In unexplained death cases it is important to be able to determine the role (if any) of the drugs detected may have played in the death. However, drug concentrations can change between the time of death and the time of the analysis of the post-mortem sample, thus the concentration of the drug detected needs to be interpreted with caution. Post-mortem redistribution (PMR) is a process that involves the passive movement of drugs after death that can lead to changes in post-mortem drug concentrations at certain sites after death. In addition, other factors that could account for post-mortem changes include the environment in which an individual is found, as certain environments could accelerate decomposition, also the circumstances surrounding the death and the length of time between the death and recovery of the body. Certain organs including lungs, liver, and heart are depots of drugs for PMR as they can have higher concentrations than surrounding sites. The bladder has traditionally not been considered a possible depot for PMR. However one study, a case report, published in Japan discussing an individual that had a PMI of nine days with higher concentrations of diphenhydramine and dihydrocodeine in the femoral vein compared to the cardiac blood, has suggested that it may be. There have been no further studies to elucidate any possible role of the bladder in the PMR process. The aim of this thesis was to determine if the bladder is a potential site for PMR and to develop methodology to allow further study. The investigation included the influence of temperature, pH, porcine bladder degradation, and solution volume on diffusion from the bladder using in vitro diffusion through porcine bladder sections, whole porcine bladders and finally in vivo diffusion from the bladder in rat models over nine days. This thesis looked at three methods to investigate the possible diffusion of drugs from the bladder. 1) porcine bladder sections; 2) whole porcine bladders and 3) whole rats. The initial method used Franz Cells to determine the diffusion of rhodamine B, amitriptyline and amitriptyline’s metabolite nortriptyline across the porcine bladder wall. Acceptor chamber solutions were 20 mM pH 7.4 phosphate buffer (PBS) and 20 mM pH 5 ammonium acetate (AA). Donor solutions, dependent on experiment, contained 100 mg/L rhodamine B or amitriptyline and nortriptyline in the respective solutions. Sampling was over five days. Parameters included temperature (37 °C, 20 °C, and 5 °C), pH (7.4, 5), intra-variability of porcine bladder diffusion and tissue degradation. Quantitation methods of rhodamine B (UV, Agilent, Cary 60), amitriptyline, and nortriptyline (HPLC, Dionex Ultimate 3000) were validated according to SWGTOX guidelines. The femoral vein has been stated as the best site for sampling post-mortem blood and interpretation due to the isolation from the main viscera. However, due to the above case report suggesting redistribution from the bladder this is a possible factor that could affect this sampling site. The porcine bladder sections and whole porcine bladders were analysed to determine how much drug would diffuse through the tissue over the first 100 hrs after death, which is the initial steps in determining the likelihood of drugs diffusing from the bladder to the femoral vein. Whole porcine bladder studies used the validated UV method for rhodamine B. Experimental temperature was 20 °C. Full and half-filled porcine bladders contained rhodamine B (100 or 200 mg/L) dissolved in pH 7.4 PBS and pH 5 AA. Triplicate analysis performed using the UV spectrophotometer at 554 nm. The in-vivo study involved catheterizing a rat and inserting silver nitrate into the bladder then securing it for Computed Tomography (CT) analysis over nine days. There was increased diffusion of all three drugs at physiological temperature (37°C) with a peak rhodamine B concentration of 3.46 ± 2.72 mg/L (intra-bladder, pH 5), 6.69 mg/L and 6.69 ± 4.76 mg/L for amitriptyline and nortriptyline respectively (pH 7.4). The other parameters including solution pH and tissue degradation showed no significant difference for drugs diffusing through the bladder over 5 days. Concentration and volume was not a factor for rhodamine B diffusing through the whole porcine bladder tissue. There was an increase in drug diffusion over the five days with a peak concentration of 3.5 ± 1.02 mg/L (pH 7.4). The rat bladder was intact for two days, and then between 2-6 days, an opening was observed with leakage of solution. However, after day 7 this solution was not observed on the CT image. The CT data show that it is a good technique for the detection of diffusion of ions from the bladder, but would need to be further developed to look at the diffusion of larger molecular weight organic molecules. Based on this work, methods for investigating the diffusion of drugs across the bladder have been developed and validated. The use of μCT shows promise for the further visualization of PMR to investigate not only diffusion from the bladder but also diffusion from other drug depots in the body. However, based on this work it is unlikely that the bladder is a significant source of PMR to the femoral vein, at least in PMI of less than 100 hours after death.

This thesis is presented in two parts. The first is concerned with the management of patients undergoing repair of hip fracture while the second part describes a randomised controlled trial examining analgesic options after total hip replacement. Musculoskeletal disease has the fourth greatest impact on the health of the world’s population (when both death and disability are considered) and is the second most common cause of disability globally. Disability due to musculoskeletal disease has risen by 45% over the last 20 years compared to the 33% average increase seen across other disease groups. This is likely to increase unless action is taken to resolve some of the problems. This has been recognised by The European Parliament Leading Committee on the Horizon 2020 Programme (the European Union Research Framework Programme) resulting in the identification of rheumatic and musculoskeletal conditions as a priority for research over the next 7 years. Glasgow Royal Infirmary is a tertiary referral centre for orthopaedic and trauma surgery undertaking a high volume of both elective and emergency procedures each year. I wished to investigate current standards of care relating to patients undergoing emergency surgery and to establish whether by benchmarking our practice against national data, we could identify areas for improvement. Hip fracture repair was chosen for analysis as it is a common, serious and costly condition that occurs in an increasingly elderly, frail and dependent patient population. Hip fracture is a worldwide concern and a significant public health challenge. Important patient outcomes such as time to theatre, 30 day mortality and length of stay were analysed and compared against national audit data. These data compared favourably. Prior to commencing this work, staff members were asked to communicate any opportunities they saw for care to be improved. Certain sub-populations were identified by staff as meriting particular attention. These were patients admitted to ICU and patients taking warfarin. The sub-population of patients who were taking warfarin and required admission for repair of hip fracture were particularly frail and resulted in a number of management challenges for staff. A quality improvement endeavour was employed in order to standardise management, reduce confusion, expedite time to theatre and ensure adequate thromboprophylaxis throughout the peri-operative period. This work resulted in the production of a protocol to guide management and is subject to ongoing review and audit. The role of anaesthesia in the performance of elective total hip replacement surgery was also investigated. Total hip replacement is one of the most commonly performed surgical procedures in the United Kingdom, can result in improved quality of life, and is considered to be cost effective. In Glasgow Royal Infirmary, anaesthesia is most commonly performed using spinal anaesthetic with the addition of an opioid. Spinal opioids, whilst effective, are associated with side-effects of which the most serious is respiratory depression. Other adverse effects such as pruritus and nausea and vomiting may delay recovery and impact upon a patient’s satisfaction with their experience. I carried out a randomised controlled, double blinded trial to assess whether a regional anaesthetic technique (ultrasound guided fascia iliaca block) could be used as an alternative to spinal morphine. This technique has not yet been assessed clinically in the published literature, though it has shown promise as being more reliable when compared to the landmark based technique. A non-inferiority design was employed in order to compare these two techniques. The primary outcome was 24 hour intravenous morphine consumption. After obtaining the necessary approvals from the West of Scotland Research and Ethics Committee and the West of Scotland Research and Development Department, recruitment was commenced in May 2011. Peer review was received from a journal of trial methodology and the protocol was published. Further peer review and funding was received from the European Society for Anaesthesia and Pain Therapy as well as a local peri-operative research fund. This study shows that ultrasound guided fascia iliaca block is not non-inferior to spinal morphine, or in other words, that ultrasound guided fascia iliaca block is unacceptably worse than spinal morphine in the provision of analgesia after hip replacement. Adverse effects were not statistically significantly different between groups and reassuringly, there were no episodes of respiratory depression or sedation in either group. This study has clear implications for practice and would suggest that spinal morphine remains an effective anaesthetic and analgesic agent in this patient group.

ST-elevation myocardial infarction (STEMI) management has evolved dramatically, with improved pharmacological treatment, rapid achievement of reperfusion with percutaneous coronary intervention (PCI) and advanced secondary prevention programmes, resulting in a decline in morbidity and mortality. However, it is well recognised that myocardial perfusion remains compromised in up to 50% of STEMI patients, despite rapid and successful mechanical revascularisation of the epicardial artery. This occurrence is called the “no-reflow” phenomenon and as a result, a substantial proportion of acute STEMI patients develop chronic cardiac failure, owing to poor microvascular function and myocardial perfusion. Although pathological and clinical observations initially seemed to support the theory that no-reflow was a consequence of microvascular obstruction (predominantly from distal embolisation of athero-thrombotic debris), irreversible microvascular injury and subsequent intramyocardial haemorrhage (IMH) are now also thought to play important factors in this process. T2*-CMR is the reference diagnostic method for imaging myocardial haemorrhage in-vivo, however technical issues have limited T2* imaging in clinical practice. The largest cohort studies of myocardial haemorrhage in STEMI patients to date, have not used T2* CMR, but instead used qualitative T2-weighted imaging methods to detect haemorrhage, which are hampered by image artefact. Because of the different CMR techniques, uncertainties have arisen surrounding the pathophysiology and clinical significance of myocardial haemorrhage, and its relationships with microvascular obstruction (MVO). In some studies, myocardial haemorrhage is associated with adverse remodelling and adverse clinical outcome, however other studies have shown that myocardial haemorrhage does not have prognostic significance beyond MVO. Recent developments in CMR imaging techniques have enabled clinically feasible, rapid parametric mapping, which allows direct determination of myocardial magnetic relaxation times (T1, T2 and T2*). These quantitative, novel mapping methods, address many of the inherent limitations associated with dark blood T2-weighted techniques, for a more objective assessment of the infarct core. The principal aim of this thesis is to define the clinical significance of myocardial haemorrhage using quantitative CMR mapping techniques and to determine whether detection of haemorrhage might improve risk stratification in STEMI survivors. In addition, I aim to characterise the evolution and inter-relationships between IMH and MVO in STEMI survivors to inform and implement targeted therapeutic interventions. Methods (1) Natural history study: We performed a single centre cohort study in 324 reperfused STEMI patients treated predominantly by emergency percutaneous coronary intervention (PCI) (The BHF MR-MI study; Clinicaltrials.gov NCT02072850). The index of microcirculatory resistance (IMR), a prognostically validated invasive microcirculatory biomarker, was measured acutely in the culprit coronary artery at the end of PCI using guidewire based-thermodilution. Infarct zone IMH and MVO were delineated as hypointense zones on T2* mapping CMR (T2* value < 20 ms) and contrast-enhanced-CMR at 1.5 Tesla, respectively, 2 days and 6 months post-MI. T1- and T2-mapping techniques were also used to assess the infarct core and evaluate IMH. (2) Time-course study: 30 patients underwent serial CMR at 4 time-points: < 1 day (4 to 12 hours), 3 days, 10 days and 6-7 months post-reperfusion. Adverse remodelling was defined as an increase in left ventricular end-diastolic volume (LVEDV) ≥ 20% at 6 months. Adverse cardiovascular events were pre-specified and defined according to internationally accepted criteria. All-cause death or heart failure were independently assessed during follow-up blind to other data. (3) Randomised proof-of-concept trial: We hypothesised that brief deferral of stenting after initial reperfusion, associated with the benefits of normal coronary flow and anti-thrombotic therapies, would reduce microvascular injury and increase myocardial salvage. We implemented a randomised proof-of-concept clinical trial of deferred PCI vs. immediate stenting (NCT01717573) (Carrick et al., 2014). In summary, the main findings of this thesis are: • Myocardial haemorrhage (defined by T2* CMR) is an independent predictor of adverse remodelling and all cause death or heart failure in the longer-term post STEMI. • Myocardial hemorrhage occurs in primary and secondary phases within the first 10 days post-MI and is a secondary phenomenon to the initial occurrence of microvascular obstruction. • Myocardial haemorrhage peaked at day 3 post-MI in reperfused STEMI patients, and the temporal changes in oedema may be a secondary process. • A hypointense infarct core on T2-mapping always occurred in the presence of microvascular obstruction and commonly in the absence of myocardial haemorrhage within 12 hours and 3 days post-MI, indicating that the presence of T2-core is more closely associated with microvascular obstruction than myocardial haemorrhage. • Infarct core pathology revealed by T2 (ms) was independently associated with all-cause death or heart failure hospitalisation during longer term follow-up. • Native T1 values (ms) within the infarct core were independently associated with adverse remodelling and adverse clinical outcome and had similar prognostic value when compared to microvascular obstruction. • IMR measured in the culprit coronary artery after reperfusion is more strongly associated with myocardial haemorrhage than microvascular obstruction in STEMI survivors 2 days later. • The proof-of-concept pilot deferred stenting trial showed that compared with standard of care with immediate stenting, brief deferral of stenting after initial reperfusion; reduced angiographic no-reflow, tended to reduce IMH and MVO, and increased myocardial salvage. The findings of this PhD are novel and have important clinical implications. Firstly, we found that myocardial haemorrhage occurs commonly and is a biomarker for prognostication in STEMI survivors. Secondly, IMR adds early prognostic information at the time of emergency reperfusion and has potential to stratify patients at risk of IMH for more intensive therapy. Thirdly, our results confirm that infarct pathologies are evolving dynamically and potentially, may be amenable to targeted therapeutic interventions. Finally, IMR has the potential to stratify STEMI patients acutely and deferred PCI is a simple intervention that could be practice changing, if the planned Phase 3 trial DEFER-STEMI confirms the hypothesis.

Pulmonary hypertension (PH) is a rare disease of the pulmonary arteries. It is characterised by vascular proliferation and remodelling resulting in a progressive increase in pulmonary vascular resistance and right ventricular failure. The functional capacity of the right ventricle is the major prognostic determinant in PH, and death usually results from right ventricular failure. Although recent therapeutic advances have improved the short-to-medium term outlook of PH patients, early death due to right ventricular failure remains inevitable in many patients. The imperative role of RV performance in the clinical status and long- term outcome in PH patients is evident. Evaluation of right ventricular function is essential in the management of patients with pulmonary hypertension. Current methods of assessment of PH patients are suboptimal. The right ventricle is difficult to assess due to its position and geometry. Recent developments in imaging techniques, such as cardiac magnetic resonance (CMR) imaging and echocardiography, have improved our understanding of the structure and function of the right ventricle. Assessment of RV function is complex and no single measurement is generally accepted in clinical practice. The experimental work performed in this thesis aimed to improve our understanding of RV function in PH patients and to provide clarity in the role of CMR in the non-invasive assessment and monitoring of pulmonary hypertension patients. A non-invasive measurement of stroke volume would be beneficial to monitor disease progression in pulmonary hypertension patients. Chapter 3 demonstrated that cardiac magnetic resonance imaging provided non-invasive measurements of stroke volume that were as accurate as those obtained by thermodilution measured during right heart catheterisation. Inert gas rebreathing using photoacoustic analysis also provided accurate non-invasive measurements of stroke volume. Chapter 4 compared two patient groups: idiopathic pulmonary arterial hypertension (IPAH) and pulmonary hypertension associated with connective tissue disease (CTDPAH). We clarified that there was no significant differences in RV structure and performance between these two distinct patient groups to account for the poorer prognosis in the CTDPAH group. Treatments for PH are always expensive, sometimes invasive and carry significant side effects. It is imperative that we are able to assess the patient’s response to therapy in a clinically meaningful, accurate and non-invasive manner. The importance of escalating therapy if a patient does not respond to initial treatment has been emphasised in recently published guidelines. Current monitoring techniques have acknowledged limitations and are suboptimal. Chapter 5 presents the results obtained from my contribution to the prospective, longitudinal multinational EURO-MR study. Longitudinal CMR examination identified significant improvements in cardiac function with the introduction of disease-targeted therapy. Baseline and 4 months post therapy CMR scans were compared. It is anticipated that CMR could be a useful monitoring technique for patients with pulmonary hypertension.

Clinical pathways define patient journeys with medical devices often utilised to diagnose and treat patients. In the contexts of screening and diagnosis, devices are utilised in the form of investigations and tests. They are utilised to detect preventable medical conditions in otherwise healthy individuals and to determine the cause of symptoms in patients presenting symptoms. Patient experiences of investigations and tests vary depending on the healthcare situation, investigation or test, and requirements, expectations and physical experiences of patients before, during and after investigations and tests. Information can be a valuable resource to inform, support and guide patients, and to contribute to quality patient experiences. However, this can only be achieved if information meets patient needs and preferences. This was the basis of the thesis, which took a user centred approach to the design, development and implementation of patient information. Two studies were conducted focussing on understanding attitudes towards investigations and tests, and informational needs and preferences. The first study examined attitudes towards different types of diagnostic procedure and the second examined attitudes towards screening for a vascular condition. Information was valuable in the former to inform about diagnostic procedures and patients’ physical involvement with them, and in the latter to inform about the medical condition, screening for the condition, the screening procedure, the benefits of being screened, and the risks of being or not being screened. Both studies also established factors affecting attitudes, providing a constructive understanding of attitudes. Ten factors were established that affected attitudes towards diagnostic procedures of which physical involvement, trust, familiarity and purpose were the most influential factors. Fifteen factors were established that affected attitudes towards screening of which benefits and risks, referring to personal benefits and risks, were the most influential factors. The established factors inspired a user centred design concept for patient information – a ‘factors based approach’ to the design of patient information. The factors based approach to the design of patient information is theoretical and consists of including and organising information based on factors. This approach was examined in two studies, which involved re-designing a patient information resource for an invasive investigation by applying appropriate factors established in the first two studies to it and examining and comparing it with the original information resource. The original resource was based on a standardised presentation of information for the investigation. The factors based resource was quantitatively no better nor worse than the standard resource; however, qualitative data found it had features that were important for its usability, which seemed to make it easier to understand compared to the standard resource. These findings demonstrated the potential of the factors based approach to the design of patient information, which led to the development of patient information guidelines. Patient information guidelines are provided for diagnostic procedures and screening. The guidelines represent the essence of the thesis and its work, and the contribution it has made to knowledge. They combine substantial data from four studies and it is hoped the guidelines assist information designers and others involved in patient information. The guidelines also aim to contribute to quality patient experiences through better meeting patient informational needs and preferences. Since the factors based approach to the design of patient information is a novel concept and the patient information guidelines are a draft, further research is recommended to better understand the potential of the factors based approach and to further develop and refine the guidelines. The guidelines have been made publicly available to use as a separate document and for further dissemination, and can be accessed and downloaded from the following link: https://db.tt/e6BQeJuu

Background: Aphasia is a language impairment affecting approximately one third of people after stroke. It can disrupt speaking, comprehension, reading and writing. This thesis concerned people with aphasia (PWA) with spelling and writing impairments (some also had reading difficulties) but relatively preserved speech and comprehension. Aims: 1. Consider the evidence for writing treatment interventions with a systematic review of the literature; 2. Conduct a pilot study testing the acceptability of a compensatory narrative writing treatment intervention using assistive technology (AT) software; 3. Report an empirical study which designed, delivered and evaluated a program to train ten PWA to operate two mainstream AT packages (Dragon NaturallySpeaking™, a voice recognition software (VRS) to support writing via dictation, and ClaroRead™, supporting reading via auditory processing). The study tested whether: a) AT could be used to produce functional narrative writing, b) reading support promoted writing success c) the intervention could be customised to suit individual goals. Methods: 1. Systematic literature review Electronic databases were searched; 53 papers meeting inclusion criteria were identified. Data were extracted, papers were critically appraised and their findings described. 2. Pilot Ten week AT training with two PWA to test acceptability of the intervention, design training schedule and materials, and test quantitative assessments and qualitative data collection methods for the main study 3. Main study Design and setting: Small group study with mixed methods, repeated measures design. Assessments and AT training in participants’ homes or at City, University of London. Participants: Ten participants meeting eligibility criteria (over 18 years old, medically stable, no significant cognitive impairment, aphasia due to stroke, presenting with acquired dysgraphia) were recruited via convenience sampling. They were not receiving speech and language therapy, had no marked evidence of neuromuscular, structural or motor-speech impairments, nor self-reported history of developmental dyslexia. Measures and procedure. Participants received 7-10 one-hour individual training sessions. Screening (language, cognition) and diagnostic (single word writing, single word reading) assessments took place at T1 (first baseline). Outcome measures (narrative writing, reading comprehension, quality of life, mood) were taken at T1 and repeated at T2 (second baseline), T3 (end of intervention) and T4 (three month follow up). Participant observation occurred throughout training; qualitative semi-structured interviews, a social participation assessment and cognitive monitoring took place at T2, T3 and T4. Results: 1. Systematic literature review Writing treatments were effective but often focused on single word production and seldom tested functional generalisation. Most were single case or small case series studies with remediatory goals; few used qualitative methodologies or investigated the impact of reading deficits. All narrative writing therapies were delivered via technology. 2. Pilot The intervention was acceptable to participants. Training schedule and materials were created and refined; quantitative outcome measures were finalised; emphasis on participant observation was increased. 3. Main study: Keyboard narrative writing was significantly improved by AT (Friedman’s χ² (3) = 8.27, p = .041), as was keyboard reading comprehension (Friedman’s χ² (3) = 21.07, p < .001), indicating compensatory effects of both AT. There was no change over time in pen and paper assessments of writing or reading, indicating no remediatory effect. A wide range of written genres were produced. Social network size significantly increased. There were no significant changes in mood or quality of life. Individual success rates varied; diagnostic and observation data suggested contributing factors were attitude, creativity, preserved speech production skills, spectrum of other aphasic traits, therapeutic goals, and cognition. Conclusion: The compensatory customisable AT training was acceptable to eight of ten participants, and resulted in significantly improved narrative writing performance. Implications: Compensatory AT interventions serve as a useful adjunct to remediatory spelling interventions, and are particularly useful for supporting functional narrative writing.

Aphasia intervention has made increasing use of technology in recent years. The evidence base, which is largely limited to the investigation of spoken language outcomes, indicates positive treatment effects for people with mild to moderate levels of aphasia. Outcomes for those with severe aphasia however, are less well documented and - where reported - present less consistent gains for measures of spoken output. In light of this issue for existing approaches, and due to the fact that non-speech focused interventions might therefore be more suitable, the current thesis explores the use of computer gesture therapy for people with severe aphasia. An initial review of gesture therapy is presented, followed by a systematic review of current computer therapy literature. A pseudo-randomised, wait-list control study of twenty participants with severe aphasia forms the experimental body of the thesis. The study investigates the effects of two purpose-built gesture therapy technologies: GeST and PowerGeST. The latter of these was developed for the purposes of the thesis. Following completion of a range of candidacy measures examining gesture comprehension, language, cognition and praxis, participants undertook a five-week intervention period comprising practice with GeST and PowerGeST. Primary outcomes were assessed using a measure of gesture production in isolation. Secondary outcome measures included an assessment of naming production, a novel assessment of interactive gesture abilities and an accessible computer use and confidence measure. These two latter measures were developed for the purposes of the thesis. Study outcomes show significant improvement in gesture production abilities for adults with severe aphasia following computer intervention. They indicate no transfer of effects into naming gains or interactive gesture. Findings reveal comparatively low levels of access to everyday technologies for this group. Outcomes therefore, indicate the positive effects of a purpose built computer-delivered therapy for a population who commonly experience challenges with access to everyday technology. Insights gained within this thesis offer encouraging results for computer therapy methods within this hitherto under-researched population and propose a case for further development of the evidence base in this field.

Background: Gestures are spontaneous hand and arm movements that frequently accompany speech and play an important role in everyday communication. When communication is impaired by aphasia, gestures are affected as well. It is important to find out how people with aphasia (PWA) use gesture as an accompaniment to speech, as a compensatory modality, and during lexical retrieval. This novel study examined the use and functions of gesture in conversation and investigated parameters (i.e., conversation partner, topic, and participant factors) that could have an influence on gesture production. Methodology: Language and conversation data of 20 PWA and 21 neurologically healthy participants (NHP) were collected. Participants took part in conversations with two conversation partners (familiar and unfamiliar) and two conversation topics (narrative and procedural). Video samples were analysed for gesture production, speech production, and word-finding difficulties (WFD). Results: The two groups of participants produced a similar number of gestures (t (37) = -1.060, p = .296). Gesture type was not examined statistically but showed some marginal differences between groups. Unfamiliar conversation partners elicited significantly more gestures than familiar conversation partners (F (1, 37) = 24.358, p < .001). Additionally, participants produced significantly more gestures in procedural than in narrative topics (F (1, 37) =44.807, p < .001). While all participants experienced a similar number of WFD, there was a difference between PWA and NHP regarding gesture production and resolution of WFD: NHP resolved the majority of all WFD, independent of a co-occurring gesture. Nevertheless, for PWA and NHP, there was a significant relationship between gesture production and the resolution of the WFD (X2 (1) = 12.356, p < .01 for PWA and X2 (1) = 40.657, p < .01 for NHP), indicating that WFD that occurred with gestures were more likely to be resolved than WFD that occurred without gesture production. Participants used gestures with different functions, such as facilitative gestures to resolve WFD or augmentative gestures to supplement speech. For PWA, different participant factures, such as fluency of speech (rs (17) = .487, p = .035), lexical production skills (rs (17) = .584, p = .009), and cognition (rs (17) = .582, p = .009) were linked to gesture production. Conclusions: These findings shed light on gesture processing and the different functions gestures can serve within conversation. Furthermore, they highlight the importance of pragmatic influence, such as conversation topic and conversation partner on the production of gestures. The significant relationships between participant factors and gesture production in aphasia extend the understanding of relevant skills needed to successfully employ gestures in conversation. Next to language skills, such as speech fluency and lexical retrieval, cognitive skills affected gesture production as well.

Despite many advances in technology and significant levels of funding, the genetic factors that regulate blood pressure in the population remain unclear. The public health implications of this lack of knowledge are conspicuous and a better understanding of the mechanisms behind hypertension would lead to better management of this important risk factor. The myriad of physiological systems involved in maintaining blood pressure can be variably dysregulated in patients with hypertension. Therefore, taking more account of hypertension as a heterogeneous condition may be a useful approach. Given the lack of success in dissecting the genetic factors to date, it seems reasonable to refocus attention on more carefully phenotyped groups of subjects, with the aim of identifying mechanisms specific to them.

The development and progression of high-grade non-muscle invasive bladder cancer (NMIBC) results from a complex interplay of environmental and heritable risk factors, including those that impact upon genetic and epigenetic pathways. Recent studies have identified epigenetic changes associated with bladder tumour development, growth patterns and clinical parameters; however, high-grade tumours have not been comprehensively studied for disease and/or subtype specific modifications. To address these shortfalls in our understanding, initial presentation and treatment naïve high-grade NMIBC tumours were analysed for inappropriate DNA methylation, histone modifications and geneexpression, and compared to low-intermediate-grade NMIBC and normal bladder. This thesis reports that genome-wide (LINE-1) methylation is significantly reduced in high-grade tumours relative to their low- and intermediate-grade counterparts and normal bladder, and that concurrent methylation of HOXA9 and ISL1 predicts adverse patient outcomes. Further comprehensive methylation assessment using HumanMethylation450 BeadChip arrays identified 256 differentially methylated genes, many of which have not been described in the context of bladder cancer. Moreover, the frequency and/or mean levels of methylation were significantly higher in the high-grade relative to the low-intermediate-grade tumour cohort for the ATP5G2, VAX2, INSRR, PRDM14, VSX1, TFAP2b, PRRX1, HIST1H4F genes. Expression analyses suggested that methylation was significantly associated with reduced transcript expression for the ATP5G2, PON3, STAT5a and ZNF577 genes, signifying a potential role for inappropriate methylation in high-grade tumourigenesis. Further array analyses identified numerous CpG sites that appeared to predict disease behaviour, and are targets for further investigations. The novel studies contained herein, are the first to report genome-wide array analyses in high-grade NMIBC, and demonstrate that methylation is a frequent event in this tumour type, and in some cases, different from other NMIBC tumours. Although inappropriate methylation was infrequently associated with changes in gene expression it did appear to have potential clinical prognostic ability, the assessment and validation of which requires further investigations.