Cassius Dio's speeches and the collapse of the Roman Republic

This thesis argues that Cassius Dio used his speeches of his Late Republican and Augustan narratives as a means of historical explanation. I suggest that the interpretative framework which the historian applied to the causes and success of constitutional change can be most clearly identified in the speeches. The discussion is divided into eight chapters over two sections. Chapter 1 (Introduction) sets out the historical, paideutic, and compositional issues which have traditionally served as a basis for rejecting the explanatory and interpretative value of the speeches in Dio’s work and for criticising his Roman History more generally. Section 1 consists of three methodological chapters which respond to these issues. In Chapter 2 (Speeches and Sources) I argue that Dio’s prosopopoeiai approximate more closely with the political oratory of that period than has traditionally been recognised. Chapter 3 (Dio and the Sophistic) argues that Cassius Dio viewed the artifice of rhetoric as a particular danger in his own time. I demonstrate that this preoccupation informed, credibly, his presentation of political oratory in the Late Republic and of its destructive consequences. Chapter 4 (Dio and the Progymnasmata) argues that although the texts of the progymnasmata in which Dio will have been educated clearly encouraged invention with a strongly moralising focus, it is precisely his reliance on these aspects of rhetorical education which would have rendered his interpretations persuasive to a contemporary audience. Section 2 is formed of three case-studies. In Chapter 5 (The Defence of the Republic) I explore how Dio placed speeches-in-character at three Republican constitutional crises to set out an imagined case for the preservation of that system. This case, I argue, is deliberately unconvincing: the historian uses these to elaborate the problems of the distribution of power and the noxious influence of φθόνος and φιλοτιμία. Chapter 6 (The Enemies of the Republic) examines the explanatory role of Dio’s speeches from the opposite perspective. It investigates Dio’s placement of dishonest speech into the mouths of military figures to make his own distinctive argument about the role of imperialism in the fragmentation of the res publica. Chapter 7 (Speech after the Settlement) argues that Cassius Dio used his three speeches of the Augustan age to demonstrate how a distinctive combination of Augustan virtues directly counteracted the negative aspects of Republican political and rhetorical culture which the previous two case-studies had explored. Indeed, in Dio’s account of Augustus the failures of the res publica are reinvented as positive forces which work in concert with Augustan ἀρετή to secure beneficial constitutional change.

An investigation into the role of interleukin-6 in linking systemic and local inflammatory responses in patients with colorectal cancer

Colorectal cancer is the second most common cause of cancer death in the UK. It is accepted that both tumour and host factors are important determinants of disease progression and survival. While systemic and local inflammatory responses are increasingly recognized to be of particular importance the understanding of the mechanisms linking these important inflammatory processes remains unclear. This thesis examines the prognostic importance of measures of systemic and local inflammation and proposes a hypothesis for a link between tumour necrosis, systemic and local inflammatory responses in patients with colorectal cancer. Chapter 3 reports the comparison of the prognostic value of longitudinal measurements of systemic inflammation in patients undergoing curative resection of colorectal cancer. In Chapter 3 the results demonstrate that there was no significant overall change in either mGPS or NLR from pre- to post- operatively. This study highlighted the associations between pre- and post- operative mGPS and NLR and T-stage (p<0.001), TNM stage (p<0.005) and cancer-specific survival. The relationships between pre-operative measurements were examined using multivariate analysis. For pre-operative measurement both mGPS and NLR were associated with cancer-specific survival while when post-operative measures were examined only mGPS was specifically associated with cancer-specific survival (HR 4.81, CI 2.13-10.83, P<0.001). Chapter 4 examines the prognostic value of the Klintrup-Makinen scoring method and the existing limitations with regard to its clinical utility. An automated scoring method using commercially available image analysis software was developed and compared with manual scoring of tumour inflammatory infiltrates. This study demonstrated that both manual K-M scoring (p<0.001) and automated K-M scoring (p<0.05) had prognostic value in patients who had undergone potentially curative resection of colorectal cancer, and that the novel automated method may provide an objective method of assessment of tumour inflammatory infiltrates using routinely stained haematoxylin and eosin sections of tumour samples. In chapter 5 a hypothesis was proposed that Interleukin-6 may link tumour necrosis and systemic and local inflammatory responses in patients with colorectal cancer. This chapter examined the basis for this hypothesis, which is presented in figure 5.1. In addition, in chapter 5 the importance of this potential link is examined. In chapter 6, the hypothesis outlined in chapter 5 was examined in a cohort of patients who had undergone attempted curative resection of colorectal cancer. This study examined the inter-relationships between circulating mediators, in particular IL-6, tumour necrosis and systemic and local inflammatory responses. This results of this study demonstrated that IL-6 was associated with tumour necrosis (<0.001) and mGPS (<0.001) independent of T-stage. Thus adding weight to the hypothesis that elevated circulating concentrations of IL-6 may play a role in modulating both the systemic and local inflammatory responses in patients with cancer. Chapter 7 further develops the hypothesis that IL-6 signalling may be important in modulating systemic and local inflammatory responses in patients with colorectal cancer. Further, in chapter 7 the basis for the role of trans-signalling in this signaling pathway was examined. In this study, we reported that neither expression of the soluble IL-6 receptor or soluble gp130 were associated with systemic or local inflammatory responses. As a result the possible reasons for these findings were explored and future work suggested. A prospective database of patients undergoing attempted curative resection of colorectal cancer in Glasgow Royal Infirmary was used throughout this thesis. This database was created and is maintained regularly by successive research fellows at the Royal Infirmary. The work presented in this thesis highlights the importance of the host response in the form of systemic and local inflammation in patients with colorectal cancer and proposes a link between these responses and tumour necrosis. In addition, this work adds weight to the body of evidence suggesting that assessment of these host responses may improve stratification to treatment for patients with colorectal cancer. Further, this work proposes a mechanistic link, between tumour necrosis, systemic and local inflammatory responses through Interleukin-6, that merits further investigation.

An investigation of the clinical utility of preoperative cardiopulmonary exercise testing in patients undergoing major pancreatic surgery

Pancreaticoduodenectomy with or without adjuvant chemotherapy remains the only modality of possible cure in patients with cancer involving the head of the pancreas and the periampullary region. While mortality rates after pancreaticoduodenectomy have improved considerably over the course of the last century, morbidity remains high. Patient selection is of paramount importance in ensuring that major surgery is offered to individuals who will most benefit from a pancreaticoduodenectomy. Moreover, identifying preoperative risk factors provides potential targets for prehabilitation and optimisation of the patient's physiology before undertaking surgery. In addition to this, early identification of patients who are likely to develop postoperative complications allows for better allocation of critical care resources and more aggressive management high risk patients. Cardiopulmonary exercise testing is becoming an increasingly popular tool in the preoperative risk assessment of the surgical patient. However, very little work has been done to investigate the role of cardiopulmonary exercise testing in predicting complications after pancreaticoduodenectomy. The impact of jaundice, systemic inflammation and other preoperative clinicopathological characteristics on cardiopulmonary exercise physiology has not been studied in detail before in this cohort of patients. The overall aim of the thesis was to examine the relationships between preoperative clinico-pathological characteristics including cardiopulmonary exercise physiology, obstructive jaundice, body composition and systemic inflammation and complications and the post-surgical systemic inflammatory response in patients undergoing pancreaticoduodenectomy. Chapter 1 reviews the existing literature on preoperative cardiopulmonary exercise testing, the impact of obstructive jaundice, perioperative systemic inflammation and the importance of body composition in determining outcomes in patients undergoing major surgery with particular reference to pancreatic surgery. Chapter 2 reports on the role of cardiopulmonary exercise testing in predicting postoperative complications after pancreaticoduodenectomy. The results demonstrate that patients with V˙O2AT less than 10 ml/kg/min are more likely to develop a postoperative pancreatic fistula, stay longer in hospital and less likely to receive adjuvant therapy. These results emphasise the importance of aerobic fitness to recover from the operative stress of major surgery without significant morbidity. Cardiopulmonary exercise testing may prove useful in selecting patients for intensive prehabilitation programmes as well as for other optimisation measures to prepare them for major surgery. Chapter 3 evaluates the relationship between cardiopulmonary exercise physiology and other clinicopathological characteristics of the patient. A detailed analysis of cardiopulmonary exercise test parameters in jaundiced versus non-jaundiced patients demonstrates that obstructive jaundice does not impair cardiopulmonary exercise physiology. This further supports emerging evidence in contemporary literature that jaundiced patients can proceed directly to surgery without preoperative biliary drainage. The results of this study also show an interesting inverse relationship between body mass index and anaerobic threshold which is analysed in more detail in Chapter 4. Chapter 4 examines the relationship between preoperative cardiopulmonary exercise physiology and body composition in depth. All parameters measured at cardiopulmonary exercise test are compared against body composition and body mass index. The results of this chapter report that the current method of reporting V˙O2, both at peak exercise and anaerobic threshold, is biased against obese subjects and advises caution in the interpretation of cardiopulmonary exercise test results in patients with a high BMI. This is particularly important as current evidence in literature suggests that postoperative outcomes in obese subjects are comparable to non-obese subjects while cardiopulmonary exercise test results are also abnormally low in this very same cohort of patients. Chapter 5 analyses the relationship between preoperative clinico-pathological characteristics including systemic inflammation and the magnitude of the postoperative systemic inflammatory response. Obstructive jaundice appears to have an immunosuppressive effect while elevated preoperative CRP and hypoalbuminemia appear to have opposite effects with hypoalbuminemia resulting in a lower response while elevated CRP in the absence of hypoalbuminemia resulted in a greater postoperative systemic inflammatory response. Chapter 6 evaluates the role of the early postoperative systemic inflammatory response in predicting complications after pancreaticoduodenectomy and aims to establish clinically relevant thresholds for C-Reactive Protein for the prediction of complications. The results of this chapter demonstrate that CRP levels as early as the second postoperative day are associated with complications. While post-operative CRP was useful in the prediction of infective complications, this was the case only in patients who did not develop a post-operative pancreatic fistula. The predictive ability of inflammatory markers for infectious complications was blunted in patients with a pancreatic fistula. Chapter 7 summarises the findings of this thesis, their place in current literature and future directions. The results of this thesis add to the current knowledge regarding the complex pathophysiological abnormalities in patients undergoing pancreaticoduodenectomy, with specific emphasis on the interaction between cardiopulmonary exercise physiology, obstructive jaundice, systemic inflammation and postoperative outcomes. The work presented in this thesis lays the foundations for further studies aimed at improving outcomes after pancreaticoduodenectomy through the development of individualised, goal-directed therapies that are initiated well before this morbid yet necessary operation is performed.

Blood donor motivation and recruitment : a comparative study in West of Scotland and the Sudan

In modern society, blood donor motivation and recruitment is a fundamental part of health care delivery. Well defined and documented programmes exist throughout the world but new ideas are always welcome. The situation in the Sudan is different and much remains to be done by way of comparison with elsewhere. This thesis outlines the objectives of a study, how it was supported, sponsored and achieved. It describes briefly the geography of the Sudan, the source of Sudanese economy, climate, culture and historical backgrounds. The problems of existing services in the Sudan are reviewed and a brief account of the demographic characteristics of the Sudanese population is given. Two surveys done in West of Scotland and in the Sudan are described in detail. This work discloses and compares the positive motives that enhances giving of blood and the negative motives that hinders its donation. The comparison is between an Eastern Society with a voluntary motivation not fully activated because of lack of understanding and awareness of the need to give blood voluntarily for strangers and Western Society with a well established voluntary system of donation. An addition to this research was the investigation into the immunity to tetanus and hepatitis in the Sudanese population. An estimate of the percentage of individuals with detectable levels of hepatitis A and B antibodies and tetanus antibodies is included since there is a need to establish a plasmapheresis programme as part of a good Blood Transfusion Service for the procurement of specific immunoglobulin's. This work has revealed major differences between the West of Scotland and the Sudan and suggestions are made for their resolution. The main conclusion and comparison are summarised in Chapter 7. It is hoped that many of the suggestions in this thesis can be introduced in the Sudan at an early date.

The Scottish Parliament in the 15th and 16th centuries

Earlier histories of the Scottish parliament have been somewhat constitutional in emphasis and have been exceedingly critical of what was understood to be parliament's subservience to the crown. Estimates by constitutional historians of the extreme weakness of parliament rested on an assessment of the constitutional system. The argument was that many of its features were not consistent with a reasonably strong parliament. Because the 'constitution' is apparently fragmented, with active roles played by bodies such as the lords of articles, the general council and the convention of estates, each apparently suggesting that parliament was inadequate, historians have sometimes failed to appreciate the positive role played by the estates in the conduct of national affairs. The thesis begins with a discussion of the reliability of the printed text of APS and proceeds to an examination of selected aspects of the work of parliament in a period from c 1424-c 1625. The belief of constitutional historians such as Rait that conditions In Scotland proved unfavourable to the interests and. effectiveness of parliament in the fifteenth and sixteenth centuries, is also examined. Chapter 1 concludes that APS is a less than reliable text, particularly for the reign of James I. Numerous statutes were excluded from the printed text and they are offered below for the first time. These statutes have been a useful addition to our understanding of the reign of James I. Chapter 2 analyses the motives behind the schemes for shire representation and concludes that neither constitutional theory nor political opportunism explains the support which James I and James VI gave to these measures. Both these monarchs were motivated by the realisation that their particular ambitions were dependent on winning the support of the estates whose ranks should include representatives from the shires. Chapter 3 examines the method of electing the lords of articles, the composition of this committee, and some aspects of its operation. The conclusion is that in the main the estates were the deciding force in the choice of the lords of articles. The committee's composition was more a reflection of a desire for a balance between representatives from north and south of the Forth and for the most important burghs and clergy to be selected than an attempt at electing government favourites. The articles did exercise a significant control over the items which came before parliament but this control was not absolute and applied to government as well as private legislation. Chapter 4 questions the traditional view that the general council and convention of estates were the same body. It is argued that they were two different institutions with different powers, but that they nevertheless worked within certain limits and were careful not to usurp the authority of parliament. Chapter 5 concedes that taxation was sometimes decided outside parliament; that the irregularity of taxation certainly weakened the bargaining power of the estates and that the latter did not appear to capitalise on these occasions when taxation was an issue. But the tendency was to ensure that, whether in or out of parliament, the decision to impose taxation was taken by a large number of each estate. The infrequency of taxation was a direct consequence of an unwillingness among the estates to agree to a regular taxation and their preference to ensure for the crown an alternative source of income. Moreover taxation was one issue, which more than any other, would be subject to contentious opposition by the estates, and could lead to the crown's defeat. Chapter 6 is concerned with ecclesiastical representation after the Reformation and the church's attitudes to the possibility of ministerial representation. Some ministers had doctrinal misgivings but the majority came to believe that the church's absence from parliament bad severely reduced. the influence of the church. That no agreement was forthcoming on a system of ministerial representation, particularly after 1597, is attributable to the estates' unwillingness to compromise and, not to the strength of opposition in the church. Chapter 7 examines the institutions which are sometime seen as 'rivals' of parliament and concludes that institutions such as the privy council were generally very careful in matters which needed the approval of parliament, and seemed aware of the greater authority of parliament. Chapter 8 which illustrates how parliament had the right to be consulted in all important matters of state, brings together the main points of the earlier chapters and offers further illustrations of the essential role which parliament played in the conduct of national affairs. Whether or not the system can be regarded as constitutionally sound, the estates in Scotland could observe parliament's day-to-day operation with some satisfaction. All in all, there is little convincing evidence that parliament was as weak as some historians would have us believe.

Optimal static and sequential design : a critical review

The aim of this thesis is to review and augment the theory and methods of optimal experimental design. In Chapter I the scene is set by considering the possible aims of an experimenter prior to an experiment, the statistical methods one might use to achieve those aims and how experimental design might aid this procedure. It is indicated that, given a criterion for design, a priori optimal design will only be possible in certain instances and, otherwise, some form of sequential procedure would seem to be indicated. In Chapter 2 an exact experimental design problem is formulated mathematically and is compared with its continuous analogue. Motivation is provided for the solution of this continuous problem, and the remainder of the chapter concerns this problem. A necessary and sufficient condition for optimality of a design measure is given. Problems which might arise in testing this condition are discussed, in particular with respect to possible non-differentiability of the criterion function at the design being tested. Several examples are given of optimal designs which may be found analytically and which illustrate the points discussed earlier in the chapter. In Chapter 3 numerical methods of solution of the continuous optimal design problem are reviewed. A new algorithm is presented with illustrations of how it should be used in practice. It is shown that, for reasonably large sample size, continuously optimal designs may be approximated to well by an exact design. In situations where this is not satisfactory algorithms for improvement of this design are reviewed. Chapter 4 consists of a discussion of sequentially designed experiments, with regard to both the philosophies underlying, and the application of the methods of, statistical inference. In Chapter 5 we criticise constructively previous suggestions for fully sequential design procedures. Alternative suggestions are made along with conjectures as to how these might improve performance. Chapter 6 presents a simulation study, the aim of which is to investigate the conjectures of Chapter 5. The results of this study provide empirical support for these conjectures. In Chapter 7 examples are analysed. These suggest aids to sequential experimentation by means of reduction of the dimension of the design space and the possibility of experimenting semi-sequentially. Further examples are considered which stress the importance of the use of prior information in situations of this type. Finally we consider the design of experiments when semi-sequential experimentation is mandatory because of the necessity of taking batches of observations at the same time. In Chapter 8 we look at some of the assumptions which have been made and indicate what may go wrong where these assumptions no longer hold.

Synthetic biology in droplet-based microfluidics

Droplet microfluidics is an active multidisciplinary area of research that evolved out of the larger field of microfluidics. It enables the user to handle, process and manipulate micrometer-sized emulsion droplets on a micro- fabricated platform. The capability to carry out a large number of individual experiments per unit time makes the droplet microfluidic technology an ideal high-throughput platform for analysis of biological and biochemical samples. The objective of this thesis was to use such a technology for designing systems with novel implications in the newly emerging field of synthetic biology. Chapter 4, the first results chapter, introduces a novel method of droplet coalescence using a flow-focusing capillary device. In Chapter 5, the development of a microfluidic platform for the fabrication of a cell-free micro-environment for site-specific gene manipulation and protein expression is described. Furthermore, a novel fluorescent reporter system which functions both in vivo and in vitro is introduced in this chapter. Chapter 6 covers the microfluidic fabrication of polymeric vesicles from poly(2-methyloxazoline-b-dimethylsiloxane-b-2-methyloxazoline) tri-block copolymer. The polymersome made from this polymer was used in the next Chapter for the study of a chimeric membrane protein called mRFP1-EstA∗. In Chapter 7, the application of microfluidics for the fabrication of synthetic biological membranes to recreate artificial cell- like chassis structures for reconstitution of a membrane-anchored protein is described.

Quantification of air quality in space and time and its effects on health

The long-term adverse effects on health associated with air pollution exposure can be estimated using either cohort or spatio-temporal ecological designs. In a cohort study, the health status of a cohort of people are assessed periodically over a number of years, and then related to estimated ambient pollution concentrations in the cities in which they live. However, such cohort studies are expensive and time consuming to implement, due to the long-term follow up required for the cohort. Therefore, spatio-temporal ecological studies are also being used to estimate the long-term health effects of air pollution as they are easy to implement due to the routine availability of the required data. Spatio-temporal ecological studies estimate the health impact of air pollution by utilising geographical and temporal contrasts in air pollution and disease risk across $n$ contiguous small-areas, such as census tracts or electoral wards, for multiple time periods. The disease data are counts of the numbers of disease cases occurring in each areal unit and time period, and thus Poisson log-linear models are typically used for the analysis. The linear predictor includes pollutant concentrations and known confounders such as socio-economic deprivation. However, as the disease data typically contain residual spatial or spatio-temporal autocorrelation after the covariate effects have been accounted for, these known covariates are augmented by a set of random effects. One key problem in these studies is estimating spatially representative pollution concentrations in each areal which are typically estimated by applying Kriging to data from a sparse monitoring network, or by computing averages over modelled concentrations (grid level) from an atmospheric dispersion model. The aim of this thesis is to investigate the health effects of long-term exposure to Nitrogen Dioxide (NO2) and Particular matter (PM10) in mainland Scotland, UK. In order to have an initial impression about the air pollution health effects in mainland Scotland, chapter 3 presents a standard epidemiological study using a benchmark method. The remaining main chapters (4, 5, 6) cover the main methodological focus in this thesis which has been threefold: (i) how to better estimate pollution by developing a multivariate spatio-temporal fusion model that relates monitored and modelled pollution data over space, time and pollutant; (ii) how to simultaneously estimate the joint effects of multiple pollutants; and (iii) how to allow for the uncertainty in the estimated pollution concentrations when estimating their health effects. Specifically, chapters 4 and 5 are developed to achieve (i), while chapter 6 focuses on (ii) and (iii). In chapter 4, I propose an integrated model for estimating the long-term health effects of NO2, that fuses modelled and measured pollution data to provide improved predictions of areal level pollution concentrations and hence health effects. The air pollution fusion model proposed is a Bayesian space-time linear regression model for relating the measured concentrations to the modelled concentrations for a single pollutant, whilst allowing for additional covariate information such as site type (e.g. roadside, rural, etc) and temperature. However, it is known that some pollutants might be correlated because they may be generated by common processes or be driven by similar factors such as meteorology. The correlation between pollutants can help to predict one pollutant by borrowing strength from the others. Therefore, in chapter 5, I propose a multi-pollutant model which is a multivariate spatio-temporal fusion model that extends the single pollutant model in chapter 4, which relates monitored and modelled pollution data over space, time and pollutant to predict pollution across mainland Scotland. Considering that we are exposed to multiple pollutants simultaneously because the air we breathe contains a complex mixture of particle and gas phase pollutants, the health effects of exposure to multiple pollutants have been investigated in chapter 6. Therefore, this is a natural extension to the single pollutant health effects in chapter 4. Given NO2 and PM10 are highly correlated (multicollinearity issue) in my data, I first propose a temporally-varying linear model to regress one pollutant (e.g. NO2) against another (e.g. PM10) and then use the residuals in the disease model as well as PM10, thus investigating the health effects of exposure to both pollutants simultaneously. Another issue considered in chapter 6 is to allow for the uncertainty in the estimated pollution concentrations when estimating their health effects. There are in total four approaches being developed to adjust the exposure uncertainty. Finally, chapter 7 summarises the work contained within this thesis and discusses the implications for future research.

Pricing derivatives with stochastic volatility

This Ph.D. thesis contains 4 essays in mathematical finance with a focus on pricing Asian option (Chapter 4), pricing futures and futures option (Chapter 5 and Chapter 6) and time dependent volatility in futures option (Chapter 7). In Chapter 4, the applicability of the Albrecher et al.(2005)'s comonotonicity approach was investigated in the context of various benchmark models for equities and com- modities. Instead of classical Levy models as in Albrecher et al.(2005), the focus is the Heston stochastic volatility model, the constant elasticity of variance (CEV) model and the Schwartz (1997) two-factor model. It is shown that the method delivers rather tight upper bounds for the prices of Asian Options in these models and as a by-product delivers super-hedging strategies which can be easily implemented. In Chapter 5, two types of three-factor models were studied to give the value of com- modities futures contracts, which allow volatility to be stochastic. Both these two models have closed-form solutions for futures contracts price. However, it is shown that Model 2 is better than Model 1 theoretically and also performs very well empiri- cally. Moreover, Model 2 can easily be implemented in practice. In comparison to the Schwartz (1997) two-factor model, it is shown that Model 2 has its unique advantages; hence, it is also a good choice to price the value of commodity futures contracts. Fur- thermore, if these two models are used at the same time, a more accurate price for commodity futures contracts can be obtained in most situations. In Chapter 6, the applicability of the asymptotic approach developed in Fouque et al.(2000b) was investigated for pricing commodity futures options in a Schwartz (1997) multi-factor model, featuring both stochastic convenience yield and stochastic volatility. It is shown that the zero-order term in the expansion coincides with the Schwartz (1997) two-factor term, with averaged volatility, and an explicit expression for the first-order correction term is provided. With empirical data from the natural gas futures market, it is also demonstrated that a significantly better calibration can be achieved by using the correction term as compared to the standard Schwartz (1997) two-factor expression, at virtually no extra effort. In Chapter 7, a new pricing formula is derived for futures options in the Schwartz (1997) two-factor model with time dependent spot volatility. The pricing formula can also be used to find the result of the time dependent spot volatility with futures options prices in the market. Furthermore, the limitations of the method that is used to find the time dependent spot volatility will be explained, and it is also shown how to make sure of its accuracy.

Machine learning techniques for implicit interaction using mobile sensors

Interactions in mobile devices normally happen in an explicit manner, which means that they are initiated by the users. Yet, users are typically unaware that they also interact implicitly with their devices. For instance, our hand pose changes naturally when we type text messages. Whilst the touchscreen captures finger touches, hand movements during this interaction however are unused. If this implicit hand movement is observed, it can be used as additional information to support or to enhance the users’ text entry experience. This thesis investigates how implicit sensing can be used to improve existing, standard interaction technique qualities. In particular, this thesis looks into enhancing front-of-device interaction through back-of-device and hand movement implicit sensing. We propose the investigation through machine learning techniques. We look into problems on how sensor data via implicit sensing can be used to predict a certain aspect of an interaction. For instance, one of the questions that this thesis attempts to answer is whether hand movement during a touch targeting task correlates with the touch position. This is a complex relationship to understand but can be best explained through machine learning. Using machine learning as a tool, such correlation can be measured, quantified, understood and used to make predictions on future touch position. Furthermore, this thesis also evaluates the predictive power of the sensor data. We show this through a number of studies. In Chapter 5 we show that probabilistic modelling of sensor inputs and recorded touch locations can be used to predict the general area of future touches on touchscreen. In Chapter 7, using SVM classifiers, we show that data from implicit sensing from general mobile interactions is user-specific. This can be used to identify users implicitly. In Chapter 6, we also show that touch interaction errors can be detected from sensor data. In our experiment, we show that there are sufficient distinguishable patterns between normal interaction signals and signals that are strongly correlated with interaction error. In all studies, we show that performance gain can be achieved by combining sensor inputs.

Antiplatelet therapy and clinical outcomes in cardiovascular diseases

Cardiovascular diseases (CVD) is a leading cause of death in the world. Despite effective treatment regimens for ischaemic heart disease (IHD) and ischaemic stroke, mortality and recurrence rates remain high. Antiplatelet therapy is on effective treatment and reduces the risk of recurrent heart attack and stroke. Nevertheless, there are patients who stopped or interrupted their antiplatelet therapy for certain reasons or some patients may be resistant or poor responders to antiplatelet therapy. Furthermore, there is evidence of rebound effect in platelet activity after antiplatelet cessation and this may associate with increased risk of cardiovascular event. This thesis is divided into five main chapters (chapters 3 to 7) which attempt to provide data to help resolve the uncertainty. Chapter 1 highlights the background of cardiovascular diseases and the global burden of cardiovascular and cerebrovascular diseases. The metabolism of platelets, antiplatelet therapy and current antiplatelet therapy guidelines are described, followed by discussion of the risk of cardiovascular event and changes in antiplatelet therapy. Chapter 2 describes the data source from Virtual International Stroke Trial Archive (VISTA) and National Health Service Greater Glasgow and Clyde (NHSGGC) Safe Haven, followed by definition of outcome measures. In chapter 3, Virtual International Stroke Trial Archive (VISTA) data was examined to test whether continue with the same antiplatelet therapy or changing to a new antiplatelet regimen reduces the risk of subsequent events in patients who experience a stroke whilst taking antiplatelet therapy. The findings indicate that subjects who switch to a new antiplatelet regimen after stroke did not have a lower early recurrence rate than subjects who continued with the same antiplatelet therapy. Observations on bleeding complications were similar in both groups. However, changing antiplatelet regimen after stroke was associated with more favourable functional outcome across a full scale modified Rankin Scale (mRS) at 90 days. In chapter 4, association between early or later initiation of antiplatelet with a recurrent ischaemic stroke and bleeding complications was assessed using VISTA data. The findings indicate that there was no association between a recurrent ischaemic stroke and timing of initiation of antiplatelet drug after stroke. However, early initiation was associated with increased risk of bleeding. In terms of functional outcomes, this study demonstrated that the mid-time and late initiation of antiplatelet therapy after acute stroke are associated with better functional outcomes compared with early initiation. In chapter 5, a nested case-control study was performed to explore the rate of antiplatelet cessation and interruption in a sample of patients with recent ischaemic stroke and to assess the risk of cardiovascular events associated with cessation and interruption of antiplatelet. It was found that there was no increased risk of cardiovascular event among patients who had early cessation or interrupted/stopped antiplatelet therapy within 90 days following acute ischaemic stroke. In chapter 6, the incidence and predictors of cardiovascular events after DAPT cessation were evaluated. The incidence of cardiovascular event while taking DAPT and following discontinuation of DAPT was 15.7% and 16.7% respectively. This study found that increasing age was associated with an increased risk of cardiovascular event, whereas, revascularization-treated patients and longer duration of DAPT, were each associated with a decreased risk. The duration of DAPT six months and less was associated a significantly higher risk for cardiovascular event. In chapter 7, an untargeted metabolomics analysis was performed while on DAPT (aspirin plus ticagrelor) and once they stopped ticagrelor to identify metabolite changes associated with cardiovascular events after stopping DAPT. Ten ACS patients were recruited in this study and data were analysed for seven patients. Three hundred eleven putative metabolites were identified. This study found 16 putative metabolites significantly altered following ticagrelor cessation. Of these, seven metabolites were from lipid pathway and down-regulated some up to 3-fold. On the other hand, adenosine, from nucleotide metabolism was upregulated up to 2.6-fold. It concluded that there are changes in numerous pathways following DAPT discontinuation and whether these changes differ in patients who have cardiovascular event after stopping DAPT warrant further investigation. In chapter 8, a summary of the findings of this thesis are presented as well as the future directions of research in this area.

Molecular probes for monitoring mitochondrial movement and function

This thesis explores two distinct parts of mitochondrial physiology: the role of mitochondria in generation of reactive oxygen species (ROS) and mitochondrial morphology and dynamics within cells. The first area of research is covered in Chapters 1-8. Mitochondrial biofunctionality and ROS production are discussed in Chapter 1, followed by the strategy of targeting bioactive compounds to mitochondria by linking them to lipophilic triphenylphosphonium cations (TPP) (Chapter 2). ROS sensors relevant to the research are reviewed in Chapter 3. Chapter 4 presents design and synthesis of novel probes for superoxide detection in mitochondria (MitoNeo-D), cytosol (Neo-D) and extracellular environment (ExCellNeo-D). The results of biological validation of MitoNeo-D and Neo-D performed in the MRC MBU in Cambridge are presented in Chapter 5. A dicationic hydrogen peroxide sensor that utilizes in situ click chemistry is discussed in Chapter 6. Preliminary work on the synthesis of mitochondria-targeted superoxide generators, which led to the development of mitochondria-targeted analogue of paraquat, MitoPQ, is presented in Chapter 7. A set of bifunctional probes (BCN-Mal, BCN-E-BCN and Mito-iTag) for assessing the redox states of protein thiols is discussed in Chapter 8 along with their biological validation. The second part of the thesis is aimed at the study of mitochondrial morphology and dynamics and is presented in Chapters 9-11. Chapter 9 provides background on the classes of fluorophores relevant to the research, the phenomenon of fluorescence quenching and the principle of photoactivation with examples of photoactivatable fluorophores. Next, the background on mitochondrial morphology and heterogeneity is presented in Chapter 10, followed by the ways of imaging and tracking mitochondria within cells by conventional fluorophores and by photoactivatable fluorophores exploiting super-resolution microscopy. Chapter 11 presents the design and synthesis of four photoactivatable fluorophores for mitochondrial tracking, MitoPhotoRhod110, MitoPhotoNIR, Photo-E+, MitoPhoto-E+, along with results of biological validation of MitoPhotoNIR. The results and discussion concludes with Chapter 12, which is a summary and suggestions for future work, followed by the chemistry experimental procedures (Chapter 13), materials and methods for biological experiments (Chapter 14) and references.