Decision-analytic models have an important role in healthcare funding decisions in the UK and internationally. However, errors have been reported in published models, which may indicate poor modelling practices, potentially leading to sub-optimal recommendations on cost-effectiveness. Little in-depth research has been undertaken to investigate the processes used by modellers in model development. The objective of this research was to explore the modelling methods used by modellers, with particular focus on problems encountered. This work involved two qualitative phases of research. In the first phase, twenty-four in-depth interviews with modellers were undertaken. Constant comparative analysis was used to compare informant practices, and identify common issues in model development. The second phase involved two separate model-building case studies with teams of modellers and clinicians. Methods of non-participant observation, qualitative interviews, and think-aloud were used to investigate model development. The findings of the case studies were compared using framework analysis. Important themes emerging from both phases of the research concerned the diversity of practices in structural development, problems with clinician involvement in modelling, and a lack of time and resources to carry out good practice methods. This work offers important recommendations for modelling practice, and suggestions for future research to improve modelling methods.

Rituximab, a monoclonal antibody directed against the human CD20 antigen, causes profound depletion of all B cells. When used in patients with autoimmune disease, IgG autoantibody titres often fall whilst serum IgG anti-tetanus toxoid antibody titres are unaffected. Antibodies of both these antibody specificities have features associated with production by long-lived CD20- plasma cells that should be resistant to Rituximab. Reasons for the differential loss of these apparently similar types of antibody were investigated. Initial experiments established multiplexed bead assays to measure, in parallel, serum titres of multiple antibody specificities. Paired acute and convalescent sera, from 11 patients treated with Rituximab for Wegener‟s granulomatosis, were then studied. During 5 months after treatment, and following clinical remission, IgG anti-Proteinase 3 autoantibody titres fell gradually. All other measured antibody titres remained little changed. These findings favour the hypothesis that autoantibody producing plasma cells are sustained by disease related inflammation. Subsequent experimental studies support a wider hypothesis -that inflamed sites can support increased plasma cell numbers. In the prolific humoral response of QM mice to immunisation with NP-Ficoll, concurrent infection with attenuated Salmonella enterica serovar Typhimurium increases splenic capacity to support plasma cells. The enhanced support may reflect locally increased IL-6 production.

This thesis incorporates five studies investigating physical activity and community mobility in individuals with multiple sclerosis (MS). 1. Pedometer step count accuracy was investigated whilst examining activity levels in individuals with neurological disease (n=43). The pedometers significantly under-estimated counts in this group. 2. The test-retest reliability of the Physical Activity Scale for the Elderly (PASE) was examined. People with MS (n=20) were found to have low activity levels with a test-retest reliability coefficient total PASE score of 0.934 (95% CI=0.62-0.97). 3. An observational study examined physical activity levels in individuals with MS using the PASE. Participants appeared to be less active than healthy individuals (69.6±50.11, 154.3±80.4 respectively). 4. A questionnaire (n=80) and focus group discussions (n=24) were used to gather user opinions regarding physical activity participation. Emerging themes were the desire to be active and the barriers and facilitators to participation. 5. A phase II RCT investigated the feasibility of a physical activity provision support system in people with MS (n=18). The approach successfully resulted in attendance at fitness centres and increased activity levels (but did not reach statistical significance). The 5 studies each present new data in the field. The implications are discussed with suggestions for further research.

Within 10 years of experiencing a deep vein thrombosis of the lower limb, up to 60% of people will be classed as suffering from post-thrombotic syndrome (PTS). The cause and risk factors for PTS are not well understood and there are no universally agreed diagnostic criteria. This thesis aimed to identify prognostic factors associated with developing PTS, the method(s) of diagnosing PTS and their relative reliability in identifying PTS. A systematic review of systematic reviews and a systematic review of primary studies was conducted to identify prognostic factors. Methods used to diagnose PTS were noted from these reviews. Prognostic factors from best evidence and methods of diagnosing PTS noted were presented to clinical experts for prioritisation via an e-Delphi study. Consensus was defined as ≥75% agreement. Fifty one potential prognostic factors and seventeen methods of diagnosing PTS were identified from the reviews and initial exploration of experts’ views. Experts reached consensus on eight prognostic factors and one method of diagnosing PTS. The prognostic factors identified can be considered for the development of a prognostic model, while the method of diagnosing PTS found to be most reliable from experts’ opinion should be considered when developing a reference standard for PTS diagnosis.

This PhD considered provision of information to potential research participants. It gathered data on the types and detail of information potential participants accessed, and determined the feasibility of electronic information provision. A systematic review found limited empirical evidence to suggest what information potential participants want when making a participation decision. An Information Provision study was designed and embedded in an existing piece of low risk interventional research. This had three components; a feasibility study of electronic communication; a RCT of an Interactive Information Sheet (IIS); an observational study that recorded information accessed by potential participants. Results suggest electronic communication did not affect consent rate (although study was not powered to detect this) and understanding and satisfaction were unaffected by level or mode of information provision. Traditional participation information sheets (PIS) may only satisfy 11.4% participants, undersupply 9.1% and oversupply 79.5%. Participants were often unable to accurately recall what information they had accessed. In conclusion, the majority of potential participants to this study would have been satisfied with a streamlined PIS. An IIS could provide additional tailored information to those who require it, with standardised verbal information provision at consent interviews ensuring consent is given in accordance with GCP guidelines.

Feedback which induces an external focus of attention, about movement effects, has been found to promote motor performance in healthy subjects. It is unknown whether this effect transfers to retraining reach-to-grasp after stroke. This thesis first explored the attentional focus of feedback used by therapists and adopted a mixed methods paradigm. Where feedback was used it predominantly induced an internal focus of attention, about body movements. The main experimental study compared feedback which induced either an internal or external focus of attention during the motor performance of reach to grasp after stroke. A counterbalanced design was used and reaching movements were recorded using motion analysis. Support was found for adopting an external focus of attention compared with an internal focus of attention, although an interaction between feedback type and order was also found. Finally, the influence of the level of arm and memory impairment on the feedback type was explored. Neither the level of arm or memory impairment was found to influence feedback type. This study highlights the complexities of providing feedback after stroke and suggests that adopting an external focus of attention may be beneficial to improving motor performance after stroke.

Simulated patients (SPs), are widely used in communication skills teaching and testing worldwide. However, little research has been undertaken regarding the linguistic structure of the simulated consultation between students and SPs. Mixed method analysis (Conversation Analysis, Discourse Analysis and statistical analysis)of 100 transcribed assessed conversations between SPs and students were analysed for linguistic markers of conversational control, namely: talking more, interrupting more, asking questions, controlling the topic development, opening and closing the conversation. Results showed that the SP rather than the student seems to have conversational control over the conversation, except in the opening of the consultation. Qualitative analysis shows that this dominance is functional, as students have little knowledge and experience. The SP directs the conversation in order to give the student opportunities to show their skills. The SP and student seem not only to follow the rules of the ‘language game of medicine’ but also the rules of the ‘language game of education’, which suggests that the language of simulated consultations should be seen as a different genre, rather than a mirror of reality. These findings raise questions about role-play in medical education, devising scenarios, communication skills assessments, and the training of SPs.

The development of lay-led chronic disease self-management programmes (CDSMPs) is considered to be an effective approach to help people self-manage chronic diseases. Current studies have, in their majority, been conducted with White participants, and it remains unclear whether CDSMPs lead to similar results for other ethnic groups, particularly high risk groups such as South Asians. This mixed methods research was constructed in two phases. Phase 1 consists of an evaluation of the Chronic Disease Educator (CDE) programme (a lay-led CDSMP). CDEs felt their role often changed during sessions, between a facilitator and educator, and were able to make content culturally applicable. Participants appreciated the group format of the programme. South Asian participants welcomed members of their community delivering the programme in community languages and were much more likely to report gaining new knowledge from attending the programme in comparison to other ethnic groups. Phase 2 consists of exploring current health beliefs with regards to chronic disease and selfmanagement within the Sikh community. Individuals from the Sikh community accessed a range of systems of support which included traditional health services, alternative remedies, the family and the community, all of which affected lifestyle, disease, symptom and emotional management.

This thesis describes study designs for the robust evaluation of complex patient safety interventions. Fundamentally, study designs available to measure the effectiveness of patient safety interventions fall into two categories – those that use contemporaneous controls, and those that do not. A review of the recent literature (245 citations) revealed that most studies were single-centre (63%), and the majority of these did not use contemporaneous controls (84%); whilst in multi-centre studies (37%) the number of studies using contemporaneous controls (49%) equalled the number of studies that that did not (51%). Studies that do not use contemporaneous controls dominate the literature, but they are weak and subject to bias. The thesis further discussed a case-study, as an exemplar for the evaluation of a highly complex patient safety intervention – the Safer Patients Initiative (SPI), which sought to generically strengthen hospitals, whilst improving frontline activities. The evaluation was a before and after study, with contemporaneous controls. It used mixed-methods, so that the triangulation of a one type of research finding could be reinforced when corroborated by the finding of another type. Uniquely, it also, compared the rates of change across control and SPI hospitals – an approach referred to as the “difference-in-difference” method.

Hepatitis C Virus (HCV) poses a global health problem, leading to progressive disease often culminating in conditions such as hepatocellular carcinoma. HCV has a propensity to persist, with 70-80% of infected individuals failing to clear the virus. Recent evidence suggests that HCV entry is dependent on at least three cellular entry factors: CD81, Scavenger Receptor B-I (SR-BI) and Claudin-1. SR-BI is a receptor for high density lipoprotein (HDL), it is predominantly expressed in the liver and steroidogenic tissue. HCV is believed to interact with SR-BI via the viral envelope protein E2, interestingly the SR-BI ligand HDL enhances HCV infection. In this study we have investigated the interaction of HCV soluble glycoprotein with cell expressed SR-BI. We have shown that over expression of SR-BI in human hepatoma cells enhances HCV infection, indicating that SR-BI surface expression levels limit infection. Furthermore, anti-SR-BI serum inhibits HCV. We demonstrate that a cell culture adapted HCV mutant has a reduced dependency on SR-BI. This altered receptor dependency is accompanied by an increased sensitivity to neutralisation by soluble CD81 and enhanced binding of E2 to cell surface expressed CD81. The adapted variant also exhibits an altered relationship with lipoproteins and a heightened sensitivity to neutralising antibodies.