Sarcopenic obesity is common among kidney transplant recipients. Fluid volume status has not been well-investigated following kidney transplantation. This thesis aimed to explore the effects of body composition, including fat mass, muscle mass and fluid volume status, on post-transplantation morbidity and fatigue. These are potential contributing factors to long-term patient- and graft- survival, as well as quality of life. Firstly, the associations between adiposity with inflammation, hepcidin and haemoglobin levels were investigated. Secondly, the effects of hypervolemia on blood pressure and levels of N-terminal fragment of pro-hormone B-type natriuretic peptide (NT-proBNP) were explored. Thirdly, the role of muscle mass and fat mass on all domains of fatigue were studied. Finally, the mechanistic aetiology of physical fatigue was examined by evaluation of muscle mass, muscular and cardiovascular functions, and fatigue perception. This thesis concluded that while adiposity displays significant independent association with inflammation, its role in determining hepcidin and haemoglobin levels remains uncertain. Reduced muscle mass may be correlated with physical fatigue, but independent contribution of fat mass in fatigue remains undefined. Hypervolemia is associated with raised blood pressure and elevated levels of NT-proBNP. The findings from this thesis set the scene for future interventional research and therapeutic strategies.

How the everyday activities of surgery mediate and reproduce surgical authority and privilege is studied by ethnographic study and interview material in and around the operating theatres of a large district general hospital, on surgical wards, and in a day surgery unit, using a case study approach. Routinised movements of staff, patients and instruments within the operating theatre suite (0T) order the activities by which patients pass through surgery. These movements are structured, and culturally designated, to ensure the safety of the patient during the dangerous transgression of boundaries in surgery. The history of surgical sterility indicates the symbolic significance of sterile garb, to mask the polluting bodies of the surgical staff and designate them purifiers of corrupting nature. Sterile techniques signify the superiority of cultural definitions over those based in 'nature'. While the surgeon is concerned with a patient's Illness, the anaesthetist is concerned with her/his Fitness. This interaction enables all operations other than those where both Fitness is reduced and Illness is not reduced, to be proclaimed 'successful'. Consequently, patients may be allocated a socially defined status of 'healed', despite no improvement in physiological status. Cross-cultural comparison suggests that surgical healing involves a social status passage from a negative status of victim to a positive one of survivor. Healing is socially reintegrative: it re-creates apparent congruence between the life-scales of the sick person and social structure, which is destroyed by illness. Case studies refine the hypothesis that this social recategorisation legitimates surgical authority and privilege. Both the operation's 'success' and patient discharge are found to be necessary for a full claim to have healed. The potential to generalise the model to all medical intervention, and the implications for surgery and the sociology of health and healing are discussed.

Background: Prolonged ischaemia time during autogenous free muscle transfer, can lead to ischaemia reperfusion (I/R) injury and local necrosis of the muscle. It has been demonstrated that the phenomenon of ischaemic preconditioning (IPC) confers biphasic infarct protection in a porcine skeletal muscle flap model. Further to this, the hybrid nitrovasodilator and KATP channel opener Nicorandil, is known to induce 24h uninterrupted infarct protection in myocardial models. We therefore hypothesised that Nicorandil could pharmacologically confer late-phase infarct protection of skeletal muscle from I/R injury. Methods: Yorkshire pigs (mean 17.9kg) with bilateral 8x13cm Latissimus Dorsi (LD) muscle flaps, received i.v. Nicorandil (3mg/kg) before being subjected to 4h ischaemia followed by 48h reperfusion. Results: Nicorandil induced late-phase preconditioning appeared at 24h after Nicorandil injection and lasted for 72h before waning. LD infarction rates were reduced to 22+/-2, 25+/-2 and 28+/-2% at 24h, 48h and 72h respectively, compared to the ischaemic control of 40+/-2%. Further to this, Nicorandil preconditioning was associated with a reduction in mitochondrial free calcium content, preservation of muscle ATP content and attenuation of neutrophilic myeloperoxidase activity during the first hour of reperfusion. Injection with the specific sarcolemmal KATP (sKATP) inhibitor HMR-1098 or non-specific KATP inhibitor Glibenclamide before Nicorandil injection completely blocked the infarct-protective effects. Injection of the specific mitochondrial KATP (mKATP) inhibitor 5-HD or Glibenclamide before the onset of reperfusion also abolished Nicorandil preconditioning. Conclusion: These findings support the hypothesis that a single dose of Nicorandil induces 48h of uninterrupted late-phase infarct protection in skeletal muscle. Further to this, sKATP and mKATP channels play a central role in the trigger and mediator mechanisms, respectively. Nicorandil is a potential new therapy to augment the ischaemic tolerance of skeletal muscle for patients undergoing autogenous free muscle transfer or composite tissue allotransplantation.

Despite improvements in risk factor awareness, diagnosis and enhanced management strategies, the incidence and five year survival of colorectal cancer, has remained largely unchanged over the last twenty years. As with many epithelial cancers, a preponderance of new colorectal cancer diagnoses occur in the over sixty five age group, making chronological age a strong risk factor. Given this indelible link between ageing and cancer in general, genetic pathways which are implicated in one process could influence the other. Thus, an understanding of the biology of ageing and factors which regulate it may provide insight into cancer pathogenesis. Telomeres are nucleo-protein complexes sited at the ends of all chromosomes and have a critical function in the protection of the genome. Telomeres are implicated in the ageing process as a result of the inadequacies of the DNA replication machinery in somatic cells meaning that a section of telomeric DNA sequence is lost during each round of cell division, thus telomere length reduces with age and is a putative marker of biological ageing. Control of telomere length is complex and involves interplay between a number of genetic and environmental factors, of which oxidative stress is particularly important. However, critically short and hence dysfunctional telomeres have been implicated in cancer development through an inability to maintain genomic intergrity and an effect on senescence. Telomeres play an integral role in the sensing and repair of DNA damage, however, cells must possess a finely tuned mechanism through which they can sense DNA damage and initiate a response. This usually involves the activation of cell cycle checkpoints, either temporarily to allow repair, or on an irreversible basis to prevent the clonal expansion of cells with deleterious mutations. If the damage is deemed irrepairable apoptotic pathways are initiated. The sirtuins are a group of genes first discovered and shown to control longevity in saccharomyces cerevisiae. Intense work has defined seven mammalian homologs termed SIRT1-7 which vary in their sub-cellular localisation, and have critical cellular functions ranging from the control of apoptosis, mitochondrial biogenesis, glucose and lipid metabolism, maintenance of genomic integrity and cell cycle control. Given these functions it is therefore no surprise that aberrancy of sirtuin expression is implicated in ageing and its commonly related diseases, particularly cancer. The aim of this study was therefore, to determine if patients with colorectal cancer display aberrancy of ageing related factors, namely telomere biology and sirtuin expression. This study was undertaken using two sources of material for investigation. Quantitative-PCR was utilised to measure telomere length in the peripheral blood leucocytes of 64 colorectal cancer patients and 1348 controls. In addition, telomere length was similarly measured in colorectal cancer tumour and normal adjacent tissue. Telomere length was then correlated with a number of clinical and pathological parameters to determine diagnostic or prognostic utility. Furthermore, an attempt was made to establish whether telomere lengths were reflected in circulating mediators of inflammation and redox control factors, including fetuin-A a circulating modulator of calcium homeostasis. Sirtuin relative transcriptional expression (SIRT1-7) was then measured in the tumour and normal tissue samples. Clinically relevant information was derived by analysing the SIRT1-7 transcriptional data in terms of clinico-pathological, inflammatory and outcome variables. Finally, sirtuin expression was correlated with other factors known to be involved with biological ageing to determine any potential association. Colorectal cancer patients had significantly shorter telomeres in their peripheral blood leucocytes (adjusted mean RelT/S=0.61) compared with chronologically older controls (mean age 75, adjusted mean RelT/S=0.70) (ANCOVA, p=0.004), indicating colorectal cancer patients were biologically older than their control counterparts. In addition, telomere length in tumour tissue (median=0.43, IQR=0.40) was significantly shorter than adjacent normal tissue (median=0.65, IQR=0.28) (p=0.004). Patients with low plasma fetuin-A levels were shown to have significantly shorter telomeres (p=0.041) and patients with rectal tumours had significantly higher levels of fetuin-A than those with colonic tumours (p=0.045). There was no correlation between telomere length and other redox factors, namely anti-oxidant vitamins, micronutrients and divalent cations. There was, however, a significant association between telomere length and systemic inflammation as determined by the neutrophil to lymphocyte ratio. SIRT 1-7 were differentially expressed between tumour and normal tissue, with significant attenuation evident in tumour samples when compared with normal tissue (p<0.0001 except SIRT2 p=0.003). SIRT2 (p=0.021) and SIRT4 (p=0.027) expression in tumour samples, was significantly associated with anatomical tumour site and pathologically determined nodal status respectively. Whilst, SIRT3 expression in normal tissue correlated with pro-inflammatory status, indicated by higher serum CRP levels. Finally, there was a significant inverse relationship with colorectal cancer tissue telomere length and SIRT3. When overall survival was considered, Kaplan-Maier analysis revealed a significant difference in survival in relation to SIRT4 expression levels. We have observed that patients with colorectal cancer display clear evidence of telomere attrition compared with controls. This is congruent with accelerated biological ageing in the pathogenesis of colorectal cancer and indicates cancer patients have ‘more miles on the clock’. An imbalance in redox control mechanisms and calcium homeostasis may be a contributing factor to telomere dynamics in these patients. The demonstration of attenuated sirtuin expression in colorectal cancer suggests a role as potential tumour suppressors and provides further evidence implicating biological ageing in the oncogenic process. Furthermore, plasma fetuin-A and tissue SIRT2 expression levels can be used to distinguish between colon and rectal cancers, providing further information regarding the molecular characteristics of these tumours. Telomere biology and the sirtuins could both play a pivotal role in the MTR (Mitochondria Telomere Ribosome biogenesis) paradigm, aberrancy of which could explain the apparent link between biological ageing and cancer. Enhancement of the understanding of the determinants of telomere length could mean that manipulation could lead to reduced colorectal cancer risk at the population level. In addition, the data provided in this thesis strengthens the evidence base which suggests that targeting individual sirtuins could be a future chemotherapeutic strategy, or indeed prove useful as markers of prognosis.

This thesis set out to explore the influence of patient factors that may be associated with outcome after total knee replacement for osteoarthritis. It starts with an introduction to the general subject, looking in detail at the methods for measuring the outcome of total knee replacement and also methods of measuring the status of various possible patient factors. This is followed by a systematic review of the evidence currently available on the influence of patient factors on the outcome of total knee replacement. This systematic review highlights a number of deficiencies in the available evidence. The next logical step was to perform an appropriate study to provide better quality evidence. However, there were six areas of uncertainty that presented significant difficulty when designing such a study. These areas of uncertainty became the focus of this thesis and were explored in detail. Through a process of experimentation and careful evaluation of the results these uncertainties were resolved. This thesis has provided the critical information required to design and conduct a multicentre study that would define which patient factors are important in determining outcome for total knee replacement for osteoarthritis.

Chapter One: This chapter reviews the relevant literature published since 1990 that has addressed the psychological impact both progressive and acute brain injury can have upon spouses of patients. The papers reviewed suggest that psychological strain or burden experienced by spouse carers is associated with a number of factors irrespective of illness type. A number of methodological limitations of the studies reviewed are discussed along with implications for clinical practice. Further research is required that explores the experience of family members to ascertain the best way forward for rehabilitation services in terms of providing family orientated interventions and support. Chapter Two: Chapter two presents a study that explores the views, beliefs and experiences of brain injury rehabilitation professionals on working collaboratively with families. Using a qualitative research approach, two focus groups were conducted with a total of 12 professionals from a range of disciplines. Focus groups were analysed using thematic analysis. A number of salient themes emerged that reflected the narrative collected. Implications for brain injury rehabilitation services and suggestions for further research are made. Chapter Three: Chapter three presents an empirical study that explores children's experiences of parental brain injury. Using a qualitative research approach interviews were conducted with twelve participants aged between 11 and 18 years living at home with a brain-injured parent. Interview transcripts were analysed using Interpretative Phenomenological Analysis (IPA). A number of themes emerged that reflected the narrative collected. A preliminary model of adaptation to parental brain injury is proposed. Implications for brain injury rehabilitation services in terms of addressing the needs of children and suggestions for further research are discussed. Chapter Four: This chapter documents the first author's experience of conducting the two empirical papers presented in chapters two and three. Specifically it highlights a number of ethical and methodological concerns associated to conducting focus groups and interviewing children. The first author's personal account and reflections in relation to each of the two research studies are also presented.

Meniscectomy is a common treatment for a young patient with a traumatic meniscal tear, despite the known negative consequences. Meniscal allograft transplantation has been performed for over thirty years in young symptomatic patients following a meniscectomy but it has never been rigorously evaluated for effectiveness. Therefore the aim of this thesis was to perform the development and pilot work to inform a future multi-centre pragmatic randomised controlled trial comparing meniscal allograft transplantation to physiotherapy. Systematic reviews in this thesis showed that in case series, meniscal allograft transplantation resulted in improved patient reported outcome measures in the short and medium term, although there were no comparator groups. There was no strong evidence for chondroprotection with either meniscal allograft transplantation or physiotherapy in this patient population. In the systematic review it was also identified that full thickness cartilage lesions were a contraindication to meniscal allograft transplantation for most surgeons. A Cox proportional hazards model was used on a case series of meniscal allograft transplantations performed locally, which showed that a full thickness cartilage lesion was a strong predictor of failure. It was therefore determined that these patients should be excluded from the pilot trial. A comprehensive cohort study incorporating a pilot randomised controlled trial was performed, with 36 participants being recruited over one year. The trial processes worked successfully and the pilot randomised trial recruitment rate was 55%. There were no losses to follow up in the randomised arm of the trial. Patient reported outcome measures showed a trend towards a bigger improvement in the meniscal allograft transplantation group, which was statistically significant in the KOOS score when the randomised and preference groups were merged. Sample size calculations for the data in the trial using the KOOS score suggest that between 70 and 114 participants would be needed in a full trial. The results of this thesis suggest that a full trial is warranted and could be deliverable within the UK, with some small adjustments to the trial design.

The ability of physiotherapists to make clinical decisions is understood to be a vital component of achieving expertise and is part of being an autonomous practitioner, yet this complex phenomenon has been under-researched in cardiorespiratory physiotherapy. Educators in this field need to understand what method of clinical reasoning clinicians are using, so that educational strategies can be designed to facilitate the development of clinical reasoning by undergraduate physiotherapy students prior to them going on clinical placement. This study explored the clinical reasoning of eight expert cardiorespiratory physiotherapists by observing their actions and behaviour whilst they assessed a simulated patient with respiratory complications in a simulated environment. The assessments were video-recorded. The physiotherapists were encouraged to think-aloud to verbalise their thought processes and had a debrief interview afterwards. The videos and the verbal transcripts from the assessment were analysed using a framework analysis and compared to other models of clinical reasoning. The study has confirmed that clinical reasoning is a complex, multi-dimensional phenomenon and the model produced shares some similarities with other models of clinical reasoning. Four key concepts have been identified as requirements for clinical reasoning development: knowledge acquisition; knowledge storage and retrieval; information processing and cognitive skill development; and metacognition and reflection. These concepts have been incorporated into a new conceptual model of clinical reasoning and embedded into a simulation learning strategy to facilitate clinical reasoning across all three years of the undergraduate physiotherapy programme.

Chapter 1: Long-term outcomes and the pattern of recurrence in patients with a retroperitoneal sarcoma: a 25-year study. Retroperitoneal sarcomas (RPS) are rare tumours with an annual incidence of 2.7 cases per million. Long-term survival for patients with RPS is poor because of the high frequency of local recurrence, as well as, the difficulty in obtaining adequate margins due to anatomical constraints and the sheer size of tumour. However, there is little-detailed information on the pattern of this recurrence. One wonders if the local recurrences do indeed recur at the site of primary resection or whether it is diffuse intra-abdominal disease. Another area of debate is the role of adjuvant therapy in particularly, radiotherapy in prolonging long-term survival and local control in these patients. Unfortunately, results to date have been controversial. Thus, the aims of this study are first to examine the long-term outcome of all patients presenting to one unit, to assess the pattern of intra-abdominal recurrence following macroscopic clearance of a primary RPS and to determine the outcome of these patients as well as those who develop distant metastases. Lastly, we would also evaluate whether radiotherapy influences overall survival and local recurrence-free survival in patients with a RPS. Results: During the study period, 137 consecutive patients were identified of which 125 had an attempted resection of sarcoma. 112 (89.6%) had macroscopic clearance of tumour while 13 (10.4%) had a debulking operation only. A total of 180 operations were undertaken in the group over the study period. The 5 and 10-year overall survival rates for all patients including those who did not have an operation or were debulked were 49.7% and 30.7% respectively. The 5 and 10-year overall survival rates for those who had macroscopic resection of their tumour were 62.8% and 42.1% respectively. On multivariate analysis, tumour grade (p = 0.048), type of surgical resection (p < 0.001) and histologic subtype (p = 0.024) were independent predictors of overall survival. For local recurrence-free survival and metastatic-free survival, both tumour grade and microscopic clearance were predictors of outcome. At a median follow-up of 6.3 years (i.q.r. 2.8-10.6 years), 69 patients have developed recurrent disease. 46 (66.7%) recurred intra-abdominal while 13 (18.8%) had distant metastases. 10 (14.5%) had both intra-abdominal recurrence and distant metastasis. Of the 46 intra-abdominal recurrences, 25 recurred at the resection site of the primary RPS while 5 had a solitary recurrence away from the resection site. 16 patients had either diffuse intra-abdominal (12) or retroperitoneal (4) sarcomatosis and had either palliative debulking or chemotherapy. The median survival for patients who developed 'true' local recurrence as their first recurrence was 15 months compared to 13 months for those who had distant metastases, P = 0.718. 33 patients received radiotherapy, and 72 patients did not. There were significantly more patients who had microscopic clearance (p = 0.0001) as well as a higher frequency of liposarcomas (P = 0.0191) in the non-radiotherapy group. Among those who received radiotherapy, the 5 and 10-year overall survival rates were 50.7% and 32.5% respectively. The median survival was 64 months (i.q.r. 38 - 90 months). The 5 and 10-year survival rates for those who did not receive radiotherapy were 67.2% and 47.2% respectively. The median survival was 117 months (i.q.r. 97 - 135 months). There was no significant difference in overall survival comparing patients who received radiotherapy with those without, p = 0.121; HR 1.54 (95% CI 0.90 – 2.65). There was also no significant difference in local recurrence-free survival between the two groups of patients, p = 0.056; HR 1.87 (95% CI 0.99 – 3.66). Conclusion: This study indicates a relatively high frequency of Grade 3 tumours and the long-term outlook for patients with a retroperitoneal sarcoma remains poor. Results suggest that tumour biology plays a significant role in determining survival even when macroscopic clearance is achieved. Our data also indicate that more than 50% of all patients who recurred develop distant metastases or diffuse intra-abdominal disease sometime during their follow-up. 'True' local recurrence occurred in 36% of cases only. It comes to no surprise that radiotherapy has no influence on overall survival in patients with a RPS as patients tend to develop multifocal disease of which systemic therapy will have a role in prolonging survival. Most likely targeted therapy, systemic chemotherapy or HIPEC will be the way forward to achieve disease control for these patients as most patients will develop diffuse disease or distant metastasis. Chapter 2: Modified Glasgow Prognostic Score (mGPS) as an independent prognostic factor in patients with a retroperitoneal sarcoma. In the last ten years, the theory surrounding the role of systemic inflammation in cancer progression and metastases has attracted some interest. The modified Glasgow prognostic score (mGPS) has been reported to be a significant prognostic factor for a range of tumours. This study examines the significance of the modified GPS for the prognosis of patients with a retroperitoneal sarcoma. Results: A total of 100 patients were available for analysis. Macroscopic clearance was achieved in 85% of cases. Tumour grade showed a significant relationship with the mGPS but conversely was not affected by age, histology, gender and type of resection. In the multivariate analysis, tumour grade (p = 0.032), type of resection (p = 0.000) and mGPS (p = 0.039) were identified as independent prognostic factors for overall survival in patients with a retroperitoneal sarcoma. For metastatic-free survival, only tumour grade (p = 0.039) and type of resection (p = 0.014) were predictors of outcome. Conclusion: This study demonstrated that mGPS independently predicts overall survival but not for metastatic-free survival in patients with a retroperitoneal sarcoma. The assessment of mGPS could assists in the identification of patients with poor prognosis and be a hierarchical factor in future retroperitoneal sarcoma clinical trials. Chapter 3: Role of minimal access surgery in the management of abdominal and retroperitoneal tumours. The role of laparoscopy in patients presenting with an abdominal soft tissue tumour is limited, and most are reports of single cases. This is a study aimed to describe the authors' experience with laparoscopic resection of an abdominal soft tissue tumour of 10 cm or less, particularly in patients who present with a histologically proven soft tissue tumour. Results: In this study, 50 patients with a median age 55 years (43 - 64 years) were assessed for laparoscopic resection of 51 abdominal soft tissue masses on CT. 48 patients had attempted laparoscopic resection while two had a biopsy of the tumour only. Macroscopic clearance of tumour was achieved in 42 (87.5%) patients. R0 resection was achievable in 36 patients (75%). The median hospital stay was two days (1 - 3 days), and the median size of the resected soft tissue mass was 62 mm (37 - 90 mm). Six patients were converted to open (12%), and there was no postoperative death. Three patients (6%) developed postoperative complications within 30 days period. 32 of the 50 patients had a histologic confirmation of a soft tissue tumour of whom 17 had a malignant pathology. Complete resection was achieved in 81.3% of all tumours while R0 resection for malignant tumours was achievable in 70.6%. The median tumour size resected was 75 mm (44 - 95 mm). One patient developed a recurrent tumour with a median follow-up of 33 months (i.q.r 17- 37 months). 11 patients had a laparoscopic resection of a retroperitoneal sarcoma. Overall survival was compared to those who had an open procedure. There was no significant difference in the 2-year overall survival between the two groups. / However, the length of hospital stay was significantly longer in the open group (P = 0.053). Conclusion: Laparoscopic resection of an abdominal soft tissue tumour, particularly a soft tissue sarcoma of 10 cm or less is feasible with macroscopic resection rates similar to that observed for open surgery.

The rotator cuff refers to a group of four muscles, which arise from the scapula and insert into the head of humerus forming a cuff around the shoulder joint. They contribute to shoulder movements and provide dynamic stability at the shoulder joint. Pathology of the rotator cuff is the commonest cause for shoulder pain and its severity can vary from subacromial impingement to full thickness tears. NSAIDs and corticosteroids are two of the commonest group of drugs used in treating subacromial impingement syndrome but with conflicting evidence about their relative efficacy and risk of complications. I explored the efficacy of a subacromial NSAID (Tenoxicam) injection in a double blind randomised controlled trial but found it to be less effective compared to a subacromial corticosteroid injection as measured by functional shoulder scores at six weeks. During the trial, I recognised that there were unresolved challenges in using Ultrasonography to diagnose rotator cuff pathology especially in differentiating between partial and full thickness tears. In this thesis, I have presented the normal ultrasound dimensions of the rotator cuff in asymptomatic young adults under the age of forty years, which has not been documented before. The study showed that the measurements are significantly different between men and women but not between dominant and non-dominant arms, suggesting that in every individual the contralateral shoulder can be used as a control, especially where the diagnosis is uncertain. Exploration of factors associated with the pathogenesis of rotator cuff tendinopathy showed that a critical zone of hypoperfusion in the supraspinatus tendon could be a factor but the evidence for it has been contradictory. An observational study presented in this thesis describes the microvascular blood flow in normal and a spectrum of pathological rotator cuffs (subacromial impingement, partial thickness tears and full thickness tears) using Laser Doppler Flowmetry in patients undergoing arthroscopic shoulder surgery. The study showed variations in microvascular blood flow in normal rotator cuffs but no evidence of a “critical zone”. Blood flow was found to be significantly lower in all groups of pathological rotator cuffs.