VictorJuiz/thesis huggingface dataset:
Issues related to the economic analysis of genomic diagnostic technologies in the UK National Health Service: an exploration of methods
Keywords: Leukemia
Chronic lymphocytic leukemia
Genetics
Economics
Chronic lymphocytic leukaemia
Health economics
Leukaemia
National Health Service
Genomics

This thesis explores the empirical and methodological issues that arise when conducting economic analyses of genomic technologies in the UK National Health Service. The main focus of the thesis is the identification of the most appropriate economic evaluation approach to use in this context. Health economists are currently uncertain as to whether existing extra-welfarist approaches are sufficient to evaluate genomic technologies. Clarification is required because alternative methods, such as the welfarist approach, may lead to different adoption decisions, which will impact on population health.
The advantages and disadvantages of alternative approaches are demonstrated using a clinical case study: the use of genomic testing to guide treatment decisions in chronic lymphocytic leukaemia (CLL). Two forms of extra-welfarist economic evaluation are conducted – a cost-effectiveness analysis (CEA) and a cost-utility analysis (CUA) – along with a welfarist economic evaluation which took the form of a cost-benefit analysis (CBA), informed by a discrete choice experiment (DCE). These analyses consider several test-treatment strategies, reflecting different combinations of testing and the use of both existing therapies and new treatments such as ibrutinib. Information is also generated on patient preferences in this context, via the DCE, and the results of a survey are presented in which stakeholders are asked to consider which form of economic evaluation best captures the true costs and benefits of genomic testing in CLL.
The results of the CEA, CUA and CBA all indicate that the optimal strategy is to not adopt genomic testing in this context. The different approaches are then compared to assess their relative merits. The key finding – which is supported by the stakeholder survey – is that the extra-welfarist approach to economic evaluation is most appropriate when assessing genomic interventions. However, an evolution in methods is required to ensure that the results of these analyses provide decision-makers with sufficient information to facilitate the efficient allocation of scarce healthcare resources in this context.
Cyclic lateral loading of monopile foundations in cohesionless soils
Keywords: civil engineering
offshore foundations
1-g model test
monopile
plasticity
laboratory testing
constitutive modelling

The monopile is the dominant foundation type for offshore wind turbines, with current design guidance based on knowledge transferred from the oil and gas industry. Whilst there are some similarities between wind turbine and oil and gas pile design, there are also a number of key differences. Notably, offshore wind turbine monopiles are subjected to many cycles of large horizontal loads during their lifetime, whereas such loading conditions are not as prevalent in oil and gas design. As a result, the pile response due to this cyclic loading is poorly accounted for in current practice.
This thesis presents experimental and theoretical research, aimed at improving the understanding of the behaviour of rigid monopiles in cohesionless soils, when subjected to lateral cyclic loading. The experimental work involves laboratory floor model tests, scaled to represent a full-scale wind-turbine monopile. The test programme is designed to identify the key mechanisms driving pile response. It is divided into four main parts, investigating loading rate effect, hysteretic behaviour during unloading and reloading, as well as pile response to long-term single and multi-amplitude cyclic loads. In particular, the results show that the pile response conforms to the extended Masing rules, with permanent deformation accumulated during non-symmetric continuous cyclic loads. This ratcheting behaviour is characterised by two features: first, the ratcheting rate decreases with cycle number and depends on the cyclic load magnitude and secondly, the shape of the hysteresis loop tightens progressively, involving increased secant stiffness and decreased loop area. Tests investigating multi-amplitude loading scenarios prove that the interaction between these mechanisms describes the pile response. Finally, the continuous cyclic test results are interpreted using the p-y method combined with the Degradation Stiffness Model, and this shows a good fit to the observed pile deformation.
The key experimental findings are used for the development of a constitutive model that captures ratcheting while conforming to the observed Masing behaviour. The model, called HARM, is rigorous yet simple, and is framed within the hyperplasticity approach presented by Houlsby and Puzrin (2006). The model is tuned to capture the macro response of the pile under monotonic and cyclic loading, and is calibrated using the experimental data. The results demonstrate that HARM can successfully reproduce the main elements of the pile response with high accuracy. The method could easily be within common design approaches, such as the p-y method.
Performance limitations in practical transparent conducting oxide thin films
Keywords: Grain Boundaries
Materials
Thin Films
Semiconductor Doping
Chemistry
Transparent Conductive Oxides
Pyrolysis

Zinc oxide (ZnO) has long been advanced as a low cost, earth-abundant transparent conducting oxide (TCO) with potential as a replacement for high-performance, but costly, indium oxide (In2O3) based materials in a wide range of technological applications. However, despite decades of research and development efforts, ZnO-based materials have still failed to displace the incumbents in any large-scale applications.
Given the compelling materials cost advantages of ZnO, it is almost certain that its poor adoption is due to deficits in its technical performance. This thesis aims to fulfill the need for systematic, fundamental work to identify and examine the factors that limit TCO performance, and in particular, those that limit ZnO relative to In2O3.
Using spray pyrolysis as the primary deposition method, many different series of ZnO and In2O3 films have been prepared and examined using a range of chemical, structural, and optoelectronic characterization techniques. After essential background information on the basic physics and chemistry of TCOs, as well as a detailed discussion of the chosen deposition and characterization methods, three main classes of performance limitations will be covered: 1) those related to the intrinsic properties of electronic transport in crystalline TCO domains, 2) those arising in the course of impurity doping, and 3) those occurring due to grain boundary effects and the polycrystalline nature of thin film TCO samples.
Taken together, these results will show that preparing ZnO-based TCOs with performance approaching that of the best In2O3-based materials, while very likely to be technically possible, will almost certainly involve overcoming significant engineering and process development challenges that, importantly, are not required to make high quality In2O3. Ultimately, whether ZnO will ever find significant, real-world use as a TCO will depend on whether the deep differences between ZnO and In2O3 performance limits that will be highlighted and examined in this thesis can be bridged in a practical and cost-effective manner.
Integrated characterisation of carotid atherosclerosis - from magnetic resonance imaging to plaque macrophage profiling
Keywords: microarray
lipid
carotid
cholesterol efflux
atherosclerosis
nicotinic acid
MRI
macrophage
laser capture microdissection
GPR109A
transcriptomic
T2 mapping

Cardiovascular morbidity and mortality remain the most serious global public health challenge. With the evolution in global socio-economic activities and the associated lifestyle changes, there is an impending epidemic of obesity, insulin resistance, metabolic syndrome, and diabetes mellitus, all of which fuel premature coronary artery disease and stroke. In the post-statin era, despite considerable efforts in anti-atherosclerotic drug development, a significant number of these potential compounds with initial success in early phase clinical studies failed to translate to clinical outcome benefits. This shows a disparity of various biomarkers and molecular disease mechanisms, and highlighted the inadequacy of current methods of risk stratification and atherosclerosis characterisation.
Atherosclerosis imaging such as by MRI does not only serve as 'gate keepers' in the contemporary drug development process; but in combination with modern "omics", would allow precise disease stratification with resolution never achieved before. This integrated characterisation of atherosclerosis will generate novel insights about plaque biology, bridge the gap between molecular insights and clinical outcomes, and help achieve the goal of stratified, personalized, medicine.
This thesis hypothesized that plaque compositional heterogeneity such as lipid content is associated with specific gene expression profiles or signatures in human carotid plaque macrophages in a spatially distinct pattern; and that this macrophage functional heterogeneity may in turn play a role in altering response to anti-atherosclerotic treatment. To test these hypotheses, human subjects with carotid atherosclerosis were recruited before carotid surgery and scanned using novel MRI T2 mapping technique. Explanted carotid plaques were then examined by immunohistochemistry-guided laser capture microdissection and microarray analysis.
T2 mapping was shown to be able to accurately and reproducibly discriminate all major plaque components, and in particular, quantify plaque lipid content with excellent histological validation. Symptomatic plaques were shown to contain larger lipid-core by T2 mapping compared to asymptomatic plaques, despite similar degree of luminal stenosis. Macrophages from the same cohorts of plaques were procured by immunohistochemistry-guided laser capture microdissection and they were shown to display distinct gene expression profiles based on their micro-anatomical locations and clinical presentations; importantly, macrophages from plaques with high lipid content detected by T2 mapping were found to activate specific interferon / STAT1 pathways. Finally, using nicotinic acid as an example, the functional significance of plaque macrophage heterogeneity was shown in vitro to affect response to pharmacological intervention.
On the histochemical labelling and quantitative stereological assessment of synaptic puncta within the dorsal horn: with a focus on synaptic remodelling following a lesion to the peripheral nerve
Keywords: connectivity
immunohistochemistry
neuropathic pain
peripheral nerve injury
synapse
microglia
dorsal horn
deconvolution
stereology

Peripheral nerve injury often results in neuropathic pain, which is chronic, maladaptive, and hard to treat. Accompanying the injury to the peripheral nerve are a series of changes within the central nervous system. Understanding these changes and how they relate to the neuropathic condition is vital in driving evidence-based treatment strategies. Neuronal connectivity is widely believed to underlie many cognitive processes, and altered connectivity may underlie the development and maintenance of neuropathic pain. Here, a tractable method of analysing connectivity, via the histological marking and fluorescence imaging of synaptic puncta, was developed. This method utilised automated image processing methods, and developed a stereological filter for unbiased object measurement. Using this approach, different synaptic markers were analysed in the superficial dorsal horn of rodents, a key component in the reception and processing of somatosensory information. Analysing PSD95 and SynaptoPhysin fluorescent puncta in naive adult rodents revealed distinct puncta distributions in the dorsal horn, reflecting gross circuit formation throughout this region. Peripheral nerve lesion to aspects of the sciatic nerve of rodents resulted in a selective loss at 21 days post injury of PSD95 puncta from lamina II inner of the superficial dorsal horn, with Synaptophysin puncta remaining unchanged. These experiments were complemented by a transgenic approach, where eGFP was expressed exclusively and permanently in sensory neurons, which also revealed no loss of sensory neuron afferent input to the dorsal horn after nerve lesion up to 21 days post injury. Finally, the hypothesis that microglial cells may be driving this synapse loss was explored by treating animals with minocycline following peripheral nerve lesion, which did not interfere with the PSD95 puncta loss observed at 21 days post injury.
The role of A1-MGBv corticothalamic feedback explored with mistuning of harmonic complex tones using ferrets
Keywords: Auditory scene analysis
Complex sound
Go/no-go task
Ferret
Auditory thalamus
Corticothalamic feedback

The A1-MGBv corticothalamic projection is one of the major descending pathways in the auditory system, projecting from the primary auditory cortex (A1) to the ventral division of medial geniculate body (MGBv). Recent evidence suggests that corticothalamic feedback can sharpen the spectral receptive fields of thalamic neurons and modulate the temporal precision of the responses. The aim of the work presented here was to investigate the role of A1-MGBv corticothalamic feedback using harmonic and mistuned complex tones (HCTs and MCTs) in adult ferrets. The MCTs used comprised a mistuned harmonic shifted to a higher frequency in the otherwise HCTs. The harmonic structure of sounds is an important grouping cue in auditory scene analysis.
We first measured the ability of ferrets to detect mistuned harmonics using a go/no-go behavioural task paradigm. Psychometric functions plotting sensitivity as a function of degree of mistuning were used to evaluate the behavioural performance using signal detection theory. The threshold for mistuning detection was 0.8 ± 0.1 Hz (mean ± sem), with sensitivity indices and reaction times depending on the degree of mistuning. The threshold range for mistuning in ferrets is similar to that previously described in other species.
The responses to MCTs in MGBv neurons were explored using extracellular recordings in anaesthetised animals. The functional organization of the ferret auditory thalamus has not previously been investigated. The ferret MGBv was identified by the short response latency and the sharply tuned frequency response areas of the recorded units and by its tonotopic organization, which was found to be comparable to that of other species. Compared to their responses to HCTs, the firing rates of MGBv neurons were modulated depending on the degree of mistuning and the fundamental frequency of the MCTs. Distinctive temporal response patterns were also observed, phase locked to the periodicities of altered phases of the MCTs.
To investigate whether corticofugal modulation contributes to mistuning detection, A1-MGBv corticothalamic neurons were selectively eliminated bilaterally by chromophore-targeted laser photolysis. Using the behavioural paradigm established above, mistuning detection was tested before and after these lesions were made. Animals with corticothalamic lesions were impaired in their ability to detect a mistuned harmonic, as indicated by decreased d’ values, increased thresholds, and a shift of the psychometric curves towards higher mistuning values.
Together, these results suggest a possible role for corticothalamic feedback in modulating the firing patterns of MGBv neurons in ways that contribute to accurate recognition of complex auditory stimuli. In other words, this top-down corticothalamic feedback may be important for auditory scene analysis.
The duty of care: a comparative common law analysis
Keywords: duty of care
negligence

The general aim of this thesis is to provide a detailed overview of the duty of care enquiry, drawing on both academic analyses and judicial experience in leading common law systems. The thesis starts by exploring the history of the duty concept, including how it first came to be an element of the negligence enquiry, and how it later came to be determined via the use of a general formula. The thesis then explores and analyses the various methods through which the existence of a duty of care has been determined. Having provided an overview of the development of the duty concept, it is then argued that the duty of care is best understood as consisting of two discrete parts: a factual aspect and a notional aspect. It is suggested that the factual aspect of the duty enquiry is superfluous and should be abandoned so that the duty enquiry is a notional issue only. It is then argued that the notional aspect of the duty enquiry is best understood as consisting of two separate types of determinations: those relating to broad situations, and those based on assumptions of responsibility. Both of these types of notional duty determinations are explored in detail. The propriety of basing situational notional duty determinations on considerations of policy, and the necessity of notional duty, are also considered. Finally, the thesis provides an overview of an empirical study of ultimate appellate court duty decisions, investigating, among other things, whether the understanding of duty provided in the thesis is consistent with the practice of the courts.
The association between radiographic knee osteoarthritis and pain: an epidemiological analysis of a twenty-year community-based cohort
Keywords: Radiography
Pain
Knee Osteoarthritis
Epidemiology

Background: Knee osteoarthritis (OA) is one of the leading musculoskeletal burdens in the world, causing both structural damage and pain to the joint. Radiographs are the most common imaging method for diagnosing OA, however the relationship between radiographic changes (ROA) and symptoms is not well understood. This thesis will establish the natural history of twenty-year ROA, compare diagnostic methods of ROA assessment, evaluate the cross-sectional relationship between ROA and pain, and will determine the long-term predictive validity of features of ROA with future knee replacements (TKRs).
Methods: Data from the Chingford women's study, a twenty-year prospective UK-based cohort was used for the analysis. Risk factors included atlas-based ROA scoring methods and quantitative joint space width (JSW), which were analysed against pain and TKR outcome measures. A novel method for assessing joint space on low-contrast x-rays was developed which had high reproducibility and validity.
Results: The twenty-year natural history of ROA showed relatively low levels of annual incidence (3.8%), progression (3.6%), and worsening (4.5%), and emphasised the involvement of both medial and lateral osteophytes. Severe joint space narrowing (JSN) had the best construct validity with pain, while any size of lateral tibial osteophyte had good construct validity. Medial quantitative JSW had good construct validity, but no predictive validity with future TKRs. Lateral JSN and osteophytes had the best predictive validity for future TKR.
Conclusion: This research demonstrates that radiographic scoring methods have strong construct and predictive validity with symptomatic knee OA. These results support the use of x-rays to identify early disease changes which indicate future joint failure.
Electron microscopy and multi-scale modelling of radiation damage recovery in tungsten
Keywords: Dislocation dynamics
Transmission electron microscopy
Multi scale materials modelling
Molecular dynamics
Langevin dynamics

The thesis is concerned with understanding the recovery mechanisms of radiation damage in tungsten. Tungsten is a key material in next-generation fusion reactors such as ITER, which will be exposed to intense neutron radiation, plasma and high temperatures, and its durability will determine the reactor’s competitiveness versus other energy sources.
The thesis makes a comprehensive, quantitative study of recovery and its depen- dence on temperature, time, and material purity. It employs both experiments (ion-beam irradiation with ex and in situ analysis via transmission electron mi- croscopy) and multi-scale deterministic and stochastic modelling techniques such as molecular dynamics and dislocation dynamics.
Annealing experiments on ultra-pure tungsten reveal the presence of several re- covery stages, and an acceleration of dislocation defect recovery and loop coarsening above &Tilde;900°C. They also reveal discrepancies with dislocation climb models in the literature, suggesting the presence of additional recovery pathways leading to coars- ening, most notably conservative self-climb.
Presence of helium is found to cause an increase in the equilibrium concentration of defects at a given temperature. Also, very high doses cause morphological changes to the radiation damage structure, from relatively homogeneous defect concentra- tions of dislocations in a narrow size range, to complex dislocations networks with voids.
Finally, modelling techniques are able to successfully predict dislocation motion phenomena observed in experiments at high temperature (including quantitatively accurate defect densities), but only after extensive modification of publicly available dislocation dynamics codes to include boundary conditions and stochastic behaviour of crystal defects.
Comprehension strategies when listening to the teacher in the ESL classroom
Keywords: learner strategies

Listening comprehension strategies have been explored almost exclusively in uni-directional listening when learners are listening to audio recording. The lack of research on students' strategy use in understanding the teacher in the classroom is surprising, given how pervasive it is for students to listen to the teacher. In order to fill this research gap, this study explored the listening strategies adopted by learners in comprehending the teacher’s input in the English as a Second Language (ESL) classroom in Hong Kong (HK). A Likert-scale questionnaire was developed and administered to 867 HK Secondary 3 students, 646 of whom also completed two tests of linguistic knowledge (LK) – a receptive Vocabulary Levels Test (VLT) and a grammaticality judgement task (GJT). A sub-sample of 59 students then took part in an innovative computer tracking programme which simulated classroom learning and incorporated different types of teacher input while eliciting learners' strategy use targeted at these inputs. Lesson observation and stimulated recall interviews were also conducted to give insight into learners’ strategy use in an authentic lesson from a more qualitative point of view.
Findings suggested that there were some strategies which were specific to the context of listening to the teacher in the ESL classroom. Furthermore, while learners with low and high LK demonstrated some differences in their strategy use, there existed a sub-group of learners with low LK who were at least comparably strategic with learners with higher LK, providing some evidence that strategy use is not wholly dependent on levels of LK. Finally, findings also pointed to the importance of the type and difficulty of teacher input on learners’ strategy use. Implications for further research and pedagogy are discussed.