VictorJuiz/thesis huggingface dataset:
Assessment of prognostic models for patients with acute pulmonary embolism

Background: Acute pulmonary embolism (PE) is a life-threatening condition. This thesis presents my research into the role of prognostic models and strategies for assessing the severity of acute PE, how these compare with recommendations in clinical guidelines and the role of physician’s clinical judgment for improving patient management.
Methods: Methods used in each element in the research were appropriate to the relevant objectives: systematic reviews for assessing prognostic markers and prognostic models; sensitivity analysis using the net benefit decision-analytic measure across a range of threshold values for low-risk PE categories in direct comparisons; survey of clinical practice; development and assessment of a case-ascertainment strategy to detect PE patients in one hospital and to explore selection bias; and development of a study protocol for a future comparative study.
Findings: Individual prognostic markers are insufficient on their own to accurately predict outcome. Prognostic models are more successful, with the PE severity index (PESI) and simplified PESI (sPESI) models being the most validated. They provided a low event rate in patients identified as low-risk, which was similar to that obtained with other, less validated, strategies, such as the Hestia hospital checklist. High-risk groups were best identified using PESI or other models at high cut-off levels or by adding clinical vital signs, biomarkers and imaging-based markers of right ventricular dysfunction/ myocardial ischemia. The net benefit analysis confirmed the superiority of PESI and sPESI over original competing models, and the incremental value of adding prognostic markers. The survey showed that emergency physicians still rely mostly on their own clinical judgment when deciding about early discharge or complete outpatient management and the case-ascertainment study showed that if case-ascertainment is incomplete, selection bias may mean that event rates and prognosis will be underestimated, prognostic models will be overoptimistic and the results of different studies cannot be compared, contrasted or combined reliably.
Conclusions: Based on current evidence, the PESI models are the most appropriate strategies for deciding on early discharge and outpatient management for patients presenting to hospital with acute PE. Future research, with complete case-ascertainment, needs to compare these models with Hestia and clinical judgement to assess their value for decisions about the management of non-selected PE patients.

Keywords: Cohort
Management
Prognosis
Prediction
Pulmonary embolism
Model
Validation
Impact
Index
Update
Severity
Course
Score
Derivation
Advisor: Clarke, M
Mismetti, P
Long term behaviour of spatial population models with heterozygous or asymmetric homozygous selection

We investigate the long term behaviour of two models for the spatial distribution of alleles in a diploid population, one with asymmetric selection in favour of the homozygotes, and one with selection in favour of the heterozygote.
We model the population with asymmetric homozygous selection using a version of the spatial Λ-Fleming-Viot process. We identify three regimes. For very small values of the asymmetry, the limiting behaviour of the process is the same as for the case with symmetric selection. This case was studied in Etheridge, Freeman and Penington (2017), and they showed, under certain rescaling and initial conditions, that the hybrid zone, the interface between two homogeneous regions of each homozygote, evolves according to mean curvature flow. However, for larger, but not that much larger, values of asymmetry, we show a new behaviour, that the hybrid zone evolves according to a different type of flow, which we call constant curvature flow. Furthermore, there is a strength of asymmetry for which elements of both types of curvature flow are present in the limit. This suggests that the behaviour found in Etheridge, Freeman and Penington (2017) is more sensitive to perturbations than first thought.
We then go on to investigate the fluctuations of this process about its limit. To do this, we specialise to the one-dimensional case. We show that, when time, space and the strength of the asymmetry are appropriately rescaled, the hybrid zone, which is a single point in one dimension, evolves according to a Brownian motion, with drift proportional to the asymmetry.
Finally, we turn to the model with heterozygous selection. We restrict ourselves to two dimensions, and investigate this process through its dual, the branching annihilating random walk. We show that, up to an arbitrary time, and with arbitrarily high probability, there exists a branching rate such that we may couple a branching annihilating random walk to a ternary branching Brownian motion. While interesting in its own right, this result lends support to a conjecture of Blath, Etheridge and Meredith (2007), that a branching annihilating random walk in two dimensions has a positive probability of survival for all time for any positive branching rate.

Keywords: Allen-Cahn Equation
population genetics
Delayed ternary-branching annihilating random walk
Spatial population model
Advisor: Etheridge, A
Spatial stochastic modelling of biological processes

Computational simulation of cellular processes can provide us with important insights into the dynamics of a cell. In particular, stochastic simulation has proven to be an invaluable tool for modelling sub-cellular environments, due to the intrinsic noise of not knowing when reactions will occur in a cell and which molecules will react. This uncertainty is amplified when there are limited numbers of molecules within a cell, as the probability of reactions occurring becomes small.
One aspect of cellular dynamics that is often overlooked in stochastic models is the effect of spatial constraints on the behaviour of a cell. Cellular processes depend not only on the number of molecules present, but also on the distribution of these molecules within the cell and how they move and interact with each other. For this reason, we hypothesised that spatial stochastic simulations of cells would prove to be more effective at recreating experimentally observed cells than spatially-averaged models. To begin testing this hypothesis, we create and compare spatially-dependent models against spatially-averaged models for three biological processes. The first two processes we study involve post-transcriptional gene regulation by small RNAs. An overarching theme across each biological process that we have studied in this thesis is the implication in tumourigenesis. We present examples in which stochasticity and spatial detail detail can produce different modelling results when compared with non-spatial models. We also show that, in many cases, the biological systems we have chosen to model behave somewhat deterministically. We have shown that there are threshold values for certain parameters, for example, molecular concentrations, at which the systems largely follow the dynamics of the deterministic models.
Gene expression is also inherently stochastic; low numbers of genes, proteins and mRNAs are found within many cells, and many genes are controlled by probabilistic interactions between these molecules. In particular, if some molecular species are scarce then the likelihood of these molecules finding a binding partner becomes probabilistic. Therefore, stochastic modelling is an appropriate technique for studying this biological process. In this thesis, we study cellular signalling processes as stochastic processes. Specifically, we built a stochastic model of the canonical Wnt/Beta-catenin signalling pathway and compared this with existing deterministic models. We present here some preliminary results and a proof-of-concept stochastic. An obvious path for further investigation would be to expand on this model by including cell-cell adhesion and movement of molecules between cellular compartments in a crowded environment.

Advisor: Byrne, H
Burrage, K
An investigation of T cell immunity and the HIV reservoir during primary HIV infection: implications for cure strategies

This work focuses on aspects of T cell immunity during the early stages of human immunodeficiency virus (HIV) infection, termed primary infection. Individuals who commence antiretroviral therapy (ART) during primary infection may have preserved immune function, making them a target group for curative strategies. The efficacy of HIV cure interventions are assessed by stopping ART and measuring how long it takes until plasma viraemia recurs. Here, the normal dynamics of this viral rebound in treated and untreated primary infection were characterised, showing that transient control of viral replication is not uncommon at this time. The prospect of HIV cure is heavily reliant on an immune response to eliminate the virus - but such responses become rapidly dysfunctional. During primary infection, changes in T cell activation, memory distribution and the expression of immune checkpoint receptors (which are associated with a type of T cell dysfunction termed exhaustion) occurred. Not all of the demonstrated perturbations in these had normalised following a year of ART which is started during primary infection. This work then turns to the HIV reservoir itself; this is the pool of cells in which the virus persists during long-term therapy and which is the barrier to HIV cure. A longitudinal analysis showed that the size of this reservoir is determined during primary infection where it is linked with aspects of the T cell response measured above. A final chapter shows that CD32, a proposed marker of the reservoir, does not appear to mark cells that comprise the reservoir as specifically as originally reported. Overall this work highlights some of the barriers to current HIV cure strategies and contributes to a body of knowledge which may in the future inform rational design of targeted therapeutic interventions.

Keywords: Primary HIV infection
Immune checkpoint receptors
Post-treatment control
Advisor: Frater, J
Willberg, C
Modelling secondary cancer risk from photon and proton therapy in medulloblastoma

More than half of cancer patients receive radiotherapy for radical or palliative purposes. Increasing survival rates in cancer patients makes it important to study long-term side effects, especially secondary cancers. Medulloblastoma (MB), a posterior fossa tumour, predominantly a childhood disease, is an example of a clinical scenario where proton therapy could have significant advantages. It is therefore used as an exemplar in this thesis to investigate the relationship between malignant induction probability (MIP) and secondary cancer risk in 3D conformal photon therapy (3DCRT) and actively scanned proton therapy by using MATLAB-based code, models, relevant parameters and input values from voxel-by-voxel dose maps.
In this thesis, work started by modelling MIP for different treatment plans to assess the relative MIP values. MIP for different modalities was investigated whilst explicitly incorporating the uncertainty in the model parameters in the modelling process. Results showed that proton therapy is less likely to induce malignancy when compared to 3DCRT (p-value &LT; 0.05). To be able to compare our results with published absolute secondary cancer risk estimates and across patients, model parameters were calibrated and benchmarked, and absolute risk values were calculated. This thesis also addresses, in part, some of the other uncertainties that affect secondary cancer modelling. The effect of spatial dose averaging on predicting MIP was studied by modelling risk using mean, and voxel-by-voxel dose. The effect of changes in radiobiological effectiveness (RBE) on modelling MIP was also studied.
This work showed that independent of the model chosen, and independent of the uncertainty in parameters, proton therapy is less likely to induce malignancy and cause secondary cancer than 3DCRT in patients with medulloblastoma. It was also shown that models used could be benchmarked and calibrated against published models, enabling the calculation of clinically realistic absolute secondary cancer risk estimates. The use of mean dose was shown to introduce a systematic error in regions of high dose inhomogeneity in comparison to the voxel-by-voxel method, making use of the high resolution voxel-by-voxel MIP calculation a necessary step in decreasing uncertainty in modelling outcomes. The work also demonstrated that using an RBE of 1.1 could lead to errors in the range of 5%, leading to potentially higher NTCP or lower local control, which is in agreement with what published literature suggests.

Keywords: Proton therapy
Medulloblastoma
Radiation therapy
Radiotherapy
Secondary cancer
Uncertainty testing
Advisor: Partridge, M
Timlin, C
Vallis, K
Hill, M
Van Den Heuvel, F
Late Stage 18F-Fluorination and 123I-Iodination for PET and SPECT Imaging

This thesis consists of the development and application of novel radiochemical transformations for both Positron Emission Tomography (PET) and Single Photon Emission Computered Tomography (SPECT). A general introduction is presented in Chapter I and covers PET, the production of fluorine-18 and the current state-of-the-art for 18F-radiolabelling. Chapter IV provides a brief overview of SPECT, production of radionuclides in SPECT and the current state-of-the-art.
The results chapters consist of three different approaches for the development and application of novel radiochemical transformations within PET or SPECT imaging. Chapter II discusses the application of the copper mediated nucleophilic 18F-fluorination of aryl pinacol boronic esters to the radiofluorination of [18F]olaparib. Subsequently, the imaging of DNA damage in pancreatic adenocarcinoma cell lines is examined. Chapter III discusses the synthesis of the novel 18F-trifluoromethylation reagent, [18F]-5-(trifluoromethyl)dibenzothiophenium trifluoromethanesulfonate and its application to the 18F-trifluoromethylation of unmodified peptides. Chapter IV is comprised of the development of the copper mediated 123I-Iodination of aryl boron reagents and its application to four clinically relevant SPECT tracers.
Finally, Chapter V provides experimental data for compounds discussed within this thesis.

Advisor: Gouverneur, V
Modelling solidification of binary alloys

Solidification processes are crucial for many industrial applications, and understanding these processes is important if one wants to improve various material production techniques. The dynamics of some solidification processes can be modelled using Stefan problems, a type of free boundary problem. The aim of this dissertation is to study different aspects of the extended Stefan problem for the solidification of binary alloys with a special interest in the manufacturing of metallurgical grade silicon. First, we derive the extended Stefan problem in an arbitrary n-dimensional domain from basic physical principles, and from this we derive more specific models for different geometries of interest. Then, we perform a linear stability analysis for the exact self-similar solutions that can be found in the semi-infinite and infinite one-dimensional planar geometries. Introducing self-similar perturbations, we find that the solutions to both problems are unstable regardless of the parameter choice, and that the instability that arises is driven by the moving boundary. Having understood the relevant dynamics in unbounded domains, we next direct our attention to the extended Stefan problem in finite domains, which are of greater relevance to realistic applications. We first consider a one-dimensional finite planar geometry. In order to obtain analytical solutions we use the method of matched asymptotic analysis in the large Lewis number limit. The analysis requires us to consider ten different layers, spread over four different time regimes. We find good agreement with numerical simulations calculated using a fixed boundary method, and with experimental data from the cast of metallurgical grade silicon performed by our industrial sponsor, Elkem. Finally, we study the three-dimensional spherically symmetric geometry, in order to model the inward solidification of a binary alloy taking the form of a sphere. To determine the asymptotic solutions, we consider the large Lewis number limit and the small Stefan number limit. We distinguish several layers, and we notice qualitative differences between the spherical and planar geometries. To validate the asymptotic results, we compare them with numerical simulations, finding good agreement.

Keywords: Binary alloys
Stefan problem
Mathematical modelling
Solidification
Asymptotic analysis
Advisor: Please, C
Van Gorder, R
From cat to dog: Investigating organisation in the infant lexicon

Do infants learn their early words in isolation? Or do they integrate new words into an inter-connected semantic system? Between the ages of one and two, infants develop a prodigious word-learning ability (P. Bloom, 2002; Fenson et al., 1994; Hamilton et al., 2000). Little is known, however, about how and when infants integrate their accumulating word-knowledge into an adult-like lexical network – one sensitive to relationships such as association and semantic category organisation.
For adults, context has a strong effect on the ease and speed of linguistic processing, and on behavioural responses to language. In lexical priming studies, both visual and auditory context are known to influence the speed of lexical processing (Antos, 1979; Meyer & Schvaneveldt, 1971; Radeau, 1983) and ambiguity resolution (Swinney, 1979), as well as guide predictive looks to contextually relevant areas of a complex scene (Huettig & McQueen, 2007; Kamide et al., 2001). And while priming studies have been conducted with children (Betjemann & Keenan, 2008; Duncan & Kellas, 1983; Hartfield & Conture, 2006; Hashimoto et al., 2007; McCauley et al., 1976; Nation & Snowling, 1999; Radeau, 1983; Schvaneveldt et al., 1977) and toddlers (Krackow & Gordon, 1998), the currently available methods are not applicable below the age of three.
This thesis presents a body of research which combines two experimental paradigms into a single new method which allows investigation of relationships within the developing infant lexicon. Over a series of experiments, this thesis develops a version of the infant-friendly Inter-modal Preferential Looking (IPL) task within the lexical priming paradigm. The method combines fine-grained temporal sensitivity with an intuitive, infant-friendly task. Priming effects were observed during lexical access for children two years-of-age and older, providing a promising new direction for investigations into the development of semantic organisation during development.

Keywords: Child Language Acquisition
Lexical access
Lexical Priming
Word Comprehension
Semantic Networks
Toddlers
Eye gaze
Advisor: Plunkett, K
Theory and practice of shortcut fusion

There are a number of approaches for eliminating intermediate data structures in functional programs by rewriting a composition of recursive functions as a single recursive function. Such a transformation is called fusion. One such approach is to encapsulate a structured recursion scheme in two combinators for consumption and production of data, and use algebraic transformations to rewrite these where possible, letting local compiler optimisations fuse the remaining nonrecursive portions of the program. This approach is called shortcut fusion, which has been implemented using various recursion schemes in the programming language Haskell. Despite their obvious similarities, however, the relationship between these techniques has not been formalised.
In this thesis, three techniques, chosen for their success in practical applications and prominence in previous literature, are analysed. Their relationship is examined on three different levels: theory, practice, and pragmatics. Theoretically, the relationship between their underlying recursion schemes is examined. In the right setting, it is possible to compare them side-by-side, which makes clearer their differences in expressibility as well as the foundations for their correctness. On the practical level, the similarities in their implementations in Haskell can be generalised using the concept of data abstraction, and a general semantic framework is developed for shortcut fusion without reference to a specific recursion scheme. Finally, the pragmatics of these techniques are investigated, and it turns out that the these, too, are not dependent on the specific technique used.
The results from this analysis demonstrate that shortcut fusion is actually a single program transformation, defined by a general semantic framework that can be instantiated for a variety of recursion schemes. Furthermore, it is possible to use this information to create a declarative infrastructure for implementing shortcut fusion within a compiler. This results in a more robust program transformation that is less complicated to implement than before.

Keywords: natural transformation
compiler optimisation
fusion
haskell
proof obligation
Advisor: Hinze, R
Search for heavy ZZ resonances in the llvv channel using proton-proton collisions at s = 13 TeV with the ATLAS detector at the LHC

This thesis provides a description of the search for new resonances in event signatures consisting of two Z bosons, where one Z boson decays to a opposite-sign same-flavour lepton pair ll (l = electron or muon), while the other Z boson decays to neutrinos which are experimentally quantified by a large missing transverse momentum. The description of the search includes the analysis selection criteria, the background estimation and the exclusion limits on the production of new physics. The analysis is divided into two signal regions, based on the resonant production mode i.e. gluon-gluon fusion or vector boson fusion. The result of the H->ZZ->llvv search is combined with the result from the H->ZZ->4l analysis to arrive at better constrains of heavy Higgs boson production and to set exclusion limits on two higgs doublet models. Additionally, upper limits are derived for spin-2 Kaluza-Klein graviton resonances for masses between 600 GeV and 2 TeV in the context of the Randall-Sundrum model. The analysis search uses data gathered from proton-proton collisions at a center-of-mass energy of 13 TeV, corresponding to a total integrated luminosity of 36.1 fb-1 collected by the ATLAS detector during the 2015+2016 data runs at the Large Hadron Collider. No statistically significant excess over the background prediction is found in the 2015+2016 data.

Advisor: Bortoletto, D