Events in utero have been linked with diseases throughout life, however there is a lack of consensus regarding the ability of neonatal tests to predict these outcomes. Systematic reviews and meta-analyses were performed, assessing umbilical cord pH and base excess at birth, standards of low birth weight, and the Apgar score, including a total of 218 papers and 26704980 individuals. The prognostic association and predictive accuracy of these tests for adverse outcomes, including neonatal mortality and morbidity, childhood morbidity including cerebral palsy, and adult outcomes, were determined. A decision-analytic model based analysis assessed the cost-effectiveness of varying the umbilical cord pH threshold, and treatment with neonatal hypothermia. This thesis determined that all of the tests examined had a strong association with neonatal mortality, and a significant but smaller association with neonatal morbidity and childhood cerebral palsy. In general, where the association was strong, tests had a high specificity and positive likelihood ratio for adverse outcome, but poor sensitivity and negative likelihood ratio, indicating that negative tests do not reduce the risk. The cost effectiveness analysis showed that the threshold of pH used in current practice to recommend neonatal hypothermia is more effective and less costly than a higher threshold.

Measles is a leading cause of mortality in infants in countries with suboptimal vaccination coverage. This disease is caused by a negative-strand RNA virus, measles virus (MeV). Wild-type strains of the virus use two cellular receptors to invade cells and establish infection: the signalling lymphocyte activation molecule f1 (SLAMF1), which is present on certain immune cells, and nectin-4, which is expressed in the lung epithelium. During infection, MeV can spread through the release of virions or by inducing cell-cell fusion. The aim of this thesis is to determine the molecular mechanism underlying viral entry and exit. Herein, I observed that, upon attachment to SLAMF1+ cells, MeV particles induce extensive but transient membrane blebbing and cytoskeleton contraction. MeV entry occurred simultaneously with fluid-uptake and was sensitive to inhibitors of macropinocytosis and cytoskeleton dynamics. In contrast, the cortical actin network restricted the early stages of MeV-induced cell-cell fusion, in RhoGTPases, ezrin and moesin dependent manner. By resolving the proteome of infected cells, conserved phosphorylated residues in the viral haemagglutinin were also shown to impact on dimerization and cell-cell fusion. These results suggest the manipulation of several cellular components and pathways during entry and exit of MeV.

Meningitis and cholera have remained major health burden in Nigeria, especially in the heavily populated northwest region – which is identified as one of the “hotspots” of climate change. The strong sensitivity that both diseases exhibit to climate is raising concern that future anthropogenic climate change may exacerbate the occurrence of the diseases. This thesis aimed at modelling the influences of climate on the incidence of the selected diseases, and assessing their future risk in northwest Nigeria. The aim is achieved by first, investigating and understanding the spatial and time characteristics of both meteorological and diseases conditions in the region. This was followed by developing and validating suites of empirical statistical models capable of explaining and predicting both diseases. Models that are specifically designed for climate change studies were applied to estimate the future impact of climate change, by forcing them with simulations from an ensemble of statistically downscaled Atmosphere-ocean Global Climate Models (AOGCMs), for three different scenarios in the early and late 21st century. Results from developed models indicate the significant roles of both meteorological and socioeconomic factors on incidence of diseases. Evaluation of models developed with 1-month lagged explanatory variables suggest the potential to predict both diseases cases up to a month to aid decision making. Projection results suggest that future temperature increases due to climate change has the potential to significantly increase diseases cases in all scenarios and time slices. It is noteworthy that the projections result represents only the climatological potential for increased cases due to climate change, assuming that the present prevention strategies remain similar in the future.

The experiments documented in this thesis investigate the use of aqueous two-phase systems (ATPS) as a viable method for the processing of influenza virus particles in a feedstock derived from embryonated hen's eggs. The virus particles are currently purified in an industrial process using stages of sucrose density gradient ultracentrifugation that produce a subunit vaccine Fluvirin which consists of the immunoprotective antigens haemagglutinin (HA) and neuraminidase (NA). The current purification scheme suffers process bottlenecks in particular, limitations of scale hence volumetric throughput and time taken to produce a batch that could be circumvented by ATPS. Manipulations of polyethylene glycol (PEG) molecular weight, tie-line length (TLL) and volume ratio were exploited for the design of aqueous two-phase systems. A simple two-stage process was designed in which, (i) 60 % (by mass) of contaminating proteins were eliminated in an ATPS comprising PEG 300 22.2 % w/w/ phosphate 17.9 % w/w at pH 7.5 and (ii) HA antigen was released from intact influenza particles in the presence of 1 % w/w Triton X100 in an optimised secondary ATPS comprising PEG 300 13.9 % w/w/ phosphate 24.3 % w/w, pH 7.5. The first purification stage using ATPS performed as well as the ultracentrifugation method. The material was produced with purification factor of 4.2 and intact virus recovery of 72 % within one hour, (as compared to a purification factor 4.0 and recovery of 109 % within 18 hours, using ultracentrifugation). Thus ATPS has demonstrated potential in fractionating particulate feedstocks in relatively short times, thus facilitating the circumvention of bottlnecks in the current commercial process.

The primary aim of the thesis was to report new cost-effectiveness evidence in the clinical area of heart disease. Following a review of published empirical work, this was achieved by undertaking three new cost-effectiveness studies: one in nurse-led secondary prevention clinics for coronary heart disease in primary care, one on cardiac resynchronisation therapy with or without an implantable cardioverter defibrillator in chronic heart failure, and the final one on a new drug therapy, nebivolol, compared with standard treatment in elderly patients with heart failure. The second aim of the thesis concerned the application of modelling methodology, with the intent being the provision of general recommendations in using Markov modelling approaches in economic evaluation conducted in the heart disease area. The focus was on extrapolation of cost-effectiveness of an intervention beyond a trial both in terms of the time horizon of the analysis and in relation to the population involved. Fundamental issues in parametric distribution functions and Markov modelling approaches have been revisited, with detailed consideration of which parametric distribution functions should be employed when extrapolating beyond a trial and how they could be adopted into model-based analyses. The need for further methodology investigations in this area is discussed in conclusion.

This study of the medical role of the urban workhouses of Birmingham and Wolverhampton after the New Poor Law addresses the following questions: what were the standards of medical and nursing practice and what treatments were used to alleviate inmates’ suffering? It considers the nature of illnesses encountered covering acute non-infective illnesses, infectious disease and chronic disability, and highlights the important role the workhouse played in providing institutional care, especially in the isolation of epidemic diseases. Birmingham workhouse had a well-developed medical service prior to the New Poor Law and this continued until the mid-nineteenth century. By comparison, Wolverhampton workhouse did not meet satisfactory levels of medical and nurse staffing until near the end of the century. The study provides a new perspective on medical care in workhouse infirmaries by showing how standards varied over time within the same institution and how medicalisation of the workhouse began in the early years after the New Poor Law. Medical care in workhouses has been viewed as important only in the context of the development of the National Health Service but this study demonstrates that it provided significant, and at times high quality, medical treatment for the poor.

Volume I comprises a review of the literature about children and young people with Coeliac Disease, a common autoimmune disease characterised by an immune response to the protein gluten, found in wheat, barley and rye. It also comprises a qualitative research paper detailing interviews with young people that aimed to tap their lived experiences of the disease. The final part of Volume I comprise a public domain briefing paper summarising both the literature review and research paper. The literature review considers the evidence for problems with adherence to treatment (a lifelong diet free from gluten) for young people with Coeliac Disease as well as psychological effects of having the disease in childhood. Studies of parental views were also included. The results suggested that there is some element of psychological distress associated with having CD in childhood, and that adherence to the treatment appears to be influenced by age and gender. Studies of parents’ views about their child’s Coeliac Disease suggested that parents’ belief in their ability to manage the disease is important to how young children adhere to treatment. The research project describes how 5 children and young people were recruited and interviewed about their experiences of living with Coeliac Disease. The resulting data were analysed using Interpretative Phenomenological Analysis and two themes were subsequently identified. These themes related to identity as a young person with Coeliac Disease and to perceptions about food. Volume II comprises five Clinical Practice Reports: Clinical Practice Report 1 describes the “challenging behaviour” of a 42 year old man with learning disabilities. Subsequently, formulations of this behaviour from a behavioural and a systemic perspective are presented. Clinical Practice Report 2 is a service evaluation conducted in the Heart of Birmingham that aimed to measure outcomes for adults with a learning disability, as well as considering outcomes separately for different ethnic groups. Clinical Practice Report 3 is a case study of a 16 year old girl with anger difficulties using CBT within the Solihull Approach model. Clinical Practice Report 4 describes cognitive-behavioural intervention with a 39-year old man suffering with anxiety as a result of residual psychotic symptoms. Clinical Practice Report 5 was an oral presentation of a piece of clinical work completed with staff at a day hospital for older adults, conducted in order to help the staff adjust in their move to a new location.

Self-tests that involve taking a biological sample to diagnose or screen for conditions without a health professional are available to the public, but they could potentially cause harm, such as false reassurance. This study aimed to describe the prevalence of their use and factors associated with using them. A systematic internet search established the availability of self-tests and informed the design of an initial questionnaire about whether people registered with general practices had used them. Interviews with respondents and a systematic literature review informed the design of an in-depth questionnaire to confirm use and investigate associated factors. It was estimated that 55 (95% confidence interval 41-68) per 1000 men and 95 (81-110) per 1000 women have self-tested excluding for pregnancy. Use was predicted (p<0.1) by: knowing about a range of tests, seeking health information, exercising less frequently, reporting not good health, having worked as a health professional, and believing health was controlled by chance and not powerful others. Being less satisfied with GP consultations and strongly agreeing that you should only see the doctor if you have serious symptoms also predicted use, implying that some use may be motivated by needs that have not been met by conventional services.

My main thesis is that Saudi culture, in the context of the field of Molecular Genetics Epidemiology (MGE) research, poses many challenges to the currently used biomedical research regulations developed by the Saudi National Committee of Bioethics (NCBE). The NCBE regulations are informed by selected international research ethics guidelines, and they are influenced by a set of assumptions about how we ought to think about ethics. The overall focus is on a version of liberalism, where there is a strong commitment to autonomy, there is a significant focus on informed consent, the harm principle guides the justification of action, and paternalism is seen as something that is to be avoided. There are no specific guidelines that regulate MGE research in Saudi Arabia. Therefore, it was important as a first step in the thesis to analyse the relevant regulations (both the Saudi and the selected international ones) and explore the related normative issues. One of the main empirical findings was an observed and reported lack of adherence to the requirements of the NCBE regulations. In this thesis I argued that the problem emerges from a mismatch between the liberal international guidelines and the nature of the Saudi context. One possible way to address this tension is to formulate a set of guidelines and research practices that build upon the nature of Saudi social relations and norms. This may result in a focus on what we can call trust-based, rather than the currently promoted autonomy-based, bioethics.

Volume one contains a systematic literature review, an empirical chapter and a public domain briefing. The review explored the phenomenology of skin picking (a self-injurious behaviour) in people with Prader-Willi syndrome (PWS). A number of characteristics were well described with some areas of limited research, e.g. frequency and duration. Skin picking in people with PWS and in the typically developing population was compared showing that there were more similarities than differences. The empirical chapter further explored the phenomenology of skin picking in people with PWS and associated management techniques by using a semi-structured interview. Informants reported on the age of onset, frequency and duration of skin picking, type of skin picked, damage caused, antecedents and the influence of pain. The most common management strategy used by parents and carers was distraction and the majority of participants with PWS did not have their own management strategy to try to reduce skin picking. Results of both chapters are discussed within the context of previous research and the clinical implications are considered. Volume two contains five clinical practice reports conducted at various mental health services; a models essay, a service evaluation, a single case experimental design and two case studies.