Total Hip Arthroplasty (THA) is a successful technique restoring lost mobility to patients suffering from osteoarthritis. A successful THA normalises the biomechanics of the hip joint so that a patient can achieve the required range of motion to fulfil their daily activities. A recent development in THA implant technologies has been the introduction of femoral neck modularity. Assessment of femoral neck modularity has been limited by two factors. Firstly, range of motion requirement is not well understood and secondly previous clinical reports have lacked a comparison against an established successful THA implant. This study has successfully addressed these limiting factors by developing an innovative range of motion benchmark which considers the activities a person is required to undertake during their daily routine. The benchmark was developed using a systematic review of the literature focussing on hip joint biomechanics. This has been the first study to provide a clinically meaningful representation of hip joint range of motion which permits operative outcome to be directly compared against an established benchmark. Integration of the range of motion benchmark within the surgical environment was achieved by using a surgical navigation measurement device. Intra-operative measurement meant that post-operative range of motion could be simulated and compared against the requirement set by the range of motion benchmark. Distinct outcome measures have been able to be developed using this comparison which has allowed the surgical process to be assessed like a manufacturing system. Using these outcome measures, it was found that femoral neck modularity has greater potential to adjust implant orientation in comparison to non-modular femoral neck implants to achieve the ideal range of motion. However, this potential is being limited due to the current modular neck options available and because of difficulty experienced by the surgeon in assessing implant orientation. These findings have been used to develop a medical device which provides guidance to the surgeon about the THA implant orientation and thus allow them to able to make the correct modular neck choice to maximise range of motion and improve the operative outcome for the patient.

Carotid endarterectomy has been demonstrated to reduce future stroke risk; however, stroke is a procedural risk. Therefore, to achieve the maximum benefit for patients, complications must be minimised. There are variations in the way that the operation is performed which may influence this peri-operative stroke risk. In particular, patch closure of the artery is a possible way of improving outcomes and the evidence is considered. Flow haemodynamics are considered to be a major aspect of the potential benefit with patch closure. The related evidence is presented, though the evidence to date is inadequate to prove that patching improves the haemodynamic profile sufficiently to improve outcomes. The hypothesis of a study is presented to try to answer this key question in carotid disease. Around one third of surgeons use primary closure with patching indicated with a median ICA diameter under 5mm. Of those surgeons who always use patch angioplasty around half use a full size patch of median 8mm diameter and the other half trim the patch width to a median of 6mm. Carotid geometry is complex but can be defined by using an index which uses the long and short axes or the cross-sectional area divided by the dimensions in the CCA proximal to endarterectomy; this index has been validated. Primary closure reduces the diameter and cross-sectional area in contrast to patch angioplasty which increases these dimensions in proportion to the width of the patch. Primary closure, in some cases, causes stenoses in the distal CCA which produces detrimental haemodynamics, whereas in those cases without a stenosis, physiological haemodynamics are produced. Patch closure produces less advantageous haemodynamics, however the larger 8mm patch is considerably worse than the trimmed 5mm patch. There is a direct link between geometry and haemodynamics. Increasing geometry index produces worse haemodynamics, the exception being a CCA stenosis in a primary closure. Increasing model size has only a limited effect on haemodynamics. This study affirms the practice of those surgeons who trim their patches. Very large bifurcations (an internal carotid diameter of around 8mm) are prone to low wall shear stresses and may be best repaired by primary closure.

Outcomes after major surgery depend partly on patients’ physiological tolerance to iatrogenic trauma. Objectively measured fitness assessments (cardiopulmonary exercise testing; CPET) show a link between poor fitness and poor surgical outcome, especially in major colorectal surgery. However evidence on fitness of surgical patients undergoing neoadjuvant chemoradiotherapy (NACRT) and/or preoperative exercise training is lacking. This thesis focuses on the physiological effects of NACRT and a preoperative structured responsive exercise training programme (SRETP) on objectively measured physical fitness using cardiopulmonary exercise testing, and the related effects on mitochondrial function using 31-phosphorus magnetic resonance spectroscopy (31P MRS) in operable advanced rectal cancer patients. First, CPET variables (oxygen uptake ( o2) at estimated lactate threshold ( L) and at peak exercise) were measured in advanced rectal cancer patients pre and post-NACRT and were followed up to 1 year postoperatively. A reduction in o2 at L and o2 at Peak exercise was observed (-1.5 and -1.4 ml.kg-1.min-1 respectively; p<0.0001), both significantly associated with in-hospital complications. This is the first direct evidence that the benefits of NACRT in tumour downsizing may be partly offset by increased perioperative risk due to a reduction in physical fitness. A SRETP was then constructed, and a feasibility and tolerability study carried out. The SRETP improved physical fitness within 6 weeks following NACRT ( o2 at L +3.3 ml.kg-1.min-1 and o2 Peak by +5.8 ml.kg-1.min-1), enough to reverse the deleterious effects of NACRT. A 98% adherence proves the SRETP both feasible and tolerable, with no adverse events encountered. Next, locally advanced rectal cancer patients were recruited to an interventional pilot study scheduled to undergo standardised NACRT and a 6-week SRETP (exercise group n=22) or a control period (n=13). A significant benefit in o2 at L of +2.12 ml.kg-1.min-1 (p<0.0001) in the exercise group was observed. This study reinforces the benefits of prehabilitation with exercise training to improve physical fitness after the deleterious effects of NACRT prior to the added insult of major surgery. Lastly, patients were randomized to the SRETP or to negative control after undergoing standardized NACRT, serial measures of whole body fitness and in vivo mitochondrial function by 31P MRS (measuring the rate constant of phosphocreatine recovery, kPCr). Significant reductions in o2 at L (-2.36 ml.kg-1.min-1) were observed with NACRT, after which the SRETP improved fitness ( o2 at L +3.85 ml.kg-1.min-1). A significant reduction in kPCr of -0.34 was found with NACRT, improved by +0.66 after SRETP. These novel, clinically relevant findings show a significant decline in fitness with NACRT in an advanced rectal cancer cohort, reversible by a tailored exercise intervention post-NACRT. Concomitant changes in muscle mitochondrial function may account for this acute loss in fitness. The improvement in mitochondrial function observed with exercise, might indicate that a structured intervention immediately after NACRT is necessary to rescue and reverse NACRT’s deleterious effect on mitochondrial function and fitness in this patient cohort.

Introduction. This thesis explored patient experiences of awake craniotomy. Existing literature is scarce and dominated by quantitative methodologies. More recently two qualitative studies have provided a rich, but contrasting, understanding of the patients‟ experience of awake craniotomy. The methodological weaknesses of the existing literature are addressed, and the rationale for the study justified. Objectives. The aim of the study was to explore seven participants‟ experiences of awake craniotomy using interpretative phenomenological analysis. Methods. Single-site ethical approval was gained to conduct the study in one NHS Trust. All potential participants were approached who had undergone the awake craniotomy procedure at the NHS Trust. Semi-structured interviews were conducted with participants. Interviews were transcribed verbatim and analysed using an interpretative phenomenological analysis framework. Results. Analysis of transcripts yielded three superordinate themes: self-preservation, operation environment and information. The superordinate themes were interpreted as interconnected with each other, as well as embedded in a core theme: relationship with the neurosurgeon. The three superordinate themes are presented and discussed within the journal article. The extended paper elaborates on two of these superordinate themes. Discussion. The relationship with the neurosurgeon appears crucial to the patients‟ experience of awake craniotomy. The relationship could impact on the participants‟ decision to have the awake craniotomy, their experience of the awake operation and their acceptance of the information given. The results are discussed with reference to previous literature. The implications and recommendations for further research are outlined.

Background: Reduced training hours, over-crowded operating rooms, and lack of focus on non-technical skills are severely affecting surgical training. In specialities such as Oral and Maxillofacial Surgery, there is an increasing need for innovation in training. On the other hand, despite the application of technological advancements including virtual reality (VR) and augmented reality (AR), twenty-eight to forty percent of novice trainees are not confident in performing major surgery. The current research aims to address these challenges by finding a suitable way to develop an evidence-based immersive virtual reality (iVR) experience. Further, the research investigates the impact of this solution on the learning and confidence of trainees. This research introduces VR Surgery, an iVR experience, to address the gaps in the knowledge. VR Surgery is the first multi-sensory, holistic surgical training experience demonstrating Le Fort I osteotomy, a type of maxillofacial surgery, using Oculus Rift and Leap Motion devices. This research demonstrates the design, development and evaluation of VR Surgery and provides a way for future studies on the use of immersive technologies for surgical education. Methods: A design science research approach was followed to identify the problem, build the solution in collaboration with expert surgeons and evaluate it. Using a combination of multimedia, VR Surgery enables trainee surgeons to experience a realistic operating room environment, and interact with the patient’s anatomy while watching the surgery in a close-up stereoscopic 3D view. Consultant oral and maxillofacial surgeons in the UK evaluated VR Surgery for Face and Content validity. Surgeons commented on the content, usability and applicability of VR Surgery to surgical training. Further, to investigate the impact of VR Surgery on the perceived self-confidence of trainees, a single-blinded, parallel, randomised controlled trial (RCT) was performed. Surgical trainees (95) from seven dental schools took part in one of the first experiments to test the role of iVR on self-confidence. Experimental group participants learnt about the Le Fort I procedure using VR Surgery on an Oculus Rift. The control group used similar content in a standard PowerPoint presentation. The primary outcome measures were the self-assessment scores of trainees’ confidence as measured on a Likert scale and objective assessment based on the knowledge. Outcomes: The expert surgeons agreed with the validity of VR Surgery. The participants of the RCT were randomly divided into the experimental (51) and control (44) groups. Trainees had a mean age of 27∙14, and they were 45∙3% female students and 50∙5% male students. A repeated measures multivariate ANOVA was applied to the data to assess the overall impact of receiving the VR surgery intervention over conventional means on the confidence of trainees. Experimental group participants showed higher perceived self-confidence levels compared to those in the control group (p=0∙034, =0∙05). Novices in the first year of their training showed the highest improvement in their confidence, compared to those in the second and third year. Interpretation: Surgical trainees improve their knowledge and self-confidence levels after using an iVR training experience. The study proves that virtual reality applications such as VR Surgery have a substantial potential to bridge the differences in the quality of global surgical training. This research provides a framework for future researchers who use mixed reality for healthcare.

Contemporary management of patients with heart failure (HF) includes treatment with cardiac resynchronisation therapy (CRT). The benefit of CRT results from several mechanisms, predominantly correction of dyssynchrony. The development of a novel method of measuring left ventricular global dyssynchrony using cardiovascular magnetic resonance (CMR), termed CMR-tissue synchronisation index (CMR-TSI) is described. A study of 225 patients with HF who underwent CMR-TSI found that HF appears synonymous with dyssynchrony. The importance of myocardial scar is illustrated in a study of 95 patients which revealed a significantly higher mortality in patients undergoing CRT who had postero-lateral (PL) scar on CMR. A study into the effects of a combination of CMR-TSI and scar imaging found that presence of either CMR-TSI >110ms or PL scar resulted in a worse outcome, whilst the presence of both was associated with the highest mortality. A final study in 148 patients allowed the development of a risk score to predict mortality from CRT on the basis of 16 candidate variables. PL scar, dyssynchrony and creatine discriminated between survivors and non-survivors and were used to derive the score. The score is discussed in the context of data derived from echocardiography and clinical studies.

This thesis defines mortality in acromegaly in a modern patient cohort, elucidates underlying explanations for the increased mortality and explores the impact of treatment, focussing on somatostatin analogue therapy. Results confirm there remains a 30% increase in mortality in patients with acromegaly. Mortality was increased in patients with GH >2µg/L, but not in patients with raised IGF-I. This is the first study showing reduced survival in patients with acromegaly following pituitary radiotherapy. Somatostatin analogue therapy was shown to be efficacious and safe. I also explored factors influencing pituitary tumourigenesis by characterising mRNA levels for 11β-HSD isozymes in normal and neoplastic pituitary tissue. Results demonstrated reduced 11β-HSDl expression and 10-fold increased 11β-HSD2 expression in pituitary tumours compared with normal pituitary, resulting in reduced active glucocorticoid concentrations within the pituitary. This may diminish the antiproliferative effects of glucocorticoids, thus contributing to the process of pituitary tumourigenesis. Finally, I explored complications of pituitary adenomas by evaluating outcome in patients presenting acutely with pituitary apoplexy. Patients presenting without visual deficit or showing evidence of early improvement in visual deficit can be managed without acute neurosurgical intervention. Results of this research will undoubtedly improve the management and outcome of patients with acromegaly and pituitary tumours.

Four clinical studies in subjects with alpha-1 antitrypsin deficiency were undertaken. The first examined CT densitometry and health status in 4 groups with discordant pulmonary physiology. It demonstrated that subjects with an isolated gas transfer abnormality had more emphysema, the least basal predominant emphysema and a worse health status than those with normal physiology. Subjects with an isolated spirometry abnormality had the most basal emphysema. The second study examined the age at which radiological, physiological and health status measures started to deviate from values expected for a normal population, and concluded that CT densitometry and gas transfers measures were the first to deviate from normal, while spirometry was the last. The third study examined the relationship of γ-glutamyl transferase to physiology, symptoms, mortality and liver disease in alpha-1 antitrypsin deficiency, and demonstrated associations between γ-glutamyl transferase and spirometry, mortality and cirrhosis after correction for associated factors. The final study described subjects with the PiSZ phenotype compared to matched PiZ subjects. CT revealed emphysema (mainly panacinar) in 46% of PiSZ index and 15% of non-index subjects. Health status was impaired in PiSZ subjects, who had less lower zone emphysema, better health status, pulmonary physiology and symptom profile compared with PiZ subjects.

Changes in oxygen levels, due to the environment or disease initiates a plethora of acute and chronic responses in the body to enable optimal physiological adaptation to overcome impaired oxygen delivery. Homeostatic regulation mechanisms in the cardiovascular and respiratory systems rapidly act to maintain oxygen supply to sustain normal metabolism; prolonged exposure to a low oxygen tension initiates changes in gene expression. In control of many of these responses is a transcription factor (hypoxia-inducible factor, HIF). Among other responses it induces changes in erythropoiesis, glycolysis and angiogenesis. This study primarily aimed to elucidate the conditions of hypoxia, local or systemic, which would initiate capillary growth in different tissues, and determine whether manipulation of the pathway (by HIF stabilisation) would enhance this response. A systemic response to hypoxia led to increased capillarity in the heart and diaphragm, and in both the local and systemic models changes in vascularity varied with degree of hypoxia, though manipulation of the HIF pathway had no effect. HIF upregulation under conditions of normoxia with muscle overload, also failed to show effects of manipulation of the HIF pathway. Therefore, ablation of individual enzymes controlling levels of HIF was utilised. A number of genes associated with angiogenesis and protein remodelling were upregulated, as seen with gene arrays, though histological evidence for the former was poor, suggesting a delay in gene expression and translation into downstream effects. We examined whether changes in plasma EPO expression were predictive of sickness upon ascent to altitude, and whether leukocytes could be used as a circulating indicator of HIF-mediated gene expression. EPO was enhanced in all subjects following exposure to hypoxia, and it may be one marker for AMS, but individual variation in gene responses to hypoxia suggests leukocytes may not be a viable indicator of the circulating systemic response to hypoxia. This study emphasises the complexity of the HIF pathway, highlighting the multitude of its effects both on a molecular and physiological level.

Increased arterial stiffness is associated with ageing, cardiovascular disease diabetes and renal failure. The aims of this thesis were to investigate the reproducibility of a tissue Doppler imaging (TDI) based ultrasound system to calculate indices of arterial stiffness, and to investigate changes in arterial wall stiffness in subjects with increased age, peripheral arterial disease (PAD), chronic kidney disease (CKD) and angiotensin converting enzyme inhibitors (ACE-Is). A reproducibility study demonstrated good reproducibility. A study of healthy subjects demonstrated a stronger relationship with age for arterial stiffness than intima media thickness (IMT). Case control studies investigating changes in subjects with PAD and CKD demonstrated a greater increase in arterial stiffness than IMT when compared to healthy controls. An epidemiological study, investigating the effect of antihypertensives on collagen turnover, suggested an association between increased collagen turnover and ACE-Is. Investigating the effect of ACE-I administration on arterial stiffness in subjects with PAD, we demonstrated an increase in collagen turnover and a decrease in arterial stiffness. We have demonstrated that the TDI-based system is a reproducible method of measuring arterial stiffness. We suggest that arterial stiffness increases more than IMT with ageing, PAD and CKD and that it may increase before cardiovascular disease develops.