Adverse drug reactions (ADRs) are common in children. They contribute significantly to patient morbidity, mortality and hospitalisation costs. There is limited data on the avoidability of ADRs in children and wide variation in avoidability rates has been reported. There is currently no standardised method for determining avoidability and many of the established tools are not suitable or designed for use in paediatrics. The aim of this thesis was to develop and test a new avoidability assessment tool that is suitable for use in paediatrics. The stimulus for this work was difficulty using other tools including the one developed by Hallas et al. (1990). Ideally the new tool should also be applicable and generalisable to a variety of other settings. A secondary objective was to identify potential strategies for clinical practice that might reduce the incidence of ADRs. Three key themes for avoidability have been established through a review of existing literature these are: inappropriate or suboptimal prescribing, inadequate monitoring and inadequate patient or parent education. The development of the LAAT was a multistep process which involved a multidisciplinary team (MDT). Individual and group assessments were conducted and qualitative and quantitative analyses of the assessments were carried out. The LAAT has undergone validity and reliability testing for groups and individuals. The newly validated LAAT was used to assess 249 ADR case reports from a prospective paediatric admissions study by one individual and compared to existing avoidability assessments conducted using the Hallas scale. Assessment of these ADR case reports using the LAAT found that 19.3% were either possibly or definitely avoidable. This was similar to results using the Hallas scale where 22% of the reactions were either possibly or definitely avoidable. Overall percentage exact agreement (%EA) between LAAT and the Hallas scale was 90%; when subcategorised into oncology and non-oncology cases the %EA was found to be 94.2 and 86% respectively. The kappa score between LAAT and Hallas scale assessments was 0.71 (95% CI 0.60 - 0.82) for all cases, 0.54 (95% CI 0.40 - 0.68) for the oncology cases and 0.73 (95% CI 0.58 - 0.88) for the non-oncology cases. The most common avoidability theme detected in this study was inappropriate or suboptimal prescribing. Assessing the avoidability of ADRs is a complex process which requires taking into account a number of factors. Strategies to avoid ADRs can be applied at different levels including: patient, ward, departmental institutional, professional, and national. A common theme that emerged from this work was the lack of available guidelines that could be used to assess whether ADRs were avoidable. Where guidelines were available few contained information about ADRs or their prevention. The majority of clinicians relied on their experience and tacit knowledge rather than on guidelines. Some of the ADRs categorised as either possibly or definitely avoidable may have been avoidable with improved prescribing, more frequent monitoring or improved education of patients and/or parents. Other possible prevention strategies include creating an awareness of ADRs in general and their prevention throughout a clinician’s training. Improved communication and documentation in patient records is a simple but effective method of ADR reduction. In summary, we have designed a novel avoidability assessment tool, developed by a multidisciplinary team, and have shown that the new tool is comparable to an existing avoidability tool, can be used by individuals and most importantly is suitable for use in paediatrics or other areas where clinical conditions extend beyond the expertise of individuals. The LAAT refers to guidelines and patient history rather than to abstract concepts such as ‘present-day knowledge of good medical practice’ and ‘effort exceeding the obligatory demands’ as per Hallas. Further work to identify potentially avoidable ADRs and strategies to prevent them is needed.

In Malawi there has been significant progress in reducing post-neonatal and under-5 deaths over the past decade but very little progress in reducing neonatal deaths. The major causes of neonatal deaths in Malawi are prematurity, infections and birth asphyxia. Neonatal sepsis has been shown to have long term complications ranging from motor deficits to cognitive impairment, epilepsy and behavioural disorders in preterm very low birth weight infants in the developed setting. Contrary to the epidemiology in the developed setting where neonatal sepsis is predominantly seen in preterm low birth weight infants, in the developing setting neonatal sepsis is also common among term babies. However, very little is known on the long term outcome of neonatal sepsis in the resource restrained setting. In this thesis the aetiology and outcome of neonatal sepsis and meningitis is investigated. METHODOLOGY This was study had 2 components; a cross sectional arm and a prospective cohort arm. The cross sectional study was looking at the aetiology, resistance pattern and in hospital outcome of severe neonatal infection cases presenting at QECH in Blantyre. The prospective cohort arm involved participants who were recruited in the cross sectional arm at QECH and were residing within Blantyre urban and infants that never had an episode of severe neonatal infection were recruited from Zingwangwa health Centre. The infants from Zingwangwa acted as controls. The participants in the prospective cohort arm were followed up to the age of 1 year where neurodevelopmental outcomes were assessed using the Bayley’s assessment tool. These participants also had detailed neurologic examination during the follow up visits at 6 and 12 months of age. A comparison between the cases and controls was made to ascertain the impact of neonatal infection outcome. RESULTS During the study a total of 412 cases were enrolled in the cross sectional arm. 75% of the cases had late onset disease. GBS was the commonest organism grown in blood culture 17/42(40%) and CSF culture 16/33(48%). 44% had abnormal serum sodium levels on admission and hypernatraemia was independently associated with an increased risk of dying in hospital (8.34[95% CI 1.95-35.7]). 51% of the gram negative organisms were multidrug resistant. In the long term outcome neonatal sepsis without overt meningitis was associated with an up to 6.6 –fold {95% CI (2.38-18.4) increased risk of developmental delay at 1 year of age. Meningitis was associated with a 17-fold {95% CI 4.89- 61.7} increased risk of developmental delay at 1 year of age. Positive blood or CSF culture and being HIV exposed were independent predictors of delay at I year of age. CONCLUSION GBS is a significant cause of neonatal infections in Malawi. The magnitude of developmental delay observed in infants who had neonatal sepsis without meningitis is worrying up to 35% of these infants were delayed. It is therefore important to employ measures that can prevent neonatal infections. Follow up is recommended in infants who had an episode of severe neonatal infection.

Objectives: Acquired demyelinating syndromes (ADS) are rare childhood central nervous system disorders. In this thesis I aimed to describe the UK incidence, clinical features, MRI characteristics and prognostic features of childhood ADS. Methods: I describe the first UK population active surveillance and one year follow up study which features multiple source ascertainment, MRI review, and blinded clinical expert panel diagnostic review. I also describe: 4 longitudinal retrospective case series delineating prognostic risk factors; outline the setup of a longitudinal cohort; and describe methodological concepts important for the design of the future clinical trials in ADS. Results: The incidence of first onset ADS in children aged 1-15 years old was 9.83 per million children per year; the highest surveillance rate reported to date. The female-to-male ratio in children older than 10 years was 1.52:1. A trend towards higher incidence rates of ADS in children of South Asian and Black ethnicity was observed compared with White children. A number of MRI characteristics distinguished acute disseminated encephalomyelitis cases (1/3 of cohort) from clinically isolated syndrome (CIS) cases (2/3 of cohort). Of CIS cases with contrast imaging, 26% fulfilled McDonald 2010 MS diagnostic criteria. Predictive risk factors for MS diagnosis included: CIS presentation; presence of periventricular lesions on MRI brain scan; and age> 8 years. Conclusions: The detailed study of ADS presented in this work will help to inform future clinical service delivery and clinical trial design.

Volume I comprises a literature review and an empirical paper. The literature review explores the link between illness representations and self-management in children and young people with chronic illness. Fourteen published empirical studies were identified for the review. A risk of bias assessment was completed for each study. Consistencies and differences between papers were identified. Overall, treatment control beliefs were most consistently associated with self-management across a range of chronic health conditions. The empirical paper details a cross-sectional study investigating associations between illness representations, self-efficacy, self-management and psychological well-being in young people with Coeliac Disease. Forty young people and 34 parents recruited from hospital outpatient clinics completed questionnaires. Results indicated timeline-cyclical beliefs and treatment concerns were associated with self-management. Timeline-cyclical, identity, treatment control and coherence were correlated with well-being. In terms of self-efficacy, young people with high levels of self-efficacy were more likely to have better self-management and positive well-being. Finally, dissimilarity in timeline-cyclical beliefs between young people and their parents was related to higher parental stress. Four full length clinical practice reports and a summary of CPR 5 (oral presentation) are included in the Volume II. Firstly, a case of a 55 year old woman presenting with depression is presented. The case is formulated from both cognitive and psychodynamic perspectives. A service evaluation of an Assertive Outreach Service is then described. Both of these clinical practice reports were completed while on an adult mental health placement. The third clinical practice report is a single case experimental design, detailing the assessment and treatment of a 15 year old boy with a mild learning disability and anxiety. This is followed by a case study of the assessment, formulation and intervention of a 15 year old boy with anger and memory difficulties. Finally, a summary of an audit of a new clinical service delivering psychosocial interventions in dementia is provided.

The distinct profiles of sociability and the development of social cognitive abilities was investigated in Cornelia de Lange (CdLS), Fragile X (FXS) and Rubinstein-Taybi (RTS) syndromes. An observational study demonstrated differences in the quality of broad social interaction skills and behaviours during a semi-structured social interaction with an examiner between individuals with CdLS, FXS and RTS. Individuals with FXS and RTS showed lower quality of eye contact, and individuals with FXS showed less person-focused attention, than those with CdLS. Associations between specific behaviours with age and autism spectrum disorder (ASD) symptomatology differed across groups. A second study assessing participant's performance on two scaled batteries of tasks assessing early (intentionality abilities) and later developing (ToM abilities) social cognitive abilities indicated that these groups do not develop these abilities in the same order as typically developing children. Different strengths and weaknesses observed between groups highlighted factors that may lead to disrupted social cognitive development in these groups. A third study showed that intentionality abilities predicted social enjoyment and social motivation, whereas ToM abilities predicted social enjoyment and ASD symptomatology in all groups. These fmdings were synthesised with previous literature to develop a preliminary model of sociability in CdLS, FXS and RTS.

Arthrogryposis, Renal dysfunction, and Cholestasis (ARC) syndrome is a multisystem disorder associated with abnormal localisation of some polarised membrane transporter proteins. Distinct apical and basolateral poles are essential for epithelial function and organ development but the molecular pathways determining the biogenesis of polarised membranes are not fully characterised. Mutations in VPS33B, a Sec1-Munc18 protein, account for 75% of ARC patients. Reduced expression of VPS33B at both the RNA and protein level was demonstrated in all ARC syndrome patients, even if mutations were not identified in VPS33B. A novel protein POLARIN (PLRN) was identified that interacts with VPS33B, and is crucial for VPS33B function. Pathogenic mutations in PLRN occur in ARC patients without VPS33B mutations. Decreased Polarin and Vps33b expression in mouse renal collecting duct cells led to abnormal localisation of specific apical membrane proteins and to disordered apical junction complex formation. In an in vivo model, knockdown of polarin in zebrafish resulted in defects in biliary tract development. These findings establish that a VPS33B-POLARINRab11a intracellular trafficking pathway is functionally distinct from another VPS33-related pathway (VPS33A/VPS16) and is required for (a) normal epithelial polarisation and apical junction complex formation, and (b) normal liver and kidney development and function.

INTRODUCTION Brain tumours are the most common solid tumour in childhood, while Magnetic Resonance Spectroscopy (MRS) studies have been performed on brain tumours previously, the majority have been performed on the adult patient population and at long echo times. The work presented in this thesis outlines work performed in the usage of short echo time MRS in the characterisation of childhood brain tumours. METHODS Short echo time MRS was performed on children with brain tumours at the time of diagnostic imaging. In addition, follow up data was accrued for some patients. Resulting spectra were assessed for characteristics either of diagnosis, prognosis or treatment response. RESULTS Spectra collected were used in assessing characteristics of an array of childhood brain tumours. Initially the technique was tested on a well understood dataset of cerebellar tumours, and was later expanded to provide diagnostic aids for both brain stem tumours and pineal region tumours. A group of pilocytic astrocytomas were assessed for differences by location within the brain, for prognosis and for response to treatment. CONCLUSIONS The additional information given by short echo time MRS was useful in the characterisation of childhood brain tumours

The evidence base for the benefits of mindfulness for children is growing and the beneficial outcomes of Mindfulness-Based Interventions (MBIs) are found in a broad range of domains. The aim of this research study was to explore and evaluate the outcomes and process of an MBI delivered in a school setting to students aged 12 and 13-years-old by a Trainee Educational Psychologist. A mixed methods approach was employed within a paradigm of pragmatism which was well suited to the complexity of phenomenon to be studied. In order to answer the research questions an intervention design was utilised in which outcomes for two groups of students were compared. Multiple of sources of data were analysed; qualitative data derived from semi-structured interviews was thematically analysed and interpreted alongside findings from a quantitative analysis of data obtained from the Child and Adolescent Mindfulness Measure and the Strength and Difficulties Questionnaire. Evidence was found for an increase in mindfulness; most students reported experiencing improved self-awareness, awareness of their environment and feelings of calm and relaxation associated with mindfulness practice. A significant difference was found between pre- and post-intervention parental total difficulties scores on the SDQ, suggesting that student’s difficulties had improved from the parent’s perspectives.

This thesis comprises a literature review and a research paper. The literature review explores the current evidence for the barriers and facilitators for a successful transition to adult services for young people with gastrointestinal disorders. Seventeen studies were identified. The findings suggest that the transition should be a flexible, gradual process that involves joint care between paediatric and adult services. The competencies of young people need to be assessed and developed to prepare them for adult care, with interventions also addressing parental involvement. The research study used a qualitative approach to explore the transition experiences of young people with coeliac disease (CD), from the perspective of both young people and their parents. Seven young people and six parents were interviewed. The data was analysed using Interpretative Phenomenological Analysis (IPA). Three super-ordinate themes were identified for each subgroup, which overlapped extensively: ‘Absence of discussion and abandonment’, ‘Understanding my coeliac disease and me’ and ‘Responsibility is an evolving process’. A lack of discussion and involvement in the transition was associated with feelings of abandonment and apprehension. Many participants felt their CD-knowledge and psychosocial needs were not sufficiently addressed. Assuming responsibility for the utilisation of services varied across participants, and parental involvement did not necessarily end with transfer to adult services.

This thesis presents a Realist Evaluation of the Brook Traffic Light Tool (TLT) which supports professionals in reducing harmful sexual behaviours (HSB) in children and young people (CYP). This is important as the numbers of HSB in CYP are rising, and no national strategy exists in the UK. The conceptual element consisted of developing a hybrid methodological approach combining: Realist Evaluation; The Kirkpatrick Model; evidence based policy, policy transfer and policy success perspectives. The empirical element involved evaluating the implementation of the TLT across Cornwall, with data collected in a three phase mixed method approach: a questionnaire with 436 responses; 60 detailed questionnaires and 13 interviews. The context, mechanisms and outcomes that emerged were complex. Conceptually, questions were raised about empirical research that underpins the TLT, with UK transfer and policy success criteria presenting a mixed picture of success. In Cornwall the TLT met the majority of its outcomes. Direct impact upon the behaviour of CYP was difficult to ascertain and categorisation anomalies were found when behaviours were not explicitly outlined in the TLT. The study found that a range of professionals were encountering both harmful and healthy sexual behaviours, yet comparison to national figures proved problematic as no baseline exists.