Background: Patellofemoral pain is a common disorder whose aetiology is complex often being described as multifactorial, increased load of the patellofemoral joint is often attributed to foot function. Foot orthoses are commonly prescribed for this condition; however the mechanisms by which they work are poorly understood. Previous studies using single segment foot models have hypothesised that it may be control of the midfoot which hold the key to understanding orthotic control. Over the last decade biomechanical analyses has advanced so it has become possible to divide the foot into segments, however no previous studies have investigated the use of orthoses on different segments of the foot when shod. The overall aim of this study was to investigate the differences seen in the kinematics and kinetics of the lower limb between a patellofemoral pain group and a group of normals when using a standardised orthosis prescription during walking and descending a step. Method: Initially fifteen healthy subjects had foot orthoses moulded to their feet, they were asked to walk at a self-selected pace and complete a 20cm step down; comparisons were made between sandals and shoes, plus two different orthoses. Kinematic and kinetic data were recorded using 10 Oqus cameras and 4 AMTI force platforms. The shoe data from the 15 healthy subjects was re-analysed and used as a control group to compare against 15 subjects diagnosed with patellofemoral pain. The foot was modelled using the calibrated anatomical systems technique (CAST) fixing the marker set directly on the feet and shoes of normal subjects which permitted comparisons of excursions between the shoes and sandals and the effects of the orthoses. Results 1: Similar changes in the pattern of movement were seen between the shoe and the sandals conditions with and without the orthoses; the shoes reduced the excursions recorded except the transverse plane of the rearfoot. At the knee maximum extension was increased and maximum flexion at toe off was reduced by the orthoses. Initial Conclusions: Expectedly the shoes reduced the range of motion over the sandal condition in most planes; however the similar effects seen with the orthoses in both types of footwear suggesting it was acceptable to use shoes in the later study. Results 2: Significant differences were seen between the healthy subjects and the patellofemoral pain subjects at the foot and the knee. Both orthoses produced statistically significant results at the foot. In addition there was a significant reduction in the knee coronal plane moment range during the forward continuum phase of step down; this was attributed to a change in the ground reaction force as there were no changes reported in the kinematics of the knee. Conclusions: The method of placement of the markers was able to detect small changes within the foot segments. This study identified potentially important differences between the patellofemoral pain subjects and the normals in both the knee and foot segments. However due to the lack of pain during the walking and step down trials it could not be determined if the changes were due to pain avoidance mechanisms or if they were causative factors. Many of the changes produced by the orthoses tended to be local to the foot, except for the knee coronal plane moment range during the forward continuum phase of step down. To the authors knowledge this work is unique in its investigation of the motion of foot segments while shod and confirmed the clinically held belief it is essential to consider footwear when prescribing orthoses to patients. The use of foot mechanics could be of interest to further research and may help to define sub-populations within this condition.

Every year, the healthcare industry collects a huge volume of data that is not mined properly and not put to optimal use. Discovery of the hidden patterns and relationships in data often goes unexploited. Data mining in the medical domain is more rigorous and complex to handle as most available raw medical data are voluminous and heterogeneous in nature. This research mines medical data related to human spine by learning patterns through the collected data and develops medical decision support systems based on intelligent system techniques. This study will help medical specialists in clinical decision making and disease diagnosis related to the spine. The human spine is a multifunctional complicated structure of bones, joints, ligaments and muscles which all undergo change as we age. For most people, these changes occur in a gradual and painless manner. However, a sudden change caused naturally or through injury, can lead to serious medical conditions, which usually result in back pain. Due to the wide diversity of spine functions, any disorder in the spine triggers various severe problems, which negatively affect quality of life and place huge financial and health burdens on the society. While ageing is inevitable, the rate at which the spine shows the effects of ageing is of clinical significance. This research reveals the growth and degenerative pattern of the human spine using intelligent system techniques. The information extracted from lumbar spine MRIs is used to classify age related changes. In this research, principal component analysis was used to detect anomalies in data and to transform the complex multivariate feature space to a smaller meaningful representation. PCA transformation reduced the complexity and dimension of the data, hence permitting a 2D visualization and knowledge of spine growth and degeneration with age. Factor analysis (FA) was used to understand the significance and correlation of spinal features with the normal ageing. Spines were ranked on the basis of their features and clusters were made to group similar samples. Studying the characteristics of the clusters helped in developing an understanding of the variations in spinal features among different age groups. An artificial neural network (ANN) was used in the estimation of age from the extracted lumbar spine features. ANNs have several benefits, including their ability to process complex data, reduced likelihood of overlooking relevant information, and a reduction in the cost and diagnosis time. The ANN model worked well for the spinal age estimation but due to its black box nature, it failed to provide valuable information about the correlations among the spinal features. A hybrid intelligent model consisting of a fuzzy inference system (FIS) and ANN, called an adaptive neuro-fuzzy inference system (ANFIS) was used to extract meaningful information from the data set in terms of fuzzy rules. Self-organizing maps (SOM) were used to visualize variations in lumbar spine features with the natural ageing. Useful information was acquired through SOM exploratory data analysis. Ward and modified Ward clustering methods were employed on SOM to group similar samples and study the characteristics of the clusters. The results from this research are helpful in setting the standards for spinal growth and degeneration with age and for understanding of the spinal disease prevalence. This research will help spine specialists in diagnosing disease from scans. It can be considered as a stepping-stone towards developing a tool for the classification of normal and problematic spines.

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.

Being among the most popular and efficient classification and regression methods currently available, implementations of support vector machines exist in almost every popular programming language. Currently four R packages contain SVM related software. The purpose of this paper is to present and compare these implementations. (authors' abstract)

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.