The primary objective of this research was to perform an in vitro assessment of the ability of microscale topography to alter cell behaviour, with specific regard to producing favourable topography in an orthopaedic ceramic material suitable for implantation in the treatment of arthritis. Topography at microscale and nanoscale alters the bioactivity of the material. This has been used in orthopaedics for some time as seen with optimal pore size in uncemented hip and knee implants. This level of topography involves scale in hundreds of micrometres and allows for the ingrowth of tissue. Topography at smaller scale is possible thanks to progressive miniaturisation of technology. A topographic feature was created in a readily available clinically licensed polymer, Polycaprolcatone (PCL). The effect of this topography was assessed in vitro. The same topography was transferred to the latest generation composite orthopaedic ceramic, zirconia toughened alumina (ZTA). The fidelity of reproduction of the topography was examined using scanning electron microscopy (SEM) and atomic force microscopy (AFM). These investigations showed more accurate reproduction of the topography in PCL than ZTA with some material artefacts in the ZTA. Cell culture in vitro was performed on the patterned substrates. The response of osteoprogenitor cells was assessed using immunohistochemistry, real-time polymerase chain reaction and alizarin staining. These results showed a small effect on cell behaviour. Finally metabolic comparison was made of the effects created by the two different materials and the topography in each. The results have shown a reproducible topography in orthopaedic ceramics. This topography has demonstrated a positive osteogenic effect in both polycaprolactone and zirconia toughened alumina across multiple assessment modalities.

The overall aim of this thesis was to investigate the effect of preoperative exercise and training on postoperative outcome. Poor cardiorespiratory fitness has been associated with poor postoperative outcome including increased length of hospital stay and postoperative complications. Thus, increasing cardiorespiratory capacity prior to surgery via preoperative exercise training could potentially alter postoperative outcome. High intensity exercise training (HIIT) has been demonstrated to be an efficient training intervention to increase cardiorespiratory capacity in as little as 2 weeks. It was hypothesised that chronic preoperative exercise training (i.e. 2 weeks HIIT) would improve postoperative outcome measures (i.e. length of stay, complications and mortality) in urology cancer resection patients in comparison to a usual-care-only group (UC). Thirty-five urology cancer resection patients voluntarily enrolled into the study, of these thirty completed the study (15 UC, 15 EXP). There was a significant increase in length of stay (LOS) in the EXP group in comparison to the UC group (4.0 ±6.0 versus 3.0 ±1.5 days, P=0.03), respectively. However, after accounting for covariates (surgical severity, number of operations) LOS was not significantly different between groups (5.8 ±0.8 versus 5.0 ±0.8 days; P=0.24) for UC and EXP patients, respectively). There were no significant differences between groups for postoperative complications on days 1-8 post-surgery (P>0.05), despite significant differences between groups for VO2peak change data (-2.2 ±0.8 ml.kg-1.min-1 versus +1.3 ±0.8ml.kg-1.min-1; Eta2:0.24; P=0.02) for UC and EXP patients). Overall, two weeks preoperative HIIT does not appear to alter postoperative outcome in urology cancer resection patients. The effect of two weeks preoperative HIIT was investigated in colorectal cancer resection patients. It was hypothesised that chronic preoperative exercise training (i.e. 2 weeks HIIT) would improve postoperative outcome measures (i.e. LOS, complications and mortality) in colorectal cancer resection patients in comparison to the UC group. Twenty-one colorectal patients voluntarily enrolled into the study and completed the study (12 UC, 9 EXP). There were no significant differences between groups for LOS, (7.0 ±8.5 versus 6.0 ±2.0 days, Eta2:0.04; P=0.38) for UC and EXP patients, respectively). The Cox Regression hazard ratio was 1.55, suggesting that there was a 55% increased likelihood of being discharged on any given postoperative time point in the EXP group when compared to the UC group (95% CI: 0.25 to 1.65; P=0.36). There were no significant differences between groups for postoperative complications for days 1-10 post-surgery (P>0.05). Though, there was a moderate to large effect size for a reduction in postoperative complications on the 2nd (Eta2: 0.09), 4th and 8th postoperative day (Eta2: 0.07), in favour of the EXP group. There were no significant differences between groups for cardiorespiratory measures (i.e. AT, VO2peak) (P0.05). Thus, 2 hours hypoxia (O2: 14.5%) did not appear to significantly alter salivary stress markers. Therefore, the role of the cross-stressor adaptation hypothesis in exercise induced cardioprotection is unclear. The overall conclusion of this thesis is that preoperative exercise appears to improve postoperative outcome measures in AAA patients. However, the benefits of preoperative exercise training on postoperative outcome in colorectal and urology patients is equivocal. Though, there was a group effect on postoperative complications on days 2, 4 and 8 post-surgery in colorectal patients, in favour of the EXP group. Lastly, an acute bout of exercise did not appear to attenuate the stress response to a subsequent stressor.

Colorectal cancer is the 4th most common cancer in the UK and the second commonest cause of cancer death. Whilst mortality rates from colorectal cancer haven fallen over the last 2 decades, around 40% of those diagnosed with colorectal cancer will die from their disease. Surgery currently remains the only chance of cure. Around 10% of patients present as an emergency with perforation, obstruction or bleeding. Outcomes from these emergency operations are substantially worse than from elective procedures. The presence of a systemic inflammatory response pre-operatively is now widely recognised as a predictor of disease progression and poor outcomes, both long and short term, regardless of tumour stage in those with colorectal cancer. Numerous scoring systems that measure various components of the systemic inflammatory response have been documented, the most commonly used are the modified Glasgow Prognostic Score (mGPS) and the Neutrophil-Lymphocyte Ratio (NLR). The NLR has the advantage of using 2 components of the differential white cell count, which is routinely measured in surgical and oncological practice, whereas CRP is less commonly routinely measured. However, studies utilising the NLR have used a variety of thresholds, making comparison of the results from study to study difficult. Whether one of the components of the NLR is more important than the other remains to be seen and indeed whether there is a more optimal score that utilises the white cell count is not clear. To date no work has examined similar scoring systems in the post-operative period. The present thesis aims to examine the impact of the innate immune response, through such systemic inflammation based scoring systems, on patients undergoing surgery for colorectal cancer. Furthermore, it analyses the nature of the inflammatory response in the post-operative period in order to ascertain whether similar scoring systems may be of clinical utility. Chapter 1 provides an overview of colorectal cancer, its presentation and treatment and its known determinants of outcomes. Furthermore, the immune response to injury and post-operative inflammatory response are discussed. Chapter 2 documents a survey of clinicians who have an interest in systemic inflammation. The survey asks the participants whether they routinely measure systemic inflammation, to what purpose and which scoring system they prefer. Unsurprisingly, the majority of participants use these scoring systems for research purposes only with an even split in terms of which scoring system they prefer to use. Their use in clinical practice remains small but their use in some oncological studies may signify a step towards their incorporation into clinical practice in the future. Chapter 3 presents data from a cohort of patients whom have undergone surgery for colorectal cancer with pre-operative differential white cell counts in order to determine whether any of the white cell count components are important in determining long term outcomes. Only the neutrophil count was independently associated with poor long term survival in patients undergoing surgery for colorectal cancer. These results highlight the importance of both the neutrophil count and the innate immune system in outcomes in patients with colorectal cancer. In chapter 4, a cohort of colorectal cancer patients and a cohort of patients with cancer were utilised in order to determine whether a pre-operative systemic inflammation based score using the neutrophil and platelet count was capable of predicting survival in these patients. This was based on the fact that recent in-vitro work had suggested that a critical checkpoint early in the inflammatory process involved the interaction between neutrophils and activated platelets. The subsequent score – the neutrophil platelet score (NPS)- was shown to be capable of predicting survival, independent of TNM stage, in patients with colorectal cancer and had prognostic value in patients with a variety of other tumours. Chapter 5 describes a systematic review of studies analysing the effect of various surgical procedures on markers of the systemic inflammatory response. Only CRP and IL-6 were found to represent the degree of surgical trauma and invasiveness of the procedure. This work provides a framework for analysing the post-operative SIR and how it is affected by surgery and peri-operative programmes such as ERAS that are reported to improve length of stay and sort term outcomes following surgery for colorectal cancer. It was of interest in the previous chapter that white cell count did not reflect the degree of surgical trauma. Whether individual white cell components act differently and represent the degree of surgical trauma was unclear. Chapter 6 sought to clarify this by analysing, in a cohort of patients undergoing surgery for colorectal cancer, the differential white cell count and whether it reflected the magnitude of injury and short term outcomes. Only the neutrophil count reflected the magnitude of trauma and development of infective complications. However, it remains inferior to other well established markers such as CRP. Whilst the pre-operative systemic inflammatory response is a well-recognised determinant of both long term outcomes and short term outcomes such as infective complications, little work has focussed on the post-operative systemic inflammatory response. In chapter 7, the possibility of the post-operative systemic inflammatory response also being capable of predicting both short and long term outcomes was explored in a cohort of patients whom had undergone surgery for colorectal cancer. A score using the combination of post-operative CRP and albumin was created and called the post-operative Glasgow Prognostic Score (poGPS). In this cohort of patients, this score predicted the development of infective complications and also long term survival. Given that these results would indicate that a reduction in the post-operative systemic inflammatory response would improve outcomes, the clinicopathological factors that may alter this post-operative systemic inflammatory response should be investigated as some of these may be modifiable and may therefore improve outcomes following surgery for colorectal cancer. ERAS programmes have changed perioperative management and are reported to be beneficial in reducing length of hospital stay and post-operative complications. It is purposed that this is due to the reduction on the surgical stress response. However it is unclear which of the components of an ERAS programme are responsible for this reduction in the systemic inflammatory response. Chapter 8 describes a systematic review analysing studies of the various ERAS components and whether there is objective evidence of a reduction in the SIR, evidenced by a reduction in either CRP or IL-6. Only laparoscopic surgery was reported to reduce the SIR in these studies, all the remaining components had either little or no evidence of a reduction in the SIR. Further work is required to ascertain whether any of the other components also reduce the SIR. This will hopefully allow streamlining of the ERAS process in order to improve outcomes. Specific clinicopathological factors that may alter the post-operative systemic inflammatory response are examined in chapter 9. Common clinicopathological factors were examined using the poGPS to ascertain which factors resulted in increased poGPS scores. In those patients undergoing elective surgery, year of operation, ASA grade, pre-operative systemic inflammation, and tumour site were associated with increased poGPS scores. These findings may have important clinical consequences as whilst factors such as ASA grade and BMI are not readily modifiable in the short time frame between diagnosis and surgery, pre-operative inflammation could potentially be targeted with anti-inflammatory medication. / However, more work is required to identify the specific agent and the timing of its delivery. In chapter 10, a cohort of patients undergoing surgery for colorectal cancer in whom there was prescription information available. Patients prescribed aspirin or statin were identified and their post-operative inflammatory response and short term outcomes were compared to those not prescribed aspirin or statins. In 446 patients, neither aspirin nor statin prescription was associated with a reduction in the post-operative systemic inflammatory response. Therefore, it would appear that these medications will not be useful in moderating the systemic inflammatory response following surgery. However, further work is required to identify which medications will be of benefit and should take the format of a randomised controlled trial. Chapter 11 provides a summary of the main findings of this thesis, discussed their implications and provides some discussion surrounding future work in this field.

The postoperative period is characterized by massive shifts of fluid between body compartments and accumulation of fluid in the extracellular space, which may manifest clinically as central and or peripheral oedema. The incidence of oedema in patients undergoing routine major abdominal surgery (MAS) is unknown and there are no objective means of quantifying or monitoring its presence. Furthermore, the aetiological factors responsible for post-surgical oedema formation in patients with no overt signs of cardiovascular disturbance are poorly understood and the relationship between the development of oedema and clinical outcomes such as the recovery of gastrointestinal function, postoperative complications and duration of hospital stay is unclear. Observational studies were therefore conducted on patients undergoing MAS. The presence of oedema was related to changes whole-body impedance (Z), obtained at four frequencies (5, 50, 100 and 200 kilohertz (kHz)) using bioelectrical impedance analysis (BIA) and to clinical outcomes. The fluid intake and output and changes in plasma concentration of albumin, total protein, C-reactive protein (CRP) and reduced glutathione in whole blood (GSH) were compared before and after surgery in patients who subsequently developed oedema (OD group) and patients who consistently remained free of oedema (NOD group) Oedema occurred in 40 per cent of the patients observed prospectively and was significantly related to age (odds ratio 1.087 (95 per cent confidence interval (c.i), 1.016 -1.163; P =0.016). The preoperative ratio of Z at 200 kHz to 5 kHz (Z200/Z5) was higher in patients who subsequently developed oedema than those who did not (0.809 v 0.799; P = 0.015), suggesting that it may be possible to identify patients who are prone to abnormal fluid shifts preoperatively. The change in (Z) was greater in the oedematous than non-oedematous groups (at all frequencies (P < 0.001)), and more so at lower frequencies (5kHz) than higher frequencies (100 kHz) (P < 0.001). The impedance quotient (ht2/Z) in the whole group changed in a similar direction at each frequency but to a greater extent in the OD compared to NOD groups. The total volumes of administered fluids in both groups of patients were similar but the average urine output per kg body weight was significantly lower in the OD compared to NOD patients (29.4(2.3) versus 40.5(3.7) mls/kg, P = 0.023). There were no significant differences before and after surgery in the concentrations of albumin, total proteins and GSH in both patient groups. Preoperative CRP concentration in the OD and NOD patients were similar but the mean (s.d) CRP concentration over duration of observation in the OD compared to the NOD patients was significantly greater (148 (54.1) versus 89.6 (43.8) mg/L, P = 0.006). Oedema was associated with a significant delay in the recovery of gut function (median (range) 6(3-17) versus 5(1-13) days, P = 0.020) and prolonged hospital stay (17(8-59) versus 9(4-27) days, P = 0.001) and increased incidence of postoperative complications (65 versus 22%, P = 0.011). This study shows that the incidence of early postoperative oedema is high and preoperative identification and monitoring of surgical patients vulnerable to abnormal fluid shifts may be possible with non-invasive techniques. Age, impaired ability to excrete administered fluid load and an exaggerated inflammatory response to surgical trauma rather than hypoalbuminaemia and hypoproteinaemia were significant factors for oedema formation. Postoperative oedema was associated with a significant increase in postoperative morbidity.

This work was performed between 1979 and 1985 when there was great interest in the role of the recently identified prostacyclin in vascular function and disorders. The discovery of this substance with its powerful vasodilatory and platelet anti-aggregatory powers raised the hypothesis that prostacyclin might be involved in the pathogenesis of portal hypertension, its associated hyperdynamic circulation and typically catastrophic haemorrhage from bleeding oesophageal varices. Partial portal vein ligation in a rat model of portal hypertension was used because of its simplicity and absence of hepato-cellular dysfunction. This model was found to result in short lived hypertension with return to normal pressure by two weeks. Anatomical studies (using venography and corrosion casting) of the changes to the portal venous circulation after partial portal vein ligation, revealed the development of a dominant portosystemic collateral draining into the left renal vein via the left anterior lumbar vein. Ligation of this collateral at the same time as partial portal vein ligation gave a reliable model of permanent portal hypertension. Accurate measurement of prostacyclin proved to be difficult. Initially a bioassay of prostacyclin-like activity was used with success. The rat was found to produce high levels of prostacyclin well within the range of accurate measurement of this assay. Prostacyclin production was shown to increase directly with pressure increase in the portal vein. This direct relationship was confirmed in the acute model where prostacyclin production fell as the portal pressure returned to normal; in the model of chronic portal hypertension, prostacyclin production remained permanently elevated. A radioimmunoassay for 6 ketoPGFIα, the stable breakdown product of prostacyclin, was developed to allow measurement of prostacyclin in human tissue and serum samples (at this time there were no commercially available RIA kits). Initially the Wellcome antiserum was used with accurate measurement in incubated human tissue samples. These studies confirmed greater intrinsic prostacyclin activity in normal mesenteric and portal vein compared to peripheral venous tissues but failed to show any difference in tissue or plasma levels of portal hypertensive compared to normal patients. A second antiserum, the Cardeza antiserum, was then used in the radioimmunoassay. Unlike the Wellcome assay, this antiserum did not require a prostanoid extraction process. Comparison of the two assays in identical samples revealed major differences with large quantities of 6 ketoPGFIα being measured using the Wellcome antiserum with its extraction step compared to virtually none detected using the Cardeza antiserum. The extraction step was resulting in production of cross-reacting prostanoid substances giving falsely high readings. Both radioimmunoassays were abandoned at this stage because of the inaccuracy of the first, and the inability of the second to detect the low levels of 6 ketoPGFIα in human plasma. The human studies were continued using a highly specific and sensitive assay of 6 ketoPGFIα, namely gas chromatography/negative ion chemical ionisation mass spectroscopy (GC/NICIMS). At the time of this work, this methodology was complex, cumbersome, with limited access and the numbers studied were small. Very low levels of 6 ketoPGFIα were found in peripheral blood of normal and portal hypertensive patients who were not bleeding from oesophageal varices, in patients without portal hypertension, portal blood levels of prostacyclin were higher compared to peripheral levels, confirming the finding in the rat and pig that prostacyclin activity is higher in the normal portal circulation compared to peripheral vein. Significantly elevated prostacyclin production was found in both the peripheral and portal blood of portal hypertensive patients who were actively bleeding from oesophageal varices. Portal prostacyclin production was found to be significantly higher in patients with portal hypertension who were actively bleeding compared to normal patients undergoing laparotomy for other conditions. These findings in bleeding patients support the hypothesis that prostacyclin activity is increased in portal hypertension and may play a role in the severity of haemorrhage. In both the animal and human studies a clear effect of surgical intervention on increased prostacyclin production was found. These studies demonstrated for the first time increased prostacyclin production in both developing, and established portal hypertension in both the experimental animal situation and in man. High levels of prostacyclin production were found in the portal circulation of portal hypertensive patients undergoing surgery for uncontrolled variceal bleeding.

CHAPTER ONE: The literature review critically evaluates research that has explored the psychological impact of parental acquired brain injury (ABI) on children. The review identifies a number of factors that affect the psychological well-being of children, including both adverse and protective factors. Evidence from the studies reviewed indicates that children are vulnerable to experiencing a range of emotional and behavioural difficulties following parental ABI. Clinical implications of the review findings are discussed, and directions for future research considered. CHAPTER TWO: The empirical paper aimed to explore the role of mutual support in Traumatic Brain Injury (TBI) survivors’ reformation of their identity among individuals attending a mutual support group. Using a Grounded Theory approach, a model of the participants experience was developed. The core category reflected how participants regained a sense of self through getting to know the “new” me. Five conceptual categories were identified in relation to identity formation: pre-injury self, comparison with others; accessing the social world of brain injury; purpose and self-efficacy; and acceptance of the post-injury self. The findings highlight a potentially important role for mutual support in identity reformation following TBI and implications for brain injury rehabilitation programmes are discussed. CHAPTER THREE: The third paper presents my personal and professional reflections of the research process and how my views have changed over the course of training. To illustrate these changes, elements of the grounded theory model proposed in the empirical paper (Chapter 2) have been applied to my own experiences. It is hoped that this approach will evidence my experience and exploration of getting to know the scientist-practitioner.

Background: Oral squamous cell carcinoma (OSCC) is the 15th most common cancer worldwide but has poor five year survival (50%). Late stage presentation and limitations of early diagnostic techniques are persistent clinical problems. Sixty percent of patients present with advanced stage disease and with the attendant increase in mortality, morbidity and risk of recurrent disease it is particularly burdensome for both patients and health economies. Early diagnosis and treatment of OSCC improves prognosis. There is an opportunity to diagnose OSCC early in patients with oral epithelial dysplasia however currently there is no way of accurately predicting which lesions will undergo malignant transformation. Aberrant methylation of tumour suppressor genes plays a significant role in the biology of early cancer and is detectable in both tumour and saliva. Saliva is a non-invasive method of longitudinal sampling and has potential as a tumour surrogate in disease surveillance programmes. This study aims to compare rates of methylation of a panel of genes in OSCC patients and a normal cohort to establish a threshold by which we could determine future disease testing in a dysplastic population. Methods: Saliva samples were collected from 219 individuals from three diagnostic groups: Normal (defined as no oral malignant or premalignant disease) n=97, OSCC n=62 and dysplasia n=60. For statistical analysis the dysplasia cohort was sub-divided into lesions of low and high risk of malignant transformation based on the histological diagnosis of the index lesion. DNA was extracted and bisulphite treated from 258 saliva samples before duplex quantitative methylation specific PCR (qMSP) assays were performed on all samples to detect the frequency of methylation in saliva of a panel of genes. The five target genes (ADAMTS9, CCNA1, CYGB, P16, TMEFF2) were selected using a candidate approach on the basis of tumour specificity from studies on tumour/normal matched tissue pairs. Clinicopathological data was correlated with the qMSP data and analysed using SPSS v.21 statistical software to look for associations with tumour and survival characteristics. Results: Only 3/97 individuals from the control normal cohort had saliva samples with detectable methylation above the analytical sensitivity of the P16 assay. Methylation of the remaining target genes (ADAMTS9, CCNA1, CYGB, TMEFF2) was not detected in normal saliva at levels above the analytical sensitivity of the qMSP assays. The most significant finding in this study was that methylation of four of the target genes (CCNA1, CYGB, P16, TMEFF2) in saliva, individually and when considered as a panel, was significantly associated with OSCC and as such could aid discrimination between malignant disease and normal saliva samples. Methylation of at least one gene in the panel was discovered in 29/67 of the binned OSCC saliva samples but only 3/97 of normal samples (Fisher’s exact p=0.001). Furthermore methylation of the gene panel is associated with high risk lesions when detected in saliva of patients with premalignant lesions (Fisher’s exact p=0.03). Conclusions: This exploratory data supports the utility of duplex qMSP as a detection method for methylation markers in saliva. The detection of methylation of this gene panel in saliva is significantly more associated with oral malignancy and high risk premalignant lesions than normal and low risk disease. This implies saliva may have merit as a surrogate tissue in an adjunctive role to clinical assessment and biopsy. The assays are specific but have limited sensitivity. However with further work, inclusive of additional genes, this methodology may identify predictive biomarkers that can be introduced into a trial surveillance of premalignant lesions.

Background Chronic pancreatitis (CP) is a disease of fibrosis of the pancreas for which alcohol is the main causative agent. However, only a small proportion of alcoholics develop chronic pancreatitis. Genetic polymorphism may affect pancreatitis risk. Aim To determine the factors required to classify a chronic pancreatic population and identify genetic variations that may explain why only some alcoholics develop chronic pancreatitis. Methods The most appropriate method of diagnosing CP was assessed using a systematic review. Genetics of different populations of alcohol-related chronic pancreatitics (ACP) were explored using four different techniques: genome-wide association study (GWAS); custom arrays; PCR of variable nucleotide tandem repeats (VNTR) and next generation sequencing (NGS) of selected genes. Results EUS and sMR were identified as giving the overall best sensitivity and specificity for diagnosing CP. GWAS revealed two associations with CP (identified and replicated) at PRSS1-PRSS2_rs10273639 (OR 0.73, 95% CI 0.68-0.79) and X-linked CLDN2_rs12688220 (OR 1.39, 1.28-1.49) and the association was more pronounced in the ACP group (OR 0.56, 0.48-0.64)and OR 2.11, 1.84-2.42). The previously identified VNTR in CEL was shown to have a lower frequency of the normal repeat in ACP than alcoholic liver disease (ALD; OR 0.61, 0.41-0.93). Homozygosity of the normal variant was more common in ALD than ACP (OR 0.53, 0.3-0.96) or Healthy Controls (OR 0.55, 0.3-1.00)). The NGS discovery phase lead on to validation of the 21 most significant SNPs with Sequenom array. This showed significance difference between ACP and ALD in allele frequency of the synonymous SNP, PRSS1_rs6666, (OR 1.99, 1.46-2.72) Conclusion A range of potential exonic and intronic sites have been identified that have association with a predisposition to developing chronic pancreatitis. These findings show that further work is justified to fully assess the interaction of the different polymorphisms and their phenotypic significance in development of the disease.

Introduction: Numerous methods exist for the assessment of the female breast. Traditionally, a subjective approach was taken for surgical planning and evaluation of the postoperative outcome. Several objective methods have been developed to support this procedure, among which are laser scanning, MRI, mammography, ultrasound and photography. Recently, 3D imaging technology has been developed. Material & Method: 3D breast assessment by multiple stereophotogrammetry was examined. A custom-made imaging system with eight digital cameras arranged in four camera pods was utilised. This system was used for breast capture, resulting in eight images obtained by the cameras. The merging of these images and 3D image construction was carried out by C3D software and the volume assessment of the 3D images was made using breast analysis tool (BAT) software, developed by Glasgow University. A validation study was conducted. Nine plaster models were investigated and their volume determined by 3D stereophotogrammetry and water displacement method. Water displacement was considered to be the gold standard for comparison. The plaster models were specially made in order to represent a variety of shapes and sizes of the female breast. Each plaster model was examined 10 times by each method. Further, the volumes of the breasts of six female volunteer live models were investigated by the same two methods and the results compared. A special focus was placed on the reproducibility of the assessment. Each live model was captured with the 3D capture system three times at two different time points after retaking a special pose in a custom-made positioning frame. Altogether, each live model was captured six times, resulting in six 3D images, each of which was measured three times with BAT software. A patient study was conducted in 44 patients after unilateral immediate breast reconstruction with Latissimus dorsi flap and no contra-lateral surgery. Each patient underwent 3D imaging with the multiple stereophotogrammetry system. During capture, the special pose in the custom-made positioning frame was taken by the patient’s leaning forward almost horizontally with the upper body for the breasts to rise off the chest wall to enable full breast coverage by the cameras. 3D images were constructed with C3D software and volumes measured with BAT. For each patient, one 3D image was constructed and measured four times with BAT software. In addition to the volume determination, a shape analysis was conducted. For this purpose, 10 landmarks were determined according to recommendations in the literature. Two landmarks, sternal notch and xiphoid, were marked, forming an imaginary midline between each other and four landmarks on each breast, i.e. the medial and lateral ends of the infra-mammary fold, and the most prominent and most inferior breast points were utilised for symmetry assessment between the right and left breasts. Each landmark was recorded four times by the operator on the 3D image and three-dimensional coordinates obtained. By assessment of the left and right breasts a breast asymmetry score was calculated. Firstly, breast asymmetry was assessed objectively on the 3D images through the centroid size, which was determined as the square root of the sum of squared Euclidian distances from each landmark to the centroid. The centroid was the geometric mean of the landmarks. Secondly, asymmetry was assessed through breast volume by application of BAT software. Thirdly, asymmetry was examined through the landmarks themselves by investigation of the mismatch of the landmark configuration of one breast and its relabelled and matched reflection. The non-operated and reconstructed sides were compared and landmarks were recorded by the operator in three dimensions in four repeated tests. A decomposition of the total landmark asymmetry into its factors was conducted by fixation of the surface of the non-operated side and translation, rotation and scaling of the surface of the reconstructed side. For comparison, a subjective breast assessment was conducted by six expert observers who rated the results after breast reconstruction by subjective qualitative assessment of the symmetry in 2D images of the same 44 patients in six poses. For this purpose the Harris scale was utilised, providing a score of 1 to 4 for poor to excellent symmetry. Results: The results revealed that differences in the obtained volumes in the plaster models were not significant. In contrast, differences in the breast volumes measured in the live models were significant. The examination of the reproducibility revealed that overall reproducibility obtained by stereophotogrammetry was better than that obtained by water displacement. No correlation between breast size and reproducibility of the measurements was found. The results of the patient study demonstrated that the reproducibility of the landmarks was within 5 mm. There was a non-significant difference of the centroid sizes between both breasts. There was a significant difference of the volumes between the two breasts, with the non-operated side being larger than the reconstructed side. Volume was considered to be a more accurate measure for comparison of both breasts than centroid size as it was based on thousands of data points for the calculation as opposed to only four points of the centroid size. The statistical analysis of the landmark data provided a mathematical formula for determination of the breast asymmetry score. The average asymmetry score, derived by landmark assessment as the degree of mismatch between both sides, was 0.052 with scores ranging from 0.019 (lowest score) to 0.136 (highest score). The decomposition of the landmark-based asymmetry revealed that location was the most important factor contributing to breast asymmetry, ahead of intrinsic breast asymmetry, orientation and scale. When investigating the subjective assessment, the inter-observer agreement was good or substantial. There was moderate agreement on the controls and fair to substantial intra-observer agreement. When comparing the objective and subjective assessments, it was found that the relationship between the two scores was highly significant. Conclusion: We concluded that 3D breast assessment by multiple stereophotogrammetry was reliable for a comparative analysis and provided objective data to breast volume, shape and symmetry. A breast asymmetry score was developed, enabling an objective measurement of breast asymmetry after breast reconstruction. 3D breast assessment served as an objective method for comparison to subjective breast assessment.

This thesis presents research carried out for the visualisation of surface anatomy data stored as large range images such as those produced by stereo-photogrammetric, and other triangulation-based capture devices. As part of this research, I explored the use of points as a rendering primitive as opposed to polygons, and the use of range images as the native data representation. Using points as a display primitive as opposed to polygons required the creation of a pipeline that solved problems associated with point-based rendering. The problems inves tigated were scattered-data interpolation (a common problem with point-based rendering), multi-view rendering, multi-resolution representations, anti-aliasing, and hidden-point re- moval. In addition, an efficient real-time implementation on the GPU was carried out.