This thesis comprises 12 publications from two decades of research into sex work and health. The papers report on the risks and determinants of HIV and other sexually transmitted infections (STI) in women selling sex in London. The research combined clinical, epidemiological and anthropological methods in a programme that aimed to inform policies and interventions to reduce STI and HIV risks and improve the health and well-being of sex workers. In the accompanying commentary, chapter 1 places the papers in a broad narrative by describing the context of the work which began with the early days of the AIDS epidemic and continued through new challenges including the impact of globalisation and migration. Chapter 2 is a critical review of the major findings in relation to HIV and STI risk, and includes new tables summarising estimates of effect sizes from across the studies. I then discuss major risk factors, placing the findings in the context of the wider literature, and suggest a conceptual framework linking the determinants. Chapter 3 provides a more detailed description of the ways that different research methods were used to test specific hypotheses. In particular, I show how qualitative work uncovers the importance of structural factors, such as the organisation of flats and the distribution and consumption of drugs, in determining individual and group level behaviours and risks. I provide a brief critique of the use of mixed methods in biomedical research, and stress the importance of grounding both qualitative and quantitative work in appropriate theoretical frameworks. Chapter 4 summarises the thesis and re-asserts the need for a model of causation that incorporates social, economic, behavioural and structural factors. The development of interventions requires a synthesis of evidence from many disciplines, together with the perspective of participants whose agency will be the key to successful implementation.

Scoring systems in medicine are not a new concept. There are examples from the early 1950s, from around the same time as the polio epidemic in Copenhagen resulted in the birth of modern Intensive Care. Many scores have subsequently been developed specifically for Intensive Care patients. The majority summarise the overall physiological state of the patient in a variety of different ways. A clinical interest in ascertaining whether haemodialysis causes cardiovascular instability in Intensive Care patients led to an initial simple experiment examining stability using a small number of cardiovascular parameters. It became apparent that to answer the question properly a physiologically based score which could be calculated automatically in real time, and which took into account the level of physiological or pharmacological support the patient was receiving would have to be developed, to counter or to mitigate the drawbacks of the main scoring systems in common use at the time. This thesis describes the development and first stage in the validation of a novel physiologically based scoring system for Intensive Care patients which overcomes some of the major disadvantages of existing scores. The score was then used to investigate other clinical questions. Myocardial damage in Intensive Care is common and associated with a poor outcome. Aspects of the developed score were used to ascertain if it is possible to detect and predict myocardial damage occurring in Intensive Care patients based on physiological disturbance rather than a rise in biomarkers. The score was subsequently used to examine Intensive Care patient outcomes. The introductory chapter describes the history of Intensive Care, the mechanism of data collection for patients in Scottish Intensive Care Units and its analysis to enable comparison of different units. Reviewing currently available scoring systems places this work in context and highlights the need for a new score. An overview of renal replacement therapy modalities follows, as an interest in cardiovascular stability during haemodialysis led to the idea for a new scoring system. Myocardial damage in Intensive Care patients is common and indicative of poorer outcomes. This is reviewed, as the developed score was used to detect and then predict where myocardial damage was occurring in critically ill patients, based on physiological disturbance rather than on raised biomarkers. In Chapter 2, data from dialysis sessions in critically ill patients was collected, prc-processed, and analysed for cardiovascular instability. Using an arbitrary definition of instability as a 20% change in mean arterial pressure or heart rate in either direction, 65% of dialysis sessions were stable and 35% unstable. This simple experiment suggested that haemodialysis is less cardiovascularly destabilising than previously believed. However a major deficiency was the lack of consideration of the level of physiological support required during dialysis. To investigate this and other clinical problems better, it became apparent that a new score would have to be developed. Chapter 3 describes the development of a novel quantitative score which takes into account the amount of physiological and pharmacological support a patient is receiving. Physiological parameters were separated into those recorded regularly and those recorded intermittently. They were subsequently divided into ranges, scoring increasing points depending upon the degree of derangement. Ranges were based on an extensive literature search, currently available scores, and clinical opinion. Two key parameters viz. mean arterial pressure and oxygen saturation, were then weighted against a range of factors which can either increase or decrease their value. A score of instability could then be calculated by adding points for the weighted and unweighted parameters. After reflection using common clinical scenarios, some of the points scored in different ranges and weightings were revised to give the final quantitative score. In Chapter 4, the quantitative score was tested against data sets from actual Intensive Care patients to produce graphs of overall cardiovascular stability against time. Although this approach did capture improvements and deteriorations it had several disadvantages. It captured the expertise of a single clinician only, gave an arbitrary number which could be difficult to interpret, and the emphasis given by the clinician to the relative importance of different physiological or pharmacological parameters would not be obvious to others. Clinical reflection led to a new approach to the problem, viz. the development of the 5 point qualitative scale described in Chapter 5. Chapter 5 describes the development of a 5 point qualitative score for cardiovascular instability, underpinned by complex physiological rules, and capturing the expertise of several senior Intensive Care Clinicians. This is the Intensive Care Unit - Patient Scoring System (ICU-PSS). I scored data sets comprising thousands of predominantly hourly commonly recorded physiological and pharmacological parameters on a 5 point scale of cardiovascular stability (A to E). I also described rules in the form of different parameter ranges to indicate why I had scored time points as stable (A) through to unstable (E). These rules were incorporated into a computer programme which scored unseen data sets which I also then scored. The computer’s predicted A to E score based on these rules and my own score were compared in a confusion matrix. Mismatches with the computer prediction (based on my initial rules) were analysed and I either rescored the data if I considered that I had not assigned the correct level of instability, or modified the rule base. Through this process clinical expertise was better captured. This process was repeated with two other clinicians using my rules as a starting point. This led to further refinements of the rule base. The result was a sophisticated set of rules underpinning a 5 point, easily understandable scale of cardiovascular stability crystallising the expertise of 3 senior Intensive Care clinicians. The ICU-PSS was tested in a discrimination experiment to ascertain if clinicians could agree with the score moving in a one step and two step change. This is the first stage in full validation of the score In Chapter 6, the first stage in the validation of the ICU-PSS is described, using 10 clinicians from a city teaching and a district general hospital. It was hypothesised that if they were shown two consecutive hourly time points of physiological data from real patients and asked whether they were improving or deteriorating, they should agree with the ICU-PSS score in more than 50% of cases (random chance). In two discrimination experiments the consultants were, in random order, shown 4 examples of each type of two step improvement or deterioration in the score, e.g. A to C, and 4 examples of each type of one step change, e.g. E to D. In the two step experiment there was 92.9% agreement with the score, and in the one step change experiment, 90.9% agreement. Both were highly statistically significant. Chapter 7 describes the first of the applications of the validated score. Myocardial damage is common in Intensive Care patients and is an independent risk factor for both short and long term mortality. The mechanism in Intensive Care patients is likely to be the so-called type II damage caused by extremes of physiological derangement leading to a myocardial oxygen supply and demand imbalance. I hypothesised that it should be possible to use aspects of the score to confirm and subsequently predict where this damage is occurs based on physiological disturbance alone rather than on a rise in cardiac biomarkers.

Cardiovascular disease (CVD) is one of the leading causes of morbidity and mortality. The literature supports a series of established risk factors for CVD: age, gender, family history of CVD, ethnicity (un-modifiable); and high blood pressure, blood cholesterol, TGs, LDL, diabetes, pre-diabetes, obesity, smoking, physical inactivity, stress and unhealthy diet (modifiable). High blood pressure (hypertension) shares many of these risk factors. However, much of the variance/risk in both conditions cannot be explained. This has led to a search for novel risk factors, including insulin resistance and subclinical inflammation, the significance of which at present are controversial, particularly in relation to hypertension. There are also ethnic differences in the incidence, prevalence, risk factors and progression of cardiovascular disease. In some populations CVD occurs at an earlier age and progresses more rapidly. In this thesis I worked on two datasets in relation to hypertension, cardiovascular disease and their risk factors: (i) the RISC (Relationship between Insulin Sensitivity and Cardiovascular disease) study (chapters 2, 3, 5 and 6); and (ii) routinely-collected national data in Scotland via the SDRN (Scottish Diabetes Research Network) and SCI-Diabetes (chapter 2 and 7). Work on data from the RISC cohort focused on the relation between clamp-measured insulin sensitivity (its unique feature), inflammatory markers and hypertension; the SDRN work addressed ethnic differences in relation to diabetes and CVD. The first study (Chapter 3) examined the importance of insulin sensitivity/resistance in the development of hypertension and change in blood pressure over three years of follow-up in the healthy European (EU) RISC population. Systolic BP (SBP) was higher at baseline in insulin resistant (IR) women. There was no difference in BP in relation to IR in men. After adjustment for age, BMI, baseline BP and other covariates, low insulin sensitivity (M/I) predicted a longitudinal rise in SBP in women but not men, and SBP over time did not increase in insulin sensitive women. The second study (Chapter 4) was a systematic review of the relationships between two markers of low grade inflammation (IL-6 and CRP) and BP/hypertension, considering the roles of adiposity and insulin resistance. The systematic review showed evidence of considerable variation in the relationships amongst low grade inflammation, adiposity, insulin resistance and the development of hypertension. There appeared to be a positive association in the literature between CRP and DBP in younger individuals, although none of the studies were adjusted for insulin sensitivity determined by clamp technique. This association was further explored using RISC study data in Chapter 5 with stratification by sex and adjusting for clamp-derived insulin sensitivity. The third study (Chapter 5) examined the relationship of inflammatory markers with the development of hypertension and change in blood pressure over three years in the same healthy European population and whether any relationship was independent of clamp-measured insulin sensitivity (IS). High sensitivity C reactive protein (hsCRP) predicted prospective change in diastolic BP independent of insulin sensitivity and BMI whereas IL-6 had no relation with BP (both systolic and diastolic) or the incidence of hypertension. The fourth study (Chapter 6) evaluated all available predictors of BP rise over time (both systolic and diastolic) in a healthy EU population; moreover the significance of different predictors was examined within subgroups defined by age and sex. This analysis showed that baseline BP was the principal determinant of follow-up BP in all age and sex groups. Obesity was the second most important predictor (BMI in adults aged 30-44 years; percent change in BMI in middle age people aged 45-60 years). Lifestyle factors influenced BP via their effect on BMI. People who maintained their BMI during the three year follow-up did not exhibit a rise in BP (whether systolic or diastolic). Other important predictors identified in this analysis were insulin sensitivity in middle aged women and hsCRP in adult men. The fifth study (chapter 7) evaluated the role of ethnicity in the development of cardiovascular disease in people with type 2 diabetes living in Scotland. Over a follow-up of seven years, Pakistani people had increased risk of CVD and Chinese people had decreased risk of CVD as compared to White population. Pakistanis had an increased risk of CVD at a younger age independent of other conventional risk factors. In summary, insulin sensitivity and inflammation influence blood pressure, but their role is not generalised across different age and sex groups. BMI and change in BMI are important predictors of follow-up BP in adults and middle age healthy people, supporting a role for maintenance of BMI in preserving cardiovascular health. In addition to the known ethnic differences in the development of diabetes, I identified ethnic differences in the development of CVD.

Aims: To explore the lived experience of patients with chronic venous leg ulceration and to establish whether themes that impact on quality of life are addressed during wound care consultations. To develop a consultation template based on these themes and to evaluate the feasibility of a future randomised controlled trial to evaluate template utility. Methods: Three phases were undertaken. The first comprised qualitative interviews with 9 patients to identify how themes impacted on the daily lives of those with chronic venous leg ulceration. The second phase used non-participant observation for 5 of the 9 patients to establish whether these themes were disclosed and addressed during consultations. A nominal group meeting of experts was undertaken to construct a new consultation template, which was verified by patient participants. The template was piloted with 9 new patient participants during the final phase to ascertain if a future randomised controlled trial to evaluate efficacy would be feasible. Results: Phase 1 established a range of themes and subthemes that served to diminish the quality of life of participants. Phases 2 revealed that many of these themes were either not disclosed by patient participants or, when raised, were often not fully addressed by the nurse during wound care consultations. The new consensus consultation template was developed and piloted during phase 3. iii Conclusion: Chronic venous leg ulceration impacts on every area of the patient’s life but often such concerns were not disclosed or effectively addressed during wound care consultations. Although the pilot of the consultation template demonstrated that a future randomised controlled trial would not be feasible, valuable information was provided to inform potential future study design.

Pituitary tumours harbour epigenetic aberrations; however, characterisation of these aberrations, on a genome-wide basis, is hampered by their infrequent occurrence and their small size. To overcome the constraint of limited tissue, whole genome amplification of sodium bisulphite converted DNA was employed and provided a consistent 25-fold amplification from individual samples. This material was used in a genome-wide analysis the DNA methylation of 27,578 CpG sites for each of the major adenoma subtypes. In a discovery cohort, on the basis of stringent criteria, pyrosequencing validated 12 of 16 hypermethylated genes. Overall, the criteria identified 40 genes in non-functional, 21 in growth hormone, six in prolactin and two in corticotrophinoma. In an independent cohort, different frequencies of hypermethylation were apparent for each of these genes; however, association between methylation and reduced transcript expression was infrequent. For the EFEMP1 gene, following its initial identification, studies of an independent cohort of tumours showed frequent reduced EFEMP1 expression, irrespective of adenoma subtype. However, reduced expression was not invariantly associated CpG island methylation. Conversely, chromatin immunoprecipitation assays (ChIP) showed histone modifications that were consonant with expression status. The causal relationship between gene silencing and epigenetic change was established by observing that epidrug challenges induced re-expression of EFEMP1 in pituitary cells that was concomitant with histone modification associated with expressed genes. Enforced expression of EFEMP1 was without effect on cell proliferation or apoptotic end-points but was responsible for decreased expression of the MMP2 transcript. This association was not apparent in primary adenomas, however, MMP7, showed a positive correlation with EFEMP1 and this may reflect cell or species specific differences, suggesting that the relationship between EFEMP1 and MMP7 requires more detailed investigation. This study is the first whole genome identification of a potential biomarker signature and their functional characterisation will provide insight of tumour aetiology and identification of new therapeutic targets.

Chronic widespread pain (CWP) is common and associated with poor health. In general practice no morbidity code for CWP exists. By identifying patients in medical records consulting regularly over five years with multiple individual regional (axial, upper limb, lower limb) problems, a previous study identified patients in one practice with features consistent with CWP. This suggests patients regularly consult for regional pains without being recognised, or managed, as having a generalised condition. The original criteria for identifying these recurrent regional consulters (RRCs) had limitations including a restricted set of musculoskeletal morbidity codes. This thesis aimed to develop the existing RRC definition, determine characteristics of RRCs, and assess the extent of unrecognised CWP in primary care. The study was set in: i) a general practice database; ii) a cohort with linked self-reported health and medical records. RRCs were identified using different code lists, over altered timeframes, and with a varied number of recorded body regions. Three-quarters of RRCs were not recorded with a generalised pain code related to CWP (e.g. fibromyalgia) and are therefore potentially unrecognised as having a generalised pain condition. Recorded prevalence of recognised CWP was lower than community CWP prevalence, suggesting CWP is under-recognised in primary care. The new approach to identifying RRCs, using all regional musculoskeletal Read codes and identifying patients prospectively between three and five years from an index musculoskeletal consultation, identified more patients earlier, and returned patients with features consistent with self-reporting of CWP (e.g. increased somatic symptoms, frequent consultation, worse general health). However, RRC prevalence overestimated CWP prevalence and not all RRCs self-reported CWP, suggesting the RRC criteria identified a heterogeneous group of frequent consulters sharing features with CWP, including those less severely affected who do not necessarily fit established CWP criteria. They nonetheless lie on the spectrum of polysymptomatic distress characteristic of CWP.

The aim of this thesis was to identify some of the ethical issues of HIV positive asylum seekers and refugees participating in clinical trials in Britain. While all individuals are to some degree vulnerable in clinical trials, I have shown in this thesis that this group is particularly vulnerable in a number of areas. Many will not have English as a first language and while they may be able to understand everyday language, the participant information sheet (PIS) may be difficult to comprehend both in terms of language and content. Cultural aspects may also influence the individuals’ participation in a clinical trial. Many will have come from a hierarchical culture where it would be unthinkable to refuse to participate if requested to do so by someone of a higher social status, such as physicians. Individuals may also be reluctant to decline an invitation to participate in a clinical trial if asked to do so by their own clinician, if they are reliant on him/her to provide letters of support for the immigration authorities.

This thesis describes biochemical and biophysical studies of two protein domains that are believed to be involved in the interaction between the merozoites of Plasmodium falciparum and human red blood cells. The parasite protein fragment derives from the erythrocyte binding antigen 181 (EBA-181) invasion protein, and the human protein fragment comes from the 4.1R erythrocyte skeletal protein. The initial goal of the PhD project was to derive structural information on the nature of this complex, with a perspective towards generating new therapeutic approaches. Extensive biochemical and biophysical characterisation of the complex was carried out and is described in detail in Chapter 3 of the thesis: the results confirm the interaction, add insights to the stability of the complex and suggest the presence of significant disorder in both the individual proteins and the complex. Structural studies were carried out using small-angle neutron and X-ray scattering, used in conjunction with selective deuteration. These studies, which are described in Chapter 4, provide low resolution images of the individual proteins and of the complex; these have been compared to structure predictions using bioinformatics. In Chapter 5, solution state NMR studies were carried out, principally on the EBA-181 protein, but with preliminary results from titration work designed to further probe the nature of the interaction between the two proteins. Chapter 6 concludes the thesis with a summary of the work placed in context of the host-pathogen interaction, and proposes directions for future work.

This thesis explores changes in medical professional work and regulation in the context of emerging 'patient safety' health policies. The study engages with three components of this policy. First, to what extent is the concept of error promoted in theory and policy being taken up within managerial practice and is this coterminous with the medical interpretation and construction of error? Second, how do medical professionals regard the introduction of new reporting systems to collect information about errors in their work? Third, what new organisational systems are being developed to analyse and control errors and how do these diverge with those approaches advocated and practiced by medical professionals? It has been estimated that one in ten of all inpatient admissions experience some form of error in the delivery of care, totalling 850,000 events a year. Given such findings a new policy framework is being developed to improve 'patient safety' in the NHS. Following the Human Factors approach a new error management system is being introduced that consists of incident reporting procedures for the collection of information about errors, matched by techniques to identify the "root causes", and promote organisational change. Of importance for this thesis is the impact of policy on established forms of medical regulation. Through predominantly qualitative research techniques, this study has been carried out within a single NHS hospital case-study involving medical and managerial occupational groups. The empirical findings suggest, firstly, that the medical construction of error is indeed divergent from that advocated in policy and practiced in management and leads to distinct trajectories for the control of error. Secondly, medical professionals are generally disinclined to participate in managerial forms of incident reporting, and where such a system is in place there is a high degree of localised professional leadership. Thirdly, it was found that alongside new managerial systems for the control of errors, there were also a range of professional-led systems embedded within medical work and the local organisation of the hospital that had precedence of other centralised hospital systems. In consequence, the ability of managerial systems to penetrate the working environment of medicine was negligible. In conclusion, it is argued that while this policy could appear to challenge the basis of medical professional regulation the social, cultural and structural context of medical work is adapting to maintain a high degree of medical control and resist managerial encroachment.

Introduction: Football is one of the most popular sports world-wide. As with any sport, there is a risk of injury during participation. Therefore screening procedures are important not only to reduce the risk of injury but also for developing subsequent injury prevention programmes. Assessing functional movement is vital in screening in order to examine an athlete’s ability to perform fundamental tasks required for a specific sport. Currently in football no standardised functional screening protocols are widely available. Aim: To Develop a Functional Movement Screening Tool for Football Method Phase 1: A modified online, two round Delphi consensus panel was utilised to establish which tests should be included in a Functional Movement Screening Tool for Football. The panel of experts consisted of Physiotherapists working in Premiership Football. Results Phase 1: 14 Premiership Football Physiotherapists participated in Round 1 and 8 Premiership Football Physiotherapists in Round 2. After the completion of two rounds, the Delphi consensus panel identified 12 tests that should be included in a Functional Movement Screening Tool for Football. Method Phase 2: An online questionnaire survey was used to explore the level of agreement of Physiotherapists working in non-Premiership football on the 12 tests selected in Phase 1. This was distributed through email, postal invites and via twitter. Each participant was asked to rate their level of agreement with each test selected for the Functional Movement Screening Tool for Football. Results Phase 2: 26 Physiotherapists working in non-Premiership football agreed with the inclusion of 10 out of the 12 tests selected by the consensus panel in Phase 1. The single-leg squat, deep squat, in-line lunge, Y-balance test, modified Thomas test, internal rotators of the hip assessment, vertical jump test, external rotators of the hip assessment, adductor/groin flexibility test and gastrocnemius test were included in the final Functional Movement Screening Tool for Football. Discussion: A total of 40 Physiotherapists working in football collectively identified 10 tests to be included in a Functional Movement Screening Tool for Football. Although 10 tests have been identified for inclusion in the screening tool, standardised procedures still need to be defined for each test. Interestingly the tests selected for inclusion in the Functional Movement Screening Tool for Football were a combination of functional, balance, performance and muscle length tests. This highlights either a lack of understanding around the term functional movement or identifies a need for an overall screening tool in football as no standardised protocol is widely available at present. Conclusion: A screening tool specific for football has been developed. The use of a modified Delphi consensus panel successfully recruited and gained the views from Premiership Football Physiotherapists, a population which is normally difficult to access. Further research into the reliability and validity of the screening tool need to be examined in future studies. Successful methods for overcoming barriers in performing football research have been identified; in particular twitter may serve as a valuable resource for knowledge sharing in football.