VictorJuiz/thesis huggingface dataset:
Subtree transfer operations on phylogenetic networks

Leaf-labelled, rooted binary trees can be used to represent a wide range of data. One way to measure the discrepancy between a pair of such trees, is to measure how many subtree transfer operations are required to transform one into the other. Four standard subtree transfer oper- ations for binary trees, used in particular for leaf-labelled binary trees, are: tree bisection and reconnection (TBR), subtree prune and regraft (rSPR), rooted subtree prune and regraft (rSPR) and nearest neighbour interchange (NNI). Each of these operations induces a metric over the class, B(n), of binary trees with leaves labelled from 0 to n−1. For a pair of trees in B(n), we investigate the maximum possible distance between them, as well as the typical distance if they were chosen randomly from some exchangeable distribution.
The TBR (and rSPR) distances between two trees are equivalent to the size of a minimal unrooted agreement forest (and minimal rooted agreement forest respectively) of the pair of trees. The notion of an agreement forest generalises to arbitrarily large sets of trees. For a fixed integer, k, we determine quite tight bounds on the worst-case size of an agreement forest for a set of k trees in B(n). We also estimate the expected size of a minimal agreement forest of k randomly chosen trees, each independently chosen from their own exchangeable distribution.
We then construct two network operations: the phylogeny subtree prune and regraft (pSPR) and the phylogeny nearest neighbour interchange (pNNI), which are generalisations of the rSPR and NNI operations, respectively. The pSPR and pNNI, which act over the class of phylogenies (phylogenetic networks with recombination), are both special cases of the edge-exchange (EEX) operation. We investigate the conditions under which it is possible to transform any phylogeny into any other phylogeny, and present some bounds on the number of operations required.
We also consider the extreme phylogenetic triple problem: For a given integer, n ≥ 3, what is the minimum size of a set of rooted binary trees, with leaves labelled 1 to n, such that every phylogenetic triplet, (a|bc), is satisfied by at least one tree in the set? We show that the answer to this question is Θ(log log n), by relating it to the nonbetweenness problem.
The final two chapters focus on two problems in communication network theory: the multiple unicast problem (the guessing game) and the information flow problem. For a fixed number of colours, s, we determine the guessing number of all large enough cycles, which answers a long-standing open question. We also provide a detailed constructive solution to the information flow problem on the full clock digraph, and on clock digraphs in general. These results solve two open problems, both had been conjectured 8 years ago.
Biostatistical and meta-research approaches to assess diagnostic test use

The aim of this thesis was to assess test use from primary care. Test use is an essential part of general practice, yet there is surprisingly little data exploring and quantifying its activity. My overarching hypothesis was that test use from primary care is sub-optimal, specifically that tests are overused (overtesting) - ordered when they will lead to no patient benefit, and underused (undertesting) - not ordered when they would lead to patient benefit. Previous metrics used to identify potential over and undertesting have been categorised into direct and indirect measures. Indirect measures take a population-level approach and are “unexpected variation” in healthcare resource use, such as geographical variation. Direct measures consider individual patient data and directly compare resource use with an appropriateness criterion (such as a guideline). In this thesis, I examined three indirect measures: temporal change in test use, between-practice variation in test use and variation between general practices in the proportion of test results that return an abnormal result. In chapter 3, I identified which tests have been subject to the greatest change in their use from 2000/1 to 2015/16 in UK primary care. In chapter 4, I identified the tests that had been subject to the greatest between-practice variation in their use in UK primary care. In chapter 5, I present a method to identify General Practices whose doctors order a lower proportion of tests that return a normal result. In chapter 6, I present a method to directly quantify over and undertesting; I conducted a systematic review of studies that measured the adherence of general practitioner’s test use with guidelines. In chapter 7 I acknowledge that the use of guidelines to audit general practitioner’s test use is flawed; guidelines are of varying quality and not designed to dictate clinical practice. In this chapter, I determine the quality and reporting of guidelines, the quality of the evidence underpinning their recommendations and explore the association between guideline quality and non-adherence. Overall, I have shown that most tests have increased substantially in use (MRI knee, vitamin D and MRI brain the most), there is marked between-practice variation in the use of many tests (drug monitoring, urine albumin and pelvic CT the most) and that some general practices order a significantly lower proportion of tests that return an abnormal result. I have also shown that there is marked variation in how often GPs follow guidelines, but guidelines based on highly quality evidence are adhered to significantly more frequently. Lastly, in my Discussion chapter, I discuss the implications of my thesis, how it fits into the wider literature and an idea for a proposed step-wise approach to systematically identify overtesting.

Keywords: Epidemiology
Big data
Primary Health Care
Meta-research
Overdiagnosis
Overtesting
Advisor: Heneghan, C
Perera, R
Aronson, J
Synthesis and reactivity studies of Group 5 imido and hydrazido complexes

This Thesis describes the synthesis and reactivity of Group 5 imido and hydrazido complexes with tridentate, trianionic ligands. Various synthetic routes towards these hydrazido compounds were explored and in which several intermediates were synthesised and their chemistry was explored. The reactivity of the imido and hydrazido complexes with unsaturated and other small molecules was also studied.
Chapter One provides a general introduction to tridentate pincer and tripodal ligands. The structure, synthesis and reactivity of Group 4 and 5 imido and hydrazido complexes is also reviewed.
Chapter Two describes three different synthetic routes towards tantalum hydrazido complexes with tridentate, trianionic ligands. Synthesis, characterization and bonding analysis of the precursor dichloride species Ta(NN2SiMe3)Cl2, which is used as starting material for two of the synthetic routes, is also described. The synthesis, characterization and bonding analysis of the tantalum dialkyl and alkyl-amido precursors prepared in the multistep route is also explored.
Chapter Three describes the synthesis and characterisation of Group 5 imido complexes with tridentate, trianionic ligands of the type Li3(NN2R) and Li3(NNNSiMe3). Reactivity studies of the imido complex Nb(NN2iPr)(NtBu)(py)2 with unsaturated and other small molecules are also explored.
Chapter Four describes the synthesis and characterisation of Group 5 hydrazido complexes with tridentate, trianionic ligands by two different synthetic routes, alongside a bonding analysis of the imido compounds M(NN2R)(NtBu)(py)2 and their hydrazido analogues M(NN2R)(NNPh2)(L)x. Reactivity studies of the hydrazido complex Nb(NN2iPr)(NNPh2)(py)2 with unsaturated and other small substrates are also described.
Chapter Five presents full experimental procedures and characterising data for the new methodologies and complexes reported in this Thesis.

Keywords: Tantalum complexes
Vanadium complexes
imido complexes
Niobium complexes
Group 5 chemistry
hydrazido complexes
Advisor: Mountford, P
Pulse oximetry in low-income settings: a case study of Kenyan hospitals

Pulse oximeters are low-cost, easy to use, and effective at detecting hypoxemia (low blood oxygen levels), a common complication of bronchiolitis, asthma, and pneumonia, the leading infectious cause of death in children worldwide. However, pulse oximeters are often unavailable in lowincome settings, and if available, often underused, yet little research investigates why.
In this thesis, I examine pulse oximeter implementation in low-income settings, focusing on Kenyan hospitals as a case study, and using a mixed-methods approach. I conducted a systematic literature review, examining how pulse oximeter use with children at admission to hospital impacts health outcomes; I then conducted quantitative analyses of 28,000 children admitted to seven Kenyan hospitals to determine with which children pulse oximeters are used, and pulse oximetry’s impact on treatment provision; these analyses informed the qualitative research component, for which I conducted interviews with 30 healthcare workers (HCWs) and staff in 14 Kenyan hospitals and employed theoretical frameworks to determine how HCWs decide whether to use pulse oximeters, and the barriers to pulse oximetry.
I found that pulse oximeter use varies substantially between and within Kenyan hospitals over time. After adjusting for case-mix and signs of illness severity, HCWs were most likely to use pulse oximeters with children with a very high respiratory rate, indrawing and/or who were not alert; children who obtained a pulse oximeter reading were more likely to be prescribed oxygen than if a pulse oximeter was not used; and children with a reading below 90% were more likely to be prescribed oxygen than those with higher readings, suggesting that HCW decision-making is influenced by international and national guidelines. However, HCWs sometimes cannot use pulse oximeters when they intend to, because of insufficient pulse oximeter availability, largely due to inefficient and confusing procurement processes and repair delays. Furthermore, HCWs sometimes use pulse oximeters incorrectly or misinterpret their results, because of insufficient training.
Pulse oximeter promotion programme planners can use the recommendations I provide to effectively target barriers to pulse oximeter uptake in low-income settings. Increased pulse oximetry implementation could enable early detection of hypoxemia, improving accurate diagnosis, and supporting prompt, effective treatment, which could help reduce mortality in children needing oxygen, in line with Sustainable Development Goal 3.

Keywords: Diffusion of innovation
Low-cost interventions
Hypoxemia
Mixed-methods
Oxygen
Implementation science
Pneumonia
Advisor: Shepperd, S
English, M
Ottoman painting and painters during the First World War

This study focuses on the Ottoman art world during the First World War and explores how the war changed the conditions of art production, its agents, and the art itself between 1914 and 1918, a topic that has remained peripheral to international cultural histories of the First World War and modern art more generally. In modern Turkish history and art history too, the art of the war years has either been overlooked―buried in the images of the Independence War that followed―or distorted for ideological purposes―emphasizing the militaristic and pro-war aspects of wartime artworks and marginalizing or excluding non-Muslim Ottoman artists from the story. This study details the diverse institutions, exhibitions, patrons, collectors, critics, and artists who made up wartime Ottoman art world, as well as the rich variety of visual images produced during the war years, from popular illustrations to easel paintings. During the war, like other belligerent governments, the Ottoman state and semi-official patriotic associations commissioned artists to produce war-related works for internal and international propaganda purposes and, as the war progressed, as a historical record of national endeavour. Whilst some Ottoman artists gained a more popular appeal via the propagandistic wartime mass culture, the current of ethnic Turkism which fed into this posed a major challenge to the empire’s well-established cosmopolitan artistic milieu. Above all, this study reconsiders the view that propaganda, jingoism, and militarism entirely dominated the cultural scene between 1914 and 1918, recovering how Ottoman artists’ paintings often figured the struggles of soldiers in battle and of civilians on the home front in ways that were, if not openly pacifistic, more complex and ambivalent than later mythmaking allowed. The thesis hopes to make original contributions to the history of modern Ottoman/Turkish art, the social history of the Ottoman home front, and the international cultural and art history of the First World War.

Advisor: Mignon, L
Assessment, trust, and cooperation in IT-security

This is a study of how IT-Security experts build trust and cooperate within and across organisations. The key research questions are 1) how do these specialists learn to trust others, and 2) why their preferences and strategies evolved the way they did.
Using qualitative interviews and quantitative network analysis, the project finds that in this microcosm of risk-aware specialists, cooperation is rational due to complexity and uncertainty, while social control mechanisms are overly costly. In order to ascertain who is trustworthy and skilled, IT-Security specialists take precautions and then screen and probe potential co-operators thoroughly by querying and triangulating multiple information sources. Experts believe that generally, trusting individuals is possible, while they tend not to trust organisations as such, due to their complexity, and their political and economic incentives. Thus, when having to rely on organisations, security experts combine bureaucratic means, like standard compliance and performing audits, with their preferred approach based on interpersonal trust, networks, and individual assessment.
Nevertheless, IT-Security experts efficiently manage assessment means and comprehensiveness. The in-depth network study of a security team finds that advice is given based on shared experience and nationality, while friendship nominations are value-driven: besides a strong tendency to not nominate anyone, the smaller group of those who see value in official certifications and education tend to nominate fewer friends, distinctly shunning those who consider these signals unimportant. This finding speaks to the growing institutionalisation and professionalisation of IT-Security caused by sector growth and state in- volvement. Most interviewees oppose this development, which is seen to water down security objectives.
This thesis is based on primary data: expert interviews with specialists from over 30 countries, and longitudinal network data from an IT-Security team. The interviews explore how trust and cooperation are established, while the network data are used to quantitatively investigate network evolution.

Advisor: Varese, F
Using metabolic medical imaging to model tumour growth and response to therapy

The number of cancer related deaths is predicted to reach over 13.1 million in 2030. Understanding the spatio-temporal evolution of tumours and their response to therapy is crucial to thwart this gloomy prognosis. Mathematical models have been used to elucidate the biological processes involved in tumour growth, but their complexity severely limits their clinical value. Eective models should base predictions on patient-specic data that can be obtained and tested in the clinic.
This thesis aims to develop novel clinically-relevant methodologies to model solid tumour growth and reaction to therapy. Models are developed that predict the macroscopic tumour evolution as a result of complex biological processes happening at the microscopic scale (such as cell proliferation, hypoxia, necrosis and oxygenation) while retaining simplicity in terms of the number of parameters that require calibration. This facilitates integration of medical imaging-derived tumour descriptor maps (e.g. for cellularity and nutrient availability) to initialise, calibrate and verify the models.
In addition to the models themselves, this thesis contributes to the literature by introducing novel frameworks to 1) derive maps of proliferative, hypoxic and necrotic cells using only Dynamic Contrast Enhanced Magnetic Resonance Imaging data; 2) apply these maps to constrain the models and obtain subject-specic predictions of tumour evolution; 3) account for tumour vascularisation, focusing on the angiogenesis-driven macroscopic changes observed longitudinally on medical imaging scans; and 4) produce a proof-of-concept updated model that could support medical decision in the treatment and management of cancer patients.
The results demonstrate the feasibility of using information derived from imaging data to quantify and predict subject-specic global and local tumour evolution and reaction to therapy. Experimentally validated comparison between model predictions and tumour imaging data obtained at later time points of the tumours' evolution show noticeable improvements in prediction accuracy, model complexity and clinical value over state-of-the-art methods. Nevertheless, additional imaging information on complementary aspects of tumour growth and response to therapy could render our models even more relevant to clinical practice.

Advisor: Chappell, M
Schnabel, J
On secure messaging

What formal guarantees should a secure messaging application provide? Do the most widely-used protocols provide them? Can we do better? In this thesis we answer these questions and with them give a formal study of modern secure messaging protocols, which encrypt the personal messages of billions of users.
We give definitions and analyses of two protocols: one existing (Signal) and one new (ART). For Signal, we begin by extending and generalising classic computational models, in order to apply them to its complex ratcheting key derivations. With a threat model in mind we also define a security property, capturing strong secrecy and authentication guarantees including a new one which we call "post-compromise security". We instantiate Signal as a protocol in our model, stating its security theorem and sketching a computational reduction.
Signal only supports encrypting messages between two devices, and so most implementers have built custom protocols on top of it to support group conversations. These protocols usually provide weaker security guarantees, and in particular usually do not have post-compromise security. We propose a new protocol called ART, whose goal is to bring Signal's strong security properties to conversations with multiple users and devices. We give a design rationale and a precise definition of ART, and again generalise existing computational models in order to formally specify its security properties and sketch a security reduction.
ART has enjoyed widespread interest from industry, and we aim to turn it into an open standard for secure messaging. To that end, we have brought it to the IETF and formed a working group called Messaging Layer Security, with representatives from academia as well as Facebook, Google, Twitter, Wire, Cisco and more. Through MLS, we hope to bring ART's strong guarantees to practical implementations across industry.
After concluding our analyses we pause for a moment, and start looking towards the future. We argue that for complex protocols like Signal and ART we are reaching the limits of computational methods, and that the future for their analysis lies with symbolic verification tools. To that end we return to the symbolic model and give a number of case studies, in each one showing how a traditional limitation of symbolic models can in fact be seen as a modelling artefact.

Keywords: protocol
cryptography
messaging
end-to-end encryption
security
Advisor: Cremers, C
Cancer imaging with fluciclovine (18F)

[18F]1-­amino-­3-­fluorocyclobutane 1-­carboxylic acid (18F-­fluciclovine) is a synthetic amino acid developed as a PET radiotracer for cancer imaging. Upon project commencement, 18F-­fluciclovine was in late phase of pharmaceutical development for recurrent prostate cancer imaging, requiring validation of clinical utility. Growing prospect in targeting of tumour metabolism in breast cancer treatment set the premise to investigate the role of amino acid imaging in this prevalent disease. The aims of this project were to: (1) establish the transport mechanisms of fluciclovine in breast cancer;; (2) explore the utility of fluciclovine in early assessment of response to treatments of related metabolic and biological targets;; (3) run a clinical study to investigate how 18F-­fluciclovine uptake can be used to characterise breast cancer biology;; and (4) run a multicentre clinical trial to investigate the impact of 18F-­fluciclovine imaging on clinical management of men with recurrent prostate cancer. Fluciclovine transport in breast cancer was found to be predominantly mediated by the high-­affinity glutamine transporter ASCT2. Increased fluciclovine uptake was demonstrated in cell lines sensitive to glutaminase inhibition with CB-­839 (known to result in build-­up of intra-­cellular glutamine);; and the opposite with bithionol and metformin which are known to reduce intra-­cellular glutamine. These results were recapitulated in animal models, and collectively raise the potential for fluciclovine to be used as an imaging biomarker of glutamine pool, in addition to early response assessment in therapies augmenting glutamine metabolism. The FRONTIER study was established to investigate how 18F-­fluciclovine can be used to characterise breast cancer biology and is ongoing. Initial data demonstrate a trend of highest uptake in triple-­receptor negative, followed by ER+ then HER2+ tumours, complementing in vitro data. The FALCON multicentre trial investigated the impact of 18F-­fluciclovine imaging on clinical management of recurrent prostate cancer. In the 32-­patient Oxford cohort, 44% of patients had their intended management plan revised following 18F-­fluciclovine PET/CT. Initial short term follow-­up data demonstrate a higher proportion of short-­term responders to 18F-­fluciclovine guided radiotherapy (71%, 5/7) compared to standard radiotherapy (53%, 8/15). This encouraging trend will require ratification with trial-­wide data. Across the trial, interim analysis found management was revised post-­scan in 52/85 (61%) patients, exceeding a pre-­ set criteria for overwhelming effectiveness (45/85), leading to early closure.

Advisor: Harris, A
Gleeson, F