Quasispecies dynamics and treatment outcome during early hepatitis C infection in a cohort of HIV-infected men

Hepatitis C virus (HCV) is emerging as one of the leading causes of morbidity and mortality in individuals infected with HIV and has overtaken AIDS-defining illnesses as a cause of death in HIV patient populations who have access to highly active antiretroviral therapy. For many years, the clonal analysis was the reference method for investigating viral diversity. In this thesis, a next generation sequencing (NGS) approach was developed using 454 pyrosequencing and Illumina-based technology. A sequencing pipeline was developed using two different NGS approaches, nested PCR, and metagenomics. The pipeline was used to study the viral populations in the sera of HCV-infected patients from a unique cohort of 160 HIV-positive patients with early HCV infection. These pipelines resulted in an improved understanding of HCV quasispecies dynamics, especially regarding studying response to treatment. Low viral diversity at baseline correlated with sustained virological response (SVR) while high viral diversity at baseline was associated with treatment failure. The emergence of new viral strains following treatment failure was most commonly associated with emerging dominance of pre-existing minority variants rather than re-infection. In the new era of direct-acting antivirals, next generation sequencing technologies are the most promising tool for identifying minority variants present in the HCV quasispecies populations at baseline. In this cohort, several mutations conferring resistance were detected in genotype 1a treatment-naïve patients. Further research into the impact of baseline HCV variants on SVR rates should be carried out in this population. A clearer understanding of the properties of viral quasispecies would enable clinicians to make improved treatment choices for their patients.

A study of ignorance: suffering and freedom in early Buddhist teachings and parallels in modern neuroscience

What might early Buddhist teachings offer neuroscience and how might neuroscience inform contemporary Buddhism? Both early Buddhist teachings and cognitive neuroscience suggest that the conditioning of our cognitive apparatus and brain plays a role in agency that may be either efficacious or non-efficacious. Both consider internal time to play a central role in the efficacy of agency. Buddhism offers an approach that promises to increase the efficacy of agency. This approach is found in five early Buddhist teachings that are re-interpreted here with a view to explaining how they might be understood as a dynamic basis for ‘participatory will’ in the context of existing free will debates and the neuroscientific work of Patrick Haggard (et al.). These perspectives offer Buddhism and neuroscience a basis for informing each other as the shared themes of: (1) cognition is dynamic and complex/aggregate based, (2) being dynamic, cognition lacks a fixed basis of efficacy, and (3) efficacy of cognition may be achieved by an understanding of the concept of dynamic: as harmony and efficiency and by means of Buddha-warranted processes that involve internal time.

Reconsidering the relationship between early Gothic literature and the Greek classics: the cases of William Beckford and Matthew G. Lewis

The view that Gothic literature emerged as a reaction against the prominence of the Greek classics, and that, as a result, it bears no trace of their influence, is a commonplace in Gothic studies. This thesis re-examines this view, arguing that the Gothic and the Classical were not in opposition to one another, and that Greek tragic poetry and myth should be counted among the literary sources that inspired early Gothic writers. The discussion is organised in three parts. Part I focuses on evidence which suggests that the Gothic and the Hellenic were closely associated in the minds of several British literati both on a political and aesthetic level. As is shown, the coincidence of the Hellenic with the Gothic revival in the second half of the eighteenth century inspired them not only to trace common ground between the Greek and Gothic traditions, but also to look at Greek tragic poetry and myth through Gothic eyes, bringing to light an unruly, ‘Dionysian’ world that suited their taste. The particulars of this coincidence, which has not thus far been discussed in Gothic studies, as well as evidence which suggests that several early Gothic writers were influenced by Greek tragedy and myth, open up new avenues for research on the thematic and aesthetic heterogeneity of early Gothic literature. Parts II and III set out to explore this new ground and to support the main argument of this thesis by examining the influence of Greek tragic poetry and myth on the works of two early Gothic novelists and, in many ways, shapers of the genre, William Beckford and Matthew Gregory Lewis. Part II focuses on William Beckford’s Vathek and its indebtedness to Euripides’s Bacchae, and Part III on Matthew Gregory Lewis’s The Monk and its indebtedness to Sophocles’s Oedipus Tyrannus. As is discussed, Beckford and Lewis participated actively in both the Gothic and Hellenic revivals, producing highly imaginative works that blended material from the British and Greek literary traditions.

An investigation into the utility of the Mini Addenbrooke's Cognitive Examination (M-ACE) for the early detection of dementia and mild cognitive impairment in people aged 75 and over

Background/Aims: The Mini Addenbrooke’s Cognitive Examination (M-ACE) is the abbreviated version of the widely-used Addenbrooke’s Cognitive Examination (ACE-III), a cognitive screening tool that is used internationally in the assessment of mild cognitive impairment (MCI) and dementia. The objectives of this study were to investigate the diagnostic accuracy of the M-ACE with individuals aged 75 and over to distinguish between those who do and do not have a dementia or MCI, and also to establish whether the cut-off scores recommended by Hsieh et al. (2014) [9] in the original validation study for the M-ACE are optimal for this age group. Methods: The M-ACE was administered to 58 participants (24 with a diagnosis of dementia, 17 with a diagnosis of MCI and 17 healthy controls). The extent to which scores distinguished between groups (dementia, MCI or no diagnosis) was explored using receiver operating characteristic curve analysis. Results: The optimal cut-off for detecting dementia was ≤ 21/30 (score ≤ 21/30 indicating dementia with a sensitivity of 0.95, a specificity of 1 and a positive predictive value of 1) compared to the original higher published cut-off of ≤ 25/30 (sensitivity of 0.95, specificity of 0.70 and a positive predictive value of 0.82 in this sample). Conclusions: The M-ACE has excellent diagnostic accuracy for the detection of dementia in a UK clinical sample. It may be necessary to consider lower cut-offs than those given in the original validation study.

The difference of Being in the early modern world: a relational-material approach to life in Scotland in the period of the witch trials

This thesis investigates how ways of being in different ontologies emerge from material and embodied practice. This general concern is explored through the particular case study of Scotland in the period of the witch trials (the 16th and 17th centuries C.E.). The field of early modern Scottish witchcraft studies has been active and dynamic over the past 15 years but its prioritisation of what people said over what they did leaves a clear gap for a situated and relational approach focusing upon materiality. Such an approach requires a move away from the Cartesian dichotomies of modern ontology to recognise past beliefs as real to those who experienced them, coconstitutive of embodiment and of the material worlds people inhabited. In theory, method and practice, this demands a different way of exploring past worlds to avoid flattening strange data. To this end, the study incorporates narratives and ‘disruptions’ – unique engagements with Contemporary Art which facilitate understanding by enabling the temporary suspension of disbelief. The methodology is iterative, tacking between material and written sources in order to better understand the heterogeneous assemblages of early modern (counter-) witchcraft. Previously separate areas of discourse are (re-)constituted into alternative ontic categories of newly-parallel materials. New interpretations of things, places, bodies and personhoods emerge, raising questions about early modern experiences of the world. Three thematic chapters explore different sets of collaborative agencies as they entwine into new things, co-fabricating a very different world. Moving between witch trial accounts, healing wells, infant burial grounds, animals, discipline artefacts and charms, the boundaries of all prove highly permeable. People, cloth and place bleed into one another through contact; trees and water emerge as powerful agents of magical-place-making; and people and animals meet to become single, hybrid-persons spread over two bodies. Life and death consistently emerge as protracted processes with the capacity to overlap and occur simultaneously in problematic ways. The research presented in this thesis establishes a new way of looking at the nature of Being as experienced by early modern Scots. This provides a foundation for further studies, which can draw in other materials not explored here such as communion wares and metal charms. Comparison with other early modern Western societies may also prove fruitful. Furthermore, the methodology may be suitable for application to other interdisciplinary projects incorporating historical and material evidence.