The multiple mini interview (MMI) is an admissions instrument designed to replace the personal interview in health care student selection. Its effectiveness has been evaluated in medical student recruitment processes (Eva et al., 2004a, Roberts et al., 2014). At the commencement of this research no reliability, validity, or acceptability studies had been published specifically in relation to student midwife selection. Study objectives: to develop, pilot and evaluate the reliability, validity and acceptability of MMIs in student midwife selection in a Higher Education Institution (HEI) in the United Kingdom (UK). A dual paradigmatic dialectical enquiry was used in a multi-method case study. A literature review and qualitative work were conducted to identify the desirable personal qualities of a student midwife. This was followed by the systematic development of a customised eight station, five-minute MMI model. Sixty-two students from the BSc Midwifery Studies, September 2011 and 2012 cohorts, at the University of Surrey, volunteered to undertake ‘mock’ MMIs in the first week of their programme. Fifty-seven participants were followed up having completed their first year. Predictive validity was assessed using students’ end of year OSCE and mentor grading; station reliability, including inter-station and internal consistency, were also examined. Interviewers’ (n=9) and candidates’ (n=62) views of MMIs were obtained from a focus group and semi-structured questionnaires respectively. The literature review revealed that acknowledgement of the importance of ‘emotionality’ or an emotional dimension in the relationship between a woman and her midwife was missing from key professional, regulatory (Nursing and Midwifery Council, 2009, 2010, International Confederation of Midwives, 2011) and government documentation (Department of Health, DH,2012). According to the Department of Health (DH, 2013), selection to all National Health Service (NHS) funded training posts should incorporate recruitment for the NHS Constitution values (DH, 2012). In the absence of any mention of ‘emotionality’ it is suggested that this requires more specific recognition in considerations of what is important to appraise at selection. No statistically significant associations were found between students’ MMI score and their subsequent performance in clinical practice. The University Registrar would not consent to ‘live’ selection using MMIs in the absence of midwifery-specific evidence; participants were therefore students who had already been accepted onto an undergraduate midwifery programme. This has been addressed in an on-going longitudinal follow up-study. Reliability (internal consistency) was ‘excellent’ with Cronbach’s alpha scores between 0.91-0.97 across eight stations. Inter-station reliability findings suggested that each station measured different independent constructs with only a moderate positive correlation between two stations, kindness, compassion and respect for privacy and dignity (p<0.01). All other stations indicated little or no relationship offering additional support to the reliability of the scales. Candidates stated that undertaking MMIs would not discourage them from applying to the University as they felt they were a fair assessment instrument. They suggested that the multi- interview format was a positive feature which allowed them to recover from a poor performance at any one station. Overall, 23 participants (37%) reported a preference for MMIs compared to 22 (35%) who preferred a one-to-one personal interview format; 44 participants (71%) found the personal interview more daunting than MMIs. Interviewers appreciated the parity of opportunity afforded to candidates through the standardisation of the interview process. They were willing to adopt MMIs in future selection processes provided any anticipated complications were resolved. MMIs were shown to be reliable in the context and model defined. The insightful information obtained has informed a ‘roll out’ to MMIs across all health care student selection at the University of Surrey as well as being used by Health Education England as a case study example (HEE, 2014).

Disorders of the central nervous system such as brain tumours, Alzheimer's disease, Parkinson's disease, Huntington's disease and others lead to a worst decline in the quality of life of patients. The possibility of using gene therapy for the treatment of these disorders is hindered due to the presence of blood-brain barrier and due to the lack of safe and efficacious gene delivery systems that can cross this barrier and express exogenous genes in global areas of the CNS. Various receptors such as transferrin receptors, lactoferrin receptors and low-density lipoprotein receptor-related proteins 1 & 2 are widely expressed on the blood-brain barrier for the transport of endogenous molecules. These endogenous transport systems could be exploited for transport of molecules across the blood-brain barrier. In this thesis, we demonstrated the synthesis and characterization of transferrin-, lactoferrin-, lactoferricin-, Angiopep-2-bearing diaminobutyric polypropylenimine (DAB) dendrimers and evaluated their brain targeting efficiencies in vitro and in vivo. Transferrin- and lactoferrin- bearing DAB dendriplexes led to a 2-fold and 6.4-fold increase in gene expression in the brain respectively, as compared to unconjugated DAB dendriplex after intravenous administration in mice, while decreasing the gene expression in other major organs of the body. Lactoferricin-bearing dendriplex did not show any gene expression in the brain after intravenous administration, whereas unexpected results requiring further investigation were obtained after intravenous administration of Angiopep-2-bearing dendriplex.

Experimental Autoimmune Encephalomyelitis (EAE) is an animal model of multiple sclerosis (MS), causing a demyelinating central nervous system (CNS) inflammation which resembles the main pathological features of MS. Mitogen-activated protein kinases (MAPKs), which are key components in the molecular response leading to MS/EAE pathogenesis, are regulated by MAPK phosphatases (MKPs), enzymes which dephosphorylate phosphotyrosine and phosphothreonine residues. It has previously been shown that MKP-2 modulates the inflammatory response during both acute lung injury and sepsis. Therefore in the present study we investigated the role of MKP-2 in the development of the neurological autoimmune disease, MS, using a murine EAE model. We first observed significantly increased expression of MKP-2 mRNA in the spinal cord of EAE mice compared with PBS controls. Subsequently, to understand the function of MKP-2 in vivo, we utilised MKP-2 deficient mice, inducing EAE in MKP-2 KO and WT littermates. Our data show that MKP-2 KO mice displayed significantly reduced EAE susceptibility, associated with diminished CNS inflammation and cellular infiltration, decreased expression of key cytokines and chemokines (IL-17, IFNγ, IL-6, IL-2 and CCL2), reduced frequency of CD4⁺ T cells, CD8⁺ T cells and B cells in spleen and dLN tissue as well as downregulated nitric oxide (NO) production in MKP-2 KO EAE mice. We further analysed the role of MKP-2 in two key immune cells involved in EAE pathogenesis. Upon LPS stimulation, MKP-2 deficient bone marrow-derived dendritic cells expressed less MHC-II while producing more IL-6, TNF-α and IL-10, whereas MKP-2 KO bone marrow-derived macrophages displayed a unique M1 and M2 mixed phenotype, with reduced NO production (M1) and increased CD206 expression (M2) but increased IL-6 and TNF-α, which are more associated with M1 responses. Therefore this report suggests that MKP-2 is essential to the pathogenic response of EAE, and that inhibition of MKP-2 expression or function may be a viable strategy in the treatment of autoimmune inflammatory diseases such as MS.

Phosphatidylglycerol (PG) is an important component of membranes and is found in bacteria. As Streptomycetes have a large amount of the PG in their cell membranes, in this study we have focused on the gene SCO5753 (pgsA) from the model organism Streptomyces coelicolor, whose product is predicted to synthesize PG the precursor of CL. Mutations in the phosphatidylglycerol-3-phosphate synthase (PgsA) operon were introduced by using the procedure for in vitro transposon mutagenesis, and gene disruptions in the pgsA operon could not be achieved which indicated the essentiality of this operon in S. coelicolor development and growth. This gene was inserted under the control of an inducible promoter tipA, to understand the effect of over production of PG in Streptomyces. It showed poor development of growth on agar, except if provided with expression of the promoter. The importance of PG in the osmotic adaptation of wild type S. coelicolor culture was investigated. Phospholipids were extracted and the appearance of spots on thin layer chromatography plates (TLC) after separation by chloroform/methanol/acetic acid/water (80/12/15/4) showed that the proportion of PG increased during growth of these bacteria in media containing high amounts of KCl within 24 hours.

The thesis consists of five chapters. The first chapter is general introduction to LC-MS, separation technology and extraction methods. The second chapter describes the development of a method to measure free and bound ropivacaine in human plasma using equilibrium dialysis and HILIC chromatography coupled with a high resolution mass spectrometery. In this chapter a highly sensitive method for the determination of the free and bound portion of ropivacaine in patients undergoing knee and hip joint surgery was developed. Patient samples were provided by the Golden Jubilee Hospital, Clydebank. The method was validated according to FDA guidelines. The third chapter describes the determination of α1-glycoprotein in the plasma of patients undergoing knee and hip joint surgeries using an already established method using HPLC with a polymeric reversed phase column, thus enabling comparison of the concentration of AGP protein with the levels of bound and unbound ropivacaine. This complete set of data should allow pharmacokinetic modelling studies to be carried out. The fourth chapter covers the determination of the steroids estradiol and estrone and their hydroxyl and methoxy metabolites following a derivatization reaction for provision of improved sensitivity. The free steroids are not readily ionized by ESI mass spectrometry and the derivatization procedure produces positively charged ions in order to enhance the detection of these steroids. Different reagents were used and the best sensitivity was obtained by using 2-fluoro 1, 3-dimethylpyridinium p-toluene sulphonate as the derivatising agent. This method was applied to samples obtained from patients with pulmonary hypertension in order to evaluate the role of steroids in the progression of disease. The fifth and last chapter covers the determination of an anti-malarial drug artemether and its active metabolite DHA in human plasma using a reversed phase C18 column coupled with high resolution mass spectrometry, the samples were provided by the University of Peshawar, Pakistan.

Background: Cystic Fibrosis (CF) is one of the United Kingdom’s most common life limiting genetic disorders. Improvement in treatment modalities over the last 20 years has resulted in this group of patients living longer. The acceptability of accessing early palliative care for patients with CF and staff perceptions of a palliative care referral for this group is relatively unexplored. Integrated care has been used as a theoretical model to underpin this study. Aim: To explore the experience and perceptions of patients with CF and staff regarding palliative care and the acceptability of this as a service early in the patient’s disease trajectory. Method: A Mixed Methods Study informed this research. This three phase study included a Focus Group (phase 1) with 8 experts from both CF and palliative care, a national survey (phase 2) with 46 experts from CF and palliative care teams, and 17 interviews (phase 3) with patients with CF and health care professionals who care for patients with CF. Results: The term “palliative care” remains a barrier for some professionals in considering a referral to palliative care. Patients interviewed did not have such a problem with the term. Patients are supportive of palliative care being introduced earlier in the disease trajectory. Currently there is evidence to suggest that over 50% of teams do not have an integrated service between CF and palliative care. Discussion: This innovative study has identified a lack of clarity relating to when a patient with CF should be referred to palliative care services. Uncontrolled symptoms and transplant have been highlighted as potential triggers for referral to palliative care services. Patients have recognised that transplant may be too late for a referral and would like to be made aware of palliative care services earlier in the disease pathway. A model of integrated care has been generated from the findings of the study. Conclusion This study has explored early palliative care in adults with CF and considered the perceptions and experiences of patients and health care professionals. This three phase study has determined the views of patients for the first time regarding early palliative care. Together with national data in phase two and in depth interviews in phase three, an integrated model between CF and palliative care is proposed that illustrates the views of the patients and health care professionals, offering considerations for organisations in the development of integrated services. Key words: Cystic Fibrosis, Palliative Care, Integrated Care, patient and health care professional perceptions and experiences.

The functional migration of immune cells during Leishmania infection is imperative for the activation of a protective immune response. In particular, migration of dendritic cells (DCs) towards the lymphatic vessel network and CCL19-producing lymph node is a key step in the induction of adaptive immunity. Consequently, manipulation of chemokines and chemokine receptors presents a potential mechanism by which parasites can evade protective host immunity. Therefore, the aim of this thesis was to investigate whether Leishmania mexicana can influence immune cell migration and identify the mechanisms underpinning this. Using a combination of in vitro and in vivo studies, the key finding presented in this thesis is that L. mexicana modulates DC migration following infection. While uptake of L. mexicana by DCs is associated with reduced surface expression of CCR7, this does not entirely account for the failure of DC migration and therapeutic targeting of DCs does not enhance protective immunity. Crucially, it is through production of cysteine protease B that L. mexicana can suppress migration of infected and bystander DCs. Parasites lacking cysteine protease B are less able to prevent DC migration and the activity of this important virulence factor is shown to be associated with cleavage of CCL19. In further experiments, it is also demonstrated that effective DC migration following L. mexicana infection may also be influenced by interactions with neutrophils and their NETs and by an early source of interleukin-4/13 acting directly on DCs. Primarily, these findings demonstrate how L. mexicana can utilise immunomodulatory virulence products, like cysteine protease B to manipulate the host immune response. Understanding these mechanisms is invaluable for the development of new drug and vaccine targets against L. mexicana, but may also aid in the development of new treatments for similar chronic infections.

Despite abundant literature about bullying, previous research has predominantly focussed upon the characteristics of those who bully, peer influences in bullying and anti-bullying interventions, with little acknowledgement of how young people who bully and their counsellors experience counselling. This research seeks to address the gap by asking; how well young people who bully feel able to express themselves to their counsellor, and what facilitates or inhibits the therapeutic relationship for both counsellors and young people who bully? These research questions derive both from existing literature and my profession as a counsellor of young people who bully. Using interpretative phenomenological analysis (IPA), data were gathered using focus groups and semi-structured interviews with a sample consisting of six participants representing four young people and two counsellors. In IPA, the researcher’s use of self is equally implicated in the collection and analysis of data (Smith & Osborn, 2003); consequently, my dual identity as counsellor and researcher has asserted differing perspectives. The three superordinate themes identified in the current study focus upon attachment states (Bowlby, 1977, 1988), the therapeutic relationship, and the influence of emotional management upon counsellors. Trust and risk emerged as pervading concerns for the young people and have been integrated into discussion of the superordinate themes. The research received favourable ethical opinion from the Faculty of Health and Medical Science (FHMS) ethics committee. Findings suggest that young people who bully experience insecurities which manifest as mistrust, inhibiting the relationship with their counsellor. It also appears that a counsellor’s life experiences and occupational identity variously affect the therapeutic relationship. Individual counselling may not be a panacea but I recommend that if undertaken expertly, it has potential. Future research could focus upon confidentiality where equivocal standards are confusing for young people who bully.

Aim This paper reports a study exploring the lived experience of fifteen men and women treated with allogeneic stem cell transplant (SCT) for haematological malignancy. Background Evidence suggests that treatment of haematological malignancy including allogeneic stem cell transplant has a significant impact on the quality of life (QoL) of recipients and quantitative studies have measured dimensions such as physical function and psycho-social and spiritual domains. Fewer studies have considered individual’s lived experience of allogeneic stem cell transplant (SCT) and their subsequent recovery. Methods The study followed an interpretive phenomenological methodology using semi-structured interviews. Fifteen participants aged between 22-68 years were purposively recruited from two specialist treatment centres and were interviewed within three months to one year post SCT between April and September 2013. Data were then analysed using interpretive phenomenological methodology to gain insights into their lived experience including their personal and social experience of the world following treatment. Findings Two overarching themes emerged from the data: The Immediacy of Illness & Existential Crisis and The Recovery Journey. The Immediacy of Illness and Existential Crisis illustrate the participants’ experiences of critical events in relation to disease onset, diagnosis and treatment and the enduring uncertainty which continues into recovery including facing their own mortality. Participants suffer major disruption to their lives physically, psychosocially and emotionally as a result of illness without a sense of when they may resume the normality of their former life. Returning home after several months of hospitalisation is a particularly daunting and challenging time for patients. Participants expressed their fear of being suddenly left in charge of their own health needs and the stark reality of the outside world compared to being cared for in the relative safety of their protective isolation facility in hospital. The responsibility for self monitoring and vigilance in the light of on-going treatment effects such as graft versus host disease (GVHD) and the threat of viral infections warrants increased support from health care professionals. Social support in order to cope with isolation, financial hardship and employment issues similarly deserves attention. Processing traumatic experiences such as life threatening diagnoses, critical events and harsh treatments can be difficult when faced with the immediacy of illness. Participants feel guilty of burdening their loved ones but could benefit from the opportunity to talk to other patients in order to gain perspective and share strategies for coping and adjustment. Conclusion Ambiguity and uncertainty characterise the illness and recovery journey for those with haematological malignancy. Whilst participants have access to specialist teams, there are opportunities for health and social care professionals to provide more support for individual’s returning home after prolonged hospitalisation and in the months that follow. In particular the development of a community based Advanced Nurse Practitioner, skilled in early recognition of treatment effects, could significantly enhance the care of patients in their first year post SCT.

People from Black and Minority Ethnic groups, in particular Guyanese people, have a higher incidence of Type 2 Diabetes. Yet, there is a paucity of research which explores women's experiences of living with the condition. In this participatory action research (PAR) inquiry, eight participants and I, ‘we’ researched together for 18 months. Participants were nine Guyanese middle class women, including myself, who had migrated to England many years ago. The inquiry aim was to listen to the women’s voices about living with Type 2 Diabetes and explore associated cultural experiences that could influence self-management. The objectives were: 1) give voice to Guyanese women stories; 2) explore their experiences living with Type 2 Diabetes; 3) facilitate a participatory action research (PAR) group and explore with them self-care trajectories and 4) consider ways ‘we’ (women and researcher) can initiate health care reform at an individual level and/or within the Guyanese community. Data generated included storytelling in one to one interviews in the safe environment of the women’s own homes, followed by 14 PAR group sessions. Participants drove the research by determining what should go on the agenda and they decided on the resultant actions. Fourteen constructs (commonalities in experience) were derived from our data and the women validated these findings and took ownership of their stories. The main focus of the PAR group conversations was on their identities as Guyanese migrant women which were constructed through the food and dietary transitions made over the time of the PAR group. The group’s social context became a fertile bed for learning. In terms of living with a chronic illness, improving diabetes self-management was accelerated within the group. Group cohesion and working together to improve their lives are two of the most important findings. In 2015 the group continues to meet. If theory is defined by its practical effects, together we have confronted the taken for granted meanings of culture, ethnicity and identity as we researched alongside each other to construct a theory of togetherness as empowerment that enabled a group of migrant women to bring about change in their lives. My thesis is that listening to the voices of Guyanese / English women who live with a chronic illness improved self-management, fostered new understandings of diabetes and empowered this group to have a say about the health services received. Through participating in a PAR group, we recognised that we are bi-culturally competent women and when we connect, we recognise the practical effect of togetherness as empowerment.