Delirium is an acute neuropsychiatric syndrome commonly affecting older people in general hospital. Dementia is common in older people in hospital with a distinct phenotype. Delirium and dementia commonly co-exist and are associated with adverse outcomes. The aims of the thesis were to developed pragmatic methods to screen for dementia in patients with delirium and to examine the outcomes of people with delirium. A prospective cohort study of older people admitted to hospital with delirium was carried out. Cognitive impairment was common among older people with delirium, with 3 in five having dementia and 1 in 5 having unrecognized dementia. Previously published dementia screening tools are scarce and not valid in people with delirium. Informant tools (the IQCODE and AD8) are highly sensitive and specific to detect dementia and combined cognitive impairment (MCI or dementia) in delirium. Delirium duration, severity, the hypoactive subtype and dysregulated inflammation were predictors of adverse outcomes in older people with delirium. This thesis confirms the close relationship between delirium and dementia in general hospitals. It offers pragmatic solutions to both screening for dementia in older people with delirium, and improving follow-up by detailing predictions of adverse outcome.

China is an emerging force in undertaking randomised clinical trials. The quality of trials from China may affect not only its own substantial population but also potentially contribute to health policy throughout the world. However, little is known about the quality of clinical trials conducted there. In this thesis, I will evaluate the quality of published Chinese randomised controlled trials (RCTs) by comparing them with Indian RCTs as well as a set of ‘gold standard’ trials reported in leading European and North American journals. I will also describe and contrast the quality and biases within Chinese RCTs. I then explore the reasons for these differences from the point of view of the major RCT stakeholders: Chinese clinicians and patients. The potential influences from Chinese traditional culture is also evaluated. Chinese medical journal editors need to undertake more training on the reporting of RCTs; all medical societies should take more concern about doctors’ research work; the Chinese public media should help the general population to understand more about RCT principles.

This PhD submission focuses on issues arising from the recent expansion of medical education in England, including widening access to medicine. It presents 11 papers published over the last 9 years which are the product of academic collaborations with colleagues and students at the University of Birmingham. The work includes outputs from local and national evaluations that have examined the expansion policy, process, and outcomes. Three research themes are identified from this body of papers; the first around predicted and observed impacts of expansion policy at local and national levels; the second concentrating on students’ and clinical teachers’ experiences of education amidst expanding provision; and finally issues relevant to widening access to medicine policy. The findings complement and add to existing knowledge in these research areas and give the basis to draw overarching conclusions about the significance of recent policy shifts for policy makers, medical schools, educators and students. In turn this work allows us to identify the need for further lines of enquiry and argues for a broad approach and conceptualisation for medical education research that is able to track macro policy changes, through meso level organisational and institutional influences, to micro level experience of educational policy and delivery.

The aim of this thesis is to help the RM industry avoid misguidedly investing in technologies that are unlikely to be cost-effective and reimbursed by healthcare providers. Health economics provides the tools to demonstrate value for money. These tools are typically used by healthcare providers to drive demand side decisions. However, they can be used by manufacturers to inform the supply side. I propose a simple approach, termed the headroom method. This ‘back of the envelope’ calculation is based on estimates of effectiveness of the proposed treatment towards the upper end of the plausible range. The method can be used either to inform an intuitive decision to continue or abandon development, or as a screening test to decide if more elaborate models are justified. One problem I encountered was the development of technologies without clearly defining the clinical problem. In particular, the marginal gain in benefit over alternative treatments is frequently overlooked. A large part of this thesis is therefore concerned with the clinical epidemiology of the conditions at which treatment is targeted. In this way, it was found, for example, the headroom for health gain from new treatment for inguinal hernia was much smaller than that for incisional hernias.

Computational toxicology is an emerging, multidisciplinary field that uses in-silico modelling techniques to predict and understand how biological organisms interact with pollutants and environmental stressors. Genome-wide metabolic reconstruction (GWMR) is an in-silico modelling technique that aims to represent the metabolic capabilities of an organism. Daphnia is an emerging model species for environmental omics whose underlying biology is still being uncovered. Creating a metabolic reconstruction of Daphnia and applying it in an environmental computational toxicology setting has the potential to aid in understanding its interaction with environmental stressors. Here, the fist GWMR of D. magna is presented, which is built using METRONOME, a newly developed tool for automated GWMR of new genome sequences. Active module identification allows for omics data sets to be integrated into in-silico models and uses optimisation algorithms to find hot-spots within networks that represent areas that are significantly impacted based on a toxicogenomic transcriptomics dataset. Here, a method that uses the active modules approach in a predictive capacity for computational hypothesis generation is introduced to predict unknown metabolic responses to environmentally relevant human-induced stressors. A computational workflow is presented that takes a new genome sequence, builds a GWMR and integrates gene expression data to make predictions of metabolic effects. The aim is to introduce an element of hypothesis generation into the untargeted metabolomics experimental workflow. A study to validate this approach using D. magna as the target organism is presented, which uses untargeted Liquid-Chromatography Mass Spectrometry (LC-MS) to make metabolomics measurements. A software tool MUSCLE is presented that uses multi-objective closed-loop evolutionary optimisation to automatically develop LC-MS instrument methods and is used here to develop the analytical method.

Low vitamin D is associated with an increased risk of autoimmune diseases, whose pathology might involve T\(_R\)\(_e\)\(_g\) and T\(_h\)17 dysregulation. Thus, understanding how vitamin D modifies CD4\(^+\) T-cell responses holds therapeutic potential. I therefore investigated the effect of 1,25(OH)\(_2\)D\(_3\), the active form of vitamin D, upon human CD4\(^+\) T-cell differentiation. 1,25(OH)\(_2\)D\(_3\), acted directly upon human CD4\(^+\) T-cells, suppressing inflammatory cytokines (IL-17, IL-21, IFN\(_y\) and IL-22) whilst enhancing regulatory markers (CTLA-4, CD25, FoxP3 and IL-10). Consistently, 1,25(OH)\(_2\)D\(_3\)-treated T-cells suppressed division of naive T-cells stimulated by dendritic cells (DCs). Strong up-regulation of CTLA-4 by 1,25(OH)\(_2\)D\(_3\)reduced B7 expression by DCs, suggesting that enhanced CTLA-4 could be important mechanistically in 1,25(OH)\(_2\)D\(_3\)modified immunity. Furthermore, pro-regulatory effects of 1,25(OH)\(_2\)D\(_3\)were maintained under inflammatory conditions and modest suppression of established IL-17 by 1,25(OH)\(_2\)D\(_3\) was observed, supporting ability of 1,25(OH)\(_2\)D\(_3\)to control T-cell phenotype at inflammatory sites. DCs could also efficiently convert 25(OH)D\(_3\)to drive 1,25(OH)\(_2\)D\(_3\)-modified T-cell responses, which might be important in-vivo, given the low level of 1,25(OH)\(_2\)D\(_3\)in serum. Whether dysregulation of the T\(_R\)\(_e\)\(_g\)/T17 balance or response to 1,25(OH)\(_2\)D\(_3\) was associated with disease outcome in early synovitis patients was also studied. Although the TReg/T17 ratio did not stratify with outcome, T-cell responses to 1,25(OH)\(_2\)D\(_3\) were observed in all patients, suggesting that their VDR signalling is intact and that 1,25(OH)\(_2\)D\(_3\)might be useful in the treatment of synovitis.

There is a tension between the need to use antibiotics to prevent adverse outcomes from infection, and a consequence of their use, which is antibiotic (treatment) resistant infection. Actions taken to control the spread of antibiotic resistant microbes, and constraints on the use of antibiotics both give rise to ethical tensions. I consider the evaluative framework and the principles that might be used to decide a just distribution of burdens and benefits associated with the use of antibiotics. Nussbaum specifies a list of capabilities. A minimum sufficiency of each capability is required for a life of human dignity. Nussbaum’s approach provides a richer framework for the evaluation of the distribution of burdens and benefits associated with the use of antibiotics than prevailing health economic, or prevalence of disease measures. There are contexts in which we cannot assure a sufficiency of capabilities. I consider the potential for Scanlon’s contractualism to provide principles for deciding the distribution of burdens and benefits associated with the use of antibiotics under differing levels of resource constraint. Finally I consider the influence of metaphor and analogy in the context of the human relationship with microbes.

Client-centred practice underpins Occupational Therapy and is defined as a partnership between the client and therapist that empowers a client to fulfil his/her occupational roles in a variety of environments. Given the importance of this approach, there has been limited exploration of what therapists and clients experience of this approach. A mixed method design examining the view of the clients and therapists was undertaken using; a systematic review to examine worldwide evidence of a clientcentred outcomes measure, a survey of a sample of therapists’ experiences and individual client and therapist interviews. Findings from this programme of work revealed that the clients’ perspective of client-centred practice was the value they placed on the attitude and behaviour of the therapist, communicating respect and treating them as equals. Therapists valued partnership but were challenged in establishing a relationship with the client and failed to negotiate goals with them. Using a client-centred outcomes measure (the COPM) reinforced partnership, demonstrated joint goal setting and evaluated client satisfaction. Implications for practice; training needed in client-centred practice, theoretical models, interviewing, risk assessment, goal negotiation and use of outcome measures. Communication, use of language and documentation should be clientcentred and reflect the client’s needs.

Following over a decade of debate, sex-selection for non-medical reasons using PGD was prohibited by the Human Fertilisation and Embryology Act 2008. The prohibition was justified on the basis of several objections to the procedure. This thesis will consider the veracity of those objections and will focus on the objections relating to: the alleged harms to individuals and families; potential sex ratio imbalance; and sex discrimination and the impact of the prohibition upon Punjabi ethnicity women. Part I will focus predominantly on the alleged harms of the procedure. It will analyse the manner in which the principles of harm and precaution were applied and interpreted during the consultations and reviews that led to the prohibition. A comparison with the approach taken in relation to ‘saviour siblings’ will demonstrate the manner in which the principles should have been applied to sex-selection. Part II will consider the issue from the perspective of the north-Indian state of Punjab. An examination of the reasons belying the sex ratio imbalance in Punjab will demonstrate the unlikelihood of such an imbalance materialising within the UK. Sex discrimination and the impact of the prohibition upon Punjabi ethnicity women within the UK will be considered against this background.

A systematic review identified limited studies exploring oral formulation-related barriers to medicines administration in children. Owing to the lack of licensed medicines suitable for use in children, manipulation is often required to deliver a specific dose or to facilitate medicines administration. Little is known regarding the prevalence and nature of issues encountered when administering medicines to children in the domiciliary setting. This study adopted a pragmatic approach to determine the nature and prevalence of oral formulation-related barriers to medicines administration in children suffering from a range of chronic conditions. Problems reported by healthcare professionals, patients and their parents/carers were identified to inform future pharmaceutical development and improve children’s medicines. Focus groups (n=4) were conducted with healthcare professionals in the West Midlands and semi-structured face-to-face interviews (n=278) were conducted with parents/carers/young people at University Hospitals Coventry and Warwickshire. Questions explored barriers to medicines administration, refusal and manipulation. In total, 31% of interview respondents reported medicines refusal. Taste was the most commonly reported barrier to medicines administration. Almost one fifth (19%) of medicines administered to children were reported to require manipulation. Findings indicate that age-appropriate medicines are required to provide both suitable dose units and acceptable taste for paediatric patients.