Background: Previous research has shown that children with a diagnosis of Asperger’s Syndrome or High Functioning Autism (AS/HFA) have difficulty with mentalising tasks. There is also limited evidence that siblings may also have subtle deficits in ‘theory of mind’ consistent with a broader autistic phenotype model. This study aims to investigate whether deficits in mentalising about others is specific to sensory modality (modular) or mediated by a global impairment in mentalising. Methods: Thirteen children who had a sibling with AS/HFA were compared to thirteen children who did not, matched on age, gender and verbal IQ. Children completed a range of self and other mentalising tasks. RESULTS: No significant differences in mentalising were detected between the groups. Descriptive statistics indicated a trend for male siblings to have higher AAQ scores and longer mean response times on the RME than female siblings and controls. Conclusions: Larger samples and replication would be required to ascertain whether any significant impairment in mentalising about others across modalities is present in siblings, and to clarify the impact of gender and social learning theory. Formal modification of the auditory test (RMV) for younger children would be helpful in order to robustly compare differences in performance across modalities both within and between groups.

Childhood obesity is a leading global public health issue. Chapter One of this thesis is a literature review of the evidence concerning the issue of childhood obesity and its management. The literature review describes this issue in terms of national and international prevalence and trends, health consequences and determinants. The literature review examines the evidence to guide effective management of childhood obesity. The role of parents in the management of childhood obesity has been identified as a promising area of research and specific attention is given to this issue. This thesis examined the effect of a family-based behavioural treatment programme for obesity in 7-11 year olds (The Malaysian Childhood Obesity Treatment (MASCOT) Study). The intervention is presented in Chapter Two. Families of obese 7-11 year olds in Kuala Lumpur were randomised to either an intervention (treatment) or control (no treatment) group. The sample was characterised by BMI z-score, health related quality of life reported by participants and their parents (PedsQL questionnaire) and objectively measured habitual physical activity and sedentary behaviour (Actigraph accelerometry). The intervention was delivered over a six month period and between group differences in changes over the six month period were examined at this time point. The sample size (n=107) was calculated as sufficient to detect an estimated difference in the reduction in BMI z-score of-0.25 in over six months between groups and the SD of the change in BMI z-score of 0.21, allowing for dropout (and with power=90%, significance=95%). The primary outcome was change in BMI z-score. This chapter also describes how the MASCOT treatment programme developed, and describes its content. The Malaysian Childhood Obesity Treatment Trial (MASCOT) was a single-blind RCT of a dietetic treatment for childhood obesity in children of primary school age (7 to11 years old) in Kuala Lumpur, Malaysia. The MASCOT comprising eight sessions, of an 8-hour family-centred group treatment programme is described, based on behavioural change techniques, covering topics on nutrition, physical activity and sedentary as well as parenting skills. All information was directed to parents, the main agent of change in which they were responsible for initiating and maintaining healthy lifestyle changes with their families. Outcomes were recorded at baseline and six months, consisting of primary outcome indicators (body mass index (BMI) z-score) and secondary outcome indicators (weight changes, health-related quality of life (HRQoL) and, habitual physical activity and sedentary behaviour) (Chapter Three). Analysis of the primary outcome found no significant group differences at the six month time point for BMI z-score (intervention: 0.0 (0.7) vs control: 0.1 (0.5), p=0.79). There were significant differences between the groups in favour of the intervention group in weight changes (intervention: 1.7(2.5) vs control: 3.5(2.0), p<0.001) and total parent score for HRQoL (intervention: 4.2(15.5) vs control -3.8(19.3), p<0.05). This thesis also reports complementary studies that examined: · the quality of life of obese children compared to pair-matched controls of healthy weight (Chapter Four) and · the physical activity levels and sedentary behaviour of obese children in the MASCOT study versus healthy weight children (Chapter Five) The study of quality of life (Chapter Four) found significant impairment in all HRQoL dimensions (Total score, Physical Health, Psychosocial Health) in the obese children compared to healthy weight children (p<0.001, respectively). In Chapter Five it was shown that obese children spent more time in sedentary behavior (intervention: 90.2% vs control: 87.5%, p<0.001) and less time in MVPA (intervention: 0.7% vs control: 1.2%, p<0.001) compared to healthy weight children. Chapter Six concludes the thesis by summarising its results and highlighting how they have contributed to the evidence base. Study strengths and limitations are described and those weaknesses would be improved by suggesting a few changes in the MASCOT programme for future research.

There is a large amount of research on BPD which highlights the pervasive and distressing nature of this disorder along with its resulting high financial cost to services. Previous research exploring intervention options for BPD have found DBT to beneficial in reducing parasuicidal behaviour and it is acknowledged as the intervention of choice for adults. The research evidence on ‘what works’ for adolescents with BPD is limited, although DBT is an intervention offered in clinical practice. This study aims to contribute to the research on the effectiveness of DBT by exploring adolescents’ experience of receiving this therapy. Five participants took part in the study and verbatim transcripts from their interviews were analysed using Thematic Analysis. The aim of the analysis was to develop understanding on what adolescents found to be the most and least helpful aspects of DBT and to help ascertain whether participants viewed this therapy as effective in reducing their presenting difficulties. Results identified four main themes which were constructed from the data set; ‘Clinical Picture’, ‘Deciding to start DBT’, ‘Evaluation of DBT’ and ‘Change’, with each theme containing between two and six sub-themes. The themes were seen to connect with each other to represent participants’ journey through therapy. Clinical implications of the research indicate that clinicians play an important role in the process of therapy and contribute to both positive and negative experiences. It appears there is a need for clinicians working with this client group to be appropriately trained and skilled to provide flexible care. In addition the findings from the current study suggest DBT did not target the multiple and varied problems the adolescents presented with, resulting in on-going difficulties and high levels of disengagement and drop-out rates. Whilst participants felt the intervention contained positive elements, overall they reported dissatisfaction with the outcome of therapy. Services may therefore need to consider alternative or additional intervention options to target adolescents’ presenting difficulties and help improve their quality of life.

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