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Cerebral small vessel disease, or SVD, refers to processes that lead to dysfunction and damage in cerebral microvessels, and is implicated in ischaemic stroke and vascular dementia. Although the pathophysiology is poorly understood, a subtle breakdown in the blood-brain barrier (BBB) has been implicated as a potential underlying mechanism. BBB breakdown is difficult to measure in-vivo however - Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI) is the dominant technique for assessing BBB integrity in clinical populations and is the focus of the work presented in this thesis. In this work, there are two main objectives: 1. Assess and optimise current DCE-MRI processing methods to provide accurate measurements of BBB breakdown. 2. Relate BBB breakdown to other features of SVD: clinical outcomes, imaging markers, and risk factors. To achieve the first objective, simulations were used to estimate the effects of various technical and modelling errors in measured BBB breakdown. By generating a realistic simulation of biological processes during a DCE-MRI sequence, sources of systematic error could be identified along with potential solutions. The implementation of MRI processing recommendations (a slow injection of contrast agent, exclusion of first-pass data from model fitting, and the use of a novel fitting method that better represents underlying biophysics) was found to reduce the sensitivity of calculated DCE-MRI parameters to the effects of variable blood plasma flow, variable water exchange rates, and injection delay by over 90%. Additionally, correction for field inhomogeneities was also found to reduce the error of calculated DCE-MRI parameters. Combining all the suggested processing methods was found to reduce the systematic error of calculated DCE-MRI parameters by up to 97%. These simulations form the basis of an open access framework and include an accessible GUI (1). For the second objective data was obtained from a prospective cohort study of mild stroke patients, and multiple linear regression was used to investigate how regional BBB breakdown is related to various patient factors. Regression models were controlled for several potential confounds and were implemented for both cross-sectional and longitudinal data. It was found that areas of hyperintensity on MRI images (which are indicative of vascular damage) presented lesser BBB breakdown when the severity of imaging markers was greater. Additionally, greater breakdown in the BBB of the basal ganglia is associated with greater disability scores, suggesting that vascular damage in this region may affect motor function and cognition. Risk factors associated with greater BBB breakdown include: age, a diagnosis of hypertension, and a diagnosis of diabetes, although the causality of these relationships is unclear. In summary, this thesis aims to improve the measurement of subtle BBB breakdown using DCE-MRI, and then use the optimised methods to investigate how BBB breakdown relates to clinical outcomes, imaging markers, and risk factors associated with SVD.

Gallstone disease is one of the most common surgically-managed conditions worldwide yet associations with other medical conditions outside of the biliary tree are poorly understood. Much like cardiovascular (CVD) and metabolic (cardiometabolic) disease (such as ischaemic heart disease, stroke, type 2 diabetes [T2DM] and non-alcoholic fatty liver disease [NAFLD]), gallstones are known to be more common in individuals who are overweight, do not exercise regularly and have a poor diet. Furthermore, gallstones, at least in populations with Western diets, are predominantly formed from cholesterol which is known to be a key determinant of cardiometabolic disease. It is therefore probable that individuals with gallstones are at higher risk of cardiometabolic disease than the general population. The relationship between gallstones and cardiometabolic disease (CVD, T2DM and NAFLD) was investigated. All three conditions were more common in individuals with gallstones than in gallstone-free controls and this increase in risk was not fully explained by established risk factors such as obesity, sedentary lifestyle or diet. Opportunistic identification of gallstones through radiology records was undertaken with natural language processing and similar increases in cardiometabolic disease identified. Gallstones are routinely managed by cholecystectomy and it was demonstrated that the apparent increase in risk of cardiometabolic disease was significantly attenuated compared to individuals who continued to live with their gallstones. This apparent reduction in risk was not explained by accounting for comorbidity or number of hospital attendances. Genetic analyses revealed a total of 75 genetic risk loci associated with gallstone formation (46 novel). These associations demonstrated heterogeneous effects on cardiometabolic disease outcomes and intermediate traits including lipids. A polygenic risk score was established with a six-fold increase in gallstone risk in the highest decile compared to the lowest. Genetic analysis of NAFLD was undertaken identifying 6 loci and confirming the suitability of electronic health records as a proxy to histological NAFLD evaluation in large cohorts. Mendelian randomisation (MR) was undertaken demonstrating a negative correlation between gallstones and CVD and no correlation between gallstones and either T2DM or NAFLD. After inclusion of additional variables in the model to account for pleiotropic pathways, the negative correlation with CVD was removed. Sensitivity analyses revealed that the negative association was driven primarily by a gain-of-function mutation in the ABCG8 gene which reduces serum cholesterol whilst simultaneously increasing biliary cholesterol saturation. Removing ABCG8 or adjusting for serum lipids both had the same effect of demonstrating no change in CVD risk in multivariable MR. These findings demonstrate a strong association between gallstones and other cardiometabolic disease outcomes that is not explained by established environmental risk factors or by shared genetic heritability. The additional risk may be explained by other, unknown or harder to measure environmental risk factors. This suggests that gallstones may act as a useful forewarning of cardiometabolic disease independent of established risk factors. Individuals with gallstones, and surgeons managing them, should be aware of their role as a sentinel presentation of cardiometabolic disease.

Born out of wartime developments, Britain's new electronics industry emerged in the interwar period as a successful and growing part of a then fragile national economy. The electronics industry was indeed one of few big growth areas in the British interwar economy, one which facilitated the sector taking on thousands of new female employees at a time when other sectors, such as telephone exchanges, had begun to mechanise and thus eliminate women's employment. This growth facilitated the mass production of wireless sets, and their essential internal components such as electronic amplifying valves, that contributed to a developing consumer culture in Britain. In turn, the development of the electronics industry brought about a variety of complicated evolutions in the roles of women and the gendered representations of them in relation to both waged work and their consumption of, and relationship to, new technologies. I argue that within the newly-developed electronics industry it was in the years of peace between the two world wars that longer-lasting changes truly took hold regarding not only the cultural perceptions of women but also in the material conditions in which they lived and worked. In this thesis I analyse three major roles women had in the interwar electronics industry: as workers manufacturing wireless technology, as the public face of the electronics companies demonstrating the technology and finally as consumers of wireless radio sets. However, I argue that alongside these changes to women's lives in relation to the electronics industry, more traditional representations of gender were still upheld even when these notions contradicted and challenged the economic, gender and social realities of the interwar years. The originality of this thesis stems from its focus on the lived realities and representations of women as manufacturers, demonstrators, and consumers of electronics. This phenomenon has hitherto received little direct scholarly attention, merely being mentioned in relation to women and interwar work as a whole. In this study I adopt a cultural history framework with a focus on visual culture to facilitate an analysis on representations using relevant visual sources as evidence in conjunction with statistics and textual sources, for my analysis. Such an approach has not previously been undertaken in relation to this specific area of study to any significant degree.

Retention has long been an issue within the academic world, with retention being a proxy for prospective students to determine institutional success and commitment to their students. Within the nursing field this problem is compounded by even lower than average retention rates within academic institutions and a field that is losing professionals at an increasing rate due to retirement and burnout. Academic institutions have attempted to address this problem through the development of a holistic education model, which theorizes support beyond academics will help students feel more committed to their institution and be less likely to attrit. The problem addressed by this study is that the average attrition rate for nursing students is 30%. The purpose of this qualitative phenomenological study was to document the knowledge and lived experiences of students who were admitted through a holistic education framework and its impact on their perceptions of support and retention at their university. The sample was 17 nursing students from a for-profit nursing university, that has multiple campus locations in multiple states. Data were collected using semi-structured open-ended interviews. The research findings showed that participants primarily were open to the holistic framework, with a smaller subset either indifferent or concerned about shifting the collegiate focus away from academics. Students felt that holistic practices would increase both their perception of institutional care and their perception of their likelihood to be retained, if those practices met the needs they had. One recommendation for further research would be to conduct a qualitative study focused on what the students felt their holistic needs were, as this study presented findings that many students felt the holistic services offered did not address their direct needs. A practical recommendation would be to include student representatives in the development of holistic materials and resources as they could define the issues being faced by the student population more directly than leadership. [The dissertation citations contained here are published with the permission of ProQuest LLC. Further reproduction is prohibited without permission. Copies of dissertations may be obtained by Telephone (800) 1-800-521-0600. Web page: http://www.proquest.com/en-US/products/dissertations/individuals.shtml.]

This thesis argues that radical emotional reflexivity - self-examination of one's emotions, 'radical' because intentional and rigorous - was a central practice in Scottish Protestantism between 1590 and 1640. It was fundamental because Scottish Protestants believed that purposeful identification of emotions could mobilise desired emotional change that would bring communion with God. They evaluated their emotions within a linguistic-conceptual framework which led them to identify their emotions as: a spiritual journey, directed by God, which involved the experience of various 'supernatural' emotions. They undertook this practice to evoke emotional change. Consequently, this process was built into corporate worship and motivated zealous Scottish Protestants to write and read personal spiritual narratives. The thesis takes a fresh approach to familiar source material - spiritual diaries, autobiographies, dialogues, poetry, liturgical guides, sermons, and theological treatises - by viewing them through the lens of radical emotional reflexivity. Recent historiography has discredited stereotypes of the emotionally repressed Scottish Presbyterian by showing that early modern Scottish piety had a highly emotional character. However, it has not sufficiently appreciated that the emotional intensity of the source material was the product of a rigorous self-reflective process used to provoke spiritual change. This is because recent writing has not engaged with the function of language about emotion built into corporate religious practice and personal piety. As a result, this project provides a comprehensive analysis of the vocabulary of emotion and its purpose in early modern Scottish Protestantism, and consequently explains why the source material was created and presented Scottish Protestant piety as highly emotional. The argument begins with an outline of the theory of emotion (chapter 1) and the end-goal against which Scottish Protestants judged their emotions: happiness in enjoying God (chapter 2). The next chapter examines the language Scots used about their emotions in corporate worship and personal piety. It argues that in both contexts Scottish Protestants evaluated their emotions as a spiritual journey under God's hand, the subjective dimension of salvation (chapter 3). Then follows an analysis of what Scottish Protestants meant when they identified 'supernatural' emotions as feelings caused by God and as perceptions of communion with God (chapter 4). Finally, the thesis argues that Scottish Protestants engaged in radical emotional reflexivity to mobilise desired emotions, which explains why they wrote and read narratives of the soul's spiritual journey (chapter 5). In sum, this study examines what judgements Scottish Protestants made about their emotions, how they made these judgements, and why they evaluated their emotions at all.

The effects of old age on musculoskeletal structure and function have been characterised in the literature through cross-sectional studies, comparing data from young and older adults in an attempt to uncover the mechanisms behind decreases in muscle mass and function. However, such work is prone to potential bias associated with differences in changes in lifestyle and genotype during human ageing. Longitudinal studies can overcome such bias, though these are of in the minority and generally outline relatively simple measures in larger epidemiological studies. The overall aim of the work described in this thesis was to assess longitudinal changes in muscle mass and function, and how these influenced the ability to perform daily life activities over a 5-year period in older individuals. Characterising a more robust model of ageing than its cross-sectional counterparts in more detail than previously reported. This aim was addressed through several objectives that are described across the Chapters. In Chapter 2, we highlight that the use of dual-energy X-ray absorptiometry (DXA) to track changes in muscle mass is a viable method when compared to magnetic resonance imaging (MRI), though DXA exhibited a positive intercept with MRI and therefore consistently overestimated muscle volume. It was reported in Chapter 2 that over the 5-year period there might be an accelerated decline in muscle mass, with no difference in relative rate of muscle loss between genders or baseline muscle mass. Loss of muscle mass in ageing is related to deficits in functional capacity, in Chapter 3 the contribution of reduced voluntary activation, fibre atrophy and fibre loss to muscle weakness are investigated. Muscle quality, measured by patella tendon specific force was found to contribute significantly to the loss of age-related muscle weakness in early ageing, though loss of muscle mass was found to be the main cause. The objective of Chapter 4 was to investigate the influence of muscle weakness on mobility performance. Significant decreases in 6-min walk and timed up and go were noted, with changes in muscle power being the key contributor to this change. Rather than the intrinsic slowing of the muscle seen in early ageing, power loss was primarily due to reductions in maximal voluntary contraction. The main conclusion of this work was that free-living septuagenarian's show an accelerated decline in muscle mass and functional performance over a 5-year period compared to cross sectional data previously reported, suggesting upon reaching the eighth decade humans neuromuscular system ages at an faster rate than preceding decades. The preferential atrophy of type II and loss of fibres are the key contributors to this loss of mass. These findings highlight the need for septuagenarians in relatively good health to have appropriate interventions designed to mitigate these age-related changes.