Search

The main aim of this research was to examine predictors of both objective (salary). and subjective (perceived) career success. Three sets of predictors were examined: (1) individual attributes, (2) organisational opportunity structures and (3) career strategies. It was expected that a different pattern of variables would predict objective and subjective career success. In addition, the mediating role of career strategies was examined. It was expected that individual attributes and opportunity structures would be positively related to the use of career strategies, and that these strategies would be positively related to career success. Cross-sectional survey methodology was employed to collect data from a sample of 723 full-time employees in administrative/ technical, academic and managerial posts at several British universities. According to expectations, a different pattern of variables was related to objective and subjective career success. The strongest predictors of objective career success were education, organisational size and extended work involvement. In contrast, the strongest predictors of subjective career success were internal labour market perceptions of structured career progression and employment security. Separate analyses by gender and occupational group revealed a similar difference in the profile of predictors of objective and subjective career success. Overall, the results suggested that the variables that related to objective career success were often not the same as those related to subjective career success. This was taken as support for the main theme of this research that objective and subjective career success, although related, are substantially distinct concepts. Contrary to expectation, however, the results provided limited support for the mediating role of career strategies in the relationship between individual attributes, organisational opportunity structures and career success (objective and subjective). Only individual attributes (education and work centrality) were positively related to the use of career strategies (extended work involvement, selfpromotion and networking), and these strategies in turn were positively related to objective or subjective career success. However, the mediating role of career strategies was weak, albeit statistically significant. A number of limitations, mainly regarding the cross-sectional nature of the study, are discussed. Educational and organisational implications of the findings are suggested. Finally, a two-dimensional model of career success is proposed, incorporating the findings of the present research with reference to the predictors of objective and subjective career success, together with suggestions for further research.

Crop emergence is a major factor limiting crop yield, especially in hot climates where soil dries quickly after rainfall or irrigation. Problems with the emergence of cotton in Pakistan are of particular importance because of the high value of the crop and its contribution to national economy. A complex interaction of factors involving climate, seed properties, soil physical properties and soil management determine crop emergence and hence establishment. This means modelling of emergence is an important way of determining the combination of conditions at which emergence becomes limited. The studies reported here show the effect of temperature, matric potential and mechanical impedance on pre-emergent root and shoot growth of cotton variety MNH-147. The effect of osmotic potential and temperature on time to germination and cumulative germination of cotton is also described with some preliminary work on wheat. Finally a small field experiment was performed in Pakistan to identify major factors limiting emergence and provide data for future validation of a computer model of emergence. Time to germination was found to be a function of temperature and metric potential. It reduced with increase in temperature and osmotic potential. A linear relationship between temperature and germination rate (1/time to germination) indicated a base temperature of 9.8 °C. Germination rate also decreased linearly with decreasing osmotic potential between zero and -500 kPa. Thus the concept of hydrothermal time can be used to model germination and parameters to fit this model were determined. Root and shoot lengths of pre-emergent cotton seedling increased with increase in temperature from 22 to 32 °C but were reduced with a further increase to 38 °C. At any temperature, lengths increased linearly with time at a rate controlled by temperature. During the first 192 h after germination, growth was divided into two distinct phases: a linear increase with time followed by no further growth.

Background: Established diagnostic pathway for detection of PCa, based on non-targeted gland sampling, has many limitations. There is strong evidence that Multiparametric MRI (MP MRI) performed prior to prostatic biopsy reduces unnecessary biopsies and over diagnosis of clinically insignificant disease as well as improves detection of clinically significant (CS) prostate cancer (PCa). At the time of writing of this thesis, pre-biopsy MP MRI has already been incorporated into the recommended diagnostic pathway for urgent suspected PCa as per NICE 2019 guidance. Although there is growing body of research on the subject, there are still areas, which lack high level data from randomised trials and studies, using radical prostatectomy (RP) specimen as a gold standard. This thesis aimed to investigate the ability of MP MRI to detect foci of CS PCa at per-lesion level, in comparison with RP specimen and to assess the added value of MR guided targeted biopsies, in addition to standard trans rectal (TRUS) biopsies, in confirming the presence of CS disease in a setting of a randomised controlled trial. Methods: The data were collected during prospective, multicentre parallel-group study with subgroup randomization, which has been granted all the necessary approvals including registration at CLINTrials.gov, NCT02745496. It comprised of two main parts: A prospective study on 89 patients suspected of having PCa, with subsequent positive pre-biopsy MP MRI, who underwent RP as a curative treatment option. In this group, diagnostic accuracy of MP MRI in detection of PCa and CS PCa with gold standard of histology of RP specimen on per-lesion and per-patient levels were performed, using customised molds for precise correlation; Added value of MR guided targeted biopsy was assessed in a setting of a prospective randomized controlled trial of 603 patients, suspected of having PCa and with positive MP MRI (assessed using PIRADS v2 system), who underwent either MRI-trans rectal US fusion targeted biopsy (FUS-TB) used in conjunction with TRUS biopsies or standard of care TRUS biopsies alone. Results: A total of 624 biopsy-naïve participants with clinical suspicion of organ-confined PCa were enrolled into the study over a period of 66 months (February 2015-August 2020). 603 participants underwent pre-biopsy MP MRI and those with positive MP MRI result (413/603) were subsequently randomised to undergo either TRUS/FUS-TB biopsies (intervention) or TRUS biopsies (standard of care). 89 participants with positive MP MRI, who opted for RP as a curative treatment option, had their MP MRI compared to RP specimen using customised molds, enabling lesion-level analysis. This revealed high sensitivity of pre-biopsy MP MRI in detection of foci of CS PCa of 72%, with relatively high specificity of 71% and reassuringly balanced PPV and NPV of 78% and 64.1% respectively, when comparing to RP specimen as a gold standard.91% of all PIRADS 5 lesions, 77% of all PIRADS 4 and 48% of all PIRADS 3 lesions corresponded to CS PCa foci on RP.Majority of PCa foci missed on MP MRI were non-significant (NS) PCa, the CS PCa missed were in large proportion situated in the anterior half of the gland and smaller than 15 mm in size. TRUS/FUS-TB pathway detected CS PCa in 130/207 (62.8%) patients, 28/130 (21.5%) by FUS-TB only, 17/130 (13%) by TRUS only and 85/180 (65.3%)by both techniques combined and NS PCa in 21/207 patients (10.1%). The MP MRI positive TRUS alone arm had detected 106/206 CS PCa (51.4%) with 18/206 (8.7%) of NS PCa. The probability of CS cancer detection by TRUS/FUS-TB pathway was statistically significantly higher (p=0.002) than by control TRUS only arm. The safety profile and reported side effects of the combined biopsy approach was clinically no different than standard TRUS pathway. Negative MP MRI performed prior to biopsy in biopsy-naïve men, with clinical suspicion of PCa, would have allowed 28% men to avoid biopsy with a risk of missing CS PCa in 5.7% of those patients. Conclusions: Pre-biopsy MP MRI detected CS PCa with high sensitivity and specificity and avoided over detection of NS PCa (only 4% of NS PCa seen on pathology were detected on MP MRI). The CS PCa missed on MP MRI were in large proportion small and /or situated in the anterior half of the gland. Combined TRUS/FUS-TB pathway in MP MRI positive patients had significantly higher detection rate of CS PCa than TRUS biopsy alone pathway with a small increase in NS PCa detection as an expense. FUS-TB biopsy alone was non-inferior to TRUS biopsy in diagnosing CS cancer with an added benefit of less cores. Not performing TRUS in MP MRI negative group would have saved 28% biopsies with a cost of missing CS PCa in 5.7% patients. Funding: The work was funded by Prostate Cancer UK (PCUK) registered charity In England and Wales (1005541) and in Scotland (SC039332), Movember and the Chief Scientist Office through a Prostate Grant (CSO-PG13-005). The study was coordinated by Tayside Clinical Trials Unit (TCTU) and sponsored by University of Dundee.

Multiparametric magnetic resonance imaging (MP-MRI) and MRI targeted biopsies (TB) are a new standard in prostate cancer (PCa) screening and diagnosis. Guidelines already include this approach for patients at risk. First, this thesis aimed to assess whether pre-biopsy MRI can narrow the discrepancy of histopathological grades between biopsy and radical prostatectomy (RP) using the Prostate Imaging Reporting and Data System (PIRADS). Second, this thesis aimed to develop a prediction model to identify patients who will benefit from performing systematic random biopsy (SB) at the time of TB. 330 men treated consecutively by RP with localised PCa were included in this study. The MRI and histopathology of the biopsies and RP specimens were assessed respectively. A multivariate model was constructed using logistic regression analysis to assess the ability of MRI to predict upgrading in biopsy Gleason score (GS) in a nomogram. A decision-analysis curve was constructed assessing the impact of the nomogram using different thresholds for probabilities of upgrading. In the SB and TB study, 198 patients with positive MRI findings who underwent both TB and SB were prospectively recruited in this study. The first outcome was to compare the detection rate of clinically significant prostate cancer (csPCa) in SB and TB. For the second outcome, a multivariate analysis using a logistic regression model and nomogram construction were used to identify patients who will benefit from SB in addition to TB. A decision-analysis curve was constructed assessing the impact of the nomogram using different thresholds for probabilities of our model. Statistical analyses were performed using IBM SPSS (version 23.0) and RStudio (version 4.0.3). Using multivariate analysis, the PIRADS v2.0 score significantly improved the predictive ability of MRI scans for upgrading of biopsy GS (p=0.001, 95% CI [0.06-0.034]), which improved the C-index of predictive nomogram significantly (0.90 vs. 0.64, p<0.05). Moreover, the detection rate of csPCa using SB and TB was 51.0% (101/198) and 56.1% (111/198), respectively, adopting a patients-based biopsy approach. The detection rate of csPCa was higher using a combined biopsy (64.6%; 128/198) compared to a TB (56.1%; 111/198) alone. This was statistically significant (χ2=15.06, df (degree of freedom) = 1, P<0.001). In the multivariate analysis, age, prostate-specific antigen density (PSAD) and PIRADS score were found to predict the detection of significant PCa by SB in addition to TB. A nomogram based on the model showed good discriminative ability (C-index; 78%). In conclusion, MP-MRI using PIRADS score was shown to be an independent predictor of postoperative GS upgrading, and that this should be taken into consideration while offering treatment options to men with localised PCa. There was a significant difference in the detection of csPCa using a combined biopsy approach. The developed nomogram could help identify those patients at risk of having PCa who will benefit from adding SB biopsy in addition to TB.

High-intensity focused ultrasound (HIFU) has attracted many research interests during the last three decades (since 1980s) for the precision of this treatment in the field of medical oncology and brain surgery. Even though the precision of HIFU application/exposure is particularly high, the overall quality of HIFU treatment is still under active development due to the need of better imaging guidance. Current technology for guiding HIFU is medical ultrasound imaging and magnetic resonance imaging, which mostly employ diagnostic imaging mode. Most recently, magnetic resonance imaging has been adapted for real-time HIFU temperature monitoring (MRI thermometry). In contrast, medical ultrasound guidance technique for HIFU still relies mostly on B-image mode and the hyperechoic contrast of the HIFU lesion. Additionally, commercial MR thermometry is relatively expensive, and is not truly 2D real-time thermometry imaging at the time of writing (ExAblate, Insightec, Israel). In either case, the imaging guidance relies on the physical changes inside the tissue, which are beyond the normal physiology range, in order to effectively track and monitor the treatment area. This limitation causes unnecessary risk to healthy tissues during the targeting and monitoring in HIFU treatment. HIFU-induced shear-wave (HiSW) imaging is proposed in this thesis as a new technique for tracking and monitoring the changes in the targeted area. The work includes HIFU transducer fabrication and characterization, in accordance with the FDA guidance. The transducers are then tested for the ability to induce shear-wave, using medical ultrasound imaging and high-resolution optical coherence tomography imaging. Ultra-fast imaging technique in medical ultrasound is developed to detect small deformation, which is caused by the propagating HiSW. Due to physical limitations of ultrasound imaging, HiSW has to operate above the thermal and mechanical FDA limit. The parameters of acoustic intensity required for adequate HiSW detection are 200 W.cm-2 for ISPPA and 10 W.cm-2 for ISATA. To avoid the low-resolution problem in medical ultrasound imaging, Optical Coherence Tomography is proposed for in-depth study of HiSW. Investigations on how HiSW behaves under different acoustic power output and pulse duration are conducted. The results indicate a linear relationship between HiSW displacement and acoustic power output, i.e. higher acoustic power output would give higher shear-wave displacement. In contrast, there is an optimum pulse duration, where HiSW displacement is highest for a given unit of acoustic energy. Final work on beam steering explores the feasibility of using phased-array HIFU transducer to improve focused ultrasound treatment. The results show improved thermal elevation when the target is in constant motion, up to 20 oC in improvement. In future work, HiSW can give elasticity information of the surrounding area by the help of beam steering.

Bladder cancer is the seventh most common cancer in the UK (2011), fourth most common cancer in men and thirteenth most common in women. The total annual cost of bladder cancers in the UK was £55.39 million. The cost per patient was £8349 per year, including diagnosing, treating and following up, as well as indirect costs like loss of earnings etc. Cystoscopy with biopsy is the current gold standard for diagnosing bladder cancer. However, it is expensive and invasive, and has difficulties in diagnosing early stage cancer or carcinoma in situ (flat tumour). Non-invasive diagnosis of bladder cancer like urine cytology and urinary biomarker tests have poor specificity therefore they are used as supportive tests rather than definitive tests. The aim of this study is to develop a detecting system for bladder cancer urinary volatile organic compounds (VOCs) biomarkers and explore its application in non-invasive diagnosis of bladder cancer. Urinary VOCs are a class of chemical compounds found in urine that generated from biological activities of cells, cancer cells have special metabolic alternations compare to normal cells, therefore having different VOCs profiles that can be used for discrimination. Compare to conventional mass-spectroscopy and e-nose techniques for VOCs detection, the fluorescence sensor array has good detection accuracy and much lower cost of use, it is especially ideal for developing non-invasive point-of-care device for bladder cancer diagnosis and surveillance purposes. This study successfully developed a fluorescence cross-response sensor array system for diagnosing bladder cancer by detecting the urinary VOCs. On this system, a distinguishing test of four urinary VOC biomarkers: ethylbenzene, hexanal, lauric aldehyde, and nonanoyl chloride, was undertaken and achieved a sensitivity of 77.75% and a specificity of 93.25%. In a proof-of-principle clinical trial involving 79 participants (38 bladder cancer patients and 41 healthy controls), this system using a PLSDA model successfully identified over 80% of urine samples (86.08% with leave-one-out, 81.76% with Mote Carlo cross-validation) with 77.42%-84.21% sensitivity and 85.82%-87.80% specificity. This study revealed the possibility of using low-cost optical sensor system for medical diagnosis purposes, and this could inform larger scale multi-centre trails of biogenic VOCs diagnosis and other possible clinical applications in the future.

Prostate cancer (PCa), the most common cancer in men across the UK, is a multifocal disease with characteristic heterogeneity and foci that can range from low-grade indolent to aggressive disease. In current clinical care, the well-established diagnosis for PCa is trans-rectal ultrasound (TRUS) guided biopsies. The TRUS procedure follows by the Gleason scoring that usually requires the expertise of a trained histopathologist. However, an inter-observer variation exists between two histopathologists besides a large discrepancy existing on initial biopsy and after the final radical prostatectomy. Therefore, a reliable diagnosis is of high demand to make an optimal decision for PCa treatment. This research work aims to apply two emerging optical imaging modalities to quantitatively evaluate the degree of malignancy. This research thesis presents the vibration optical coherence elastography (OCE) to quantify the tissue stiffness on a microscopic scale. A feasibility study of ten patients suspected with PCa was designed to scan TRUS guided biopsies with the vibration OCE. Meanwhile, the effect of fixatives on the tissue stiffness was studied with five different tissues preserved in the fixatives along a controlled timeline. A subsequent clinical study involving 60 more patients was conducted to follow the feasibility study, which leads to a large clinical study containing a total of 840 core biopsies. Additionally, the second harmonic generation (SHG) microscopy focused on the cells and surrounding matrix within the prostate tissue. The SHG study with 42 core biopsies was intended to investigate the reason of stiffness increase of the cancerous tissue in the prostate. The experimental results indicates that the vibration OCE is capable to provide 2D and 3D high-resolution elastogram of biopsies with different malignancies. Moreover, a high diagnostic accuracy of differentiating malignant biopsies from benign ones is confirmed, as well as a significant difference in Young's modulus of biopsies of different Gleason scores. For SHG, distinct patterns of collagen distribution are shown for PCa of different Gleason scores, along with a ratio of anisotropic to isotropic (A: I ratio) that correlates with the disease aggressiveness. To sum up, the two techniques described in this research thesis are complementary, where one depicts the stiffness of prostate tissues and the other illustrates the orientation of collagen structure around the cancerous lesion. With further development, these approaches may help in vivo diagnosis of PCa quantitatively and characterise grade of cancer as well.

Short-term shading of part of the canopy was studied in grapevines (Vitis vinifera L.) cv. Pinot noir and apples (Malus pumila) MM106 cv. Gala. In most experiments shading caused a rapid increase in the net photosynthesis (A) and stomatal conductance (gs) of the illuminated part of the canopy. The fully expanded new leaves appeared to be most sensitive to shading in both crops and A and gs increased by 55 and 20% respectively, for grapevines within 30 minutes. This response was reversed when the shading was removed. Fruiting grapevines had a higher A and gs (4.7µmol CO₂ m⁻²s⁻¹ and 0.08 mol H₂O m⁻²s⁻¹, respectively), than non-fruiting vines (2.9 µmol CO₂ m⁻²s⁻¹ and 0.05 mol H₂O m⁻²s⁻¹, respectively), and water-stress reduced A and gs compared to well-watered vines. Intercellular CO₂ concentration (Cᵢ) was unaffected by shading or crop loading. The overall response by vine S to partial shading was similar across all water stress and crop loading treatments. It is concluded that in grapevines and apples, the rapid changes in A and gs in the illuminated part of the canopy caused by partial shading elsewhere, are regulated by hydraulic processes. However, the mechanisms by which stomata sense those changes are still unknown.

Bladder cancer is among the most common cancers in the UK, responsible for significant patient morbidity. Current techniques for detection suffer from low sensitivity, particularly for early stage disease, therefore new techniques are urgently sought. Among the suggested techniques to augment bladder cancer detection is the use of autofluorescence spectroscopy. Autofluorescence arises from a number of molecules in human tissue, giving a wealth of structural and metabolic information. Autofluorescence spectroscopy has previously been applied to the detection of a wide range of cancers, however clinical implementation of the technique to bladder cancer diagnosis is inhibited by a poor understanding of the contributions of individual fluorophores to autofluorescence. I sought primarily to use the multi-functional laser based diagnostic system “LAKK-M” to study the autofluorescence profiles of bladder cancer at the cell and tissue level, with the aim of developing a better understanding of bladder autofluorescence characteristics in health and disease. The significant findings of this research are threefold: 1. Autofluorescence flow cytometry of cell optical redox ratio reveals metabolic abnormalities in bladder cancer cells, specifically a glycolytic switch in bladder cancer cells culminating in an increased optical redox (NADH/flavin, ex360em425-475/ex488em515/545) ratio relative to healthy bladder cells. 2. Lab grown bladder cancer organoids show progressive changes in autofluorescence ratios relative to control samples – specifically reductions in the NADH/flavin (ex365em490/ex365em550), elastin/NADH (ex365em450/ex365em490) and elastin/flavin ratio (ex365em450/ex365em550), suggestive of structural and metabolic changes in developing cancer. 3. Analysis of human bladder tissue reveals significant differences in key fluorophores and diagnostic ratios between healthy and cancer tissue, amounting to increased porphyrin fluorescence and a decreased optical redox ratio (ex365em490/ex365em550) in cancer tissue compared to healthy control. These findings better inform our understanding of the autofluorescence properties of the bladder in health and disease at both the cell and tissue level, contributing to future development of diagnostic techniques. Additionally, in this thesis, I discuss the diagnostic worth of collagen analysis in bladder cancer using second harmonic generation imaging, the application of bladder tissue computer simulation to better elucidate fluorophore properties, and progress in novel laser therapy techniques for bladder cancer. The ultimate goal of this research is the development of a combined laser-based system for bladder cancer diagnosis and therapy.

The prognostic role of chromosomal copy number aberration in renal cell carcinoma (RCC) has been explored in several studies. Chromosome 9p deletion was reported as an independent prognostic factor in clear cell subtype (ccRCC). The findings from these studies initially appeared promising however they were of limited clinical applicability due to lack of standardisation of molecular techniques employed and short periods of follow-up. In addition these studies did not integrate 9p loss in well established, externally validated prognostic models to assess its impact on survival. The current research aimed to assess the impact of somatic copy number deletion of chromosome 9p using I-FISH to allow clinical and analytical validation of previous studies. In the current study, a variety of cytogenetic and molecular techniques was employed to assess copy number variation and zygosity status at chromosome 9p on two cohorts of patients with a minimum of eight years follow-up. A comprehensive protocol was designed for I-FISH scoring using a dual colour probe that hybridises to the CDKN2A region to facilitate further validation in future studies. There was a good degree of inter-observer agreement in the current study. Somatic copy number loss of chromosome 9p was associated with adverse histopathological features in ccRCC. It was also associated with a higher risk of recurrence and cancer-specific mortality. The integration of chromosome 9p loss improved the predictive accuracy of validated prognostic models for recurrence and cancer-specific survival respectively. The findings from microsatellites analysis on the same cohort of cases confirmed that loss of heterozygosity involving chromosome 9p21 in particular LOH at the coding region of CDKN2A portends a worse prognosis in ccRCC in long term follow up and also validate the findings from I-FISH-based analysis of 9p deletion. Sixty percent of cases with LOH detected by microsatellites were copy number neutral (CNNLOH). A lack of sensitivity of microsatellites analysis in reference to FISH to detect copy number loss LOH was noted. Therefore, the current study has highlighted the importance of both techniques being considered complimentary, to assess copy number aberrations on chromosome 9p. The integration of the combination of copy number loss and LOH analysis at CDKN2A to prognostic models enhanced further their predictive accuracies expressed by concordance Index C. Immunohistochemistry was employed on the same cohort to assess if copy number loss or LOH was associated with reduced protein expression by certain genes on chromosome 9p. The genes examined were those reported to be implicated in cancer progression. There was no association between copy number aberrations on chromosome 9p and levels of expression. However, the higher expression levels of ADFP and CAIX and lower levels of p14, p15 and p16 in ccRCC were in keeping with the more aggressive nature of this subtype compared to the other less common subtypes. The array-based analysis within a different small cohort has demonstrated that copy number loss of the whole chromosome 9p is a common event in ccRCC and is more common than a segmental loss. It also validated the findings from the first cohort showing a survival advantage in patients without 9p loss. The current research not only validates previous reports on chromosome 9p in ccRCC but also had a more robust study design, in a large cohort with the longest follow-up known worldwide to date. It highlights the role of CNV in predicting outcomes and opens the way for further studies to explore the underlying mechanisms responsible for ccRCC progression. It also justifies the need for further prospective studies assessing CNVs with zygosity status in addition to epigenetic changes and their effects on gene expression and the outcomes of surgically treated renal cell carcinoma.

A method of 3D modelling of high intensity focused ultrasound (HIFU) treatment through ribcage using patient data is described. This is further tested experimentally to derive at various parameters which could be indirectly useful in defining amount of energy and alteration needed in treatment protocols for the upper abdominal pathologies covered under ribcage. In the last ten years, feasibility and safety of HIFU treatment have been tested in a growing number of clinical studies. However, there are still challenges, such as the treatment through the ribcage. HIFU propagates through the ribs could lead to insufficient energy delivery to the focal target and heat deposition at the ribs may lead to surrounding soft tissue damage due to the bones properties of absorption and reflection to the ultrasound wave. Current research has not involved the physical human anatomical structures into the experimental study of the HIFU treatment through the ribcage. Therefore, our aim was to build a patient-specific physical ribcage model that possesses human anatomical structures to investigate its effect on HIFU treatment. Ribcage model was reconstructed based on patient data. This prototyping model possessed human anatomical structures and provided useful information in the treatment planning by applying HIFU sonication on tissue mimicking phantoms. In order to determine the optimal phantoms for medical imaging and HIFU application, the properties of tissue mimicking materials (TMMs) were characterised, including acoustic, thermal and elastic properties. Acoustic pressure distribution, acoustic power delivery and focus splitting were investigated with and without the presence of ribcage model in the focused ultrasound field. Multi-channel phased array transducer was applied to investigate the changes in temperature at focus and temperature was monitored by magnetic resonance imaging (MRI) thermometry. Sonications on phantom with varied focal lengths and ribcage locations using robotic arm were performed. Thermometry revealed that heating at focus can be controlled either by changing power or duration of application in order to achieve optimal results. Focal temperature change related to the shadow area on the transducer elements caused by the ribcage model in HIFU beam path. The experimental data based on the patient-specific ribcage model may contribute to design and optimise the sonication protocol in pre-clinical planning stage. It is believed that the HIFU sonication experiments using realistic phantoms based on patient data would be a step towards translation of this technology into more widespread clinical practice.

The research presented in this thesis set out to contribute to knowledge seeking to advance the state-of-the-art in laser based, multi-functional, non-invasive diagnostic systems. The results of the work have contributed to the development of methodological generic approaches to the development of devices using light to detect and analyse biomarkers relevant to human health and disease conditions. Following the development of methodologies the research then progresses to examine in-vivo the potential of the integrated spectroscopic technologies to detect changes and rhythms in the micro-vasculature of the skin relevant to the response of the subjects to emotional and physical stress. The results uncover myogenic rhythm synchronisation as a potential marker of adaptive response. The complexity of monitoring and interpreting key biomarkers of metabolism, NADH and FAD and the derived redox ratio is addressed in detail. Analysis of results of around 3,000 functional scans, including tissue oxygen saturation and laser Doppler flowmetry, provides new insights into bio-technological issues. The challenges identified with biological characteristics include sampling zones and physiological features of the skin. Technological, photonics, electronics and computing challenges emerge from the results. These should be considered in advancing the integration of bio-photonic technologies toward realising meaningful diagnostic poly-bio-markers relevant to developing algorithms capable of delivering consistent, reliable and meaningful diagnostic information with utility in clinical practice for early diagnosis of disease conditions such as cancers and cardio-vascular diseases in individuals from the global population. The results have been published in peer-reviewed international journals and presented at major international conferences in the field.