It is clear that sub-clinical inflammation is a key factor that triggers type 2 diabetes mellitus (T2DM) and is directly influenced by weight gain. Current studies highlight that obesity, particularly central obesity, heightens the pathogenesis of T2DM. Additionally, factors produced by adipose tissue (AT), referred to as adipocytokines, can influence the degree of insulin resistance as well as inflammation, due to their duality of function. A recently implicated adipocytokine, visfatin, has been identified as a potential insulin mimetic, an enzyme associated with mitochondrial biogenesis and an inflammatory factor. However, current studies lack a clear understanding as to the role and influence of visfatin in human AT and insulin resistant states. Therefore, this thesis examined visfatin expression within specific human AT depots and the influence of adiposity - with specific consideration given to insulin resistant states including T2DM, non-alcoholic fatty liver disease (NAFLD) and human immunodeficiency virus (HIV). Further, serum studies addressed how different insulin resistant states influenced circulating visfatin levels, whilst mechanistic studies explored how the role of visfatin was altered by insulin, an insulin sensitiser, inflammation and/or disease. This current thesis identified that visfatin was abundant in both abdominal depots, with highest expression in the omental (Om) AT, and isolated adipocytes, with an apparent relationship with insulin resistance. Subsequent in vivo and in vitro analysis further identified that, whilst insulin appeared to increase visfatin protein expression in isolated abdominal subcutaneous (Abd Sc) adipocytes, the use of an insulin sensitiser - either used in cultured Abd Sc adipocytes or as part of an oral therapeutic treatment in subjects with T2DM - decreased circulating visfatin levels. In addition, intracellular signalling studies highlighted that visfatin regulation within AT appeared to be dependent upon both nuclear factor (NF)-B and c-Jun N-terminal kinase (JNK) activation, influencing interleukin (IL)-6 as part of a visfatin regulatory feedback mechanism. Following the potential influence of visfatin in T2DM, this thesis explored its’ potential role in disease associated with other insulin resistant phenotypes, such as liver disease and HIV. From serum assessment of visfatin in subjects with NAFLD, it was identified that progression of liver disease was accompanied by a reduction in circulating visfatin levels – a finding that occurred independently of diabetic status. However, circulating visfatin still remained significantly higher in NAFLD with T2DM than those without. Finally, this thesis examined a potentially severe insulin resistant phenotype noted in HIV patients, due to an apparent lipodystrophy - a condition which alters fat oxidation and mitochondrial activation or regulation. In such a condition, circulating visfatin levels and visfatin mRNA AT expression remained unaltered by HIV status or drug therapy. Due to the capacity of visfatin to act as an enzyme involved in nicotinamide adenine dinucleotide (NAD) biosynthesis, essential for mitochondrial function and oxidative phosphorylation (OXPHOS), its role in AT remained unchanged by disease status, whilst other mitochondrial and fat metabolism factors were altered by both disease state and drug treatment. Taken together, these current data suggest a duality of function of which visfatin appears to be regulated by insulin, in addition to inflammation, in different disease states and therefore expands our current understanding of this multi-functional adipocytokine.

This thesis explores aspects of Streptococcus pneumoniae (pneumococcus) epidemiology and control, in view of the possible widespread introduction of conjugate vaccines in England and Wales. A review and analysis of a range of different epidemiological data sources showed that the burden of pneumococcal disease in England and Wales is high and remains mostly a condition of the very young and the elderly. A meta-analysis demonstrated the effectiveness of the polysaccharide vaccine against invasive pneumococcal disease among healthy elderly, to whom vaccination was not recommended at the start of this work. Using this result, a costeffectiveness analysis assessed the economic acceptability of such a programme, from the public health perspective. A better understanding of pneumococcal carriage and transmission is required to assess the effectiveness and cost-effectiveness of mass vaccination strategies with the pneumococcal conjugate vaccine. A novel model framework was developed and fitted to a longitudinal dataset of carriage in UK families. The results demonstrated an inverse relationship between duration of carriage and age and highlighted the importance of both family size and composition for persistence in a household. Great dissimilarities were estimated among the specific serotypes in terms of transmissibility, duration of carriage and level of competition. Realistic age structured dynamic models were developed and used to investigate the impact of a range of vaccine strategies. The importance of serotype replacement, as a consequence of vaccination, was demonstrated. The economic acceptability of alternative interventions with the conjugate vaccine depended on the magnitude of its indirect effects. Herd immunity had a considerable impact on the overall cost-effectiveness of the programmes since it may substantially reduce the burden of disease in older age groups. However, serotype replacement may counterbalance this reduction and lead to a non cost-effective result.

This thesis presents a study of the transmission dynamics of nosocomial pathogens in hospital wards, with particular reference to methicillinresistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). The work makes use of mathematical models, and observational and epidemiological studies. Transmission dynamics of a potential pathogen are first explored using a stochastic host-vector epidemic model, where health-care workers' hands are assumed to be the vectors. Consequences of changes in patient management are presented, and stochastic effects are shown to be essential to an understanding of ward dynamics. Observations of carer handwashing behaviour and carer-patient contact patterns are described, and the factors associated with hand washing compliance and contact rates explored using statistical models. Patient-carer mixing patterns are investigated. Refinements to the host-vector model are used to show how different aspects of observed contact patterns may both increase and decrease the spread of nosocomial pathogens. For contact patterns typical of intensive care units, the model predicts that infection rates will increase as the staff-to-patient ratio decreases, so understaffing may result in more cross-infection even if handwashing levels do not change. The effect of antibiotic treatment on the spread of resistant strains is studied using a two-strain model. Changing patterns of antibiotic use are shown to be capable of causing large and rapid changes in ward prevalences of resistant strains. To investigate possible fitness costs, growth kinetics of methicillin-sensitive and methicillin-resistant S. aureus strains are compared. No evidence for differences in growth rates is found, though there is a suggestion that MRSA stains may have longer lag periods. Finally, a Markov chain Monte Carlo (MCMC) approach is developed to enable model parameters to be estimated from the incomplete data typical of ward-based epidemiological studies. The approach is used to estimate parameters using S. aureus and VRE transmission data. With the latter data, transmission rates were related to patient antibiotic use. All antibiotic combinations considered were associated with increased acquisition rates, the effect being strongest for cephalosporins.

A forward projection model was used to estimate the numbers of, both current and former, IDUs who acquired HCV infection and progressed to mild, moderate and severe HCV disease in Glasgow and Scotland between 1960 and 2030. The model was developed initially for Glasgow because more epidemiological information exists for this region, than elsewhere in Scotland, to calibrate model outcomes with local data relating to HCV and its consequence. Insights gained from the model fitting process in Glasgow were then used to extend the model to the rest of Scotland. First, the incidence and cessation of injecting drug use in Glasgow during 1960-2000 were derived through the use of a modified Delphi approach. Instead of the usual iterative process to refine experts’ estimates, the elicitation of IDU incidence and cessation provided an opportunity to combine these data and examine coherence with capture-recapture IDU prevalence estimates. Coherent estimates indicated that incidence (median: 28 to 49) and cessation (1 to 24%) remained low and stable during 1960-1975, rose steeply between 1975-1985 (incidence from 49 to 1,335; cessation from 2% to 6%), and by 2000 there had been a decline in incidence (1,195) but a further rise in cessation (15%). Secondly, stochastic simulation was used to model the transmission of HCV among current IDUs in Glasgow, according to their injecting risk behaviours, and estimate the past incidence of HCV infection. The model that considered higher infectivity during acute viraemia following infection produced seroprevalences (median: 62-72%) and incidences (18-30 per 100 susceptible injector-years) consistent with observed data during the 1990s. The annual number of new HCV infections among current IDUs in Glasgow was estimated to be low during 1960-1976 (median: 10-60), rise steeply during 1960-1976 (median: 10-60), rise steeply during the early 1980s to peak in 1985 (1,120), stabilise during 1991-1997 (510-610) and rise again during 1998-2000 (710-780). Scenario analyses indicated that potentially as many as 4,500 HCV infections (10th and 90th percentiles: 2,400-7,700) had been prevented in Glasgow during 1988-2000 as a result of harm-reduction measures. Scenario analyses also permitted the gauging of changes in risk behaviours required to effect appreciable reductions in the incidence of HCV infection. Incidence can be successfully reduced if IDUs who, unavoidably, share needles/syringes confine their borrowing to one person; with this strategy alone, an estimated 5,300 HCV infections (10th and 90th percentiles: 4,100-6,700) could have been averted in Glasgow during 1988-2000. Such insights will inform those responsible for developing new ways to prevent HCV transmission among IDU populations. Thirdly, linkage of laboratory data on diagnosed HCV antibody positive persons in Scotland to clinical data from hospital and death records provided a unique national epidemiological dataset to estimate the number who had progressed to severe HCV disease.

Background and aims: Recent decades have seen material shifts in global migration flows. Migrants now come to the UK for an increasing number of reasons and from an increasing number of countries. This presents a challenge for health services that must provide care to individuals with a broad range of needs. In particular, there is concern that asylum seekers and refugees (ASRs) are at heightened risk of poor wellbeing and of receiving suboptimal healthcare. Concurrent with these shifts in migration, increasing attention is being paid to noncommunicable diseases (NCDs), which are now the most significant drivers of morbidity and mortality in most regions of the world. In the UK, the burden of NCDs is not evenly distributed, with inequalities related to ethnicity and socioeconomic status shaping an individual’s risk of ill health. Little is known, however, about how diverse migrant groups, including ASRs, conceptualise health and respond to health prevention messaging. Against this backdrop, this thesis aims to understand the health-related experiences of one such group – asylum seekers and refugees (ASRs) from Sub Saharan Africa living in Glasgow Scotland. Specifically, it explores: a) perceptions of health, wellbeing, and illness causation, b) experiences of accessing primary and preventive healthcare, and c) the factors influencing these perceptions and experiences. It also seeks to elucidate professional perspectives on ASR health. Methods: To gain an in depth understanding of ASR health perceptions and experiences, as well as professional perspectives, a focused ethnography was undertaken. This approach utilised four qualitative methods: community engagement, participatory focus groups, semistructured interviews, and go- along interviews. In total 12 primary care and public health professionals were interviewed, and 27 ASRs took part in either a focus group, an interview, or both. The thesis took a theoretically informed approach, seeking to determine whether and how two theories – ‘candidacy’ (Dixon-Woods et al 2005) and ‘structural vulnerability’ (Quesada et al 2011) – might deepen our understanding of ASR health. Results: Candidacy enhanced understanding of how ASRs identified and responded to messages about ‘healthy lifestyles’. ASR participants considered keeping healthy to be an individual responsibility, with diet and exercise highlighted as especially important. At the same time, however, perceptions and experiences of health and wellbeing were shaped by a number of structural influences, which limited the capacity of ASRs to engage in health practices. Therefore, while ASRs considered health to be an individual choice in theory, they did not necessarily feel they had the ability to be healthy in practice. The theory of structural vulnerability proved useful in identifying the wider structural determinants that impacted on an individual’s capacity to respond. There were several important structural influences, including poverty, racism, discrimination, and language barriers. The greatest negative influence, however, and one that compounded all the others, was the asylum process. This diminished individuals’ capacity to identify as candidates for prevention messages, engage in preventive health practices, and/ or access care in an optimal fashion. Conclusions: Efforts to engage ASRs in preventive health programmes and practices must take into account the ways in which the immigration and asylum system acts as a determinant of health, affecting both what it means to be healthy and what capacity individuals have to engage. The NHS, together with non statutory bodies, has a role to play in mitigating some of the vulnerabilities to which ASRs are subject.

Background: Early detection strategies for oral cancer aim to decrease the mortality rates and improve outcomes of the disease through early diagnosis and treatment. Guidance and regulatory bodies have an expectation that general dental practitioners will be able to promptly detect and refer patients with suspected oral cancerous lesions. However, the opportunities for early detection of oral cancer in primary dental care settings (particularly considering the low overall volume of the disease, the potentially increasing incidence rates, and the possibility of certain communities exhibiting particularly high rates) have not yet been investigated. This thesis examines the feasibility of early detection of oral cancer in primary dental care services, and undertakes risk-stratification to identify “high-risk” communities that can be utilised to target future early detection efforts. It further explores potential or missed opportunities for early detection in dental and other healthcare settings (both primary and secondary care), and assesses the feasibility of exploring routes to diagnosis. Aim: The aim of this thesis was to investigate opportunities for the early detection of oral cancer in Scotland by measuring the current burden of the disease, examining the feasibility of early detection in a dental setting, and exploring the potential role of alternative health care settings in early detection efforts. Methods: Descriptive epidemiological and data linkage cohort studies utilising national routine administrative health datasets were undertaken. The descriptive epidemiological analysis included all cases of head and neck cancer diagnosed between 1975 and 2012 and registered on the Scottish cancer Registry and annual midterm population estimates. These data were used to examine the incidence trends between 1975 and 2012 and the projected burden up to 2025 by individual subsites (oral cavity cancer, oropharyngeal cancer, and laryngeal cancer), age, sex, health board region, and socioeconomic status. The cohort study included all patients diagnosed with oral cancer between 2010 and 2012 and registered on the Scottish Cancer Registry. The individual patient data were linked to NHS dental service activity in the two years prior to diagnosis, and this linked cohort dataset and published NHS Scotland dental workforce and registration and participation statistics were used to examine dental attendance rates and the feasibility of early detection of oral cancer in the primary dental care setting. The individual patient data from the cohort were also linked to the hospital outpatient, hospital inpatient/day case, primary dental care, and general practitioner prescription databases. These four healthcare services were selected based on data availability. The linked data were used to examine all healthcare service contacts made by the cohort in the two years prior to referral. Additionally, a preliminary exploration of the referral period (defined as the one-month period prior to diagnosis) was also undertaken. Results and conclusions: The findings of this thesis showed that the incidence rates of head and neck cancer had increased in Scotland between 1975 and 2012, and this appeared to be largely driven by a dramatic rise in the rates of oropharyngeal cancer in recent decades. This burden was predicted to continue to rise up to 2025, with the rates of oropharyngeal cancer bypassing the rates of oral cavity cancer, which were expected to exhibit only a modest increase. Males, individuals above 60 years of age, and those from the most deprived areas of Scotland consistently exhibited the highest rates of cancer, irrespective of subsite. Moreover, an almost dose-like effect was seen to exist, with the rates of cancer increasing with the level of deprivation. Therefore, contrary to previous reports that oropharyngeal cancer exhibited an inverse socioeconomic profile, Scotland country-level data showed that those from the most deprived areas consistently bore the greatest incidence burden of head and neck cancer. Despite these increasing trends, the overall burden of oral cancer in Scotland was relatively low, and just over half of the cohort examined in this thesis had not contacted a general dental practitioner in the two years prior to diagnosis, thus automatically limiting opportunities for early detection. Dentists were estimated to potentially encounter one patient with oral cancer every 10 years, one patient with oral cavity cancer every 17 years, and one patient with oropharyngeal cancer every 25 years. Therefore, strategies for early detection must consider the rarity of oral cancer incidence and the poor dental attendance patterns of patients, and the expectations of dentists in these efforts must be tempered. These results also highlight the importance of improving access and uptake of dental services among those at the highest risk of developing oral cancer (i.e. those from the most deprived communities). When examining the linked cohort data and undertaking a look-back analysis of their healthcare service contact history, just under half (45%) of the patients diagnosed with oral cancer were seen to have actually visited a primary care dental service clinic in the two years prior to the start of the referral period. However, the majority of the patients with oral cancer had contacted one of the four healthcare services examined (hospital outpatient, hospital inpatient/day-case, primary dental care, and general practitioner prescription) at least once over the same period, suggesting that there were potential or missed opportunities for the early detection of oral cancer in primary dental care and alternative healthcare settings. The proportions of patients contacting the four services increased closer to the start of the referral period, as did the mean number of contacts made with each service. Although not all of these instances would have necessarily been associated with missed opportunities for early detection, it was highly likely that there were potential or missed opportunities amongst at least some of the patients with oral cancer. The two most common services contacted most recently before the start of the referral period were general practitioner prescription and hospital outpatient, and there was a possibility that these services were the sources of referral. The hospital specialties contacted most frequently during the one-month referral period were ENT, oral surgery, oral and maxillofacial surgery, and general surgery, suggesting that these contacts were likely to have been associated with the signs and symptoms of oral cancer. While no significant opportunities for the early detection of oral cancer in hospital or secondary care settings were identified, these findings demonstrated considerable potential in other primary care settings, particularly general medical practices and community pharmacies.

The global population is rapidly urbanising, with East Africa experiencing some of the fastest rates of urban growth. Urbanisation drives changes in diet, including increased consumption of animal source products (ASPs), and livestock value chains are becoming increasingly long and complex to meet these demands. This may place urban consumers at increased risk of food-borne infectious diseases. Evaluation of food-borne disease (FBD) risk to urban consumers in developing countries has been hampered by a lack of data on the composition of urban diets, and a lack of methodologies to systematically assess risk along food value chains which are typically informal, unregistered, and unregulated. This research used a value chain risk assessment approach (VCRA) to evaluate food-borne infectious disease risks along dairy value chains supplying Moshi Municipality, the regional capital of Kilimanjaro, Northern Tanzania. Our findings demonstrated that by far the most frequently consumed products were unpackaged milk and mtindi (fermented milk). While there was some role for urban livestock keepers in supplying these products to their communities directly, most of the milk and mtindi sold within Moshi originated with milk produced by smallholder farmers in rural areas surrounding the towns. Both the milk and mtindi value chains involved similar value chain nodes and actors, with a large degree of overlap between the formal and informal sectors and little to no formal education or training on milk handling and hygiene for chain participants. VCRA identified the bulking, wholesale and retail stages of the value chain as potential hotspots for introducing infectious disease risk. Consumers were well informed about many of the FBD risks posed by milk, and took active steps to mitigate these risks by boiling before consumption; however they perceived mtindi as posing a lower risk and were unable to mitigate risks with any preparatory step as mtindi is consumed as purchased. The highest risk to consumers was estimated to be posed by mtindi rather than milk, particularly mtindi made from leftover unsold milk, as this milk had a high risk of contamination. More studies are needed to investigate the infectious hazards present in both mtindi and other fermented milk products which are consumed widely across the region. The practice of valorising leftover ASPs as alternative products for human consumption may represent a particular source of FBD risk to urban consumers in developing countries.

The dominant political ideology emphasises the patient as a consumer and partner in health care. Correspondingly, the move towards patient-centred nursing, based on the principles of humanism and individualism, emphasise the central role patients' should play in the nurse-patient encounter. Additionally, changing social and demographic trends highlight the importance of medication as a health care issue. Thus, current health care policy and practice contexts highlight the importance of patients' participation in health care as consumers and partners and, nurses' ability to make an effective contribution to educating patients about medication as part of their role in health education and promotion. However, despite the significance of this context, little is known about the extent and manner of patient participation, or the contribution that nurses make to this important health promotion activity. Therefore the purpose of this study is to extend knowledge in this area by describing and explaining patient participation in medication interactions, as it occurs within the reality of the clinical context. In order to study patient participation in medication interactions in the reality of the clinical context, a case study approach was adopted. Three case sites were sampled and included: 1) an acute medical ward, 2) a community hospital rehabilitation unit, and 3) a community mental health service. Data collection methods employed to explore and describe patient participation in medication interactions included: non-participant observation, audio-recording of nurse-patient interactions, nurse interviews, patient interviews, reflective field notes, focus groups and documentation. The data analysis framework included the use of conversation analysis for nurse-patient interaction data and content analysis for other qualitative data. The findings indicate that patient participation can be understood at least in part by the communicative practices and choices that nurse and patients/clients make. More specifically a range of conversational strategies were employed by nurses to initiate and control conversations and by doing so inhibited patients' participation. However a comparison of findings across sites indicates that there were both differences and similarities in the extent to which nurses facilitated and inhibited patient participation. A number of influencing factors were identified that helped to explain these findings. These include: power, nurses' communicative style, knowledge, skills and experience, patients' age, acuity of illness and level of knowledge, and the organisation and philosophy of care. The findings from the study make a unique contribution to the body of knowledge in a number of ways. First, as the only study to describe patient participation in medication interactions between nurses and patients, it identifies that participation can occur at an interactional level, as well as a more practical level via, for example, the potential to self medicate and independently manage medications. Related to this, it has also contributed to the conceptual clarity and development of the concept of patient participation. This study has highlighted that patient participation may be realised and understood more fundamentally, at the level of the nurse-patient interaction, in contrast to previous research that conceptualises participation as making choices and involvement in decisionmaking. Furthermore, by the successful use of conversation analysis, this study has also advanced knowledge about potential ways to investigate patient participation at the level of nurse-patient discourse. Finally, this study provides a contribution to advancing theoretical explanations of patient participation through the construction of a framework of explanatory factors influencing patient participation. A framework for enabling participation has been developed based on the specific conclusions and principles for action drawn from the findings and from the philosophy of Freire (1972; 1983), which acknowledges an individual's potential to be empowered and assume control. The framework proposes that addressing attitudinal, interactional, relational, educational and contextual issues, might facilitate patient participation. Implications and recommendations reflect the practice and education requirements needed to implement such a framework.

Within healthcare, the concept of specialisation remains both poorly defined and under-debated in the literature. This research analyses the concept of specialisation and assesses the maturity of the concept of the diabetes specialist podiatrist; tracing the origins, change over time and current status of podiatric specialisation in diabetes. Literature pertaining to the legal implications of specialist practice, settings and titles is reviewed and a definition of specialisation within the context of healthcare is proposed. The initial concept analysis led to refinement of research questions which directed further enquiry. Because answers to the research questions lie within the knowledge and experiences of key actors, managers and individual podiatrists who have held specific posts; a qualitative methodology featuring focus group and key actor interviews was utilised. The meaning of podiatric specialisation in diabetes, how diabetes evolved as a podiatric specialty, the impact of specialist titles and the longer-term, wider implications which accompany specialisation were explored. In presenting analysis of the data, the researcher focuses on theory which illuminates the findings. The centrality of Weber’s concept of charismatic authority to the development and contemporary face of specialist practice is illustrated by the data; thus it represents a guiding theoretical concept within the author’s thesis. Documentary analysis was used as a triangulation strategy, in a bid to corroborate findings elicited through interview techniques. The documentary data also illustrates both the scale of and the context within which podiatric specialisation in diabetes evolved – not in isolation, but rather as one of many specialist foci.

Multiple sclerosis (MS) is a chronic autoimmune disease characterised by inflammatory attacks on the central nervous system. Fatigue is a common symptom in MS, yet its aetiology, exacerbating factors, and manifestation in everyday life are unclear. Given its role in regulating inflammation, energy metabolism and stress responses, cortisol is a relevant psychobiological target for MS fatigue research. The primary aims of this thesis were to examine diurnal fatigue patterns and contextual effects of daily stressors and mood in people with relapsing-remitting MS (RRMS); explore cortisol secretory activity in RRMS in everyday life; and investigate associations of cortisol with fatigue at baseline and change in fatigue 6 months later. Data were collected in an ecological momentary assessment study incorporating repeated real-time selfreports and salivary cortisol assessments over 4 consecutive weekdays in an RRMS group (n = 38) and healthy control group (n = 38), matched for age and sex. Statistical analysis was predominantly by multilevel modelling. The analysis presented in the first empirical chapter (Chapter 3) demonstrated that RRMS fatigue typically follows an increasing (but decelerating) within-day fatigue trajectory, distinct from linear trajectories in controls. Fatigue was sensitive to stressor and mood fluctuations within-subjects in both groups. The analysis presented in the second empirical chapter (Chapter 4) described larger cortisol awakening responses in RRMS compared to controls, but similar diurnal cortisol slopes. Cortisol reactivity to daily life stressors was apparent in both groups, mediated by self-reported distress. A systematic review was conducted (presented in Chapter 5) showing attenuated diurnal cortisol variability is most-frequently associated with fatigue across clinical populations; cortisol output appeared less relevant. However, the analysis presented in the final empirical chapter (Chapter 6) showed greater cortisol variability in the morning (larger cortisol responses to awakening) was associated with RRMS fatigue. Flatter diurnal cortisol slopes were associated with fatigue in controls. Chronic stress and depressive symptoms did not moderate associations, and there was no relationship between cortisol and change in fatigue 6 months later in either group. The original research presented confirms MS fatigue is not a stable symptom experience in everyday life, is sensitive to psychosocial contextual factors, and is associated with cortisol, potentially via pro-inflammatory immune mediators.