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To date, research examining psychological adjustment to cleft lip and/or palate (CL/P) has produced conflicting findings. As a consequence, large gaps in our understanding of CL/P remain, ultimately impacting the ability to implement and evaluate psychological support for this population. The work presented in this DPhil discusses the conceptual and methodological challenges associated with this field in accordance with three key underlying themes: outcomes, methods and neglected groups, in an attempt to explain why these conflicting findings occur and to offer an alternative perspective. Specifically, this doctoral thesis proposes the need for an approach which is holistic rather than narrow, inclusive rather than exclusive, normalising rather than pathologising, appreciative of the patient perspective and encompassing of patient strengths and positive growth.

This thesis investigates the principal factors responsible for early failure of femorodistal vein grafts. Chapter 1 provides an overview of severe lower limb ischaemia which is their principal indication. Chapter 2 outlines the role of surgery in the management of the severely ischaemic limb, concentrating on the development of distal bypass using autogenous vein. Chapter 3 considers the multiple causes of vein graft failure, concentrating on the early period and includes an account of currently employed methods designed to reduce the problem. Chapter 4 is a retrospective review of the results of 130 in situ vein grafts performed at Leicester Royal Infirmary in the 8 year period prior to the commencement of this study. The primary early failure rate was 30%, with two thirds of patients undergoing amputation. Chapter 5 outlines the methods used in a series of 42 patients undergoing distal vein bypass. Preoperative assessment included arteriography and 3 methods using Doppler ultrasound. Doppler signal augmentation by dependancy and by Pressure Generated Runoff (PGR) were compared. Intraoperative methods included on-table arteriography, prebypass resistance measurement, completion flow and resistance measurement, and completion arteriography. A new system of continuous monitoring using Doppler ultrasound was employed to study the early postoperative period. There were 10 early failures, 9 of which resulted in amputation. None of the preoperative investigations was able to discriminate between successful and failed cases, although dependant Doppler and PGR provided additional qualitative information regarding distal runoff. Prebypass resistance was the best single investigation for predicting outcome prior to reconstruction. Measurement of graft resistance provided the best means of bypass assessment, although maximum benefit was achieved when combined with arteriography. The continuous monitoring system proved to be a reliable means of following early graft haemodynamics and was able to predict outcome in 93% of cases.

Although several clinical human islet transplants have been performed, allograft rejection has been a major problem. Encapsulation in sodium alginate/poly-l-lysine has been proposed as a method to protect the islets from rejection and autoimmune destruction. The aims of this project were to determine optimum capsule composition and to assess encapsulated islet function following transplantation using the spontaneously diabetic BioBreeding (BB/d) rat as a model of autoimmune insulin-dependent diabetes. The membrane integrity of islets, determined by microfluorometry, was not adversely affected by encapsulation. During perifusion, the stimulation increase of encapsulated islets was decreased relative to controls, but the stimulation index and response time were unaffected. Capsule composition did not affect these results. The biocompatibility of the capsules was related to their composition. The presence of an outer layer of alginate, and the preparation of alginate used, reduced the severity of pericapsular fibrosis. Capsules implanted in the peritoneal cavity provoked a more severe response than those placed in the renal subcapsular space. BB/d rats displayed a marked response to the capsules. Transplantation experiments demonstrated that 3000 non-encapsulated or 5000 encapsulated islets were the minimum number required to reverse streptozotocin-induced diabetes when transplanted into the peritoneal cavity. An intense pericapsular fibrosis led to failure of the encapsulated grafts. Further transplants into the BB/d rat were postponed to allow the cause of fibrosis to be investigated. The alginate was found to be contaminated with protein and this was removed by dialysis. In vitro experiments with the dialysed alginate demonstrated that treatment of the alginate did not affect the viability of encapsulated islets. Biocompatibility studies showed that capsules coated with dialysed alginate remained free from pericapsular fibrosis, even in the BB/d rat, when tested over the time interval which had resulted in the development of severe fibrosis of capsules coated with untreated alginate.

The treatment of Type 1 (Insulin-Dependent) Diabetes Mellitus by the transplantation of isolated islets of Langerhans is an attractive concept, but one which has been difficult to realise in clinical practice. Insulin-independence has been relatively rare following human islet allotransplantation, due partly to immunological rejection of islets, but also due largely to the problems inherent in the isolation of sufficient numbers of purified islets from the native pancreas. The purification of islets prior to transplantation is desirable for several reasons, and is usually achieved using large-scale density gradients. Current techniques of density-dependent separation of islets are inefficient, however, and result in an unacceptable loss of islet yield. The purpose of the work described in this thesis was therefore to examine the possible factors limiting the efficiency of islet purification using density gradients, and to investigate ways in which these factors may be usefully modified. Using a standardised, quantitative system for assessing the efficiency of islet purification on density gradients, it was demonstrated that the separation of purified human and porcine islets was highly dependent upon the physico-chemical environment of pancreatic tissues throughout the isolation process. In particular, it was shown that islet purity is compromised by exocrine tissue swelling occurring during the isolation procedure, but that this swelling can be reversed, and islet purity thereby markedly improved, by suspension of the dispersed, collagenase-digested pancreatic tissues in appropriate storage solutions. The optimal, composition of such solutions was defined, and their combined use both for storage of the dispersed pancreas and as a solvent for novel density gradient media was examined. The results obtained in this way have contributed to an improved understanding of the factors potentially influencing islet purification, and may therefore assist in expediting the clinical application of islet transplantation as a therapy for diabetes.

Introduction: The biomechanical model of back pain has failed to find distinct relationships between intervertebral movement and pain due to limitations and variation in methods, and errors in measurement. Quantitative fluoroscopy (QF) reduces variation and error and measures dynamic intervertebral motion in vivo. This thesis used recumbent QF to examine continuous mid-lumbar intervertebral motion (L2 to L5) in patients with assumed mechanical chronic non-specific low back pain (CNSLBP) that had been clinically diagnosed. It aimed to develop kinematic parameters from the continuous data and determine whether these could detect subtle mechanical differences by comparing this to data obtained from healthy volunteers. Methods: This was a prospective cross sectional study. Forty patients with CNSLBP (age 21 to 51 years), and 40 healthy volunteers matched for gender, age and body mass index underwent passive recumbent QF in the coronal and sagittal planes. The patient group completed questionnaires for pain and disability. Four kinematic parameters were developed and compared for differences and diagnostic accuracy. Reference intervals were developed for three of the parameters and reproducibility of two were assessed. The radiation dose was compared to lumbar spine radiographs and diagnostic reference levels were established. Finally, relationships between patient’s pain and disability and one of the kinematic parameters (continuous proportional motion CPM) were explored. Results: Reproducibility was high. There were some differences in the coronal plane and flexion for each kinematic parameter, but no consistency across segments and none had high diagnostic accuracy. Radiation dose for QF is of the same magnitude as radiographs, and there were no associations between patient characteristics of pain and disability and CPM. Conclusion: Although the kinematic differences were weak, they indicate that biomechanics may be partly responsible for clinically diagnosed mechanical CNSLBP, but this is not detectable by any one kinematic parameter. It is likely that other factors such as loading, central sensitisation and motor control may also be responsible for back pain that is considered mechanical. QF is easily adapted to clinical practice and is recommended to replace functional radiography, but further work is needed to determine which kinematic parameters are clinically useful.

Introduction Laparoscopic colorectal surgery and enhanced recovery programs have been shown to improve patient outcomes and reduce length of stay following surgery. The use of regional analgesia is usually a fundamental element of an enhanced recovery program. A proposed benefit of regional analgesia in colorectal surgery is suppression of the post-operative stress response. No data is available to indicate if this is applicable in laparoscopic colorectal surgery. In addition there is no direct evidence addressing whether there is an appropriate type of fluid, crystalloid or colloid, to use in goal-directed fluid therapy. The aim of this study was to examine the effects the choice of analgesia and intravenous fluid had on physiological and biochemical outcomes following laparoscopic colorectal surgery in patients within an enhanced recovery program. Methods A randomized clinical trial (NCT 01128088) was conducted between 2010-2011 at a single institution. All patients underwent laparoscopic colorectal surgery for benign or malignant conditions within an established enhanced recovery program. Patients were randomly assigned to receive either a spinal or morphine PCA as their primary post-operative analgesia. In addition, patients were randomly allocated to receive either 6% Volulyte or Hartmann’s solution, which was administered as directed by an oesophageal Doppler monitor in order to achieve stroke volume optimisation. Blood was taken to measure aspects of the stress response at pre-op, 3, 6, 12, 24 and 48 hour time intervals. Various other physiological and patient outcomes were measured. Results One hundred and twenty patients were analysed in the study. There was no significant difference in patient characteristics between the groups. No significant difference was seen between the analgesia groups at pre-op, 3, 6, 12, 24 or 48 hours in the levels of insulin, IL-2, 4, 6, 8, 10, 12, TNF-α, VEGF or IFN-γ. Median cortisol (468 nmol/l (IQR: 329-678) vs 701 nmol/l (IQR: 429-820); p=0.004) and glucose (6.1 mmol/l (IQR: 5.4-7.5) vs 7 mmol/l (IQR: 6-7.7); p=0.012) levels were significantly lower at 3 hours post-op in the spinal group and thereafter the same. Patients receiving Hartmann’s solution received significantly greater volumes of fluid in comparison to those receiving 6% Volulyte (20.98ml/kg (IQR: 16.68-25.73) vs 13.95ml/kg (IQR: 11.76-18.1); p<0.0005). There was no significant difference in the median length of stay between either fluid (6% Volulyte 2.75 days [IQR: 2.08-3.6] vs Hartmann’s 2.29 days [IQR: 2.01-3.59]; p=0.807) or analgesia (spinal 2.25 days [IQR: 1.89-3.13] vs PCA 2.9 days [IQR: 2.09-3.93]; p=0.059) groups. The number of complications was no different between the two types of fluids but patients receiving spinal analgesia (20% vs 37%, p=0.013) had a significantly reduced number. Conclusion Following laparoscopic colorectal surgery within an enhanced recovery program the use of spinal analgesia in comparison to morphine PCA significantly reduces the levels of cortisol and glucose at 3 hours only. This difference does not translate to a reduction in length of stay. There is no effect on other aspects of the stress response at various post-operative time intervals. A significantly greater quantity of Hartmann’s solution is required to achieve stroke volume optimisation in comparison to 6% Volulyte. This, however, did not make any difference to the incidence of post-operative complications or length of stay. Either fluid is acceptable in the quantities given in this study.

Aim: This paper aimed to examine how patients with chronic back pain understand and experience the messages about pain and treatment in their first specialist medical (pain clinic) consultation. It also aimed to compare what doctors believe they communicated with patients’ own ‘take home’ messages. Method: Sixteen patients were interviewed immediately after their first consultation at a pain clinic, and their corresponding doctors were interviewed shortly afterwards. Thematic analysis was conducted on the patient interviews to address the first research aim, and then framework analysis was employed to compare understandings of the consultation within the patient-doctor dyads. Results: Thematic analysis of patient interviews resulted in four higher-order themes: the central role of medical treatments in the treatment of pain; a dilemma about hoping when there are ‘no guarantees’; the importance of trying all recommended medical interventions and, for a minority of patients, relief to be recommended non-medical pain management. Although there was considerable overlap within the patient-doctor dyads, clinically relevant areas of mismatch included the explanation of pain, the likely long-term treatment plan, and patients’ role in their treatment. Conclusions: Patients’ understandings of the consultation messages seemed to influence their beliefs about the likelihood of their pain being relieved, and their sense of control over it. There seemed notable areas of mismatch between doctors’ and patients’ understandings of the consultation which are likely to impact upon treatment success and patient satisfaction.

In this thesis a new approach to sensing soft tissue damage in the diabetic foot is presented and multiple sensor modalities including linear and rotational accelerometers, temperature, humidity and galvanic skin response (GSR), pressure/-force, blood oxygen heart rate and fore foot flexure will be investigated with the aim of using multi modal sensing to improve understanding the diabetic foot. Bioimpedance is proposed and investigated as a novel measurement modality that directly observes the response of the tissue under test as a means of estimating tissue condition. The new sensing system and data collection with critical assessment is presented complimenting the existing metric of assessment. Diabetes is currently one of the greatest health risks facing the developed world where typically 6% of the population is diabetic and an estimated 1 in 3 people are currently in a pre-diabetic state. The condition adversely affects the body’s glycaemic control mechanisms leading to macro vascular stiffening alongside the possible onset of peripheral neuropathy thus increasing the risk of secondary pathologies such as retinopathy, kidney failure and diabetic foot disorder. For those living with diabetes the loss of a foot due to diabetic foot disorder is one of the most debilitating and feared side effects of diabetes. The national health service (NHS) in the United Kingdom (UK) currently amputates circa 100 lower legs a week due to diabetic complications of which about 85% are avoidable. As amputation leads to increased morbidity and mortality (68% at five years post 1st amputation) as well as a marked reduction in quality of life, this concern is well founded. Many metrics have been investigated as indicators of diabetic foot disorder, though none have shown sensitivity and specificity that would enable their use as a reliable diagnostic or predictor of ulceration. The following contributions to the body of knowledge will be presented: 1. Novel associations of sensors for monitoring the diabetic foot see Table 6.6. 2. The development of a novel bioimpedance measuring device. 3. The development of a novel wearable extensible multimodal sensing system. 4. Demonstrate direct current (DC) through textile GSR measurement. 5. Demonstrate the effect of caffeine on GSR coherence for the first time.