An analysis of over 34,000 free-text messages assigned by pharmacists to prescription orders over a 12-month period showed a sub-optimal exchange of information with the physician. Focus groups and observational research were conducted to provide a more in-depth understanding of the factors involved. The use of CPOE did not reduce opportunities for personal interaction. The capability to communicate electronically facilitated a non-interruptive workflow, beneficial for staff time and for limiting distractions. It also improved clinical documentation, which helped coordinate care of patients between members of the pharmacy team. However, the research identified several barriers to the effectiveness of communication via the CPOE system, including: the increased frequency of messages sent; poor display characteristics of the message; poor access to information to inform decision-making; one-way communication; and no assigned responsibility to respond. These factors need to be considered in the design of systems and supported by interprofessional training to optimise communication between the professionals.

Recent studies have shown the numerous advantages associated with specific drug delivery to the colon, highlighting its favourable conditions and long transit time as the main advantages. A number of in vitro studies also show that the delivery of liposomes to the colon could provide further advantages due to bonding to the colonic mucosa in both healthy and inflamed regions. Despite these apparent advantages no oral liposomal formulation has been developed for targeted delivery to the colon as yet. Initially, experiments were conducted in which liposomes were directly coated with the pH responsive polymer Eudragit S100. Although the coating was shown to slow drug release in simple pH buffers, it was realised it could not protect the lipid membrane from the model bile salt sodium taurocholate. Development of the formulation moved onto the production of Eudragit S100 microspheres to provide a solid barrier to protect the liposomes. Due to the solvents required in the microsphere production it was essential to protect the liposomes, which was done by coating them with the enzyme controlled polymer chitosan. The final stage involved encapsulating chitosan-coated liposomes within the Eudragit microspheres to produce a novel, colon targeting liposome-in-microsphere (LIM) formulation.

The active accumulation of iodide into the thyroid, mediated by the sodium-iodide symporter (NIS), is vital for thyroid hormone production, which is essential for neurological development and metabolism throughout life. This system is the target of thyroid cancer treatment post-surgery, as NIS facilitates radioiodide uptake into, and subsequent ablation of, cancer cells. While this is a largely successful therapy, it is ineffective in patients with radioiodide-refractory thyroid cancers due to the loss of functional NIS. Unfortunately, the lack of alternative treatment options for these patients results in an extremely poor prognosis. Consequently, it is of great interest to improve our understanding of NIS regulation, with the ultimate clinical aim of re-introducing functional NIS expression in such patients to enable successful treatment with radioiodide. Since dimerisation is important for the function of many membrane proteins, it is significant that NIS has been suggested to exist at higher molecular weights indicative of dimerisation, although this has not been explored in depth. This thesis demonstrated the occurrence of NIS dimerisation using three distinct methodologies. Although investigations revealed that previously proposed motifs are unlikely to be involved in NIS dimerisation, an alternative role in protein folding was offered for these motifs. Consequently, a novel homology model of NIS dimerisation was created based on the dimeric crystal structure of the family member protein vSGLT, which revealed a putative dimerisation interface. Mutational studies demonstrated that interactions between residues Q471, Y242 and T243 mediate NIS dimerisation and suggested that dimerisation might be involved in protein trafficking.

Engineered gold nanoparticles (AuNPs) can be modified to produce functionalized AuNPs with potential biomedical applications. However, prior to medical use, an understanding of cellular uptake and fate is critical to assess their potential toxicity. This thesis studied 20 nm AuNPs coated with a luminescent ruthenium complex (RubySS) to fonn RubySS.AuNP, which were fully characterised prior to cellular studies in A549 cells treated for 2-72 hours. The size of internalised particles as quantified by transmission electron microscopy (TEM) was in agreement with characterisation data of particles in solution and particle size remained unchanged after up to 72hours treatment indicating non-aggregation of internalised RubySS.AuNP. Particle number increased over time, and this was confinned by quantitative analysis of confocal images, TEM and inductively coupled plasma mass spectrometry. Macropinocytosis and clathrin-mediated endocytosis were shown to be the route of uptake, with particles trafficked via the endo-lysosomal pathway as confirmed by co-localisation with fluorescent markers of early endosomes, lysosomes and autophagosomes in a time-dependent manner that, ultimately involved autophagy as confirmed by western blotting of LC3 protein. Cellular accumulation of RubySS.AuNP also caused cellular changes related to oxidative stress including depletion of glutathione and DNA-strand breaks, but the mechanism of action remains to be elucidated.

This research explores professional identity formation amongst occupational therapy students. Professional identity is examined within an occupational science framework. Much has been written, in recent years, about the professional identity development of occupational therapists during the first stages of their career focusing on preceptorship (Morley, 2006, Tryssenaar, 1999) but the concept of initial professional identity formation remains under examined. This thesis addresses that gap by following one student’s journey of becoming an occupational therapist from enrolment to graduating on an undergraduate occupational therapy course. Five in-depth interviews were carried out over three years. This was situated against a series of focus groups drawn from the same cohort. The Kawa model (Iwama, 2006) was used as a data collection and analytical tool. Three overarching themes which highlight the processes involved in professional identity formation, were identified • Establishing occupational coherence; the participants needed to make sense of their occupational history. It was important for participants to explain and present themselves as having developed occupational coherence over time. • Managing occupational adaptation; the participants dealt with many challenges as they coped with transitions and a changing sense of self. It was important that they developed agency and feelings of competence on their professional journey. •Developing a new identity; the participants explored how they adapted to new possibilities as they experienced the doing of occupational therapy. Their new occupational identity was congruent their own personal values. This interpretative phenomenological analysis makes a significant contribution to the small body of knowledge around professional identity formation in occupational therapy. The longitudinal approach created a nuanced narrative which expounds the complex ongoing process. It highlighted the importance of paying attention to the processes of doing, being, belonging and becoming. The fundamental importance of enabling students to develop an occupational perspective to understand their developing professional identity is identified.

Volume one Volume one of the thesis comprises of three research chapters examining the use of therapeutic homework in second and third wave cognitive behavioural therapy. The first chapter is a correlational meta-analysis examining the relationship between mindfulness homework and improvement over a mindfulness course. The second chapter is an empirical study exploring the phenomenological experience of cognitive behavioural psychotherapists in using therapeutic homework. The final chapter is a public dissemination document providing an accessible summary of the meta-analysis and empirical paper. Volume two Volume two of the thesis consists of five clinical practice reports. The first report presents a cognitive behavioural and psychodynamic formulation of low self-esteem in an 18 year-old man. The second report evaluates the care package received by cluster eight clients in an adult mental health service. The third report describes a cognitive behavioural and systemic narrative intervention with a 72 year-old woman experiencing health anxiety. The fourth report presents a single-case experimental design to investigate the effectiveness of a behavioural intervention for challenging behaviour in a 32 year-old man with Rubinstein-Taybi Syndrome. The final report is an abstract of an oral presentation of clinical work completed in an early intervention service.

Perhexiline is a metabolic modulator considered to be an alternative pharmacotherapeutic agent in heart failure (HF), a debilitating condition characterised by severe metabolic disturbances (i.e. impaired substrate utilisation and energy production) in which morbidity and mortality are high. However, perhexiline therapy requires regular plasma monitoring, which is clinically unattractive. Moreover, its exact cardioprotective mechanism(s) remains unknown. The work in this thesis aimed to investigate the protective effects and underlying molecular mechanism(s) of perhexiline ex vivo, in Langendorff-perfused mouse hearts and in vivo, in the abdominal aortic constriction model of HF, and to determine whether the effects could be replicated by the novel perhexiline derivative, fluoroperhexiline-1 (FPER-1), which has better pharmacokinetics. Ex vivo, 2 μM perhexiline or 10 μM FPER-1 perfusion increased cardiac contractility and relaxation pre-ischaemia and improved post-ischaemic haemodynamics and hypercontracture magnitude. This involved enhancing the contractility-relaxation pathway (phospholamban (PLB) deactivation) pre-ischaemia and improving glucose metabolism (pyruvate dehydrogenase (PDH) activation and glycogen synthase kinase 3αβ (GSK3αβ) deactivation) during ischaemia. In vivo, 4-week gavage with 70 mg/kg perhexiline or FPER-1 attenuated hypertrophy and cardiac remodelling at end-diastole whilst decreasing the expression of uncoupling protein 3 (UCP3), a redox-sensitive protein. Additionally, perhexiline alone improved systolic function (i.e. improved left ventricular ejection fraction and fractional shortening) in parallel with PLB deactivation. Taken together these results provide novel evidence that perhexiline protects the heart against ischaemic injury and delays progression from hypertrophy to failure by metabolic and non-metabolic (PLB) mechanisms, most of which were replicated by FPER-1.

After the discovery of cisplatin, the development of metal-containing anticancer drugs has been the subject of much research, with the aim of achieving high activities with minimal side effects. Metallocene derivatives are now common place within this field. Building on work previously published work by the Tucker group on ferrocene-containing nucleoside analogues, further research has now been undertaken to explore structure activity relationships. Firstly, the study has involved changing the substitution pattern through the synthesis of a series of regioisomeric derivatives, while maintaining other parameters. Secondly, the central metal ion has been changed to ruthenium from iron. The series of compounds have been characterised both spectroscopically and electrochemically and have, also been assessed for their anticancer activity in various cell lines. The latter show that both the substitution pattern and the metal ion play an important role in determining the biological properties. The other metallocene compounds, a tetrasubstituted dicytosine ferrocene and two disubstituted ruthenocene derivatives have also been prepared for incorporation into DNA strands by automated synthesis. The resulting oligoes have been characterised by HPLC and mass spectrometry.

Prescribing errors affect the safety of patients of all ages, however, the risk of prescribing errors may be higher in paediatric patients. This is due to the complexity of calculating doses, age-specific pharmacokinetic and pharmacodynamic changes and the higher usage of unlicensed and off-label medications. This research explores the prevalence and nature of prescribing errors in children and the interventions used to reduce such errors. A multi-centre observational study was conducted to evaluate the prevalence and nature of prescribing errors in paediatric settings. Clinical pharmacists working in thirteen different UK hospitals were asked to identify prescribing errors in inpatient medication orders. The overall error rate was 8.7% of total orders which was similar to the rate of prescribing errors in adults (8.9%) in the EQUIP study. Dosing errors were found to be the most common and the majority of errors were classified as minor. Severity assessment of these errors was conducted by an expert panel to evaluate the severity of all errors which are reported in chapter 2 as data were missing from some of the original error reports. Although there were discrepancies between the panel’s and the original pharmacists’ assessment in 234 of 892 errors, minor errors were still the most common. A second observational study was conducted to evaluate the prevalence and nature of paediatric prescribing errors in electronic medication orders as data for electronic prescribing were only reported from one hospital. Pharmacists were shadowed in their routine clinical work by the researcher who documented all prescribing errors identified by the pharmacists. The overall rate of errors was 5.2% of total orders which was significantly lower than the rate of errors found in the written orders (8.7%) in the previous study conducted in the same hospital using the same methods and before the introduction of an electronic prescribing system. The most common types of errors identified were omission of regular medications on admission followed by under-doses, non-measurable doses and overdoses. Most errors were classified as significant followed by minor errors due to the increased numbers of omission of regular medications on admission. Education is frequently recommended as being key to reducing prescribing errors therefore a systematic review was conducted to identify and evaluate educational interventions which have been used to reduce prescribing errors in children. Only 25 studies met the inclusion criteria. These studies used various educational interventions such as lectures and feedback. Eighteen studies reported that the interventions were effective in reducing errors. Multi-faceted interventions seemed to be more effective than single-strategy interventions. It was difficult to compare the various strategies due to differences in study definitions, denominators and methods of data collection. The impact of interventions is often evaluated by testing the prescribing ability of the doctors involved. A systematic review was therefore conducted to examine the literature on the tests used to assess prescribing competency in doctors caring for children. Only 16 studies met the inclusion criteria. Six studies were designed specifically to evaluate doctors’ dose calculation skills, seven studies used assessments asking the participants to write prescriptions according to given clinical cases and three studies had general questions about prescribing in children. The validity and reliability of the identified tests were not evaluated in any of the studies however. This project has contributed to the field of prescribing errors in children by providing more information about the prevalence and nature of such errors including the most common types and serious errors. Further research is still needed to identify the best ways of avoiding these.

Metal-based photoactivated chemotherapy (PACT) involves a class of metal- based prodrugs, which may overcome the limitations and side effects of current metal-based chemotherapeutic agents on account of their novel mechanism(s) of action. In this thesis, a number of vibrational spectroscopic methods were developed and applied to study the mechanisms of metal-based PACT agents upon activation with light. A particularly promising PACT agent is the diazido Pt(IV) anticancer prodrug, trans,trans,trans-[Pt(N3)2(OH)2(py)2] (1, py = pyrdine), in which photoinduced cleavage of ligands from platinum yields reactive species, which are likely implicated with the observed biological activity. However, monitoring the azido and hydroxido ligands, and the metal centre simultaneously remains challenging. Vibrational spectroscopy is a potentially powerful tool to study both metal and ligand vibrations without the requirement of labelling and is non- destructive at the same time. The essential first step was the screening of 1 by a range of vibrational spectroscopic methods, including Attenuated Total Reflection Fourier Transform Infrared (ATR-FTIR), Raman and synchrotron radiation far-infrared (SR-FIR), aided by Density Functional Theory (DFT). This yielded an extensive vibrational fingerprint of 1 containing individual ligand (pyridine, hydroxide and azide) and platinum to ligand vibrations. The established methodologies provided the necessary basis for elucidating further photodecomposition and photoreaction pathways. Successive ATR-FTIR studies allowed for examinations of the photodecomposition of 1 complemented by transient electronic absorption and UV-Vis spectroscopy under 420 nm or 310 nm irradiation. Chemometric data evaluation using Principal Component Analysis (PCA) and Multi Curve Resolution Alternating Least Squares (MCR-ALS) on the steady state UV-Vis and ATR-FTIR spectra captured the formation of a Pt(II) intermediate, trans-[Pt(N3)(py)2(OH/H2O)] and a final product, trans-[Pt(py)2(OH/H2O)2], in which the trans pyridine scaffolds were retained. Upon irradiation, the rapid removal of the hydroxido stretching vibration was found to correlate to a shift in the anti-symmetric azido vibration, indicative of a possible second intermediate. Experimental evidence of subsequent azido dissociation from platinum suggests that at least one hydroxyl radical is formed in the reduction of Pt(IV) to Pt(II) under such conditions. Additionally, photoproducts formed upon irradiation of 1 in the presence of the DNA nucleotide 5’-guanosine monophosphate (5’- GMP) could be systematically studied using ATR-FTIR, mass spectrometry and DFT calculations. Underpinning methodologies were subsequently applied to study a series of photoactivatable ruthenium-based CO releasing complexes of the formula [RuLCl2(CO)2] (L = 2,2’-bipyridine with 4’ methyl and/or carboxyl substituents). A three-step mechanism involving the sequential formation of [RuL(CO)(CH3CN)Cl2], [RuL(CH3CN)2Cl2] and [RuL(CH3CN)3Cl]+ was deduced upon 350 nm irradiation in acetonitrile. Rapid removal of the first CO ligand (k1 ≫ 3 min−1 ) and a modest rate for the second CO ligand (k2 = 0.099 – 0.17 min−1 ) was observed, with slowest rates found for the electron-withdrawing carboxyl substituents. Aqueous media considerably slowed down the photodecarbonylation (k1 = 0.46 – 1.3 min−1 and k2 = 0.026 – 0.035 min−1 ) and the carboxyl groups were shown to have a less pronounced effect on the rate constants, revealing the possible implications for the design of such candidates intended for clinical application. State-of-the-art synchrotron based infrared spectroscopy was utilised with continued focus on the mechanism of action of 1. ATR-FTIR and synchrotron radiation far-infrared were combined (SR-ATR-FIR) to enable the rapid screening of samples, exposing changes to the metal to ligand vibrations of 1. Additionally, in situ irradiation using liquid transmission SR-FIR revealed the removal of in the platinum to oxygen (hydroxide) and platinum to nitrogen (azide) vibrations simultaneously. Moreover, a mid-infrared live single cell study of 1 on acute myeloid leukaemia cells (K562) by Synchrotron Radiation Infrared Microspectroscopy revealed significant changes to DNA base stacking and lipid vibrations after only four hours of low dose irradiation at 350 nm (2.58 J cm- 2 ). Lastly, the low wavelength excitation of the earlier described photoactivatable metal-based anticancer prodrug candidates was considered, which commonly hamper their clinical feasibility. A range of lanthanide-doped upconverting nanoparticles (UCNPs) were synthesised, allowing for near-infrared light excitation and visible light emission as a potential platform for wavelength activation of PACT agents in a clinically-relevant window.