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Introduction. Fused Positron Emission Tomography and Computed Tomography (PET/CT) is an emerging investigative tool in cardiovascular disease that provides an imaging-based quantification of pathophysiological processes of interest. The purpose of this thesis was to study the application of PET to identify fundamental pathophysiological processes driving 3 forms of cardiovascular disease: aortic stenosis, myocardial infarction, and atherosclerosis. Methods. Aortic Stenosis. Patients with a spectrum of calcific aortic valve disease (n=121) who underwent PET-CT imaging for the identification of valvular calcification (18Ffluoride) and inflammation (18F-fluorodeoxyglucose, 18F-FDG) underwent serial imaging and clinical follow-up over 2 years. Baseline imaging findings were compared with echocardiographic and CT markers of disease progression and clinical outcome. Myocardial Infarction. Patients underwent PET-CT imaging with 18F-fluciclatide (a novel αvβ3-selective radiotracer highlighting active angiogenesis, inflammation and fibrosis) after ST-segment elevation MI (n=21), alongside stable patients with chronic total occlusion (CTO) of a major coronary vessel (n=7), and healthy volunteers (n=9). Myocardial radiotracer uptake was compared with clinical and cardiac magnetic resonance imaging (CMR) markers of infarction and remodeling. Atherosclerosis. Patients with a spectrum of atherosclerotic disease categorized as stable or unstable (recent MI) underwent PET/CT imaging with 18F-fluciclatide (n=46). Thoracic aortic 18F-fluciclatide uptake was compared with aortic atherosclerotic burden quantified by CT plaque thickness, plaque volume and calcium scoring. Histological validation. Tissue from the aortic valve, myocardium and carotid arteries of study subjects was acquired and examined ex vivo using histology and autoradiography. Results. Aortic Stenosis. Baseline valvular 18F-fluoride uptake correlated strongly with the rate of progression in AVC (r=0.80, p < 0.001) and with haemodynamic progression (mean aortic valve gradient r=0.32, p=0.001). It emerged as independently associated with clinical outcome after age and sex-adjustment (HR 1.55 [1.33-1.81], p < 0.001). 18F-FDG demonstrated moderate correlations with disease progression as assessed by CT (r=0.43, p=0.001) and echocardiography (18F-FDG r=0.30, p=0.001), and was associated with clinical outcomes independent of age and sex (HR 1.35 [1.16-1.58], p < 0.001). Valvular 18F-fluoride uptake correlated with immunohistochemical markers of calcification activity. There was no correlation between 18F-FDG uptake and inflammation. Myocardial Infarction. 18F-Fluciclatide binding was demonstrated in ex vivo peri-infarct myocardium and uptake was increased in vivo at sites of acute infarction compared to remote myocardium (tissue-to-background ratio (TBRmean) 1.34±0.22 vs 0.85±0.17 respectively, p < 0.001) and myocardium of healthy volunteers (TBRmean 1.34±0.22 vs 0.70±0.03; p < 0.001). There was no 18F-fluciclatide uptake at sites of established prior infarction in patients with CTO, with myocardial activity similar to healthy volunteers (TBRmean 0.71±0.06 vs. 0.70±0.03,p=0.83). 18F-Fluciclatide uptake occurred at sites of regional wall hypokinesia (wall motion index ≥1 vs 0; TBRmean 0.93±0.31 vs 0.80±0.26 respectively, p < 0.001), was increased in segments displaying functional recovery (TBRmean 0.95±0.33 vs 0.81±0.27, p=0.002) and associated with increase in probability of regional recovery. Atherosclerosis. 18F-Fluciclatide vascular binding ex vivo co-localised with regions of increased αvβ3 integrin expression, and markers of inflammation and angiogenesis. 18F-Fluciclatide uptake in vivo correlated with measures of aortic atherosclerotic burden: plaque thickness (r=0.57, p=0.001), total plaque volume (r=0.56, p=0.001) and the CT aortic calcium score (r=0.37, p=0.01). Patients with recent MI had greater aortic 18F-fluciclatide uptake than those with stable disease (TBRmax 1.33 vs 1.21, p=0.01). Conclusions. In a range of cardiovascular diseases, PET-CT can provide insights into key pathophysiological processes, guide patient risk stratification and prognosis, and identify important biomarkers of disease activity that can be used for the development of future therapeutic interventions.

Recent scholarship has suggested that transformist ideas had a wider currency in Edinburgh in the first half of nineteenth century than had previously been acknowledged. The first objective of this study is to delve deeper into the reception of transformist theories there in the years 1790 to 1844. The main figures whose theories on the transmutation of species were discussed in contemporary sources are Carl Linnaeus (1707–1778), George-Louis Leclerc, Conte de Buffon (1707–1788), Erasmus Darwin (1731–1802), Jean-Baptiste Lamarck (1744–1829) and Étienne Geoffroy Saint-Hilaire (1772–1844); this study therefore concentrates on the reception of their work. The principle Edinburgh contexts in which the reception of their theories is explored are the University of Edinburgh, the extra-mural medical schools and the city’s various learned societies and scientific journals, although the opinions of all those in Edinburgh known to have discussed transformism in this period are considered. The sources examined reveal that transformist theories were largely received with interest. Discussion of them was generally confined to scientific, or naturalistic, arguments, except in the cases of some Evangelical natural historians, who rejected them outright on theological grounds. This thesis also explores how some thinkers in Edinburgh went beyond discussing received ideas about transformism and developed their own theories, synthesising the work of earlier thinkers. The most important of these were Robert Edmond Grant (1793– 1874), Robert Jameson (1774–1854), Robert Knox (1791–1862) and Henry H. Cheek (1807–33). This thesis also explores the genesis of the later transformist theory of Robert Chambers (1802–71), the anonymous author of Vestiges of the Natural History of Creation (1844), to establish to what extent he may have been influenced by the earlier transformists of the 1820s and 30s. Events in Edinburgh in the 1820s also had a wider resonance for the history of evolutionary ideas in Britain, as Charles Darwin (1809–1882) was a student at the University of Edinburgh between 1825 and 1827. It has long been suspected that his experiences in Edinburgh had a larger part to play in the development of his theory of evolution than he later cared to admit. Careful to avoid associating himself with the more speculative theories of earlier transformist thinkers, Darwin made little mention of them in his published writings. We already know, however, that Darwin had a close relationship with Grant during his time in Edinburgh and must have been familiar with his transformist ideas. This thesis aims to show to what extent the intellectual environment that Darwin found himself in was suffused with the idea of the transmutation of species. In broad outline, it can be concluded that transformism was much less controversial in Edinburgh in the first half of the nineteenth century than might be supposed from the prevailing historiography and had a significant number of sympathisers and adherents.

This thesis describes the development of a novel linearisation technique for use in high-frequency power amplifiers. The need for linear power amplifiers is identified, and existing linearisation schemes are outlined and appraised in terms of their complexity, cost and efficacy. It is shown that currently-available linearisation schemes tend to have an effectiveness that is proportional to their complexity, and hence their cost of implementation. Analysis and simulation results are presented to illustrate the mechanism through which the new linearisation technique reduces in-band distortion. The theoretical work is then verified with experimental measurements, initially using two unmodulated carriers and a feedback topology, and progressing to become a feedforward or injection technique using four unmodulated carriers. The agreement between the simulated and measured performance was found to be excellent throughout. The application of the technique to modulated real-world signals is then investigated, with theoretical analysis, simulations and measured results presented to demonstrate the applicability of the technique to both single and multiple modulated-carrier input signals. It is shown that Second-Order Bias Injection can typically provide 15-18dB of in-band distortion improvement, and that the technique has potential for use in next-generation (2G+ and 3G) mobile telecommunication networks.