICH was significantly higher in participants with first-ever lobar compared with non-lobar ICH. Among lobar ICH participants, the risk of recurrent ICH was significantly higher in those classified as high risk on the CT-only Edinburgh criteria for CAA-associated lobar ICH compared with those classified as low risk. Predicting death or disability is also important in ICH. I found that the severity of SVD on the diagnostic brain CT was an independent predictor of death or disability at one year after the ICH, after adjusting for known prognostic factors. Brain imaging biomarkers, particularly on brain CT, are potentially useful for identifying the type of SVD associated with ICH. Having developed the CTbased Edinburgh criteria for CAA-associated lobar ICH, I performed preliminary multicentre studies assessing their diagnostic accuracy and prognostic value. In the future, I aim to perform the full analyses of these diagnostic test accuracy and prognostic studies to determine the clinical utility of the Edinburgh criteria. Other research should assess the clinical and economic effect of the Edinburgh criteria on the prognosis of ICH. More work is needed to investigate the prognostic relevance of coexistence of CAA and non-CAA SVDs in lobar ICH, and whether these groups can be differentiated using imaging biomarkers.

Proximal humerus fractures are common, accounting for 5% of fractures to the appendicular skeleton. Neck of humerus fractures (NHF) account for approximately 80% of all fractures of the proximal humerus – the remainder being isolated fractures of the greater, or lesser tuberosity. NHF should be considered as a separate entity to isolated tuberosity fracture as both injuries have distinct epidemiological characteristics, natural history and treatment principles. Despite this, many of the studies which form the basis for our understanding of NHF are in series which include all proximal humerus fractures. There are important unanswered questions regarding the epidemiology and determinants of outcome of NHF, and no robust evidence base to guide their management. Furthermore, there is no existing fracture classification system that is of proven value in predicting outcome. As a consequence, patients with similar injuries may receive very different opinions about the severity of their fracture, its likely prognosis, and its best treatment, dependent on the unit in which they are treated and the surgeon who treats them. This thesis aims to investigate the epidemiology of NHF, identify the prevalence and risk factors for nonunion and develop and evaluate a novel fracture classification. In CHAPTER 2 the study setting and method of case ascertainment was described. In CHAPTER 3 and CHAPTER 4, a large prospective database of 2,368 fractures collected over 7 years was used to define the epidemiology of NHF. Radiographs for these factures were analysed and the prevalence of nonunion was determined. Multiple logistic regression analysis of the data was performed to identify those radiographic factors that are prognostic of nonunion. The statistical method used provided weighted significance for each of those factors, and thus a mathematical formula predictive of nonunion was constructed. In CHAPTER 5 a novel classification for NHF based on clinically relevant fracture patterns and radiographic predictors of nonunion was described. In CHAPTER 6 and CHAPTER 7 a second database of 419 fractures collected over a one-year period was used to prospectively to evaluate the novel fracture classification as well as the mathematical formula’s ability to predict nonunion. NHF occurred predominantly in the older female patient following a simple fall. The prevalence of nonunion was 7.1%. Worsening social deprivation and cigarette smoking were the patient factors associated with nonunion. The radiographic predictors of nonunion were increasing humeral head-shaft translation, increasing varus angulation of the humeral head, separation at the fracture and absence of an associated tuberosity fracture. A mathematical formula for predicating nonunion was developed based on these risk factors. The formula performed well when evaluated on a second prospectively collected dataset. A novel fracture classification was described based on clinically relevant fracture patterns and the radiographic predictors of nonunion. The majority of fractures had a ‘stable’ configuration according to the novel classification. Fractures with a ‘stable’ configuration had a very low rate of nonunion and fractures with an ‘unstable’ configuration had a higher rate of nonunion. In summary, the prevalence of nonunion after NHF has been established. Risk factors for nonunion have been identified and a predictive formula has been developed which could improve patient counselling and decision making in fracture management. A novel prognostic fracture classification has been introduced which could facilitate better comparison between individual fracture subtypes in future studies.

The importance of social relationships for health in later life has been explored over the past decades. Loneliness has been found to be an adversity associated with ageing. People who feel lonely are at greater risk of experiencing increased morbidity and mortality. However, the existing evidence on the determinants of loneliness as well as the effects of loneliness on health are exclusively based on relatively young-old people (65 years and over) with the oldest old (80 years and over) under-represented. Compared to the young-old people, the oldest old are more likely to experience health problems and have fewer ties or contacts with others; therefore, they might be more likely to suffer from loneliness. This thesis aims to investigate loneliness in the oldest old. Specific thesis objectives are (1) exploring the individual-level determinants of loneliness, identifying how patterns of loneliness change with age and the individual-level factors associated with loneliness transitions; (2) investigating the effects of loneliness on health (i.e. all-cause mortality and cognitive decline); and (3) examining the relationship between loneliness and health service and social care utilisation. In order to investigate the objectives, data from the Cambridge City over 75s Cohort (CC75C) study were used. The CC75C study is a population-based study of the very old. It started in 1985, surveying a representative sample of men and women aged 75 years or older living in Cambridge. Partial proportional odds model and multi-state modelling were used to explore the determinants of loneliness, identify the changing patterns of loneliness as well as examine the risk factors associated with loneliness transitions. Cox regression models and generalized estimating equations (GEE) were used to explore the effects of loneliness on all-cause mortality, cognitive decline, and health service and social care utilisation, respectively. The findings reveal clear associations between loneliness and all-cause mortality, cognitive function, as well as health and social care service use of the oldest old, possible mechanisms and the importance of developing societal approaches to alleviate loneliness.

Scientific interest in the clinical implications, public health importance, and risk factors of anxiety disorders has grown substantially in the past two decades. Despite this, the evidence base on anxiety is insufficient to inform health care planning and policy-making. Further research on the outcomes and risk factors associated with anxiety disorders, and ways of mitigating these risks is needed. One of the aims of this thesis was to provide an overview of the existing literature on the prevalence of anxiety in adults living in countries across the globe, and to describe the prevalence in the context of various health states and life stages. Because generalised anxiety disorder is one of the most common psychiatric conditions in the population, the remainder of the thesis focused on this disorder and aimed to explore its links with health service use and mortality. Risk for this condition was also explored and area deprivation was studied as a possible determinant. Since depression is commonly studied alongside anxiety, the relationship between the residential environment and major depressive disorder was also assessed. Finally, to provide insight into the mitigation of risks of generalised anxiety disorder, a study of coping mechanisms was undertaken. Primary study findings from this thesis are based on the European Prospective Investigation of Cancer in Norfolk, a large, population study of British people over the age of 40. Results from the systematic review showed that anxiety is common in population sub-groups around the world, with women, younger people, and those suffering from chronic physical conditions, such as cancer and cardiovascular disease being particularly affected. Results from the primary studies of the thesis showed that generalised anxiety disorder is associated with increased risk for deaths, though it is not significantly associated with non-psychiatric hospital admissions. Results from the risk factor analyses showed that living in a deprived area is associated with generalised anxiety disorder in women and major depressive disorder in men. The risk mitigation analysis indicated that sense of coherence is an important coping mechanism that can protect against generalised anxiety disorder among women living in disadvantaged circumstances. My work has shown novel associations and attempted to provide a more complete picture of one of the most common psychiatric conditions in the population by focusing on several angles: health outcomes, risk factors, and ways of mitigating risks.

Background: Research in Posttraumatic Stress Disorder (PTSD) and Complex PTSD (CPTSD) has traditionally focused on either children or adults, while older adults tend to be under-represented in trauma research. This has led researchers to argue that PTSD/CPTSD is under-diagnosed and under-treated within this population. A better understanding of the presentation and correlates of posttraumatic symptoms in later life is needed in order to inform assessment and the development of targeted interventions for older adults. Method: A systematic review was conducted to explore factors associated with PTSD/CPTSD severity in older adults. This review identified gaps in the literature, including a dearth of research exploring childhood trauma. The subsequent empirical study attempts to address this gap by investigating the link between childhood trauma, Early Maladaptive Schemas (EMS), and CPTSD symptoms. Results: The systematic review showed that coping/response, physiological and psychopathological factors exhibited the most consistent associations with PTSD severity. The empirical study added to this literature by demonstrating that EMS mediated the relationship between childhood trauma and CPTSD symptom severity. As CPTSD is a relatively new construct, this is the first study exploring its association with EMS and offers preliminary evidence on the potential efficacy of schema informed interventions following traumatisation. Conclusion: Both the empirical study and the systematic review highlight factors affecting posttraumatic symptom severity in older people and have important implications for PTSD/CPTSD identification and treatment.

Background: Cardiovascular disease is a leading cause of premature mortality in renal transplant recipients. Predicting the risk of future cardiovascular events in this patient cohort is challenging due to the prevalence of non-traditional risk factors. Biomarkers of cardiovascular disease have been demonstrated to improve the accuracy of cardiovascular prediction models in the general population, but their potential utility in renal transplant recipients is unclear. Aims and Objectives: This thesis aims to assess whether established biomarkers of cardiovascular disease are predictive of adverse outcomes in stable renal transplant recipients. Patients and Methods: A cohort of 379 renal transplant recipients were studied. Prospective follow-up data (median of 16.2 years) were available for adverse outcomes including mortality, major adverse cardiovascular events (MACE) and graft loss. C-reactive protein (CRP), troponin T (TnT), N-terminal pro-B-type natriuretic peptide (NT-proBNP) and soluble ST2 (sST2) were measured from stored plasma/serum samples and investigated for an association with these outcomes. Discrimination metrics were derived to quantify the incremental value of adding biomarker concentrations to existing cardiovascular risk prediction models. Results: Cardiovascular disease was the leading cause of mortality in the cohort and accounted for 47% of deaths. Malignancy (28%) and infection (22%) were also common causes of mortality. All of the biomarkers associated with all-cause and cardiovascular mortality, though the strength of association varied considerably. CRP, TnT and NT-proBNP were also associated with MACE. Overall, TnT and NT-proBNP moderately improved the accuracy of risk prediction models. Several biomarkers were associated with secondary outcomes including death-censored graft loss and infection-related mortality, highlighting a potential role for these biomarkers outside of cardiovascular risk prediction. Conclusions: Data from these studies suggest that established biomarkers of cardiovascular disease may have a role in predicting adverse outcomes in renal transplant recipients, including several which are unrelated to cardiovascular disease.

The purpose of this study was to describe the prevalence and incidence of caries in the permanent teeth in a cohort of children over a 7-year period, particularly the disease trajectory of caries in the permanent teeth defined by the presence or absence of caries in the primary teeth (aged 7-9 y); and to explore the role of potential risk factors (demography, dietary and oral health promoting behaviours) in future caries development. In addition, the study aimed to determine whether caries experience in late childhood was predictive of adolescent obesity (ages 12-16 y) to inform the use of a common risk factor approach (CRFA) for prevention. The study also explored the attitudes and beliefs of adolescents towards dental caries and their use or non-use of caries prevention regimens. With ethical approval granted, pupils in Year 3 (aged 7-9 y) at state-funded primary schools in an area of North West England in February 2006 were invited to take part. Positive informed consent was obtained. Clinical examinations (CE1-4) to assess oral health were performed at four time points (mean ages 8, 10, 13 and 15 y) by trained and calibrated dentist examiners using a standardised, national diagnostic protocol. The diagnostic threshold for caries was visual assessment of caries into dentine. At the last two time points, questionnaires were used to assess self-reported oral health related behaviours; and Body Mass Index (BMI) category was calculated from height and weight measurements using age and gender specific cut-offs. In June 2014, semi-structured interviews (n-19) were conducted in 4 secondary schools with a sample of participants (age 16 y). At baseline (CE1), 5470 children (ages 7-9 y) consented. Most identified as White (75.9%) or Asian (22.8%) with over 60% from more deprived backgrounds. The socio-demographic characteristics of consenting pupils were similar to non-consenting pupils. Intra-oral examination was completed at all time points by 2117 children and at least one time point by 6651 children. Mean caries prevalence (%D3MFT > 0) was 16.7% at CE1, increasing to 31.0%, 42.2%, and 45.7% at subsequent examinations. A population-averaged model (generalised estimating equations) was used to model the longitudinal data. The main finding was that estimated mean values indicated a rising D3MFT count as pupils aged (consistent with new teeth emerging) that was significantly higher (4.49 times; 95% confidence interval, 3.90-5.16) in those pupils with caries in their primary dentition than in those without. The odds of developing caries between CE3 and CE4 for those in the most deprived category were 3.37 times those in the least deprived category (OR 3.37, 95% CI 1.71 to 6.65). BMI category in adolescence (available for 2958 (54.1%) participants) was not shown to be significantly associated with: the presence or absence of caries in late childhood (P=0.61); in adolescence (P=0.06); gender (P=0.91); or deprivation (P=0.35). The dominant influence over oral health behaviours was habitual practice of toothbrushing encouraged by parents from a young age but this behaviour was unstable and mitigated by environmental factors later e.g. access to free sugars. This thesis illustrates the life-long consequences of developing caries in early childhood. Children with caries in their primary dentition followed a steep disease development trajectory in their permanent dentition. Children who are caries free and caries active in their primary dentition should be considered as two different populations with targeted and whole population prevention strategies to address their different risk profiles. This also emphasises the need to focus on early prevention to stop children entering the 'rapid' disease trajectory. The finding that deprivation remains an important predictor of future caries, and that adolescent behaviours are mitigated by environmental factors supports strategies that include actions to address social determinants throughout childhood. Two significant future research questions are raised: how do we keep children caries free, and once a child develops the disease how do we slow down the process?

Purpose: The systematic review summarised the research investigating potential risk factors for impulsive behaviours in forensic populations. The empirical study examined the predictive utility of clinician rated, self-report and behavioural measures of impulsivity in detecting violence and antisocial behaviour in forensic mental health inpatient settings. Method: The review is comprised of 9 studies identified through electronic database searches using a structured search strategy and predetermined inclusion criteria. The empirical study employed a cross-sectional design using retrospective and prospective statistical analysis. Forty-three participants were recruited from secure forensic mental health inpatient settings across Scotland and data collected from clinician rated, self-report and behavioural measures of impulsivity. Results: The review found original evidence to suggest that traumatic brain injury, substance and alcohol misuse, trauma and sleep as possible predictors of impulsive behaviour in forensic populations. The empirical study found a relatively consistent relationship between impulsive behaviour and violent or antisocial behaviour in a sample of forensic mental health inpatients. Conclusions: The systematic review identified a limited number of risk factors thought to influence impulsive behaviour in forensic populations. The review highlights the need for future research with improved methodological design to further explore contributory factors for increased levels of impulsivity. Findings from the empirical study reveal clinician rating of impulsive behaviour to be the most sensitive in predicting future incidents of violent and antisocial behaviour, which may be supplemented by the addition of a self-report measure.

Cardiovascular diseases (CVD) are the leading cause of death worldwide and the atherosclerotic process that precedes CVD starts during childhood. Physical activity (PA), cardiorespiratory fitness (CRF) and exercise are well known as preventive strategies for CVD. One possible mechanism for such prevention is the role of PA, CRF and exercise on the arterial and autonomic systems. The aim of this thesis was to investigate using observational and experimental studies the role of PA, CRF and exercise on the autonomic and arterial systems of healthy adolescents. Chapter 4 systematically reviewed observational cross-sectional studies and provided level one evidence for a significant and positive association between resting parasympathetic function and moderate-to-vigorous PA in youth. Chapter 4 also indicated that gaps exist in the literature such as the associations between PA intensities, CRF and heart rate variability (HRV). These findings were furthered in Chapter 5 which showed that vigorous PA (VPA) and moderate PA (MPA) were positively related with HRV at rest and cardiac autonomic recovery following exercise in adolescents. In Chapter 6 a high-fat meal was used aiming to increase CVD risk in the postprandial state, and it was demonstrated that PA levels and CRF are not significantly associated with postprandial HRV and arterial stiffness in adolescents. Aiming to investigate possible associations between the vascular and autonomic system, measures of baroreflex sensitivity (BRS) were introduced. Chapter 7 showed that BRS and its autonomic and vascular components present a between-day coefficient of variation lower than 20% whilst within day coefficient of variations were lower than 34% in adolescents. In Chapter 8 acutely following high- and moderate-intensity interval exercise a decrease in blood pressure was observed concomitantly with decreases in BRS. This was mainly mediated by decreases in the autonomic modulation, and the duration of the decreases in blood pressure was higher following high-intensity interval exercise. Chapter 9 extended these findings by demonstrating that the changes in BRS following the ingestion of glucose was not altered by the high or moderate-intensity exercise performed before glucose ingestion. Chapter 10 showed that following four weeks of high-intensity exercise interval training no improvements were observed in BRS and its autonomic and vascular components at rest or acutely following exercise. Collectively, the present thesis contributes significantly to the literature by providing novel evidence in healthy adolescents on the role of PA intensities, CRF and exercise on the arterial and autonomic systems at rest, acutely following exercise and in the postprandial state. The results gathered in this thesis indicate potential of the autonomic and vascular function as targets of CVD risk reduction in youth.

Background: The burden of cardiometabolic disease (CMD) is rising in sub-Saharan Africa (SSA). However, there are limited population-based prevalence estimates of CMD risk factors to inform public health initiatives for the prevention and management of CMDs in these populations. This thesis aims to contribute to this evidence gap by assessing the prevalence and distribution of established and emerging CMD risk factors, associations between risk factors, and tools for their identification, in a South African population. Methods: The Durban Diabetes Study (DDS), a population-based cross-sectional survey of CMD risk factors, was designed and data were collected on 1204 participants from the eThekwini Municipality, South Africa. Key findings: In this urban South African population, the prevalence of most CMD risk factors was high, and varied across demographic and socioeconomic groups. The prevalence of smoking and alcohol consumption was higher in men, whilst the prevalence of obesity, hypertension, dyslipidaemia, and hyperglycaemia was higher in women. Wealth was associated with obesity and hypercholesterolemia, whilst education level and employment status were associated with smoking, physical activity and diabetes. Despite several potential advantages, the use of glycated haemoglobin (HbA1c) for diagnosis of diabetes is not established in SSA. Using plasma glucose measures as the reference, HbA1c ≥6.5% detected diabetes with high sensitivity and specificity. Furthermore, the association of anaemia, HIV, and antiretroviral therapy (ART) with HbA1c was modest and no statistically significant differences in the prevalence of diabetes were found in those with anaemia or HIV based on plasma glucose and HbA1c measurements. This is the first evidence for the utility of HbA1c for the diagnosis of diabetes in a black SSA population. There is emerging evidence for the association of HIV and ART with CMD risk factors. In the DDS, the prevalence of HIV was high (43.5%) and untreated HIV was associated with low high-density lipoprotein cholesterol, whilst ART-treated HIV was associated with high triglycerides. Finally, 30.8% of participants were at high risk of CMD based on metabolic syndrome, but only 7.9% had high 10-year cardiovascular disease risk based on the Framingham risk score. Conclusion: This thesis has added to the evidence base on CMD risk factors in South Africa. These findings highlight the need for longitudinal studies to investigate the aetiology of CMDs and robustly assess the utility of tools to identify risk of CMD in SSA populations.

Southeast Asia carries a large burden of endemic zoonotic diseases, in livestock and humans, especially in countries where livestock production is increasing among rural households for income generation and poverty reduction. This thesis explores the risk factors for transmission of pig-associated zoonoses – particularly Q fever, brucellosis, hepatitis E, and Japanese encephalitis – in northern Lao PDR, with a view to development of recommendations for “catch-all” control measures to impact on multiple diseases, improving biosecurity and preventing disease transmission to the human population. Research included (i) a qualitative assessment of the knowledge, attitudes, and practices of villagers related to pig-associated zoonoses and their risk factors using focus group methodology; (ii) an assessment of health seeking behaviour at hospital/health centre and village level to examine factors that influence choice of health care provider and determine the impact of health seeking behaviour on illness and treatment costs, and an examination of non-conventional health care sources to understand the complexity of health seeking behaviour and influences on choice of health care provider and, lastly, (iii) health care provider and service delivery assessments to determine healthcare facility routine service delivery procedures and assess capability in diagnosing and treating illness. In terms of disease, the most common illnesses reportedly seen by all those interviewed were respiratory illness, acute febrile illness and diarrhoea, confirming them as the leading causes of morbidity. Knowledge and awareness of the etiological agent of pig-associated zoonoses among villagers, patients, and health care providers was very poor for brucellosis and Q fever, with limited awareness of hepatitis E. Most were aware of Japanese encephalitis. Clinical diagnosis and symptomatic treatment of illness is the normal practice and identification of causative agents in human illness does not often occur. All three empirical assessments identified poor diagnostic capability as a major concern. Focus group discussions revealed that knowledge and awareness of disease risk factors, and of zoonoses in general, was low among villagers. Practices related to food consumption, latrine usage, hand hygiene and sanitation, which are known disease risk factors, were found to be a concern in study villages. Attitudes and practices adopted by villagers in relation to human and animal health and health seeking behaviours were strongly influenced by financial circumstances, access to appropriate healthcare facilities, spiritual beliefs, and a lack of knowledge and resources to maintain the health of both animals and humans. The first point of care when experiencing illness was often the health centre or a local traditional healer or spiritual healer or pharmacist/drug seller, depending on location. This was followed by the district hospital, if nearby. Many villagers described going back and forth between traditional medicine and modern medicine service providers, with 76% (19/25) of participants reportedly seeing more than one type of healthcare provider for a given episode of illness. Self-medication was the most common practice (84% of all participants) irrespective of the care provider consulted. Attendance at a healthcare facility was dependent on available funds and the perceived severity of illness. Overall household costs ranged between no cost, because of the “poor patient” policy that exempts vulnerable groups from paying for care, and $2500 USD for medical treatment, hospital stay, transportation and sometimes food. Healthcare workers at all facility levels (from health centre to provincial hospital) expressed a lack of confidence in making an accurate diagnosis for these pig associated zoonoses due to poor diagnostic capability in their respective facilities. A One Health approach to zoonotic disease surveillance that incorporates transdisciplinary methods and partnerships will lead to improved understanding of the underlining social determinants of health and their impact on health-seeking behaviours, disease transmission and ultimately disease reporting.

Risk factors for psychological insult following deployment to Operation Enduring Freedom or Operation Iraqi Freedom among veterans: A systematic review: The systematic review aimed to establish more clearly the risk factors for mental health problems in the veteran population. Five databases were searched. Included studies (n = 10) required that veterans served in Operation Enduring Freedom (OEF) and/or Operation Iraqi Freedom (OIF) and included risk factors of mental health problems among the veteran population. Data from included studies were extracted and critically appraised based on critical appraisal tools following a narrative approach to synthesise data. All of the studies reviewed identified risk factors, although due to their heterogeneous nature key findings varied considerably. However, it was consistently reported that combat exposure and deployment experiences were associated with emergence of post operational mental health problems. The current review provides preliminary evidence that there are a number of specific risk factors that may increase susceptibility to mental health problems subsequent to military deployment. It is suggested that interventions are needed in order to mitigate risk factors and bolster protective factors. A cross-sectional study investigating the impact of disease activity and disease related cognitions on adjustment in Inflammatory Bowel Disease: The research journal aimed to investigate the degree to which psychological illness related cognitions will mediate the effect of disease activity on Quality of Life (QoL). In addition, to assess the impact of disease activity, and several psychological factors, in several adjustments outcomes in IBD to see whether the adjustment variables are significant predictors of multiple outcomes. Mediation was used followed by an exploratory cross-sectional correlational design. Three hundred and thirty eight participants were recruited through an IBD charity and invited to respond to a self-report questionnaire online. Measures targeted different aspects of the IBD profile to give an indication of adjustment associated with IBD diagnosis, psychological factors and Quality of Life (QoL). Mediation analysis found support for significant indirect effects on the relationship between disease activity and QoL through Gastrointestinal (GI) anxiety, perceived disability and illness representations. The subsidiary analysis indicated that pain catastrophising, disease activity, stigma, illness representations and GI anxiety were found to be significant predictors of adjustment in IBD. The results indicate that there is an important relationship with the adjustment factors, QoL, and psychological functioning. In addition, stress, depression, anxiety and QoL were found to be predicted by the adjustment factors. The current study has provided insight into psychological factors and adjustment indicators from a multi-faceted perspective, which will facilitate advancement of managing IBD from a biopsychosocial framework with a view to enable more effective disease management.

Background. The incidence of starting renal replacement therapy (RRT) among young people (< 20 years of age) in 2013 in Scotland was 7.7 per million (age-related) population. Little knowledge exists about cardiovascular risk factors (CVRFs), long-term survival and cardiovascular disease (CVD) outcomes in patients who initiated RRT in childhood. The main source of routine data for these patients is available from the European Society of Paediatric Nephrology/European Renal Association- European Dialysis and Transplant Association (ESPN/ERA-EDTA) registry. In Scotland nationally comprehensive data on patients receiving RRT is available from the Scottish Renal Registry (SRR). Aim and objectives. The overall aim of the thesis is to review relevant literature and conduct retrospective cohort studies describing CVRF prevalence, all-cause mortality and incidence of CVD outcomes in patients who initiated RRT in childhood. ESPN/ERA-EDTA registry data were used to describe the prevalence of anaemia, hypertension, dyslipidaemia and BMI categories and their association with all-cause and CV mortality. SRR data were used to describe all-cause mortality and CVD incidence and their association with age at start of RRT, sex, primary renal disease (PRD), type of RRT and period of start of RRT. Methods. Systematic searches were performed to identify relevant literature. For the ESPN/ERA-EDTA analyses patients who started RRT between 0 and 20 years of age and who had CVRF data were included. Patients were followed from date of first CVRF measurement until the earliest of death, loss to follow-up, reaching 20 years of age or the end of follow-up (December 31st 2012). Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for mortality, comparing patients with and without each CVRF. For the SRR analyses, patients who started RRT under 18 years of age in the period from 1963 to 2013 were included in the analyses. To describe CVD incidence the SRR data were linked to national registers for death and CVD hospital admissions available from 1981 onwards. These analyses, therefore, included patients who started RRT between 1981 and 2013 with follow-up until first CVD event after start of RRT, end of follow-up period or censoring at death. Cox proportional hazard models were used to examine the association of age at initiation of RRT, sex, PRD, type of RRT and period of initiation of RRT with all-cause mortality and CVD incidence. Results. The systematic reviews revealed a gap in current knowledge about CVD incidence and the association of CVRFs with CVD outcomes in patients who initiated RRT in childhood. In total, 7,845 patients were included in the ESPN/ERA-EDTA registry analysis. The mean age of the patients was 9.5 (SE 0.06) years, 58.9% were male, and the most common PRD was congenital anomalies of kidney and urinary tract (CAKUT). The prevalence of dyslipidaemia, hypertension, anaemia overweight/obesity and underweight was 87.5%, 79.3%, 36.0%, 29.9% and 4.3%, respectively. During median follow-up of 3.7 (IQR 1.7-6.8) years 357 patients died. HRs for anaemia were 2.19 (95% CI 1.64-2.93) and 2.55 (95% CI 1.27-5.12) for all-cause and CVD mortality, respectively. The HR for all-cause mortality for underweight was 1.81 (95% CI 1.30-2.53). No other studied CVRFs were statistically significantly associated with all-cause and CVD mortality. In total, 479 patients were included in the SRR analyses of all-cause mortality. The most common PRD was CAKUT and 55.3% of patients were male. During a median follow-up of 18.3 (IQR 8.7-27.0 years) years 126 patients died. Twenty-year survival among patients initiated RRT in childhood was 77.6% (95% CI 73.8-81.3). Age at start of RRT, PRD and type of RRT were significantly associated with all-cause mortality. HR for all-cause mortality for patients who started RRT under 2 years of age was 2.50 (95% CI 1.19-5.25) compared to patients who started RRT at 12 to 18 years old. HR for all-cause mortality for patients with PRD other than CAKUT or glomerulonephritis (GN) was 1.58 (95% CI 1.05-2.39) compared to patients with CAKUT. HRs for all-cause mortality for patients who only received either HD or PD during follow-up were 19.4 (95% CI 10.4-36.4 and 19.5 (9.65-39.7), respectively, compared to patients who received a renal transplant. In total, 381 patients were included in the SRR analyses of CVD incidence. During a median of 12.9 (IQR 5.6-21.5) years of follow-up after initiation of RRT 134 patients (35.2%) developed CVD. The overall crude CVD incidence was 2.6 (95% CI 2.2-3.0) per 100 person-years. HRs for CVD were 1.69 (95% CI 1.05-2.74) for males compared to females, 1.72 (95% CI 1.02-2.91) for PRD other than CAKUT or GN compared to CAKUT and 8.38 (95% CI 3.31-21.23) and 7.30 (95% CI 2.30-23.16) for patients who only received either HD or PD during follow-up, respectively, compared to patients who received a renal transplant. Conclusions. This thesis has contributed to knowledge about CVRF prevalence, longer-term survival and CVD outcomes in patients who initiated RRT in childhood by identifying high prevalence of CVRFs and that CVD is a common complication. This study did not investigate whether anaemia, hypertension, dyslipidaemia and obesity are associated with a higher risk of developing CVD after start of RRT. Future research is needed to study whether treatment of anaemia, hypertension, dyslipidaemia and controlling body weight will reduce the risk of CVD and mortality in patients who initiated RRT in childhood.

Despite Africa accounting for ~20% of the global cattle population, prevalence estimates and related risk factors of bovine tuberculosis (bTB), caused by Mycobacterium bovis, are still poorly quantified in many countries across the continent. Control of bTB in Africa is difficult due to poor monitoring of cattle movements and limited abattoir surveillance. Also M. bovis is zoonotic and risk factors for transmission include living in close contact with cattle and consumption of unpasteurised milk. Cattle keeping is integral to some rural populations in Cameroon and understanding the epidemiology of bTB in cattle populations is important both to bovine and public health. Detection of bTB in cattle is difficult due to variability of immune responses to M. bovis infection. The interferon-γ (IFN-γ) assay maybe useful to estimate bTB prevalence and identify bTB risk factors in Cameroon. However its performance can vary at different stages of bTB pathogenesis and in different cattle populations. Recently Fasciola hepatica co-infections have been reported to suppress IFN-γ responses in M. bovis infected cattle but the potential effect with F. gigantica co-infections on bTB prevalence estimates in Cameroon is unknown. An abattoir study was conducted in Cameroon to assess the performance of the IFN-γ assay. In 2012-13; 2064 slaughtered cattle were sampled from Bamenda abattoir (North West Region; NWR) and Ngaoundere abattoir (Vina Division; VD). Individual animal data was collected from routine meat inspection including identification of bTB and Fasciola pathology. Cattle were also tested for bTB using the IFN-γ assay and an M. bovis antibody ELISA. In the absence of a gold-standard diagnostic, the IFN-γ assay was compared to other diagnostic tests to assess agreement and identify factors that affected performance of the assay. Agreement between IFN-γ assay, TB lesion identification and an M. bovis antibody ELISA was poor-moderate, probably partly related to differences in immune response detected. A presence of Fasciola gigantica also increased the odds of false negative IFN-γ assay results. On further investigation co-infected cattle had increased odds of TB lesions and reduced IFN-γ responses that potentially could lead to ~20% reduction in test sensitivity. In an attempt to take into account the potential impact of F. gigantica, when estimating bTB prevalence, an antibody ELISA was developed to detect the exposure in live cattle. To highlight the awareness of disease in cattle-rearing communities, estimate prevalence and identify risk factors of bTB in cattle populations; two cross-sectional studies were conducted in 2013. A stratified clustered cross-sectional study of pastoral cattle herds, in the NWR and the VD, sampled 1448 pastoral cattle reared by 100 pastoralists. A smaller cross-sectional study sampled 60 dairy cattle from 46 small-holder co-operative dairy farmers. Individual animal data and herd-level data were collected and animals were screened by both the single comparative intradermal skin test (SCITT) and IFN-γ assay. Awareness of zoonotic TB was low yet consumption of raw milk was high in cattle-keeping communities highlighting the need for accurate bTB prevalence estimates. Despite the high awareness of the clinical presentation of bTB, clinical signs identified by pastoral herdsmen were not associated with cattle being bTB positive. The SCITT was used to compare two manufacturers cut offs for the IFN-γ assay, ≥0.05 and ≥0.1, and highlighted that these two diagnostics may detect different populations of bTB positive cattle. Using the IFN-γ assay at ≥0.1, bTB prevalence was highest in dairy cattle (21.67%) and was also present in pastoral cattle in the NWR and VD (11.33% and 6.55% respectively). Importantly, as F. gigantica is endemic in Cameroon and its influence could mean the true prevalence of bTB could be higher. Female pastoral cattle were at lower odds of being IFN-γ assay positive potentially due to immunosuppressive factors had lower odds of disease. Husbandry practices also decreased the odds of being IFN-γ assay positive such as drinking from streams, antelope and contact with herds at grazing. Age increased the odds of pastoral cattle being IFN- assay positive potentially being a confounder to chronicity of bTB and other co-infections may influence IFN-γ responses. Dairy cattle herds had different risk factors for being IFN- positive likely due to differences in husbandry practices. Considering the potential risk to public health of M. bovis this thesis highlights the extent of bTB across two major cattle keeping regions in Cameroon and the public health risk in cattle-rearing communities. Furthermore the relationship between Fasciola co-infection and IFN- responses to M. bovis described has potential implications for bTB diagnosis in cattle populations where the parasite is present across the globe.

Although the female menopause has been extensively characterized as a well-defined symptomatic state of oestrogen deficiency, which responds relatively well to oestrogen replacement therapy, the symptomatic state of androgen deficiency in men is poorly defined and uncertainty exists whether it responds to testosterone replacement. It has been proposed that hypothalamic-pituitary-testicular (HPT)-axis function (responsible for the production of androgens) and regulation could be viewed as a ‘barometer’ of health status in older men and that potential alterations in HPT-axis function and regulation reflect subclinical and clinical deficits in function and health, which may result in an aged phenotype of human health and disease in older men. The HPT-axis constitutes a well-defined, tractable, clinically-relevant, biological system, which may permit insight into the mechanisms underlying the expression of ageing-related phenotypes of human health and disease. By using a different lens – such as the genetic background; the compensatory responses within the HPT-axis; the syndromes of androgen deficiency; the ethnic background of an individual or the life course trajectory of function and health from conception into older age – to magnify potential dysregulation in the HPT-axis will it be possible to visualize and understand the phenotypic expression of human male ageing as a gradient of functional and health outcomes. This will allow for a better understanding of the physiological mechanics underlying symptomatic expression of dysregulation in the HPT-axis.

The consumption of unsafe fresh vegetables has been linked to an increasing number of outbreaks of human infections. In Lebanon, although raw vegetables are major constituents of the national cuisine, studies on the safety of fresh produce are scant. This research employed a holistic approach to identify the different stages of the food chain that contribute to the microbiological risks on fresh produce and the spreading of hazards. A thorough analysis of the institutional and regulatory framework and the socio-political environment showed that the safety of local fresh produce in Lebanon is at risk due to largely unregulated practices and shortfalls in supporting the agricultural environment as influenced by the lack of a political commitment. Microbiological analysis showed that the faecal indicator levels ranged from < 0.7 to 7 log CFU/g (Escherichia coli), 1.69-8.16 log CFU/g (total coliforms) and followed a significantly increasing trend from fields to the post-harvest washing area. At washing areas, Salmonella was detected on lettuce (6.7% of raw vegetables from post-harvest washing areas). This suggested that post-harvest cross-contamination occurs predominantly in the washing stage. At retails, a combination of observation and self-reported data provided an effective tool in assessing knowledge, attitudes and practices. It showed that the food safety knowledge and sanitation practices of food handlers were inadequate, even among the better trained in corporate-managed SMEs. Overall, the microbiological quality of fresh-cut salad vegetables in SMEs was unsatisfactory. The link between Staphylococcus aureus and microorganism levels on fresh salads vegetables and the overall inspection scores could not be established. On the other hand, inspection ratings on individual components, e.g., cleanliness and cross-contamination preventive measures showed significant correlation with Listeria spp. levels. Together, results confirmed that inspection ratings don’t necessary reflect the microbiological safety of fresh vegetables and that the application of control points of risk factors that likely to contribute to microbial contamination in the production environment are essential. The washing methods were limited in their effectiveness to reduce the contamination of parsley with Salmonella. In general, the pre-wash chopping and storing of parsley at 30ºC reduced the decontamination effect of all solutions, including sodium dichloroisocyanurate which was reduced by 1.3 log CFU/g on both intact and chopped leaves stored at 30ºC. In such conditions, the transfer rate of Salmonella from one contaminated parsley to subsequently chopped clean batches on the same cutting board(CB) recorded 60%-64%. Furthermore, the transmission of Salmonella persisted via washed CBs stored at 30°C for 24 h. It is recommended to keep parsley leaves unchopped and stored at 5ºC until wash for an optimum decontamination effect and to apply vigilant sanitation of CBs after use with fresh produce. This research presented important data for quantitative risk assessment for Salmonella in parsley and useful descriptive information to inform decision-makers and educators on microbial hazards associated with fresh produce in Lebanon. It also highlighted the risks areas that require urgent interventions to improve food safety. Considering the complex institutional and political challenges in Lebanon, there is an obvious need to direct development programs and support towards local agriculture production, effective education strategies and growing awareness of consumers and stakeholders on food safety related risks.

Introduction Non-union (NU) is a fracture that will not unite. With over one million fractures per annum in the UK long bone non-union has serious social and economical implications. There is little epidemiological data available specifically looking at this NU patient cohort. Studies that are bone specific quote rates of non-union as a proportion of their study group but there is no data quantifying the incidence of NU in the population or per fracture. Studies have highlighted risk factors associated with atrophic non-union including age, diabetes, non-steroidals, and cigarette smoking. There is scientific interest regarding how best to classify non-unions and the role of biological agents in treating them. Aims • To quantify the incidence of non-union in a large population and calculate the risk of non-union per fracture according to age, sex and anatomical distribution. • To assess the causes contributing to non-union and outcomes of treatment in a non-union cohort and validate a new non-union scoring system. • To test the treatment potential of a novel molecule (monobutyrin) and a growth factor in a small animal model of non-union. Method • Using the ICD-10 data from the Scottish population as collected by NHS Scotland the incidence of non-union and fractures were calculated. • A cohort of 100 non-union patients were studied for risk factors associated with their non-union, treatment outcome and to assess a new NU classification system. • A rat model of tibial non-union was used to assess the potential of monobutyrin and BMP-2 in treating non-union in an animal model. Results • Fracture non-union is very rarely found in children (1 in 500 fractures) and occurs in up to 1 in 50 adult fractures. Non-union of a fracture has a significantly higher risk in young adults than the elderly by about 3 fold. Osteoporosis may not be a risk for non-union. The tibia and clavicle are the sites with the greatest potential for fracture non-union. • Non-union is multifactorial in two out of three patients. Biomechanical stability, patient host factors and infection must all be considered in every patient. Occult or unexpected recurrent infection is present in up to 10% of patients. When all factors are considered in treatment the outcome is 95% successful with 88% requiring 2 or less procedures to heal the non-union and only a minority requiring adjuvant graft or biological agents. The proposed new classification system is complex and did not clearly identify those patients who would require adjuvant treatment (eg bone grafting or BMP) or those likely to have unsuccessful non-union treatment. • Monobutyrin and BMP-2 when tested on the small animal non-union model did not improve the success rate of union. Conclusions Non-union affects approximately 1000 people per year in Scotland, this figure is not as high as 5-10% of all fractures. It is associated with fractures in young adults and of the clavicle and tibia, treatment can have a very high success rate without the need for adjuvant biological polytherapy when all contributing factors are considered and managed appropriately. A new non-union classification needs to incorporate the multifactorial aspects of non-union without being too complex to use in everyday clinical situations.

Project risk assessment is an effective tool for planning and controlling cost, time and achieving the technical performance of a building construction project. Construction projects often face a lot of uncertainties, which places building construction projects at the risk of cost, time overruns as well as poor quality delivery. Considering the limited resources of developing countries, there is need to complete building projects on-time, on-budget, and to meet optimal quality hence, risk management is an important part of the decision making process in construction industry as it determines the success or failure of construction projects. In line with this need, this research aims to establish a system to improve the time, cost and quality performance of building construction projects in developing countries, through a comprehensive risk management model that ensures the expectations of clients are met. To achieve the aim of this research, a mixed methodological approach was adopted. Through the review of literature, a conceptual risk management framework suitable to elaborate risk assessment of building construction projects especially for developing countries was developed. A questionnaire survey using a nonprobability sampling technique was conducted to elicit information from construction professionals in Nigeria to assess their perception of 79 risk factors identified from literature review based on the likelihood of occurrence and impact on projects using a five point scale. Responses from 343 construction professionals were drawn from 305 contractors and subcontractors and 38 clients (private and public) within the Nigerian construction sector. Response data was subjected to descriptive statistics to depict the frequency distribution and central tendency of responses. Subsequently, the risk acceptability matrix (RAM) was adopted to categorise and prioritise risk factors. 27 critical risks that affect building construction projects were identified. A Bayesian Belief Network (BBN) model was developed by structural learning and used to examine the cause and effect relationship amongst the 27 critical risk factors. The developed BBN model was subjected to validation using a multiple case study of two building construction projects in Nigeria. The result showed the interrelation between the 27 risk factors and how they contributed to cost and time overruns as well as quality problems. The critical risks directly affecting the cost of building construction project were: fluctuation of material prices; health and safety issues; bribery and corruption; material wastage; poor site management and supervision; and time overruns. The critical factors identified to directly affect quality were: supply of defective materials; working under harsh conditions; improper construction methods; lack of protective equipment; ineffective time allocation; poor communication between involved stakeholders; and unsuitable leadership style. Time overruns on building construction projects was directly caused by: quality problems; low productivity; improper construction methods; poor communication between involved parties; delayed payments in contracts; and poor site management and supervision. As a consolidation of the findings of this research, a BBN model for identifying risk factors that directly affect time, cost and quality on building construction projects has been developed which has the potential for assisting construction stake holders to manage risks on their projects. In view of the findings, a best practice system for risk management in building construction projects in Nigeria has been developed with an implementation guide to help building construction practitioners to successfully implement risk management on their building construction projects. Suitable risk responses, also in the form of recommendations have been identified. The strategies include actions to be taken to respond to risks based on their perceived significance or acceptability as well as some positive risk responses, such as exploiting, sharing, enhancing and accepting, and other negative risk responses, such as avoidance, mitigation transfer and acceptance.

Background Mental health of the adolescents is an important global public health concern as a leading cause of illness and disability not only for the adolescents, but also their family, and the community. In recent years the broader definition of mental health suggests an overall improved well-being as well as absence of illness. Despite the global recognition of the significance of adolescents’ mental health it remains a seriously neglected area in research and policy in Pakistan. This thesis attempts to understand the epidemiology of mental health among Pakistani adolescents by drawing from developmentally informed framework. This thesis proposes that perceptions of relationship with parents and attachment underlie the adolescents’ successful ability to regulate emotions and perceive social support. It also attempts to understand the role of cultural orientation in the pathway of associations between the factors mentioned above. Objectives A quantitative cross sectional design was applied to investigate the state of mental health among Pakistani adolescents. The study also aimed at investigating the validity of constructs of attachment, parental bonding, emotion regulation, social support and cultural orientation in Pakistan and how these factors interrelate in relation to adolescents’ mental health. Methods A sample of eleven hundred and twenty four was recruited from eight secondary schools from the district of Rawalpindi, Pakistan after formal approval from concerned authorities. A battery of self-report measures was administered in class-room setting. Confirmatory factor analysis (CFA) and Structural equation modelling (SEM) were used to analyse the data. Results Prevalence of depression and anxiety among this sample was 17.2% and 21.4% respectively. Results from the CFA of the Urdu versions of the instruments used in the current study replicated the original factor structures in case of well-being, depression, anxiety, parental bonding, emotion regulation, and social support with minor modifications. However, a two factor model of cultural orientation is supported in the current study. In case of parental bonding, a second order factor was found for mother and father bonding showing that both form common factors of parental warmth, protectiveness and authoritarianism. Present study found support for the hypothesized structural equation model examining pathway of association between attachment, parental bonding, social support, emotion regulation and cultural orientation in understanding depression, anxiety and well-being among Pakistani adolescents. Discussion Findings of this study suggest that parental bonding, attachment, emotion regulation, social support and cultural orientation play a crucial role to further our understanding of adolescents’ depression, anxiety and well-being in Pakistani cultural context. Therefore, these are central constructs within a developmental framework and are important when considering long-term psychosocial functioning of individuals. Further implications are discussed regarding the recommendation of promoting and utilizing a developmentally informed approach when working with adolescent population. These findings may be used as base line information in making policy level decisions regarding evaluation, prevention and intervention and of mental health problems among Pakistani adolescents.

Background: Chinese populations have been reported to have a higher stroke incidence as well as different stroke epidemiology compared with white populations. However, reliable comparisons have been precluded by a lack of methodologically robust studies. I aimed to systematically evaluate the incidence of stroke, the distribution of its main types/subtypes, and risk factor distributions among stroke types/subtypes in Chinese, and to compare these with data from white populations. Methods: I performed a series of systematic reviews and meta-analyses of studies conducted since 1990 which had data on (1) incidence of stroke, (2) pathological types of stroke or ischaemic stroke subtypes, and (3) frequency of risk factors among pathological types of stroke or ischaemic stroke (IS) subtypes in Chinese populations, and in white populations for comparison. I calculated age-standardized stroke incidence and the proportions of each pathological type and ischaemic subtype. For each risk factor, I calculated study-specific and pooled odds ratios (ORs) using a random effects model for intracerebral haemorrhage (ICH) versus IS, for each IS subtype versus other subtypes, and for overall IS patients, comparing findings for Chinese versus Whites. In addition, I conducted individual patient analyses of data from the National Taiwan University Hospital (NTUH) Stroke Registry, which consecutively recruited 6675 acute stroke patients from 2006-2011, comparing risk factor profiles among stroke types and subtypes and using logistic regression to adjust for potential confounding factors. Results: From my systematic reviews, I found a younger onset of stroke, a slightly higher overall stroke incidence and higher proportion of ICH in Chinese versus white populations. Although the overall proportion of lacunar infarct appeared higher in Chinese from hospital-based studies than white populations, confirming the different distributions of ischaemic subtypes will need further comparable population-based studies. In my meta-analyses comparing risk factors for ICH versus IS, in Chinese - but not Whites – hypertension (HTN) and alcohol intake were significantly more frequent, while mean age was lower in ICH than IS. In IS, the overall prevalence of hypertension, diabetes, smoking, and alcohol intake were similar between Chinese and white IS patients, whereas hypercholesterolaemia, ischaemic heart disease (IHD) and atrial fibrillation (AF) were less common in Chinese IS patients. As for IS subtypes, the relative frequencies of risk factors were mostly qualitatively similar (although different in size) in Chinese and white populations. Compared with other ischaemic subtypes: large artery atherosclerosis (LAA) strokes were associated with diabetes; cardioembolic (CE) strokes were associated with AF and IHD; small vessel disease (SVD) strokes or lacunar strokes were associated with hypertension and diabetes. Analyses of NTUH individual patient data showed that HTN and alcohol intake were independent risk factors for ICH versus IS in a Chinese population in Taiwan, regardless of age, sex, or other risk factors. The results were consistent with my previous risk factor meta-analyses for ICH versus IS. In IS analyses, the prevalence of hypertension, diabetes, AF, and hyperlipidaemia in overall IS patients based in Taiwan were higher than the pooled results in my risk factor meta-analysis for IS for all Chinese populations including mainland China. In terms of risk factor associations with IS subtypes, the findings after controlling for potential confounders were mostly close to my previous meta-analysis results with the exception of stronger associations of hypertension and diabetes with SVD (lacunar) strokes. Conclusion: I have shown a younger onset of stroke, a higher overall stroke incidence, an around twofold higher proportion of ICH and different distribution of IS subtypes, as well as some differences in risk factor distributions among pathological types of stroke and IS subtypes in Chinese compared with white populations. My results help to inform us of different stroke mechanisms in different populations, to guide further well-designed research in this area, and to direct better strategies for stroke prevention in Chinese populations.

This thesis uses a combination of cognitive-neurophysiological and genetically-sensitive longitudinal designs to study the associations of attention-deficit/hyperactivity disorder (ADHD) with bipolar disorder (BD) and preterm birth, as well as with the risk or protective factors IQ and physical activity. Previous research on preterm-born individuals and individuals with BD suggests ADHD-like symptoms and cognitive impairments, but direct comparisons are limited. Here, we first examine how cortical activity patterns differ between women with adult ADHD and women with BD during rest and task conditions to identify impairments that are specific to or shared between the disorders. The findings provide evidence for commonalities in brain dysfunction between ADHD and BD: frontal theta power may play a role as a marker of neurobiological processes in both disorders. Second, we investigate whether the ADHD-like symptoms and cognitive-neurophysiological impairments seen in preterm-born adolescents are identical to those in ADHD by directly comparing ADHD symptom scores and performance on a cognitive-neurophysiological test battery sensitive to impairments in ADHD across preterm-born adolescents, term-born adolescents with ADHD and term-born controls. We find that ADHD symptoms are increased in the preterm group compared to controls. The analyses further indicate similarities in brain function between ADHD and preterm birth, as well as unique impairments in the preterm group. Taken together, these results suggest that preterm birth may present a risk factor for both ADHD and additional impairments. Third, using twin data we carry out a developmental-genetic analysis of the association between ADHD and IQ, showing that ADHD symptoms and IQ scores significantly predict each other over time. Finally, we explore a putative protective factor for ADHD by investigating the effect of physical activity on ADHD symptoms. Using a population-based sample of twins, we show that physical activity is inversely associated with ADHD symptoms, even after adjusting for unmeasured confounding. Overall, we demonstrate certain commonalities in brain dysfunction between ADHD and BD. Whereas preterm birth and lower IQ present risk factors for ADHD, physical activity emerges as a potential protective factor.

The contacts and collisions that are inherent to elite Rugby Union, alongside changes to players’ physical characteristics and match activities, have raised concerns regarding the level of injury burden associated with the professional game. This programme of research was therefore undertaken to investigate injury risk in this setting. The first study of this thesis (Chapter 3) presents a meta-analytic review of injury data relating to senior men’s professional Rugby Union, which shows an overall match incidence rate of 81 per 1000 player hours; this value is high in comparison with other popular team sports. In Chapter 4, the importance of injuries in the context of performance is demonstrated by showing a substantial negative association exists between injury burden and team success measures. Chapter 5 investigates subsequent injury patterns in this population and identifies injury diagnoses with a high risk of early recurrence, whilst also demonstrating that subsequent injuries are not more severe than their associated index injury. Playing professional Rugby Union on an artificial playing surface does not influence overall acute injury risk in comparison with natural grass surfaces (Chapter 6). Chapters 7 and 8 identify intrinsic risk factors for injury (previous injury, match and training loads) for the first time in this setting, and may be used to inform policies on these pertinent issues. Finally, predictive modelling techniques show some potential for predicting the occurrence and severity of injuries, but require further refinement before they can be implemented within elite Rugby Union teams. Overall, this programme of work highlights the importance of injury prevention for all professional Rugby Union stakeholders, addresses the need to use appropriate statistical techniques to account for the dynamic and clustered nature of sport injury data, and demonstrates approaches through which the injury burden associated with elite Rugby Union may be reduced.

Resilience, as a trait, process or outcome, is the negation of an undesirable outcome or of an expected maladjustment in the context of an adversity. Young people represent a developmental stage in which there is a vulnerability to experience deleterious outcomes during adversity. The literature on risk and promotive factors for resilience in youth is compounded by narrative reviews which have not applied a rigorous search methodology and which have failed to operationalise resilience. To date, the majority of research in resilience for emotional distress has focussed on data collected in high income countries. The first paper presents a systematic review of the literature on risk and promotive factors for trait resilience in youth. The findings indicate that there are differences in the magnitude of association between trait resilience and various risk and promotive factors, which were conceptualised into biological, intrapersonal, interpersonal and environmental factors. The largest body of evidence reviewed pertained to intrapersonal risk and promotive factors for trait resilience. Factors predicting trait resilience were also identified. Implications for future research include addressing the methodological and sampling limitations of the reviewed studies. The second paper presents an empirical study investigating factors within a microsystem which differentiate adolescents with resilience for emotional distress and those vulnerable to emotion distress in India (N = 967) and in Peru (N = 606). Factors which predict low emotional distress in each country and factors which differentiate between low emotional distress Indian and Peruvian adolescents were additionally investigated. A cross-sectional exploratory investigation of secondary data was employed. The findings suggest that the profile of low vulnerability for emotional distress differs between different cultural contexts and contribute to an extraordinarily limited evidence-base in low and middle income contexts. Extensive additional research is required to delineate culturally-specific profiles of resilience for emotional distress in a bid to develop culturally-sensitive treatment targets.

There is limited research into the impact of non-specific factors on the outcome of Cognitive Behaviour Therapy (CBT). This current study aimed to investigate the relationship between client and therapist attachment styles and client interpersonal problems to the therapeutic relationship and symptom reduction over eight sessions of CBT. Seventeen therapist-client dyads were asked to complete measures of interpersonal problems, attachment style and report on the therapeutic relationship. Results showed that in this small sample there was a relationship between core alliance, as rated by clients, to reduction in symptoms of depression over the course of eight sessions of CBT (TB=0.423, p<0.05) but not anxiety. Client level of confidence in relationships was negatively correlated with the reduction in anxiety symptoms over time (TB =-.320; p<0.05). The level of difference in scores on a measure of ‘confidence in relationships’ between therapists and clients was found to be positively correlated to the level of reduction in anxiety scores over eight sessions (TB = .0428; p<0.05) and negatively correlated to the therapist rated core alliance (TB=-.428, p<0.05). These results indicate that the role of attachment styles in CBT warrants further investigation and both clinical and theoretical implications of these findings are discussed. Key words: Cognitive Behaviour Therapy, therapeutic relationship, treatment outcomes, attachment, interpersonal problems Service Improvement Project Title: What is helpful about attending an Alzheimer’s café: does it do what it says on the tin? Abstract: Alzheimer’s Cafes were developed in 1997 in the Netherlands and have since been set up all over the world. They are a post-diagnostic support group for people with dementia and their families with an aim to reduce stigma around having dementia. As yet there have been very few evaluations of these cafes. This project aimed to find out what family carers of people with dementia found helpful about attending one of two Alzheimer’s cafes. Seven carers took part in a focus group and two were interviewed individually about what they found helpful about attending an Alzheimer’s Café and what they thought could be improved on in the future. Results showed that people found the opportunities to socialise with others ‘in the same boat’ the most helpful aspect as well as meeting professionals outside of the clinic. The results of this study will enable the development of a questionnaire that can be used to continue to evaluate the café and the feedback provided used to guide future service development. Key words: Alzheimer’s Café, social support, dementia, service evaluation Critical Literature Review Title: Risk and protective factors for psychological adjustment of children born with a cleft lip and/or palate and their families: A review of the literature Abstract: Research suggests that around 30-40% of children born with a cleft lip and /or palate will develop psychological difficulties. Services supporting these individuals need to be able to identify those that might be vulnerable as early as possible so that preventative support can be offered. This review summarises findings from research studies looking at within-group differences in samples of children with a cleft and their families. Risk factors found included being male, experiencing bullying or having additional difficulties. Protective factors included satisfaction with appearance and social support. The methodological strengths and weaknesses of these studies are discussed along with implications of the findings for theory and clinical practice.

Multiple sclerosis is a complex immune mediated condition of the central nervous system characterized by myelin loss and progressive neurodegeneration. The risk of developing MS is influenced by both genetic and environmental agents and, among them, several lines of evidence support a role for vitamin D deficiency, Epstein-Barr virus (EBV) infection and smoking in the aetiology of this disease. The aim of this work was to further elucidate how nature and nurture act in the causal cascade leading to MS. In chapter 1, I show that the main genetic factor in adult MS (the HLA-DRB1*1501 allele) plays an equally important role in paediatric cases of MS (PMS) and that EBV negative PMS patients represent a separate entity characterized by lower age at disease onset, lower female to male ratio and a trend towards a lower frequency of the HLA-DRB1*1501 allele. In chapter 2, I provide evidence in support of month of birth having a role on MS risk and T cell production and that vitamin D may underlie this effect. In chapter 3 I demonstrate the presence of a link between vitamin D deficiency and the immune response against EBV, whereby the proportion of EBV seropositive MS patients and controls increases with increasing latitude and high dose vitamin D supplementation appears to reduce the level of antibodies against this virus. In chapter 4, I show that MS associated genetic variants are located in genomic regions that exert a regulatory function and are active in immune cell types. In chapter 5, I illustrate how vitamin D receptor binding is also located within active regulatory regions in immune cells and that this is particularly evident near MS associated genes. Finally, in chapter 6, I use chromatin data on more than 100 different cell types and conclude that MS associated genetic variants are particularly active in T helper, T cytotoxic and B cells. Further work is needed to elucidate how genetic and environmental agents play a role in the cause of MS and to develop effective strategies for disease treatment and prevention.

Over the past 20 years there has been a clear shift in Peru’s mortality profile towards non-communicable diseases. As part of this transition, childhood overweight and obesity (O&O) has become a growing public health concern. In order to address this challenge, context-specific information is needed concerning prevalence, associated factors and culturally appropriate interventions. To this end, I conducted a mixed methods study using a socio-ecological framework to investigate childhood overweight and obesity in Peru. This study found a prevalence of 19.2% overweight and 8.6% obesity among children aged seven to eight in a pro-poor cohort in Peru. Factors associated with being overweight in this cohort included: a high socioeconomic status, living in metropolitan Lima, an O&O mother, being male and being an only child or having only one sibling. The quantitative analysis highlighted the prevalence in O&O in this population and revealed a number of relationships explored in more depth via interviews and focus group discussions. The qualitative component of this research explored these associations amongst a sub-sample of children, parents and teachers in three distinct geographical regions in Peru. My qualitative research showed that parents, teachers and children are aware of the health implications of childhood overweight and obesity and that they have a sophisticated understanding of the many factors that influence its aetiology. Participants also had many suggestions for ways to address this issue in their community. This information was complemented by a systematic review and meta-analysis of the evidence of childhood O&O interventions that took place in Latin America published between 1990 and 2011. A combination of diet, physical activity and pharmaceutical strategies have shown modest effect on BMI reduction in O&O children, but more evidence is needed for effective population-level prevention strategies. The findings highlight the need for comprehensive, multi-level interventions. Notable intervention components include: kiosco reform, junk food taxation, creation of recreational space and enhancement of school-based physical activity programmes. To accomplish this, communities need to be mobilised and work together with school administration, municipal and national government.

Background: Child abuse in South Africa is a significant public health concern with severe negative outcomes for children; however, little is known about risk and protective factors for child abuse victimisation. This thesis investigates prevalence rates, perpetrators, and locations as well as predictors of physical, emotional and sexual child abuse victimisation. It also examines the influence of potential mediating and moderating variables on the relationships between risk factors and child abuse. Methods: In the first study, a systematic review of correlates of physical, emotional and sexual child abuse victimisation in Africa was conducted. The review synthesised evidence from 23 quantitative studies and was used to inform the epidemiological study. For study two to four, anonymous self-report questionnaires were completed by children aged 10-17 (n=3515, 57% female) using random door-to-door sampling in rural and urban areas in two provinces in South Africa. Children were followed-up a year later (97% retention rate). Abuse was measured using internationally recognised scales. Data were analysed using descriptive statistics, multivariate logistic regressions, and mediator and moderator analyses. Results: The first study, the systematic review, identified high prevalence rates of abuse across all African countries. It identified a number of correlates which were further examined using the study data from South Africa. The second study found lifetime prevalence of abuse to be 54.5% for physical abuse, 35.5% for emotional abuse, 14% for sexual harassment and 9% for contact sexual abuse. Past year prevalence of abuse was found to be 37.9% for physical abuse, 31.6% for emotional abuse, 12% for sexual harassment and 5.9% for contact sexual abuse. A large number of children experienced frequent (monthly or more regular) abuse victimisation with 16% for physical abuse, 22% for emotional abuse, 8.1% for sexual harassment and 2.8% for contact sexual abuse. Incidence for frequent abuse victimisation at follow-up was 12% for physical abuse, 10% for emotional abuse and 3% for contact sexual abuse. Perpetrators of physical and emotional abuse were mostly caregivers; perpetrators of sexual abuse were mostly girlfriends/boyfriends or other peers. The third study found a direct effect of baseline household AIDS-illness on physical and emotional abuse at follow-up. This relationship was mediated by poverty. Poverty and the ill-person’s disability fully mediated the relationship between household other chronic illnesses and physical and emotional abuse, therefore placing children in families with chronic illnesses and high levels of poverty and disability at higher risk of abuse. The fourth study found that contact sexual abuse in girls at follow-up was predicted by baseline school drop-out, physical assault in the community and prior sexual abuse victimisation. Peer social support acted as a protective factor. It also moderated the relationship between baseline physical assault in the community and sexual abuse at follow-up, lowering the risk for sexual abuse victimisation in girls who had been physically assaulted from 2.5/1000 to 1/1000. Conclusion: This thesis shows clear evidence of high levels of physical, emotional and sexual child abuse victimisation in South Africa. It also identified risk and protective factors for child abuse victimisation which can be used to inform evidence-based child abuse prevention interventions.

Current treatment practice guidelines in a number of countries mandate the assessment of violence risk in all patients diagnosed with schizophrenia. Although more than 100 different instruments have been developed to facilitate the assessment of violence risk, few have been specifically validated for use in those with schizophrenia. Recent work instead suggests that these instruments are typically associated with lower predictive validity in samples with schizophrenia when compared to that achieved in diagnostically heterogeneous samples, leading to concerns that these instruments omit risk factors that may be specific to the prediction of violence risk in this population. The present thesis therefore aimed to investigate the predictive validity of a number of risk factors for violence in those with schizophrenia. Firstly, to identify key risk factors for violence, a meta-analysis was undertaken, finding that although a number of criminal history risk factors are strongly associated with violence risk, nonetheless a number of risk factors rarely assessed by existing violence risk assessment instruments were significantly associated with violence in those with schizophrenia; most notably a history of attempted suicide. Results of this review also suggested that although the criminal history domain is most strongly associated with violence risk, nonetheless, there is considerable variability in the magnitude of association for the individual risk factors. Study two therefore aimed to investigate this variability and found that a history of violence was most strongly associated with subsequent violence. Study three aimed to identify whether suicidal behaviour, which has rarely been considered risk factors for violence in previous work, incrementally contributes to the prediction of violence. A simple risk model composed of young age, comorbid substance use disorder, previous violence, and a history of suicidal threats, explained as much predictive validity, as measured by the area under the receiver operating characteristic curve, as established risk assessment instruments such as the HCR–20, LSI–R, PCL–R, and VRAG. Current risk assessment approaches may therefore need revision in light of these findings.

Background: The opioid crisis in the United States has affected millions of individuals, causing high levels of opioid addiction among the population. With the onset of synthetic opioids, deaths from opioid-related causes have increased drastically. This study aims to understand the effect of opioid addiction and methods of controlling the problem for adult African Americans and Latinos at Pathways to Recovery Counseling and Education Services, Hazleton, Pennsylvania. Methods: The theories guiding this study are the Intersectionality Model and the Bay Area Regional Health Inequalities Initiative (BARHII) model. These theories reveal that factors such as age, ethnicity, and gender have a significant impact on opioid misuse patterns. Results: The study revealed that opioid addiction negatively impacted cognition, social life, and emotional control, as 45% of the participants felt isolated from friends and family, 35% of the participants experienced anger issues and frequent arguments, loss of employment among 30%, and an increased tendency to engage in crime, evident by the fact that 30% of the participants had been to prison or a correctional facility. About 60% of the participants started using opioids to control physical pain and emotional trauma, while 55% obtained non-prescription opioids from illegal sources. Gender did not appear to have an impact on opioid use, as men and women showed a similar pattern of using opioids. Conclusion: The use of opioids among adult Latinos and African Americans was influenced by their ethnicities, in addition to other factors, which limited their ability to access quality health services from healthcare facilities.

Behaviour difficulties displayed in childhood and adolescence have pervasive and long term effects into adulthood and across various domains of functioning (Healey, et al. 2004, Woodward, et al. 2002). The numbers of children who suffer with them remain worryingly high (Green et al. 2005). Children with special educational needs and disabilities (SEND) are considered particularly at risk of displaying behaviour difficulties; however, despite representing around one fifth of the school population (DfE 2011), little research to date has explicitly investigated these problems in this population. The present study therefore aimed to investigate risk, promotive and protective factors for behaviour difficulties in children with SEND across multiple ecological levels. Data were collected through a concurrent research project evaluating Achievement for All (Humphrey et al. 2011). The sample comprised children identified with SEND in years 1, 5, 7 and 10, from ten local authorities deemed representative of England. A final sample consisted of 2660 primary pupils nested in 248 primary schools and 1628 secondary pupils nested within 57 secondary schools. Predictor variables were measured at the individual and school levels at baseline, along with a teacher reported measure of behaviour difficulties which was assessed again eighteen months later. Analyses were carried out using multi-level modelling revealing that primary schools accounted for 15% and secondary schools 13% of the total variance in behaviour difficulties, with the remainder being at the individual level. Significant risk factors for these problems across both school types were: being male; eligibility for FSM; and being a bully. Risk factors specific to primary schools included being autumn born, being older in the school, having poor positive relationships, and attending schools with lower levels of academic achievement. Risk factors specific to secondary schools included being younger in the school, having poor attendance, having poor academic achievement, being a bystander to bullying and attending a larger school. Results showed evidence for a cumulative risk effect that increasing numbers of contextual risk factors, regardless of their exact nature, resulted in heightened behaviour difficulties. This relationship was non-linear with increasing risk factors in an individual’s background having a disproportional and detrimental increase in behaviour difficulties displayed. The specific type of risk was however, more important than number of risk factors present in an individual’s background in accounting for behaviour difficulties displayed. Finally, results revealed significant protective factors at the school level; specifically attending primary schools with high academic achievement and with more children on the SEND register at school action can protect against the display of behaviour difficulties when these children are at risk in terms of having poor positive relationships. Attending urban secondary schools can also protect against the display of behaviour difficulties, when these children are at risk in terms of having poor academic achievement. The implications of these findings are discussed along with directions for future research.