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(2022) Cao, JunThesisThis thesis focuses on the development and applications of magnetic resonance electrical properties tomography (MREPT), which is an emerging imaging modality to noninvasively obtain the electrical properties of tissues, such as conductivity and permittivity. Chapter 2 describes the general information about human research ethics, MRI scanner, MR sequence and the method of phase-based MREPT implemented in this thesis. Chapter 3 examines the repeatability of phase-based MREPT in the brain conductivity measurement using balanced fast field echo (bFFE) and turbo spin echo (TSE) sequences, and investigate the effects of compressed SENSE, whole-head B_1 shimming and video watching during scan on the measurement precision. Chapter 4 investigates the conductivity signal in response to short-duration visual stimulus, compares the signal and functional activation pathway with that of BOLD, and tests the consistency of functional conductivity imaging (funCI) with visual stimulation across participants. Chapter 5 extends the use of functional conductivity imaging to somatosensory stimulation and trigeminal nerve stimulation to evaluate the consistency of functional conductivity activation across different types of stimuli. In addition, visual adaptation experiment is performed to test if the repetition suppression effect can be observed using funCI. Chapter 6 explores if resting state conductivity networks can be reliably constructed using resting state funCI, evaluates the consistency of persistent homology architectures, and compares the links between nodes in the whole brain. Chapter 7 investigates the feasibility of prostate conductivity imaging using MREPT, and distinctive features in the conductivity distribution between healthy participants and participants with suspected abnormalities.
Computed tomography-defined sarcopenia in patients with head and neck cancer – an exploration of assessment and association with outcomes(2023) Vangelov, BelindaThesisBackground: Assessment of body composition, specifically evaluation of skeletal muscle (SM), has gained momentum in studies of patients with head and neck cancer (HNC). Depletion of SM measured via computed tomography (CT), known as CT-defined sarcopenia, has emerged as an independent prognostic indicator in HNC. International standard SM measures use the cross-sectional area (CSA) of a single axial slice at the third lumbar vertebra (L3). However, diagnostic CT scans for HNC do not always extend to this level, limiting assessment opportunities. This thesis investigates the feasibility of alternate vertebral levels for SM evaluation in HNC. Methods: A systematic review was undertaken to determine current evidence for SM evaluation at alternate vertebral levels in patients with cancer. Gaps in the literature led to a five phase plan to investigate the use of a cervical (C3) and thoracic (T2) level for SM assessment in patients with HNC who received a diagnostic or radiotherapy planning CT scan. This included evaluation of an existing prediction model (used to estimate L3-CSA with SM at C3), and formulation of population-specific models for use when L3 is not available. Novel methodology for SM evaluation at T2, and thresholds for low skeletal muscle index (SMI) values were also introduced. Results: The progressive findings of the five studies have indicated that; SM assessment at C3 should be applied with caution; prediction modelling should be population and sex-specific; thoracic SM measures at T2 deplete in similar proportions to L3 over time, cervical SM does not; SM at T2 is predictive of sarcopenia risk (HR=62.78, CI 27.59-164.08, p<0.001); and T2-SMI thresholds for sarcopenia stratified for sex and body mass index were effective in determining patients at risk of critical weight loss during treatments, and overall survival outcomes. Conclusion: This body of work has identified key concerns with the use of SM at C3 for muscle evaluation in patients with HNC, and has provided evidence for the use of SM at T2 as an alternative to L3. The anatomical position of T2 is not likely to include tumour infiltration, contains musculature that is sensitive to depletion, and is visible in CT scans taken in routine practice for HNC. Population and tumour-specific SMI thresholds for sarcopenia are required in this population for effective diagnosis and appropriate service delivery to ensure optimal nutritional and survival outcomes in this patient population.
(2023) Bradbury, TomThesisBackground: Chronic Obstructive Pulmonary Disease (COPD) is a minimally reversible, inflammatory condition of the lower airways. Addressing exacerbations – acute episodes of symptom worsening - has emerged as a priority in the development of COPD management strategies and shapes the ethos behind trial design and concepts of efficacy in this field. Currently, there is poor consensus as to how the different aspects of exacerbations should be integrated into clinical trial outcomes. Furthermore, as COPD exacerbations are a relatively newly defined clinical entity there is a need to re-examine previous assumptions regarding the clinical efficacy of established interventions, incorporating updated knowledge and research methods. Aims: The aim of this thesis was to investigate how COPD exacerbations are represented and used as a measured outcome of efficacy and safety in past and current clinical trials of exacerbation prevention and management. The secondary aim was to develop a range of skills needed to conduct original research in this area. Methods: Five studies were conducted. These were a systematic literature review of exacerbation-based outcomes in published clinical trials, qualitative analysis of original interview data to assess COPD patient priorities in exacerbation treatment and future research, and a case series of an app-based exacerbation identification system. Quantitative analyses of the TASCS (Theophylline and Steroids in COPD Study) and PACE (Preventing Adverse Cardiac Events in COPD) trial datasets were performed to advance our understanding of how pharmacological agents modulate exacerbation properties in different COPD patient phenotypes. Results & Conclusions: The heterogeneity and evolving understanding of the pathophysiology of COPD is new knowledge which should be incorporated into clinical trial design and conduct. This was shown in the analyses of the TASCS and PACE trial data, where established understandings of exacerbations and different patient phenotypes were challenged by the findings. The results of the remaining three studies suggest that: (i) trial outcomes pertaining to exacerbations should be standardised and validated, and (ii) how these outcomes are defined, valued by patients, and measured should be clearly communicated and accurately cited. This will improve data quality, enhance representation of patient values in future research and minimise ambiguity in communicating research results.
Chemical incorporation of NAD+ intermediates into an extended-release drug delivery system to provide new avenues in oncofertility(2023) Sehnert, RebeccaThesisCellular deficiencies in nicotinamide dinucleotide (NAD+) have been linked to a wide range of pathophysiologies. Boosting NAD+ levels via supplementation with its metabolic intermediates, such as nicotinamide mononucleotide (NMN), has been shown to be a potential treatment for many diseases. Notably, NMN administration is a promising solution to prevent female fertility damage due to chemotherapeutic insult. However, this strategy is severely limited due to a lack of drug delivery application methods. To address this need, we propose a drug-loaded hydrogel system that can be implanted at the location of interest. By chemically conjugating the NMN drug molecule to a poly (vinyl alcohol) (PVA) polymer via a linker of biodegradable ester bonds, it is hypothesised that we can prevent burst release while providing targeted, prolonged release duration through hydrolytic cleavage. PVA previously conjugated with photo-crosslinkable methacrylate pendants was chosen as the base system, as this allows for easy hydrogel formation. This work’s aim was to achieve conjugation of NMN into this PVA system, characterisation of the synthesis pathways utilised, as well as evaluation of the resultant hydrogel systems. It is proposed that a linear pendant containing multiple ester groups could be grown from the hydroxyl moieties on the PVA backbone via a series of carbodiimide reactions. Conjugation of the NMN to this pendant was investigated via three different synthesis pathways: 1) “Linear” amine building block, 2) “Reverse” amine building blocks and 3) “Fmoc” protecting group method. Each strategy has individual benefits and drawbacks, and each was evaluated for key parameters such as efficiency of reaction, maximum NMN loading achieved, and cytocompatibility. This work demonstrates the first known incorporation of NMN into a hydrogel system for the purpose of sustained drug release. These results demonstrate that NMN has been chemically conjugated into a PVA hydrogel system in a controlled, non-toxic and reproducible manner, allowing for eventual use in drug delivery applications.