Dynamic treatment regimes are functions of treatment and covariate history which are used to advise on decisions to be taken. Murphy (2003) and Robins (2004) have proposed models and developed semi-parametric methods for making inferences about the optimal dynamic treatment regime in a multi-interval study that provide clear advantages over traditional parametric approaches. The main part of the thesis investigates the estimation of optimal dynamic treatment regimes based on two semi-parametric approaches: G-estimation by James Robins and Iterative Minimization by Susan Murphy. Moodie et al. (2006) show that Murphy's model is a special case of Robins' and that the methods are closely related but not equivalent. In this thesis we rst describe and demonstrate the current theory, then present an alternative method. This method proposes a modelling and estimation strategy which incorporates the regret functions of Murphy (2003) into a regression model for observed responses. Estimation is fast and diagnostics are available, meaning a variety of candidate models can be compared. The method is illustrated using two simulation scenarios taken from the literature and using a two-armed bandit problem. An application on determination of optimal anticoagulation treatment regimes is presented in detail.

BACKGROUND: Patients who present physical symptoms in the absence of physical pathology are common in primary care. They are often considered by doctors to be amongst the most difficult patients to manage and their overinvestigation and treatment has been well documented. Whilst the finger is often pointed at the patient as the instigator of such treatment, there is currently little objective evidence implicating the patient directly to this potentially iatrogenic treatment process. The concept of `patient demand' largely stems from anecdotal evidence of doctors concerning their feelings of being pressurised by such patients. AIMS AND OBJECTIVES: To investigate how patients with unexplained physical symptoms talk about their symptoms during routine primary care consultations with GPs and to determine whether or not somatically oriented interventions for these patients can be attributed to patient demand for this treatment. METHODS: Initial qualitative investigation: audio recording, transcribing and thematic analysis of 36 primary care consultations between GPs and patients with unexplained physical symptoms. Second quantitative investigation: audio recording, transcribing and coding of 420 primary care consultations between GPs and patients with unexplained physical symptoms using a coding scheme developed during the qualitative phase of the study. Hypotheses generated during the qualitative phase of the study were tested with Wilcoxon or Friedman tests. RESULTS: There was little evidence from the qualitative analysis to support the suggestion that patients with unexplained physical symptoms receive somatic interventions because this is what they direct their GPs to provide. However patients presented their symptoms in characteristic ways which might conceivably pressure GPs for somatic intervention. Aspects of GP speech were also identified that had the potential to influence somatic treatment decisions. Results of the quantitative analyses showed that GPs proposed somatic treatment in more consultations than did patients. Patients requested explanation for their symptoms in a greater number of consultations than they advocated any treatment intervention. Patients criticised GPs in a substantial number of consultations in the larger quantitative sample. This type of speech may be a particularly powerful source of pressure for somatic intervention. CONCLUSIONS: The over-investigation and treatment of patients with unexplained physical symptoms can no longer be attributed to overt patient demand for such interventions. The findings of the present analyses implicate both patient and GP in the decision to provide somatically oriented treatment. Patient influence, where apparent, involves the different and complex ways that patients talk about their symptoms rather than their specific requests for intervention. The type of explanations GPs offer for patients' symptoms may prompt some patients to respond in ways that might conceivably pressure GPs for somatic intervention. The provision of somatically oriented treatment for patients with unexplained physical symptoms might therefore be more appropriately explained as the outcome of critical doctor-patient communication processes rather than patient demand for such intervention.

The placebo effect is arguably accounted for in sport science research by the convention of the placebo-controlled trial. However, little research has sought to quantify or explain the effect itself. This thesis examines the placebo and pharmacological effects of caffeine in cycling performance using a multi-method approach. Methods: Extensive piloting was conducted to establish the suitability of caffeine as a vehicle for investigation, the efficacy of substance administration procedures, and the reliability of the cycle protocol. An experimental deceptive administration protocol (the balanced placebo design) was subsequently employed to quantify the relative contributions of psychology and pharmacology to the response to ingested caffeine and placebo in 14 well-trained cyclists, whilst semi-structured interviews were employed to corroborate and explicate the nature of observed effects. Finally, psychometric methods were used to identify any associations between placebo responsiveness and personality. Results: Caffeine ingestion enhanced cyclists' performance by 2.6% (95% CI 0.9-4.3, P = .002) whether they believed caffeine to have been ingested or not. No significant placebo effects were observed (1.2%, 95% CI -0.3- 2.8, P = .31), however, individual placebo responses were evident. Interview data revealed that observed placebo effects reflected both direct effects of belief on performance, and indirect effects, mediated by psychological changes and pacing decisions. Perceptions of enhanced performance were not always reflected in overt performance, raising the question as to what exactly constitutes a placebo effect. Synthesis of data suggest that certain personality traits such as Openness to experience and Neuroticism may relate to placebo responding. Conclusions: Caffeine ingestion may enhance the performance of a well-trained cyclist independently of their beliefs as to whether caffeine has been ingested or not. The belief that caffeine has been ingested might elicit a performance enhancing effect in certain placebo responsive individuals. Implications for placebo effect research and sports performance research and practice are discussed alongside directions for further research

This thesis explores the therapist's use of professional knowledge in their relationship with patients. It addresses a gap between theory and practice and the challenges to therapist expertise in a postmodern climate in which there are a multiplicity of competing perspectives about psychological problems. In semi-structured interviews eight NHS Psychodynamic Psychotherapists revealed narratives that underpinned their practice about the nature and treatment of psychological problems. These were organised as narratives about living the `good life' psychologically, and the origins and treatment of psychological problems. The central finding of this thesis is that, rather than relying on professional knowledge conceived as conventional psychodynamic theory, therapists engage in a largely intuitive process I have termed `clinical reasoning' which is practice-based, `reflection-in-action' that involves tacking principally between their professional knowledge base, their experience with the patient and their personal beliefs and experience. Such a process, I argue, constitutes a `hazardous journey' in a postmodern climate in which the value of a psychodynamic perspective cannot be taken for granted. A key implication is the value of therapists becoming more explicitly aware of their own particular narratives and the effect these have on the therapeutic encounter.

The clinical applications of metal-based anticancer drugs are limited by their poor water solubility and stability, and shortfalls in their pharmacological activities. Recently, much emphasis has been placed on the use of drug targeting and delivery (DTD) systems in order to mitigate these drawbacks. One example of such DTD systems which is under intense scrutiny is the use of vector molecules, such as tamoxifen to achieve selective transport of a chemotherapeutic agent to cancer cells. Tamoxifen is a selective estrogen receptor modulator (SERM) used for the treatment of all stages of estrogen-dependent breast cancers. However, the clinical use of tamoxifen is also limited by the development of resistance and an increase in the incidence of endometrial cancer. Additionally, estrogen-independent breast cancers are also insensitive to tamoxifen. Consequently, it has been proposed that organometallic SERMs (tamoxifen- metal complex conjugate) could be an efficient target against both types of breast cancers, by exploiting the intrinsic activities of both the tamoxifen ligand and the metal complex. The work presented within this thesis builds on this concept by developing novel organogermanium-based SERMs as potential anticancer drugs. The organogermanium compound, germanium sesquioxide (Ge-132) was chosen to be coupled to tamoxifen analogues, as it has shown a range of biological activities including antitumour activity, both in vitro and in vivo with no detectable chronic toxicity or side effects.

This research project develops an ontology-based technique to exploit the information contained in free-text surgical pathology reports for breast cancer patients. A novel ontology for the domain is designed and several tools for information extraction and reasoning are developed, supported by machine learning algorithms aiding the identification of the relevant information within the documents. The research shows that information extraction from surgical pathology reports can be significantly enhanced by machine learning pre-processing, which will select the appropriate extraction technique for the report layout and filter out irrelevant portions of text. Also, such a system can be coupled with clearly defined, formal semantic models of both the reality, which will support the information extraction tasks, and of coding systems, which will enable to automatically assign clinical codes with complex rules. As a whole, it can alleviate the burden for cancer registry staff, researchers or clinicians of reading pathology reports, calculating cancer staging codes' and entering information on a database. The main benefits of this research will result in cost savings and in the augmented completeness and accuracy of both routine cancer registrations and study-specific cancer data collection for cancer registries. The outcomes of this research will also be appreciated by the management of pathology laboratories. Increasing their awareness of the reports' use in automated contexts will hopefully induce relevant modifications in the writing styles of the documents or, even better, encourage the adoption of structured collection of information for, at least, the essential data items used for cancer epidemiology.

The interaction between a tumour and the surrounding non-malignant stroma impacts on nearly every aspect of malignant progression. The heterogeneity of the tumour microenvironment (TME), however, makes mapping this interaction difficult. Each stromal population contributes to various functions and each tumour type has its own distinct pathway of interaction with different stromal populations. The majority of these interactions are mediated by soluble factors secreted into the TME. The aim of this study was to elucidate the role that IL-8 signalling may play in prostate tumour interaction with the TME and to determine the mechanism by which IL-8 signalling impacts on tumour-associated stromal cells to enhance tumourigenicity. IL-8 in the prostate TME is primarily derived from the tumour cells and bone-marrow derived myeloid cells are capable of responding to tumour-derived IL-8 via high levels of cell surface IL-8 receptors CXCR1 and CXCR2. Direct co-culture of the highly invasive prostate cancer cell line PC3 and a bone marrow-derived, macrophage representative line, THP-1 enhances invasion through Matrigel (2.4-fold, p=0.0098) and increases wound closure after 6 h (50.63% v 25.65% for PC3 cells alone; p=0.010B). Inhibition of IL-8 signalling by neutralizing antibody (i) or PEPducin inhibition of CXCR1 and CXCR2 (ii) inhibited macrophage-dependent invasion and wound closure: (i) 90% decrease in normalized invasion and 43% decrease in wound closure, p<0.001 and p=0.03 respectively relative to IgG and (ii) 38% reduction in wound closure, p=0.0002 compared to non-targeting peptides. Development of a stable PC3-based CXCL810w cell line, PC3-120p, confirmed these findings. PC3-120p cells were unable to initiate THP-1-potentiated motility and invasion, however, this response was rescued by addition of exogenous human CXCLB. Exogenous CXCLB was shown to up-regulate secretion of RTK-activating cytokines and growth factors from THP-1 cells. Addition of the RTK inhibitor cabozantinib (XL 184) but not crizotinib abrogated THP-1-dependent invasion and wound healing response of PC3 cells. Differential analysis of RTKs regulated by both cabozantinib and CXCLB neutralizing antibody in co-culture identify multiple RTKs as potential downstream regulators of CXCLB-dependent, monocyte-enhanced PC3 invasion. Together, this data supports the adjuvant targeting of molecules involved in tumour-stroma interactions to enhance the efficacy of prostate cancer treatment.

Daunorubicin and its congener, doxorubicin, are two of the most important anti-tumor antibiotics used in cancer chemotherapy. Both agents exhibit a broad range of activity against solid tumors and hematologic malignancies, yet their clinical potential is limited by severe dosedependent cumulative cardiotoxicity. So far, over 2000 analogs have been synthesized comprising numerous chemical modifications, substitutions and conjugations to the tetracyclic ring, the side chain or the amino-sugar. However, only few of those have reached the stage of clinical development and approval. Furthermore no analog offers a definite advantage over daunorubicin and doxorubicin in terms of activity or toxicity. The search for a better anthracycline may consequently require a radically different approach. These drugs are synthesized by a type II polyketide synthase consisting of a number of fully dissociable enzymes. Although the structural, regulatory and resistance genes of the daunorubicinldoxorubicin biosynthetic clusters have been identified, their functions characterized and a general scheme for the biosynthetic pathway has been proposed, little is known about the structural organization of these enzymes within the PKS and how this affects catalysis. Furthermore, the exact mechanism of starter unit selection remains elusive. Knowledge of the above would help us modify the biosynthetic pathway in order to engineer new anthracycline natural products with improved activity and pharmacological properties. To accomplish these goals, all dps proteins were expressed and purified to homogeneity. Two enzymes, the ketosynthase subunits (DpsAlB) and the malonyl transferase (DpsD) were expressed for the first time. Functional interactions between the dps components were then identified in vitro by ITC and 1FT and, based on the interactions data, a model for the architectural organization of the PKS was proposed. The roles of DpsC and DpsD as the starter unit specifying enzymes were also examined in detail. Our analysis showed that, contrary to previous reports, DpsD seems to be the starter unit specifying enzyme. Finally, crystals of DpsC and DpsE were obtained and diffraction data collected that could aid in structure elucidation for these components.

Until the last few years, focussed ion beam systems were primarily used within the semiconductor industry as tools for modifying prototype integrated circuits, but owing to the development of commercial systems and the concomitant reduction in costs, they are rapidly becoming more popular within academic institutions for research purposes. This work investigates the potential application of the focussed ion beam to the study of patterned magnetic media, which is an area of increasing interest as new methods of extending the performance limits of current magnetic storage media are sought. The effects of quasihomogeneous Ga ion implantation and micro-machining on the structural properties and magnetic behaviour of thin Fe films have been studied by various microscopy techniques. Doses on the order of 8 X 10 15 ions cm"2 were found to induce structural changes in the polycrystalline microstructure, but the ferromagnetic properties were found to be reasonably resistant to ion implantation. The formation of magnetic domains within patterned arrays of simple geometric shapes was studied using magnetic transmission X-ray microscopy and Xray magnetic circular dichroism. Hysteresis properties of the patterns were determined by magneto-optical measurements using a specially designed dual photoelastic modulator-based polarimeter. A detailed description of the polarimeter is given along with a new calibration method, which improved the accuracy of the measurement system in comparison to a more conventional approach.

The unpopularity of gerontological nursing is well established and, although numerous studies have sought explanations for this, few have explored how work with older people can be promoted as a more fulfilling and challenging career choice. Underpinned by a constructivist methodology, this thesis provides new insights into how the experiences of student nurses during their training influence their predisposition to work with older people. Using a two stage approach, data were collected from longitudinal focus group interviews with student nurses from four schools of nursing over a period of eighteen months, together with case studies in seven clinical placement areas where students had identified a positive experience of learning to care for older people. The study was part of a larger national investigation funded by the English National Board for Nursing, Midwifery and Health Visiting. Data analysis revealed that a positive experience of work with older people in a range of settings was key to determining whether gerontological nursing was seen as an interesting and exciting career option. Both 'impoverished' and 'enriched' environments of care were identified and analysed in terms of the 'Senses Framework' (Nolan et al 2001a). 'Enriched' environments ensured that students, staff and patients/carers each in their various ways experienced a sense of security, belonging, continuity, purpose, achievement and significance. The longitudinal nature of data collection also indicated that these senses varied in importance as students' experiences unfolded, and a number of foci for students' efforts emerged. These were: self as focus; course as focus; professional care as focus; patient as focus; and person as focus. Findings suggest that only in the most enriched environments will students have a vision of care that has the person as its focus. Based on the interdependency implicit in the data, the thesis concludes by arguing that future policy, practice and education in gerontological nursing should be informed by relationship-centred care, as opposed to person-centred care.