Femoroacetabular impingement syndrome is a disorder of the hip joint in which irregular contact occurs between the joint surfaces during motion, typically because certain hip shapes (cam or pincer morphology). In this thesis a systematic review demonstrated that the point prevalence of cam and pincer morphology was not known. This systematic review identified that there were no established diagnostic criteria for cam and pincer morphology. A consensus development conference was used to define FAI syndrome and how it should be diagnosed. This consensus conference was unable to establish the radiographic criteria to define cam and pincer morphology. A case control diagnostic study was undertaken to identify the optimal measures to identify cam and pincer morphology, using cross sectional imaging. These definitions were applied to a sample representative of the general population in order to determine the point prevalence of cam and pincer morphology. The same diagnostic criteria were applied to a group of professional golfers, in this population, asymmetry between left and right hips, and cam and pincer morphology were found to be associated with reduced hip related quality of life. A systematic review identified there was evidence to show that cam morphology caused hip osteoarthritis. However, the evidence to show that pincer morphology and FAI syndrome caused OA was presently lacking. No experimental studies were identified assessing whether treating cam and pincer morphology or FAI syndrome altered the risk of developing OA. A feasibility randomised controlled trial was conducted to determine whether proxy markers of osteoarthritis, measured on magnetic resonance imaging, could be used in a trial to determine whether surgery alters the natural history of FAI syndrome.

The aims of the thesis are to elucidate the incidence of post-operative supraventricular arrhythmias (SVA) in patients that undergo thoracotomy for lung or oesophageal resection in the local population and to determine risk factors associated with the development of SVA. Further objectives are to compare methods of SVA detection and to prospectively evaluate the role of magnesium sulphate as a preventative measure. The incidence of post-thoracotomy SVA in the local population was 25.5% which was found to be higher than reports in the literature. Yield of arrhythmia detection did not differ between continuous electrocardiogram monitoring and 12 lead electrocardiogram recordings. Risk factors identified were increasing age, the presence of ischaemic heart disease and hypertension, and undergoing a pneumonectomy. There was a trend towards a higher mortality in the group that developed an arrhythmia, in the pilot study. The amount of lung resected was also found to be significantly associated with an increasing incidence of SVA post-operatively. The prophylactic, peri-operative administration of intravenous magnesium sulphate did not reduce the incidence of SVA post-thoracotomy overall. The peripheral administration of magnesium sulphate was not well tolerated secondary to the minor side effect of stinging, although no major side effects such as respiratory depression were observed. However, it did significantly reduce the incidence of SVA in the higher risk cohort pneumonectomy subgroup. Further work is anticipated in this group along with further research into risk factors and aetiology.

Donor organ shortage is a major barrier to the progress of liver transplantation; options to widen the donor pool include use of marginal donor grafts and those from donors after circulatory death (DCD), despite risks of early graft failure. This thesis studies the key metabolic feature differences between DCD and from donors after brain death (DBD), using combination of microdialysis for tissue fluid sampling, and colourimetry, Coularray and Fourier Transform ion Cyclotron Resistance - mass spectrometry(FTICR-MS) as analytical platforms. The initial study proved feasibility of above methods to identify metabolic changes through cold storage to reperfusion, and the involvement of energy and amino acid metabolism pathways. Comparison of DCD and DBD grafts by microdialysis combined with colourimetry proved energy depletion, and increased lactate/pyruvate ratio in DCD grafts. Metabolomic studies consolidated the findings of primary impact on energy metabolism pathways during cold storage. Both CEAD and FTICR-MS identified key biomarker differences and the effect on tryptophan and kynurenine pathway, and this finding was reproduced in all three metabolomic studies conducted. Over expression of these metabolites in DCD grafts and failed allografts may be related to energy metabolism, and tryptophan and kynurenine could potentially be developed as biomarkers predicting liver graft function.

Current transplant immunosuppression regimens have numerous limitations. Recent evidence suggests histone deacetylase inhibitors (HDACis) may represent a class of drug with immunosuppressive properties. This study initially assessed a panel of experimental and established HDACis, identifying a novel HDAC6-specific inhibitor (KA1010) to compare with cyclosporin and the pan-HDACi suberoylanilide hydroxamic acid in models of alloreactivity. Proliferation and MLR-based assays were used to determine the immunosuppressive effect of compounds, and a murine model of allogeneic skin transplantation was adopted to assess the in vivo effects of HDAC6 inhibition. KA1010 displayed superior inhibitory effects on the activation of PBMCs using in vitro models of transplantation. In a one-way MLR, KA1010 (5μM) reduced parent cell proliferation from 92% to 64% (p=0.001). A two-way MLR, adopting IFN-γ production as a marker of alloresponse, resulted in up to 91% reduction. Dose-response curves revealed dose-dependent profiles with a greater potency of HDACis over CyA. Mice treated with KA1010 displayed no significant features of skin allograft rejection upon histological analysis at 70 days and graft survival of upto 80%. Immunological assessment, revealed a significant increase in regulatory T cells (from 18% to 25%, p=0.0002) and a corresponding reduction in CD4\(^+\) T cells (from 58% to 42%, p=0.0009). HDAC6 may represent an optimal target for future immunosuppressant therapeutics with a particular role in transplantation. In this thesis, we have demonstrated a superior immunosuppressive effect of KA1010 over both CyA and SAHA, in the models of allotransplantation adopted.

OBJECTIVE: Patients undergoing open repair of asymptomatic abdominal aortic aneurysms (AAA) demonstrate a prothrombotic state that initially deteriorates in the peri-operative period before improving beyond the pre-operative state. We hypothesised that a similar haemostatic improvement occurs following endovascular AAA repair (EVAR) and that the initial prothrombotic derangement may increase the risk of myocardial injury. METHODS: 60 patients[57 men; median(IQR) age, 77 (72-82) years] underwent EVAR. Patients were assessed at baseline, 24-hours and 1-month post-procedure. Thrombin-antithrombin III-complex (TAT), tissue-plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI-1), and soluble (s) P-selectin levels were assessed as biomarkers of coagulation, fibrinolysis and platelet activity, respectively. Cardiac Troponin T (cTnT) levels were assessed as a biomarker of myocardial injury (MI). RESULTS: An increase in sP-selectin levels occurred between baseline[median(IQR), 80.5(68-128) ng/ml], 24-hours[median(IQR), 89.5(73-112)ng/ml; p=0.003] and 1-month[median(IQR), 110(89-143)ng/ml; p=<0.0001] post-EVAR. There was a trend towards increased TAT levels at 24-hours[median(IQR), 21.65(13-33.1)μg/l; p=0.069] compared to pre-operation[median(IQR), 7.15(4.7-31.3)μg/l] followed by a significant decrease at 1-month[median(IQR), 8.1 (5.4-14.85)μg/l; p=<0.0001]. cTnT levels were raised (>0.03ng/ml) in 16% of patients. There was a positive correlation between cTnT and TAT levels at 24-hours post-EVAR(r=0.38, p=0.039, Kendall-tau-B=0.26) CONCLUSION: These novel data suggest that the peri-operative pro-thrombotic state following EVAR may be associated with an increased risk of MI.

Myocardial protective strategies during cardiac surgery continue to improve yet they remain imperfect. Patients with left ventricular hypertrophy (LVH) are considered to be at greater risk of myocardial injury post cardiac surgery. Perhexiline is an anti-anginal agent known to modulate myocardial metabolism towards a more efficient glucose metabolic pathway. This metabolic modulation may improve myocardial protection. In this thesis I present a multi-centre double-blind randomised placebo controlled trial evaluating the role of perhexiline as an adjunct to standard myocardial protection in patients with LVH secondary to aortic stenosis undergoing an aortic valve replacement. Perhexiline does not augment myocardial protection. Magnetic Resonance Spectroscopy based energetic studies, echocardiographic and functional assessments in a homogenous patient cohort show no added benefit with perhexiline therapy in LVH. Therefore perhexiline should be limited to those patients refractory to maximum medical therapy. Metabolomic assessment of LVH has shown no change in the metabolomic profile within the myocardium. However any changes that do exist may be subtle. In LVH there is an increased activity of some innate cardioprotective mechanistic pathways in patients that do not sustain a low cardiac output episode post cardiac surgery. Further examination of these cardioprotective regulators is warranted.

Aim: To evaluate the role and utility of acute kidney injury biomarkers in renal transplantation. Method: Analysis of levels of a panel of biomarkers in deceased organ donors correlated to renal graft outcome; ABO incompatible renal transplant recipients correlated to rejection and HLA incompatible renal transplant correlated to rejection. Results: The panel of biomarkers showed comparable ability to creatinine in predicting the outcome of the renal graft following transplant from deceased donors. Of the panel of biomarkers tested to predict rejection, notably NGAL and IP-10 had good ability to predict those HLAi recipients who subsequently developed rejection. Conclusion: Biomarkers previously identified in the context of AKI may have a role in the assessment of deceased organ donor suitability but more promisingly have an excellent ability to identify those patients at risk of rejection following HLAi transplant and would now benefit from evaluation in a wider population prior to adoption in a clinical trial.

The prediction of adverse outcomes following major non-cardiac surgery is complex. Clinical variables and risk factors, functional status, electrocardiography and non-invasive cardiac investigations can all be used to assess and stratify the risk of post-operative cardiac morbidity or mortality. Multiple factors can be combined into bed-side scoring systems. Increasingly, cardiac biomarkers such as b-type natriuretic peptide (BNP) have been shown to predict heart failure and mortality in non-surgical populations. In the studies in this thesis, I have investigated the incidence of peri-operative cardiac morbidity and mortality in patients undergoing major non-cardiac surgery and identified clinical variables that predicted adverse outcomes. I have tested the utility of BNP for prediction of cardiac complications. I have investigated the long-term survival of the patients in the cohort to identify predictors of reduced survival. I have examined the predictive value of the pre-operative 12-lead ECG for adverse outcomes. I have also studied the utility of a commonly used risk scoring system, the revised cardiac risk index (RCRI), for prediction of cardiac events. The study was a prospectively performed observational study of consecutive patients undergoing major surgery. The cohort consisted of patients undergoing aortic surgery (25.8%), lower limb bypass surgery (29.8%), amputation (25.2%) and laparotomy (20.0%). The patients underwent post-operative screening for myocardial infarction; consisting of serial ECG and troponin measurement. The end-points were major adverse cardiac event (MACE), defined as myocardial infarction or cardiac death and all-cause mortality. Long term follow-up was performed following discharge. Three hundred and forty-five patients were recruited to the trial. Forty-six patients (13.3%) suffered a peri-operative MACE and twenty-seven patients (7.8%) died in the post-operative period (six weeks). Independent predictors of peri-operative MACE were pre-operative anaemia, urgent surgery, a history of hypertension and age > 70 years. Pre-operative BNP was significantly higher in patients who subsequently went on to have a peri-operative MACE, compared with those who did not. An elevated BNP was an independent predictor of both MACE and peri-operative mortality on multivariate analysis. A low BNP was highly indicative of an uneventful post-operative period, with a negative predictive value of 96% for MACE and 95% for all-cause mortality. Traditional clinical markers of heart disease, such as past history of ischaemic heart disease, prior myocardial infarction, cerebro-vascular disease or history of cardiac failure provided no predictive utility for either MACE or mortality. The mortality rate at 1 year was 19.1%. The median follow-up period was 953 days (IQR 661-1216 days). Age > 70 years, diabetes, hypertension, renal impairment, a history of left ventricular failure, anaemia and urgent surgery were associated with reduced long-term survival. A BNP concentration of 87.5 pg/ml provided the best combined sensitivity and specificity for prediction of long-term mortality. Patients with an elevated BNP (>87.5 pg/ml) had a significantly reduced survival and BNP >87.5 pg/ml independently predicted reduced survival on Cox regression analysis. Urgent surgery and anaemia were also independent predictors of reduced long-term survival. An abnormal ECG was observed in 41% of patients recruited. An abnormal ECG was associated with an increased peri-operative MACE and mortality rate. Ventricular strain and prolonged QTc (>440ms) were ECG abnormalities that predicted MACE on multivariate analysis. Patients with an abnormal ECG, but no prior cardiac history, represent a high risk group that may benefit from optimisation. The studies in this thesis have identified that BNP, a simple pre-operative blood test, provides valuable information regarding the risk of both peri-operative morbidity and mortality, and long-term survival after major non-cardiac surgery. Improved risk stratification could allow targeted intervention and medical optimisation prior to surgery with the aim of modifying the risk of adverse outcomes.

Joint replacements are a common treatment of osteoarthritis, rheumatoid arthritis, or fractures of both the hip and knee. The rising number of procedures being performed each year means that there is a need to assess the performance of an implant design in the general population. The majority of computational studies assessing implants do not take into account inter-patient variability and only use a single patient model. More often than not, it is then assumed that the results can be extrapolated to the general population. This thesis describes a method allowing population-based assessment of joint replacements, focussing on the tibial tray component of a total knee replacement. To generate a large population of models for finite element analysis, two statistical models were used. One was of the tibia, capturing both the variability of the morphology and bone quality, and the other was of the internal knee loads during a gait cycle. Assessment of the statistical models showed that they could adequately generate representative tibiae and gait cycle loads. An automated method was then developed to size, position, and implant the tibial tray in the generated population of tibiae in preparation for finite element analysis. The use of a population-based study, a unique approach compared to current studies, was demonstrated using three case studies assessing the performance of the tibial tray. The first case study examined the factors which might increase the risk of failure of the tibial tray and the effect of under sizing the tibial tray on primary stability. Factors such as bone quality and patient weight were seen to increase the risk of failure. It was found that under sizing the tibial tray did not significantly affect the primary stability of the tibial tray. It was also observed that the peak strain occurred during swing phase of the gait cycle, whereas peak micromotion occurred at the beginning of stance phase of the gait. The second case study investigated the effect of tibia resection depth on primary stability of the tibial tray. A more distal resection was found to increase the peak strain and micromotion of the bone-tray interface. The worsening primary stability with a more distal resection, suggest that to obtain optimal primary stability of the tibial tray it is necessary to resect as little bone as possible. The third case study compared three tibial tray designs. It was ound that the trays with pegs or flanges surrounding the stem tended to perform better, reducing the strain and the micromotion at the bone-tray interface. It was noted that the performance of the trays predicted by the analysis was similar to that observed clinically. This shows the potential use of population-based studies to help predict the clinical outcome of joint replacements.

Hip fracture is one of the most common, serious injuries in old people in England, and with a growing older population it is increasingly important to understand the impact of hip fracture from the patient perspective in order to develop relevant and appropriate healthcare services. The aim of this study was to explore the lived experience of hip fracture in older people in England to inform service development. A scoping review of the literature highlighted the lack of current evidence for hip fracture experience in England, with a particular dearth of evidence concerning the lived experience of hip fracture following discharge from hospital. However, the reviewed highlighted some international evidence around the lived experience of hip fracture while in hospital, and during initial rehabilitation. A meta-synthesis of the data was therefore conducted providing a more interpretive approach to analysing this data, and establishing a better understanding of the current literature on hip fracture patient experiences. The gaps in the evidence reported in the current evidence base provided a rationale for a qualitative study. Hip fracture patients were interviewed at their place of residence 12 to 16 weeks after surgery. Interpretative phenomenological analysis methodology was used for 24 interviews, and patient and public involvement was integral to the study. The study reported the impact on self, and the role of biographical disruption in triggering feelings of incompetency and frustration, particularly in those who had been relatively active prior to hip fracture. Participants perceived that others labelled them as ‘old’ and ‘disabled’ as they became less mobile and more dependent on those around them. Macro health care policies limited individualised care practices, and a greater emphasis is needed on discharge planning and continuity of care after discharge home. The study also reported the need for improved information provision and verbal communication throughout the care trajectory, and a key worker to co-ordinate their care to provide realistic expectations, reassurance and support throughout the recovery period is recommended. A model of continuity of care is presented to provide insight for the development of patient centred health care for this population.