VictorJuiz/thesis huggingface dataset:
The cardiovascular toxicity of antimalarial drugs

Malaria is an ancient mosquito-borne parasitic disease from which over a thousand – mostly children in sub-Saharan Africa – still die of needlessly every day. For half a millennium, quinine and quinine-like antimalarial drugs have been the mainstay of malaria treatment and prevention. In the 18th century, the chance observation of their ability to quell palpitations led to their becoming the first anti-arrhythmic agents. Some of these anti-arrhythmic antimalarials later came to define the adverse drug reaction of repolarisation-related cardiotoxicity as sudden deaths, ventricular tachyarrhythmias, and electrocardiographic QT interval prolongation were in turn causally associated with their use. With increasing population-level use of antimalarials for malaria elimination, there has been renewed global interest in defining the cardiovascular toxicity of key members of this drug class to guide antimalarial choice and dosage for development and deployment.
In this thesis, I investigate the repolarisation-related cardiotoxicity of the quinoline and structurally-related oral antimalarials mostly widely used in malaria treatment, prevention, and drug development. In Chapter 3, I find that the risk of sudden unexplained death after dihydroartemisinin-piperaquine, a leading candidate for mass drug administration and intermittent preventive therapy for malaria, is no higher than baseline. In Chapter 4, I report how torsade de pointes and other clinically significant arrhythmias have not been documented after front-line antimalarials at standard malaria doses despite extensive use. In Chapter 5, I identify independent effects of malaria severity and fever on the QT interval accounting for the greater post-drug prolongation in malaria patients compared to healthy individuals. In Chapter 6, I present the QT interval prolongation and heart rate reduction from artesunate-amodiaquine compared with other front-line antimalarials and propose bradycardia may underlie amodiaquine-associated asthenia.
I conclude that chloroquine, piperaquine, amodiaquine, and lumefantrine remain safe at World Health Organization-recommended doses and combinations for the treatment, prevention, and global eradication of malaria.

Keywords: Severe malaria
Seasonal malaria chemoprevention
Uncomplicated malaria
Artemisinin-based combination therapy
Vivax
Falciparum
Mass drug administration
Case management
4-aminoquinolines
Intermittent preventive treatment
Advisor: White, NJ
‘Care going public’ in the familialist welfare regime? ideas and politics of Taiwan’s elder-care reform

East Asian familialist welfare regimes have experienced major elder-care reforms over the last two decades under socio-economic and political pressures. This raises questions regarding the policy continuity and change of the familialist trajectories and its explanations. Adopting too narrow a focus on policy change, and viewing it as an automatic response to functional and political pressures, or as a static trajectory of the existing cultural and institutional legacies, the existing East Asian welfare state literature has found it difficult to understand the dynamics and outcomes of these rapid policy reforms. This thesis addresses these questions by undertaking a case study of Taiwan’s elder-care reform between 2004 and 2016, based on an analysis of documents from governmental and non-governmental sources and in-depth interviews with high-profile government officials, legislators, and representatives of advocacy groups. By developing a comprehensive framework based on the concept of defamilialisation, which covers the major policy domains of elder care, including legal caring obligations, care services and provision, cash benefits, and care leave, this thesis demonstrates that Taiwan’s elder-care reform involves a high degree of policy continuity with the familialist trajectory. This policy continuity results from the interaction between policy ideas and political agency operated differently in two distinct periods of reform. Calling for stronger public responsibility for elder care, policy actors promote diverging reform ideas, which involves different treatments of the defamilialisation of care responsibility and the formalisation of informal care labour. Strategic policy actors are not only able to bring forward new policy ideas through power imbalance among actors (policy ideas of powerful political actors), but, in a different setting, they can also resist policy change through the exercise of the ideational ambiguity of ‘care going public’ (policy ideas empowering political actors). Examining the interplay between ideas and politics in Taiwan’s elder-care reform, this thesis furthers the understanding of East Asian social policy development by moving beyond the conventional functionalist, democratisation, and cultural theses, and also enriches general analyses of the transformation of social care and policy change.

Keywords: East Asia
politics of social policy
older people
ideas and social policy
familialist welfare regime
elder-care reform
long-term care
Taiwan
public welfare
Advisor: Daly, M
Salvation through science alone: the soteriological potential of science in case studies of Ursula Goodenough, Sam Harris, and E.O. Wilson

Traditional religion has collapsed in the West, at least according to many theorists of the modern religious landscape such as Charles Taylor. This has led to a diversification of what Lois Lee has identified as existential cultures—tropes and communities that address the questions, frailties, and limitations of human life. Mary Midgley’s work on the culture of science has demonstrated that science is one such existential culture. Taking Midgley’s lead, this thesis explores the soteriological potential of science insofar as it has the ability to remediate existential anxiety, meaning that it can facilitate a transition from negative affect to neutral or positive affect regarding the embodied limitations of human life. This requires three moves that comprise part I of the thesis: 1) the responsible deployment of evolutionary theory and cognitive science in the humanities, 2) a robust understanding of the material power of affectivity, and 3) an exploration of salvation as a “religion-like thing” that is not specific to religious doctrine but rather is an affective, phenomenological potentiality inherent to subjects across traditional religious-secular divides. Part II entails three case studies: biologist Ursula Goodenough, who is saved from the thought of death by interpreting the germ-soma distinction of multicellular organisms, popular philosopher Sam Harris, who is saved by the ability science has to disambiguate questions of morality, spiritual belief, and spiritual practice, and zoologist E.O. Wilson, who is saved by the ways in which science helps him develop a more intimate relationship with nature as his sacred home. Identifying science as salvific for these thinkers provides a means by which to theorise about experience beyond traditional religious-secular bounds and demonstrates the affective power inherent to science not just as a discipline but also as a salvific cultural phenomenon.

Keywords: Lisa Sideris
Ursula Goodenough
science studies
theory of religion
soteriology
Sam Harris
evolutionary epic
E.O. Wilson
affect theory
religion and science
new atheism
religious naturalism
Advisor: Schaefer, D
Bishop Leofric and the Exeter Cathedral Chapter, 1050-1072 : a reassessment of the manuscript evidence

Few eleventh-century English bishops can be studied in detail owing to a lack of evidence, but Bishop Leofric is an exception. Although conventional historical sources yield little, a detailed picture of Leofric's personality, interests and relationship with his Chapter and diocese can be built up from his obituary notice (Oxford, Bodleian Library, MS Bodley 579, fol. 3-3Y), the list of his donations to his cathedral (Exeter, Dean and Chapter, MS 3501, fols 1-2.) and especially from a codicological and palaeographical study of the manuscripts and charters which were either written at Exeter during his episcopate or given by him to his cathedral church.
Because the use of this type of manuscript evidence is unusual, a detailed study had to be made of all the manuscripts to which an Exeter origin had been ascribed to build up a picture of the scriptorium at work. The 'Exeter' style, whose existence was already recognised, was defined in detail along with a consideration of its English models.
Exeter was revealed as a centre where English and continental influences mingled. As William of Malmesbury said, Leofric was trained in Lotharingia, and at a time when the Gregorian reform movement was beginning there. Leofric moved his diocesan seat from rural Crediton to urban Exeter and set up a Chapter of celibate secular canons following the Rule of Chrodegang. Leofric and the canons worked together to build up the material and spiritual (books and relics) endowments of the cathedral church, partly to prepare themselves for pastoral work amongst the laity, to which the Rule enjoined both bishop and canons. Leofric (and probably other Lotharingian bishops appointed by the Confessor) anticipated by some twenty years many of the ecclesiastical reforms propagated by Lanfranc.

Keywords: Catholic
bishop
English
manuscript
Church
chapter
manuscripts
diocese
Leofric
Advisor: Parkes, M
Daniel Purcell : a biography and thematic catalogue

Daniel Purcell (c.1670-1717) was a musician, composer, socialite and punster. He was a child in the choir of the Chapel Royal, organist at Magdalen College, Oxford, and composer-in-residence at the Theatre Royal in Drury Lane. His output was prolific, consisting of music for some fifty plays, as well as many anthems, cantatas, songs, odes, and instrumental sonatas.
Of Daniel’s works, it is probably the theatre music which is most of interest, ranging from single songs for sometimes ill-fated productions to whole ‘Purcellian’ dramatick operas such as The Island Princess (Motteux, 1699), and The Grove, or Love’s Paradise (Oldmixon, 1700). His cantatas ‘after the Italian Manner’ (1713) were some of the first examples of their style in the English language, and, whilst he held no official appointment, his composition of odes for Princess (later Queen) Anne, and various other members of the Royal family, show his close connections with court life.
This study is in two parts. First, a thorough biographical study uncovers a number of documents which shed much light on Daniel Purcell’s life, and reopens the debate of the genealogy of the whole Purcell family. The London theatrical scene after the death of Henry Purcell is examined in detail, and Daniel’s compositions are placed in their historical perspective. Second, a comprehensive thematic catalogue of his works includes multi-stave incipits for each movement of each piece which Daniel wrote, listing every printed and manuscript source in which the music is found. This catalogue is intended to be a starting point for scholars wishing to study the music of this period in general, and of Daniel Purcell in particular.

Keywords: thematic
Purcell
catalogue
Daniel
catalog
catalogues
biography
catalogs
Advisor: Burden, M
Transnational Networks and Intellectual Authority in Islam in Europe: The Case of Mohammed Arkoun, Nasr Hamid Abu Zayd, and Abdolkarim Soroush

This thesis explores the socio-political mechanisms that shaped the authority of three Muslim thinkers – Mohammed Arkoun, Nasr Hamid Abu Zayd and Abdolkarim Soroush – in the European-Anglophone intellectual field between 1989 and 2010. Specifically, it investigates the role of transnational networks of individuals and institutions in the intellectual legitimation of these three thinkers. Moving beyond existing literature that focuses on their intellectual contributions, this research situates their discourses within a specific socio-political context. Relying on government papers, newsletters, interviews, bibliometric data, as well as academic and journalistic publications by and about them, the study maps and investigates the modus operandi of their networks. For this purpose, it engages and expands on Pierre Bourdieu’s notion of social capital (resources embedded in an individuals’ network) and field theory, to explore how ‘power’ operates among different fields of interaction to shape their ‘legitimacy’.
In unpacking the process of intellectual legitimation, this study identifies three interacting elements: 1) the socio-political context concerning the domestic and global emergence of Islam, and the polarisation of attitudes towards Muslims which renewed interest on authoritative ‘moderate’ voices speaking for Islam; 2) their identities and ideas, which reflected this demand for specific profiles – Muslim organic voices positioned between academia and the public sphere, engaging with a synthesis of Islam and modernity, democracy, and human rights; 3) their social capital, in the form of networks of actors they engaged with: these functioned as the infrastructure through which knowledge and resources were mobilised and ultimately converted into symbolic capital, leading to their intellectual legitimacy. The nodes of these networks, this study argues, promoted their ideas and facilitated their access to resources and institutions. The conversion of this social capital into symbolic capital, and therefore legitimacy, was conditioned not only by the internal dynamics of each field they engaged but also the power relations across the fields through which they migrated (such as Middle Eastern vs European academia or academia vs the public sphere). While this thesis accounts for the socio-political dimension of these thinkers’ emergence, it also addresses their agency in negotiating their position within different fields.

Keywords: Muslim intellectuals
Knowledge production
Intellectual authority
Advisor: Katouzian, H
Herzig, E
Novel techniques to study cardiopulmonary physiology in a preclinical, saline-lavage model of the acute respiratory distress syndrome

The acute respiratory distress syndrome (ARDS) affects 24.4% of all patients requiring mechanical ventilation and has an associated mortality of up to 46%. The complex pathophysiology of the cardiopulmonary system is difficult to study, particularly in the critically ill patient. Pre-clinical models of ARDS afford the possibility to investigate this complex physiology, which allows increased understanding of that physiology and the potential to develop tools which could be translated to clinical practice. This thesis presents experimental studies of two novel techniques to study cardiopulmonary physiology in a mechanically ventilated porcine saline-lavage model of ARDS.
Using fluorescence quenching real-time measurement of PaO2 and dynamic computed tomography (CT), the cyclical recruitment/derecruitment of atelectasis (CA) is demonstrated and the previously accepted hypothesis that CA is the main determinant of cyclical oscillations in PaO2 is challenged. Real-time changes in PaO2 over the course of breath-hold manoeuvres are used to estimate the effective lung volume (ELV). PaO2 measured ELV is compared against ELV measured using whole lung CT scans. The PaO2 model follows the expected linear relationship with CT volumes and is able to track changes in lung volume with good concordance.
The Inspired Sinewave Technique (IST) is a non-invasive technique which can provide measurements of ELV and cardiac output (Q˙). IST’s measurements of ELV compare well to those made with SF6 washout and CT. IST’s ability to track PEEP-induced changes in ELV shows excellent concordance with both SF6 and CT. Comparing IST’s measurements of Q˙ against those made with intermittent pulmonary artery thermodilution (PATD), IST tracks changes in Q˙ well in the uninjured animal model. Agreement between Q˙ measurements taken with IST and PATD show less agreement in the injured animal model.
The presented results support translational research into both real-time PaO2 measurement and IST. Both techniques have the potential to provide bedside monitoring of important physiologcial parameters in mechanically ventilated patients.

Advisor: Farmery, A
Formenti, F
Perceptual decision making, and the construction of confidence

Perceptual decisions are of fundamental interest, and it is increasingly recognised that a sense of confidence supports decision-making. The drift diffusion model (DDM), provides an excellent account of decisions and response times. It also features the optimal property of tracking the difference in evidence between two options. However, the DDM struggles to account for human confidence reports. Possibly because of this, much confidence research has used non-normative models of the decision mechanism. Motivated by the idea that perceptual decision-making will reflect optimal computation, we consider 10 variants of the DDM. Motivated by the idea that the brain will not duplicate the representation of evidence, in all model variants confidence is read out from the decision mechanism.
We compare the models to benchmark findings and make 3 qualitative predictions that we verify in a preregistered study. We develop new computationally cheap predictions for confidence in DDM accounts. Using these predictions we model confidence on a trial-by-trial basis, finding that a subset of model variants provide an excellent account of the precise quantitative effects observed. Specifically, models in which confidence reflects a miscalibrated Bayesian readout perform best. Focusing on the idea of a Bayesian readout, we explore the claim that evidence associated with a selected option is overweighted in confidence. Although this idea appears to challenge Bayesian confidence, we do not find this overweighting in three previously collected datasets, and we suggest an explanation for previous results. Finally, we examine whether the DDM remains normative in settings where rapid learning is more important than the theoretical possibility of achieving maximal reward rate.
These results support the claim that confidence is based on the decision mechanism, which is itself optimal. In particular, the DDM with a miscalibrated Bayesian readout is supported on both theoretical and empirical grounds.

Keywords: Confidence
DDM
Bayesian
Perceptual decisions
Advisor: Yeung, N
Bogacz, R
Julian of Norwich: a phenomenology of health and home

The thesis offers a new reading of the Julian of Norwich texts using a theoretical framework based on post-Heideggerian philosophy, specifically the phenomenological hermeneutics of health and medicine. By redirecting attention to the complex network of phenomena which constitute the visionary text, it argues for a consideration of the relationship between contemplation and wellbeing, proposing spiritual seeking as a means to being ‘wele’. Engaging recently developed phenomenological models based on Heidegger’s concept of ‘homelikeness’ (Heimlichkeit), the thesis redefines health as a holistic condition not solely confined to full physiological function, but of phenomenological ‘being-at-home’, or ‘homlyhede’, in Julian’s terms. In doing so, it considers the impact of Julian’s illness on her being-in-the-world, arguing for the ensuing disruption of Julian’s subjectivity as a precedent for the divine showings which follow. It subsequently proposes an interpretation of Julian’s near-fatal illness and revelation as contingent phenomena constituting a single lived experience, which brings forth the anchorite’s highly original theology of love. Following this event, Julian devises a participatory model of salvation which offers the possibility of ‘homlyhede’ on earth, as well as in heaven. Through a close reading of this vernacular theology, the thesis offers the Julian texts as an instructive and tranfigurative tool for developing personal and communal wellbeing. Focusing particularly on Julian’s language of homeliness, it demonstrates the efficacy of this concept as a metaphor for understanding the salvation narrative and issues of postlapsarian living, including pain and tribulation. Finally, it calls attention to the insufficiencies of modern thinking and vocabulary related to these issues, insisting upon the continued relevance of the genre of medieval contemplative literature to present day concerns. It concludes with an invitation to participate in the communal project of Julian’s Revelation of Love, through a compassionate programme of reading and contemplative seeking.

Keywords: philosophy of theology
medieval
Heidegger
medieval literature
philosophy
philosophy of health
medieval mysticism
devotional literature
religious literature
Julian of Norwich
Middle Ages
theology
14th century
Advisor: Gillespie, V
Exploiting replication stress induced by IGF blockade in cancer therapy

In recent work from our group, we found that genetic or pharmacological inhibition of type 1 insulin-like growth factor receptor (IGF-1R) promotes accumulation of cells in S phase and causes endogenous DNA damage by inducing replication stress. Blocking IGF signalling reduces expression of the regulatory subunit M2 of ribonucleotide reductase (RRM2) and disturbs deoxynucleotide triphosphate (dNTP) supply. The aim of my project is to develop approaches to exploit this effect in therapy. Therefore, with the objective of enhancing replication stress induced by IGF blockade to intolerable levels, a compound screen was conducted in combination with an IGF neutralising antibody drug that is currently being evaluated in clinical trials. Five breast cancer cell lines were screened; top hits include inhibitors of EGFR/HER2, ATM, PARP, RAD51, and CHK1. Low throughput validation focused on inhibition of checkpoint kinase CHK1, which has been reported to induce replication stress through downregulating RRM2. Co-inhibition of IGF and CHK1 significantly suppressed cell viability and cell survival in both 2D cell culture and 3D spheroid culture models. In IGF-1R depleted or inhibited cells, inhibition of CHK1 further downregulated RRM2, reduced dNTP supplies and delayed replication fork progression. Combining IGF blockade with CHK1 inhibition led to accumulation of DNA damage and single-stranded DNA (ssDNA), a replication stress marker, and significant increase in cell death, suggesting replication catastrophe. Exogenous RRM2 expression rescued these replication stress phenotypes, indicating a mechanism in which RRM2 regulation is a critical target of the interaction between IGF blockade and CHK1. Final experiments confirmed that the replication stress was also exacerbated by co-inhibiting IGFs and WEE1, which was a screen hit in one of the five cell lines and had also been reported to regulate RRM2 expression. Combining WEE1 inhibition and IGF-1R depletion induced RRM2 downregulation, delayed replication fork progression, and caused accumulation of DNA damage and ssDNA, resulting in cell death. These results may help to identify novel therapeutic vulnerabilities and provide guidance for future clinical trials of IGF inhibitory drugs.

Keywords: Replication stress
Breast cancer
WEE1
IGF
Cell cycle checkpoint
CHK1
Advisor: Rieunier, G
Macaulay, V