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.

Effects of modality, urgency and situation on responses to multimodal warnings for drivers

Signifying road-related events with warnings can be highly beneficial, especially when imminent attention is needed. This thesis describes how modality, urgency and situation can influence driver responses to multimodal displays used as warnings. These displays utilise all combinations of audio, visual and tactile modalities, reflecting different urgency levels. In this way, a new rich set of cues is designed, conveying information multimodally, to enhance reactions during driving, which is a highly visual task. The importance of the signified events to driving is reflected in the warnings, and safety-critical or non-critical situations are communicated through the cues. Novel warning designs are considered, using both abstract displays, with no semantic association to the signified event, and language-based ones, using speech. These two cue designs are compared, to discover their strengths and weaknesses as car alerts. The situations in which the new cues are delivered are varied, by simulating both critical and non-critical events and both manual and autonomous car scenarios. A novel set of guidelines for using multimodal driver displays is finally provided, considering the modalities utilised, the urgency signified, and the situation simulated.

Are we all castrati? Venanzio Rauzzini: ‘The father of a new style in English singing’

Though the castrato has been absent from the operatic stage since the nineteenth century, this voice is often described as the mysterious link in understanding the vocal techniques attributed to bel canto. The mystery lies in the fact that the voice of the operatic castrato cannot be heard by modern ears; and yet its legacy can be seen in the vocal tuition of several successful opera singers at the turn of the nineteenth century. What is unusual about this period is that some of the most successful singers of the day, including Nancy Storace, John Braham and Elizabeth Billington were British and shared the same vocal teacher. The castrato Venanzio Rauzzini (1746-1810) began his career as a primo uomo on the continent and while he established himself in various areas of musical activity, his main contribution and legacy was as a vocal teacher. During his residency in Britain from 1774 until his death, he trained several leading British professional singers who were the stars of opera in London and on the continent. They each demonstrated a use of techniques associated with the castrato vocal aesthetic and popularised a new vocal style, which can be traced to Rauzzini. Through this thesis, I will draw attention to the importance of Rauzzini’s impact on vocal teaching practice in Britain and his wider influence on the development of vocal style. I will demonstrate that Rauzzini should be considered part of the vocal teaching canon to which Pier Francesco Tosi (c.1653-1732), Nicola Porpora (1686-1768) and Manual García II (1805-1906), three other foreign vocal teachers, who were resident in Britain, already belong. By examining exactly what the expected vocal aesthetics were for all singers, castrato, non-castrated male and female during the period in which Rauzzini was active, I will demystify the castrato technique and provide a more tangible understanding of what this encompassed, demonstrating that many of these techniques were learned, performed and popularised by other voice types such as the female soprano and the male tenor.

'Expanding Horizons': investigating the Glasgow 2014 legacy for young people in the East End of Glasgow

The recent staging of Glasgow 2014 drew universal praise as the ‘Best Games Ever’. Yet the substantial undertaking of hosting the Commonwealth Games (CWG) was sold to the nation as more than just eleven days of sporting spectacle and cultural entertainment. Indeed, the primary strategic justification offered by policymakers and city leaders was the delivery of a bundle of positive and enduring benefits, so-called ‘legacy’. This ubiquitous and amorphous concept has evolved over time to become the central focus of contemporary hosting bids, reflecting a general public policy shift towards using major sporting mega events as a catalyst to generate benefits across economic, environmental and social dimensions, on a scale intended to be truly transformative. At the same time, the academy has drawn attention to the absence of evidence in support of the prevailing legacy rhetoric and raised a number of sociological concerns, not least the socially unequitable distribution of purported benefits. This study investigated how young people living in the core hosting zone related to, and were impacted upon, by the CWG and its associated developments and activities with reference to their socio-spatial horizons, the primary outcome of interest. An ‘ideal world’ Logic Model hypothesised that four mechanisms, identified from official legacy documents and social theories, would alter young people’s subjective readings of the world by virtue of broadening their social networks, extending their spatial boundaries and altering their mind sets. A qualitative methodology facilitated the gathering of situated and contextualised accounts of young people’s attitudes, perceptions, beliefs and behaviours relating to Glasgow 2014. In-depth interviews and focus groups were conducted before and after the Games with 26 young people, aged 14-16 years, at two schools in the East End. This approach was instrumental in privileging the interests of people ‘on the ground’ over those of city-wide and national stakeholders. The findings showed that young people perceived the dominant legacy benefit to be an improved reputation and image for Glasgow and the East End. Primary beneficiaries were identified by them as those with vested business interests e.g. retailers, restaurateurs, and hoteliers, as well as national and local government, with low expectations of personal dividends or ‘trickle down’ benefits. Support for Glasgow 2014 did not necessarily translate into individual engagement with the various cultural and sporting activities leading up to the CWG, including the event itself. The study found that young people who engaged most were those who had the ability to ‘read’ the opportunities available to them and who had the social, cultural and economic capital necessary to grasp them, with the corollary that those who might have gained most were the least likely to have engaged with the CWG. Doubts articulated by research participants about the social sustainability of Glasgow 2014 underscored inherent tensions between the short-lived thrill of the spectacle and the anticipated longevity of its impacts. The headline message is that hosting sporting mega events might not be an effective means of delivering social change. Aspirant host cities should consider more socially equitable alternatives to sporting mega events prior to bidding; and future host cities should endeavour to engage more purposefully with more young people over longer time frames.