Kidney Transplantation is the gold standard treatment for patients with end-stage renal failure. Most kidneys used for transplantation are from deceased donors and ensuring successful outcomes depends on many factors. One of these is organ storage. Hypothermic Machine Perfusion (HMP) of deceased donor organs has been shown to have several benefits. However, it has not been widely adopted and the underlying mechanism is poorly understood. The first section of this thesis examines the introduction of HMP into clinical practice. HMP outcomes were similar to those of standard storage techniques but with the additional benefit of increasing safe storage times. This was likely due to inherent benefits of the machine itself, improved recipient preparation and better peri-operative conditions. The second part of this study analysed HMP perfusate using metabolomics (Nuclear Magnetic Resonance) to identify potential predictors of graft outcome. Differences were identified in the metabolic profiles of perfusate from kidneys with immediate and delayed graft function. These may have a future role in viability assessment. Improved understanding of metabolism during storage may help target optimization strategies for deceased donor organs. The final part of this study describes the development of a porcine model of transplantation to test future hypotheses.

This thesis reports a clinical study designed to assess myocardial, renal and lung outcomes following cardiac surgery. In a single centre, prospective randomized, placebo intervention-controlled trial the effects of intermittent upper limb ischaemia (remote ischaemic preconditioning (RIPC)) were compared in non-diabetic adult patients undergoing on-pump multi-vessel coronary artery surgery. Patients, investigators, anaesthetists, surgeons and critical care teams were all blind to group allocation. Subjects were randomized(1:1) to RIPC(or placebo) stimuli (3x upper limb (or dummy arm) 5 minute cycles of 200mmHg cuff inflation/deflation) during sternotomy and conduit procurement. Anaesthesia, perfusion, cardioplegia and surgical techniques were standardized. Groups were well matched on demographic and operative variables. In contrast to prior smaller studies, RIPC did not reduce troponin T (48 hour area under the curve (AUC); 6hour and peak) release, improve post-operative haemodynamics (cardiac indices; low cardiac output episodes incidence; IABP usage; inotrope and vasoconstrictor use; M mode, 2D contrastenhanced echocardiography and tissue Doppler imaging) or offer antiarrhythmic benefit (de novo left bundle branch block or Q waves; ventricular tachyarrhythmia incidence). RIPC did not afford renal (peak creatinine, AUC urinary albumin-creatinine ratios, dialysis requirement) or lung protection (intubation times, 6hour and 12 hour pO2/FiO2 ratios). Case urgency did not influence RIPC effect.

Poly-ether-ether-ketone (PEEK) is a high performance aromatic thermoplastic with proven biocompatibility. Recently, it has been proposed as a promising bearing material for cervical total disc replacement (TDR). A new bearing combination of PEEK-on-PEEK based self-mating articulation has been used, which may overcome current bearing materials related complications. For ball-on-socket based cervical TDR designs, PEEK based bearing articulation is expected to operate under a boundary lubrication regime regardless of the radial clearance used. The contact stress encountered by the bearing surfaces is insufficient to result in either material yield or fatigue failure. High-cycle fatigue tests were performed on PEEK 450G specimens via three-point flexural bending. The obtained fatigue results (104.1 ± 5.8 MPa) show superiority over the historical polymeric bearing material UHMWPE (31 MPa). Moreover, it demonstrates a good resistance to sterilisation and thermal ageing. Laboratory wear simulation was also conducted, using spine simulators and following ISO 18192-1 standard. For PEEK-on-PEEK self-mating articulation, a steady state wear rate of 1.0 ± 0.9 mg/million cycles is obtained, which is comparable as the historical bearing combination (UHMWPE against CoCrMo). The results of this work suggest that PEEK-on-PEEK based articulation is a possible alternative for future cervical TDR designs.

This thesis evaluates and explores the effectiveness of post discharge physiotherapy exercise following total knee arthroplasty (TKA) for osteoarthritis in three ways. 1. A systematic review evaluated the effectiveness of post discharge physiotherapy exercise on function, walking, range of motion, quality of life and muscle strength, for patients following elective primary TKA. Functional physiotherapy exercise interventions following discharge resulted in short term, but not long term, benefit. Effect sizes were small to moderate for function (0.33). Weighted mean differences were small to moderate for motion (2.9) and small for quality of life (1.66). 2. A randomised clinical trial compared the effectiveness of a post discharge physiotherapy intervention in improving patient function versus usual physiotherapy for patients undergoing primary TKA. No significant statistical differences were observed between the two groups for all outcomes. This early trial was underpowered and impacted upon by some important factors which could potentially have masked any treatment trends occurring in the home visit group. 3. Since blinding procedures are often assumed to indicate trial quality, the feasibility of achieving blind outcome assessment in a pragmatic physiotherapy rehabilitation trial involving older people was explored. Reasons for unblinding were explored and successful blinding rates of 81-91% were achieved.

Artificial discs have been developed to replace and restore motion to degenerated intervertebral discs. The most common configuration for these devices include ball and socket articulation surfaces that can induce high frictional torques and wear rates. When these particles interact with the surrounding tissues they can induce inflammations leading to osteolysis, subsidence of the implant and then revision surgery. A new device has been developed to reduce friction and eliminate wear migration that incorporates an elastomer sheath to encapsulate the disc, retaining debris and an optimised bio-lubricant. The artificial disc has been assessed with an experimental programme that compared the resistive torques of the artificial discs both with and without encapsulation, for a range of motions. Durability tests were also conducted to 2M cycles and gravimetric wear rate was measured in accordance with BS 18192-1: 2011. Encapsulating the articulating surfaces reduced resistive torques and completely eliminated debris migration. Wear rates within the sheath ranged from 10.1 to 11.3 mg/million cycles, well within acceptable levels for this type of device. The encapsulated discs successfully contained all wear debris and displayed durability in excess of 2M accelerated life cycles. The concept of an encapsulated artificial disc has been shown to be feasible and could replace current technologies.

No description available.

Lung cancer is the most common cause of cancer death in the UK and although the best opportunity for cure is provided by lung resection, surgery is associated with high rates of cardiorespiratory complications and long-term morbidity. Existing studies indicate right ventricular dysfunction occurs following lung resection and may be implicated in any post-op deterioration. Evaluation of right ventricular function is challenging, with its complex shape, marked load dependence and retrosternal position meaning there is no reliable, non-invasive method of assessment. The majority of previous work examining right ventricular function in the lung resection population has been performed using the volumetric pulmonary artery catheter, the reliability of which has been challenged. The first section of this thesis reviews the right ventricle in terms of anatomy, physiology and assessment, providing context for future investigations (Chapter 1). A review of the literature examining the right ventricular / pulmonary vascular response to lung resection is then presented, along with the rationale for further investigations (Chapter 2). As there is a high frequency of complications in this population, often requiring critical care support, the first investigation (Chapter 3) of this thesis characterises those patients admitted to intensive care following surgery. It also examines the incidence of right ventricular dysfunction in this population. Given the methodological concerns regarding the techniques previously used to assess right ventricular function following lung resection, cardiovascular magnetic resonance imaging was used to sequentially assess the right ventricular response to surgery (Chapter 5). Cardiovascular magnetic resonance is a reference method for assessment of right ventricular function and has not previously been used sequentially in this population. This investigation demonstrates right ventricular function (measured by right ventricular ejection fraction) deteriorates following lung resection with impairment still evident two months following surgery. There were no changes in left ventricular function over the same period. With the difficulties associated with cardiovascular magnetic resonance imaging in this population and its limited use outside of research settings, an alternative method for assessment of right ventricular function would have utility in this population. Trans-thoracic echocardiography is the most commonly used non-invasive method for assessment of right ventricular function with widespread availability and low cost. Chapters 6 and 7 attempt to validate conventional and novel echocardiographic methods for assessment of right ventricular function in this population. The main finding is that established echocardiographic methods; fractional area change, tricuspid annular plane systolic excursion and S' wave velocity at the tricuspid annulus, are not suitable for assessment of right ventricular function in this population. Speckle tracked strain echocardiography is a novel method of assessing right ventricular function that has shown promising results in other patient groups. Chapter 7 demonstrates that right ventricular global strain is not useful, but that right ventricular free-wall strain may have value in this population. Biomarkers of myocardial dysfunction (B-type natriuretic peptide and high sensitivity troponin-t) were measured contemporaneously with the imaging studies (Chapter 8). This investigation demonstrates that both biomarkers increase following lung resection and that their plasma concentration two days following surgery are associated with right ventricular function. There was no association with parameters of left ventricular function suggesting the biomarkers are released in response to changes affecting the right ventricle. On an exploratory basis the association between the peri-operative biomarkers and functional capacity following surgery is also assessed. Finally, potential mechanisms of right ventricular dysfunction following lung resection are explored (Chapter 9). This demonstrates that as pulmonary artery acceleration time (a surrogate measure of right ventricular afterload) increases, right ventricular ejection fraction deteriorates. Using a cardiovascular magnetic resonance surrogate, a deterioration in the matching of right ventricular function with right ventricular afterload (coupling) is also demonstrated. In combination these studies provide a robust answer to the question "what happens to right ventricular function following lung resection?" It provides validated methods for future work in this population and suggests an association between post-operative right ventricular function and right ventricular afterload.

Prostate cancer is the most common male cancer in the UK. Although incidence is increasing, prostate cancer mortality is decreasing, mainly owing to the over diagnosis of disease that would not have become clinically apparent during the patient’s lifetime. The gold-standard for prostate cancer diagnosis is transrectal ultrasound guided biopsy of the prostate. Whilst prostate biopsy can inform on diagnosis, it’s prognostic ultiltiy is poor. Currently clinicians lack pathological biomarkers to differentiate between patients with prostate cancer who have indolent disease that can be safely managed with surveillance strategies, and those who will go onto develop aggressive disease which requires early radical curative treatment. Phosphorylation of the androgen receptor has been extensively investigated in relation to prostate cancer development and progression. Androgen receptor phosphorylation has been shown to regulate cellular localisation, transcriptional activity, cell growth and sensitivity to androgens in prostate cancer. However, only a small number of studies have investigated the prognostic significance of androgen receptor phosphorylation, and only consider a limited number of serine residues in clinical specimens. The research presented in this thesis sought to investigate the prognostic and predictive significance of AR phosphorylation at serine 578 in hormone-naïve prostate cancer. It was hypothesised that pARS578 would be associated with poor outcomes in prostate cancer and may be utilised as a prognostic marker at diagnosis in prostate cancer and predict response to drug treatment with a PKC inhibitor. It was also hypothesised that PKC, the putative kinase for phosphorylation at serine 578, would be associated with poor outcomes and may offer a potential therapeutic target in prostate cancer. In the current study, the phosphorylation site of primary interest was serine 578. Scansite 2.0, an online kinase search tool, predicted that PKC is the putative kinase mediating phosphorylation at serine 578 on the androgen receptor. Phosphorylation of the androgen receptor at serine 578 has been linked with increased AR transcriptional activity, cell growth, nuclear cytoplasmic shuttling, modulation of other AR phosphorylation sites and DNA-repair mechanisms. The prognostic significance of androgen receptor phosphorylation at serine 81 was also investigated in this study. Serine 81 is phosphorylated in response to DHT via an alternative pathway to that of serine 578. Serine 81 phosphorylation is associated with increased androgen receptor transcriptional activity and increased cell growth in prostate cancer. It was therefore hypothesised that androgen receptor phosphorylation at serine 578 and serine 81 would be associated with poor outcome measures in prostate cancer. Immunohistochemical analysis was performed in a cohort of 105 hormone-naïve prostate cancer patients undergoing active surveillance, representing a cohort of patients with low-risk disease, as defined by current clinical markers such as PSA and Gleason score at diagnosis. Nuclear PKC expression was significantly associated with pARS578 expression in the clinical specimens, supporting the prediction of Scnasite 2.0 that PKC is the kinase responsible for phosphorylation of the AR at this site. High cytoplasmic expression of pARS81 was associated with decreased time to intervention (HR 2.76 (95% CI 1.1-7.3), p=0.032). There was no association between pARS578 and time to intervention in this cohort. Analysis of combined expression of both phosphorylation sites revealed an association between high dual expression of cytoplasmic pARS81 and cytoplasmic pARS578 and decreased time to treatment intervention (HR 2.35 (95% CI 1.2-4.6), p=0.031). These results suggest a synergistic prognostic effect when these two phosphorylation sites are combined and identifies a sub-population of low-risk prostate cancer patients who are at increased risk of disease progression. A second study was conducted to investigate if these results could be replicated in a cohort of prostate cancer patients with all stages of disease at diagnosis. Immunohistochemical analysis in 90 hormone-naïve prostate cancer patients found that high expression of nuclear pARS81 (HR 2.1 (95% CI 1.1 – 4.2), p=0.030), nuclear pARS578 (HR 2.24 (95% CI 1.0-4.9), p=0.036) and cytoplasmic pARS578 (HR 4.54 (95% CI 2.0-10.4), p= < 0.001) was associated with decreased disease survival. Furthermore, high expression of cytoplasmic pARS578 was associated with decreased time to biochemical relapse (HR 2.1 (95% CI 1.0-4.2), p=0.034) and decreased disease-specific survival following biochemical relapse (HR 3.2 (95% CI 1.0-9.9), p=0.034). Dual expression of nuclear, cytoplasmic and total pARS81 and pARS578 were all associated with decreased-disease specific survival, suggesting that there is a sub-population of prostate cancer patients who may benefit from dual targeted therapy with androgen deprivation therapy and PKC inhibitors. A validation cohort of 243 hormone-naïve prostate cancer patients with all stages of disease was utilised to verify the results of the second cohort. Unfortunately, due to technical issues and time constraints, IHC could not be completed for the phosphorylation sites of interest in all patients. Despite this, high expression of cytoplasmic pARS578 was significantly associated with decreased time to biochemical relapse (HR 2.9 (95% CI 1.0-8.2), p=0.037) and trended towards an association with decreased overall survival (p=0.076). Interestingly, dual expression of high cytoplasmic pARS81 and cytoplasmic pARS578 was associated with decreased overall survival (HR 2.1 (95% CI 1.3-3.3) p=0.001) despite neither phosphorylation site independently predicting decreased overall survival. Lastly, a study to develop a technique for isolation, propagation and characterisation of primary prostate cancer cells from TRUS biopsy specimens was undertaken. Two primary prostate cell cultures were developed which were confirmed to have a malignant luminal epithelial cell phenotype with a functional AR using flow cytometry, RT-PCR and immunofluorescence. This technique is of high translational relevance, as it provides a model with potential to identify biomarkers to predict individual patient’s response to prostate cancer therapies. Overall these results suggest that androgen receptor phosphorylated at serine 81 and serine 578 are associated with poor outcomes in prostate cancer and are potential targets for new drug therapies. Additional studies are required to validate these results in a larger multi-centre cohort of prostate cancer patients before either of these phosphorylation sites can be utilised as a biomarker in clinical practice.

Colorectal cancer is the second most common cause of cancer death in the United Kingdom (UK). At present, surgery remains the cornerstone of its management and is the mainstay of curative treatment. However, surgery for colorectal cancer is associated with significant postoperative morbidity and mortality. These postoperative complications, whether classified by their type or severity, are associated with poorer quality of life, increased socioeconomic and direct healthcare costs, and poorer oncologic outcomes. The stress response to surgery is a neurohormonal and immune response to trauma which seeks to stop haemorrhage, prevent infection, and promote healing. However, an inappropriately exaggerated postoperative systemic inflammatory response is now understood to be associated with infective complications following surgery for colorectal cancer. It is thought that this may occur through the suppression of the adaptive immune system by this overwhelming innate response. However, it’s effect on the longer term and oncologic outcomes is less clear. In addition, the factors which influence this postoperative systemic inflammatory response are unclear. Furthermore, it remains to be determined whether attenuation of the postoperative systemic inflammatory response will improve short and long term outcomes following surgery for colorectal cancer. The work presented in this thesis further examines the relationship between the postoperative systemic inflammatory response, postoperative complications, and long term oncologic outcomes following surgery for colorectal cancer. Several perioperative factors which might influence the postoperative systemic inflammatory response are examined. Finally, the question as to whether attenuation of the postoperative systemic inflammatory response might result in improved outcomes following surgery for colorectal cancer is examined. The magnitude of the postoperative systemic inflammatory response, in particular, exceeding C-reactive protein (CRP) concentrations of 150mg/L on postoperative days 3 or 4, has been reported to be associated with the development of infective type postoperative complications. Chapter 3 examined the relationship between the postoperative systemic inflammatory response and complication severity, reporting that exceeding these CRP thresholds was associated with major complications as defined by Clavien Dindo grades 3 to 5. Although postoperative complications are recognised to have a negative prognostic impact, the relationship between the postoperative systemic inflammatory response and long term oncologic outcome is less clear. The results of Chapter 4 suggest that an exaggerated postoperative systemic inflammatory response has a negative prognostic impact independent of complications following surgery for colorectal cancer. There is already some evidence to suggest that patient and operative factors such as the use of laparoscopic surgery, body mass index (BMI), comorbid disease, and the presence of preoperative systemic inflammation influence the postoperative systemic inflammatory response. Chapters 5 to 11 examined some other important patient and perioperative factors which might have an influence on the postoperative systemic inflammatory response. Chapter 5 reported that BMI and visceral obesity measured by preoperative CT scans are associated with the magnitude of the postoperative systemic inflammatory response and complications in female patients only. Chapter 6 reported no significant association between poorer exercise tolerance, a lower anaerobic threshold as measured by cardiopulmonary exercise testing (CPEX), and the magnitude of the postoperative systemic inflammatory response in a small number of patients. Chapter 7 reported no association between the formation of a temporary defunctioning stoma (at the time of anterior resection for rectal cancer), and the magnitude of the postoperative systemic inflammatory response. Chapter 8 reported that operation duration is not directly associated with the postoperative systemic inflammatory response, instead suggesting that the surgical approach is more important. Chapter 9 reported no association between perioperative blood transfusion and the magnitude of the postoperative systemic inflammatory response, but did find a significant association between preoperative inflammation and anaemia. Chapter 10 reported no association between preoperative neoadjuvant chemoradiotherapy (nCRT) and the magnitude of the postoperative systemic inflammatory response in patients undergoing surgery for rectal cancer. Chapter 11 compared the postoperative systemic inflammatory response of patients undergoing surgery for colorectal cancer in the UK and Japan, using propensity scoring to match patients from each country by various demographic, pathological, and perioperative variables. The results suggest a significant difference in the magnitude of the postoperative systemic inflammatory response, possibly dependent on ethnicity, which appears to be confirmed on further examination of the literature. Chapter 12 examined the possibility of a new paradigm of postoperative care following surgery for colorectal cancer. At present the investigation of potential complications following surgery is primarily reactive in nature and based on markers of patient physiology such as heart rate, core body temperature, blood pressure etc. Chapter 12 proposed the use of CRP on day 4 to prompt early investigation of such potential complications by computed tomography (CT) in the presence of an exaggerated postoperative systemic inflammatory response. The results suggest that such a postoperative care protocol could result in the earlier and more accurate diagnosis of postoperative complications. Chapters 13 to 15 examined the use of single dose preoperative corticosteroids for the attenuation of the postoperative systemic inflammatory response and whether it might improve short term complications following surgery for colorectal cancer. Meta-analysis of the existing randomised controlled trials in gastrointestinal cancer surgery in Chapter 13 reported that corticosteroids result in lower postoperative CRP concentrations and fewer postoperative complications, but only in patients undergoing oesophageal and hepatic surgery and not in patients having a colorectal resection. In Chapter 14, a propensity score matched analysis of the GRI cohort of patients given dexamethasone at the induction of anaesthesia, for the prevention of postoperative nausea and vomiting (PONV), reported a significant reduction in postoperative CRP concentrations and complications. Finally, Chapter 15 set out a protocol for a randomised controlled trial of preoperative dexamethasone to assess dose response with relation to the magnitude of the postoperative systemic inflammatory response. In summary, the postoperative systemic inflammatory response may impact on the short and long term outcomes of patients undergoing surgery for colorectal cancer. Attenuation of this postoperative systemic inflammatory response might reduce the rate of postoperative complications, although the impact of such strategies on long term outcomes is as yet unknown. Future research in this area might examine various methods of attenuating the postoperative systemic inflammatory response; including anaesthetic techniques, the use of minimally invasive surgery, and pharmacological techniques such perioperative steroids and other anti-inflammatory drugs, and their impact on short and long term outcomes after surgery for colorectal cancer.

Minimally invasive surgery (MIS) is fast becoming a preferred choice for patients and surgeons, due to its biological, aesthetic and commercial benefits. The dynamic hip screw (DHS) is the standard implant for the treatment of fractures of the proximal femur, which is considered to be the most frequent injury in the elderly. The aim of this research was to develop MIS for the treatment of these fractures utilising the principle and surgical technique of the DHS implant. During the research, a thorough medical device design process was conducted to develop three new medical devices 13 a new angle guide, a new ergonomic T-handle and a new implant. The design process for each of the new medical devices conformed to requirements of the relevant standards. The designs of the new medical devices were verified using methods such as risk analysis, finite element analysis and mechanical testing of manufactured prototype. Finally, an operative technique applying a minimally invasive approach with the new medical devices was developed to treat the fractures of the proximal femur.