The aim of this study was to determine the extent of dissemination of pCT, a blaCTX-M-14 carrying plasmid, and to investigate the factors which allow pCT to stably persist within bacterial populations. DNA sequencing of pCT allowed the design of a PCR assay for rapid detection of pCT, which showed pCT has disseminated worldwide in bacteria from humans, animals and the environment. pCT was stably maintained in the absence of β-lactam antibiotic pressure in four different bacterial host strains over ~70 generations, and conferred neither a fitness advantage nor disadvantage to two host E. coli strains. Seven pCT genes of interest in relation to plasmid success were identified and insertionally inactivated to investigate their role in the ‘success’ of this plasmid. Inactivation the conjugation pilus reduced the frequency of pCT transfer however inactivation of the five other pCT genes had no consistent effect on the host bacterial strain persistence or dissemination. In conclusion, pCT was shown to be a globally successful plasmid. The persistence and spread of pCT is postulated to be due to a combination of stability, a lack of a fitness burden and proficient conjugation, rather than any one particular gene or phenotypic benefit conferred to the host.

This body of work sought to explore kinematic impairments which may underlie falls incidences during turning following stroke and review the evidence for the effectiveness of interventions aimed at improving aspects of locomotor coordination which are key to controlling turning. A systematic review of the literature identified insufficient homogeneity of high quality evidence to determine if task specific locomotor practice interventions are effective in improving aspects of gait coordination which are key to the controlling turning. The review highlighted a need for a better understanding of the nature of coordination deficits in functional walking tasks, such as turning, after stroke. In order to provide a base of knowledge regarding abnormalities in the coordination of locomotor patterns during turning while walking, two experimental studies were undertaken. The studies employed analysis of full-body kinematics during turns made under pre-planned and reactive conditions as well as turns of different magnitudes and those made by participants with and without a falls history. Findings from Study 1 showed a strong trend for participants with stroke (in particular those with lesions involving the basal ganglia) to initiate pre-planned turns later than their age-match counterpart. Turns made in response to an external cue were made in a similar manner to healthy controls. Results from study 2 indicate that while participants with stroke and falls history took significantly longer to turn, all other aspects of the movement pattern were similar to healthy controls and non-fallers. Therefore, incidences of falls during turning following stroke may not be due to impaired movement patterns alone. On this basis, we suggest that rehabilitation efforts and further studies should address the interplay of impaired movement production with other factors such as attention.

Carboxyl-modified polystyrene nanoparticles (COO-PS-NPs) have many potential applications, for example drug-delivery systems, but their toxicity remains poorly assessed. In the current study, characterisation, uptake and toxicity of two sized COO-PS-NPs in cultured BEAS-2B lung epithelial cells were investigated. The 20nm sized COO-PS-NPs tended to aggregate heavily in the cell culture media yielding larger aggregates, in contrast the 100nm COO-PS-NPs were stable. Electron and confocal microscopy demonstrated that COO-PS-NPs rapidly accumulate in vesicle-like structures within cells and fluorescent organelle co-staining showed the presence of 20nm COO-PS-NPs in mitochondria and the 100nm COO-PS-NPs in Golgi apparatus. Cellular studies revealed that COO-PS-NPs cause GSH depletion and induce ROS generation resulting in oxidative stress. Studies in a cell-free system showed that COO-PS-NPs directly deplete levels of GSH in solution. Size- and concentration-dependent DNA strand breaks (by comet assay) were also observed and both 20nm and 100nm COO-PS-NPs induced caspases-3/7 activation in a Ca2+ independent manner, however a significant decrease in cell viability was observed only at high concentrations of 20nm COO-PS-NPs. In summary, this in vitro study demonstrated that toxicity of the 20nm COO-PS-NPs is mediated by oxidative stress after co-localisation to the mitochondria and that further studies are needed to assess the safety of COO-PS-NPs.

Rheumatoid arthritis (RA) is the most common inflammatory arthritis and patients require appropriate information and education. Cardiovascular disease (CVD) accounts for 50% of its mortality, due to both clustering of traditional risk factors and the novel role of systemic inflammation. However, there are no educational materials about CVD designed specifically for people with RA; existing generic resources are likely to be inadequate as their advice is not set in the context of the physical and psychosocial constraints of RA. Using a recommended framework for the design of complex interventions, qualitative stakeholder research was undertaken which informed the design of an eight week cognitive-behavioural education programme, underpinned by social cognition models and stages of change theory. An appropriate outcome questionnaire was developed and psychometrically validated. A randomised controlled trial of this programme showed that, compared to controls, patients achieved significant improvements in knowledge, which translated into changing their psychological views, particularly intentions, to make behaviour change and, in turn, an improvement in diastolic blood pressure was observed. The implications of this study are that patient education has a significant role to play in CVD risk factor modification for patients with RA and furthermore a theoretically-driven process of developing patient education materials is the approach most likely to yield dividends.

In Europe, Health Technology Assessment (HTA) bodies produce coverage decisions that guide public funding of pharmaceuticals. This thesis examines and weights those factors that drive HTA coverage decisions, focusing on the National Institute for Health and Clinical Excellence (NICE) in England and Wales, the Scottish Medicines Consortium (SMC), the Dutch College voor Zorgverzekeringen (CVZ), and the French Haute Autorité de Sante (HAS). To address the research question, a dataset of approximately 1000 HTA coverage decisions by NICE, SMC, CVZ and HAS from the period 2004-2009 was created, containing more than 30 clinical, economic, process and socio-economic factors extracted from published HTA reports. A three-category outcome variable was used, defined as the decision to ‘recommend’, ‘restrict’ or ‘not recommend’ a technology. Multivariate analyses were conducted to assess the relative contribution of the explanatory variables on coverage decisions both within and between HTA bodies. Results demonstrate that different combinations of clinical/economic evidence, process and socio-economic factors drive HTA coverage decisions by NICE, SMC, CVZ and HAS. In addition, the same factor may behave differently according to the nature of the coverage decision. The analysis further suggests there is a significant difference between HTA bodies in the probability of reaching a ‘restrict’ or ‘not recommend’ decision outcome relative to a ‘recommend’ outcome, adjusted for evidence, process and context factors. This thesis contributes to the understanding of factors driving HTA coverage decisions by examining multiple European HTA bodies, enhancing the comprehensiveness of the factors examined through descriptive and multivariate analyses and by identifying and weighting the key drivers of the coverage decisions made by the four HTA bodies between 2004 and 2009. This research further provides relevant insights to variation among HTA bodies in the determination of patient access to pharmaceuticals, and implications for collaboration between European HTA bodies.

Schizophrenia is a chronic illness which has severe consequences for the lives of patients and their families. The costs associated with treating individuals with schizophrenia are considerable. This thesis examined the relationship between non-adherence to medication, patient-, environmental- and medication-related factors and the costs associated with health and social care services used and the wider societal costs in treating individuals with schizophrenia. Analysis was undertaken of data from the 1993-4 and 2000 Psychiatric Morbidity Surveys and the Quality of Life following Adherence Therapy for People Disabled by Schizophrenia and their Carers study. An individual’s level of education, having had a recent inpatient stay and alcohol abuse were found to be associated with a greater likelihood of non-adherence in individuals taking antipsychotics. These results were not observed in analyses of individuals taking antidepressants. Common factors associated with non-adherence across individuals taking antipsychotics and antidepressants included experiencing side-effects and severity of illness. Community-based services were found to be used more by individuals with interruptions in their antipsychotic medication. In this group there may also be additional costs in hospitalisations and overall health and social care services attributable to non-adherence. Benefits to patients may be accrued by enabling health and social care professionals, particularly those working in the community, to encourage medication adherence in individuals with schizophrenia and to provide information on new interventions that are cost-effective in improving adherence. National Institute of Clinical Excellence (NICE) guidelines for treating individuals with schizophrenia, revised in 2009, address some key findings in my analyses, such as emphasising the role of carers and family members in successful management of the illness, the potentially adverse impact that illicit drug use can have on therapeutic effects and issues around service provision to individuals from ethnic minorities. Further analysis of data from long-term studies is required to determine the clinical, economic and personal consequences of non-adherence.

This study explores the changing nature of employment and employment management within multi-organisational public services ‘partnerships’. In line with international trends, a major feature of the 1997-2010 New Labour government’s public policy was encouraging partnerships between organisations of all sectors to run public services. Within healthcare, central government has increasingly been seen as taking on a role of market regulator, with organisations from all sectors allowed to plan as well as provide public services (Illife and Munro, 2000). As part of this picture, bringing private companies into partnership arrangements with the National Health Service has been seen as a catalyst for workforce re-configuration and employment change through furthering the reach of private sector type Human Resource Management. However, research has illustrated how inter-organisational contracts can also restrict an organisations choice of employment practice, disrupt the direct relationship between managers and employees, and undermine any aspirations for fair or consistent employment (Marchington et al, 2005). In more recent healthcare partnerships, employment is further complicated as partnerships involve powerful professional groups with their own protected employment systems and established norms of practice. This study seeks to investigate the prospects for HRM within such a professionalised partnership context through comparative case study of two Independent Sector Treatment Centres (ISTCs) operating under differing employment regulations and contractual agreements. In both cases, private sector management sought to impose a more ‘rationalised’ and standardised approach to work with a greater focus on outputs and productivity, placing ISTCs at the forefront of the Fordist ‘scientific-bureaucratic’ (Harrison, 2002) approach to medicine. However, the study identifies a number of limits to the degree to which the management of the private health care companies could shape HRM practices in line with these aims. The thesis also examines how being separate from, or integrated with, existing National Health Service organisations can lead to different types of contingencies affecting work and employment, and multiple varieties of inconsistency across the workforce. The findings of the study are explored in terms of the implications for public policy, health service management and HRM theory.

The twin concerns of the thesis are (a) to develop a labour process analysis that is able to account for professional work and (b) in so doing to explain the reasons for hospital doctors various responses to the introduction of computer systems into medical work. This thesis constitutes a study of hospital doctors (clinicians) use of information technology in their clinic work. The first part reviews the literature and general developments in medical computing in relation to a theoretical analysis of the organisation and control of the clinic/medical labour process. The second part consists of an ethnographic study of the introduction of computer-based medical information systems into three hospitals; two being case studies of renal units and associated clinics and the third a study of an outpatients' department at a small acute hospital. The computer systems involved either replaced or supplemented the traditional form of the medical records and for this reason it was possible to focus on the role of these organisational records in the maintenance and reproduction of dominance and subordination within the labour process of clinic/medical work.

There is an urgent need for additional HIV prevention options for women. Evidence supporting the benefit of microbicides in reducing the risk of vaginally acquired HIV acquisition has provided a major breakthrough. Despite the wealth of evidence supporting microbicide acceptability in Africa, there are still gaps in our understanding about how women will incorporate microbicides into their everyday lives. In this thesis I examine whether vaginal microbicides are compatible with socio-cultural norms regarding sexuality and sexual health in a predominantly rural area of KwaZulu-Natal, South Africa. Using qualitative and quantitative data collected as part of the MDP 301 clinical trial at the Africa Centre, I adopt a mixed methods approach to evaluate microbicide acceptability from a cultural perspective. I explore the compatibility of microbicides with socio-cultural norms that relate to intravaginal cleansing, intravaginal insertion, love medicines and sexual communication. I found that the desired effects of using intravaginal insertions to enhance sexual pleasure are compatible with the experiences of using microbicides; that contemporary socio-cultural norms relating to sexual communication in the context of the HIV epidemic are compatible with the introduction of microbicides; that women distanced microbicides from ‘love medicines’ in terms of separating microbicides from the supernatural; and, finally, that postcoital intravaginal cleansing practices could undermine a microbicides roll out programme if we fail to address these practices. Overall I found that microbicides are compatible with socio-cultural norms relating to intravaginal insertion and sexual communication, but they may be less compatible with norms relating to intravaginal cleansing and love medicines. While incompatibility with socio-cultural norms raises challenges for intravaginal cleansing, the fact that love medicines are incompatible with microbicides could be advantageous for their introduction. Ultimately these findings have implications for future research and service delivery, as well as offering insights into microbicides, sexuality and gender equality.

This thesis is based on research on the epidemiology and prevention of HIV among adults in rural Masaka district, Uganda (1989-2010). Arising from this research are 10 published papers, which I have used to explore three research questions: (i) what are the trends in HIV prevalence and incidence in rural Uganda? (ii) what are the key determinants of these trends? (iii) what new strategies could be used to prevent HIV infection in this population? The studies involved four adult cohorts: a general population cohort to monitor HIV prevalence and incidence trends through annual household and serological surveys; an STD/behavioural intervention cohort; a cohort for HIV vaccine preparedness studies; and a cohort of HIV-negative women in discordant couple relationships to evaluate HIV biomedical interventions. The findings from the published papers are summarised. Additional analyses were conducted to include prevalence and incidence data up to 2008. The time trends were examined using a proximate-determinants framework. A comparison of the observed trends was also made with other available national data as well as data from two other African countries. There was a significant decline in HIV prevalence for all ages in the 1990s followed by an increase in the 2000s. Similarly, HIV incidence declined significantly in the 1990s in all adults although there were no clear trends in the 2000s. A net outflow of HIV positive migrants, mortality among HIV positive individuals and a decrease in risky sexual behaviour in the 1990s seem to have been important factors in explaining the decline. The increase in prevalence in the 2000s is explained partly by improved survival due to ART and possibly complacency leading to increased risky sexual behaviour. Two HIV intervention trials (of STDlbehaviour change and a phase 3 vaginal microbicide) are also discussed. Neither trial showed any effect on HIV transmission. To explain the findings from these trials, a conceptual framework for discussing negative results from HIV prevention trials has been used. The possible explanation for the negative results was that the concepts were right but the actual interventions were "inert" or insufficient to demonstrate impact. There was also evidence that there were deficiencies in the design and delivery of the school-based component of the behavioural intervention. In recognition that the epidemic continues unabated, I have addressed priorities for future HIV prevention research on biomedical and behavioural interventions. The cohorts established and research capacity built will continue to provide new opportunities for monitoring and preventing the transmission of HIV in this population.