Background: Obesity is a global problem that resulted from excessive positive energy balance. Decreased physical activity and other dietary, environmental and genetic factors all contribute to its development (Han et al., 2010). On a larger scope, social, economic and cultural factors also predisposed to its occurrence globally (WHO, 2000). Of particular concern is the rise in paediatric obesity with subsequent rise in morbidity during childhood, adolescence and young adulthood, and rise in morbidity in adulthood, including adult obesity, as well as increased risk of premature mortality in adulthood (Reilly and Kelly, 2011, Reilly, 2006). In Kuwait, paediatric obesity prevalence is high and may be continuing to rise in all age groups (Mirmiran et al., 2010, Al-Isa and Thalib, 2008, Al-Isa and Thalib, 2006). Affluence and rapid transformation of Kuwaiti society after the discovery of oil is one theory behind the changes that took place in the dietary and physical activity patterns which could be the main mediators for the obesity epidemic in Kuwait (Ng et al., 2011). However, despite the paediatric obesity problem in Kuwait there is not a widely available treatment solution or attempts to find obesity treatment solutions locally (Al-Isa et al., 2010b). At an international level, effective treatment strategies were traditionally confined to the Western world, particularly the Epstein group in the USA (Epstein et al., 2012, Oude Luttikhuis et al., 2009, Epstein, 1996), though other successful treatment programmes have been published since the early pioneering work of Epstein (Ho et al., 2012). The aim of the thesis was to: a) test the hypothesis that obesity impairs health related quality of life in Kuwaiti adolescents and test the differences in health related quality of life assessed by self-report and parent-proxy report, b) determine the prevalence of cardiometabolic risk factor abnormalities and metabolic syndrome in a sample of obese Kuwaiti adolescents, and c) test the effectiveness of a treatment intervention for adolescent obesity and compare it to a primary care control. Methodology: Chapter 4 describes the health related quality of life study (HRQL) that was conducted at baseline comparing the HRQL between obese and healthy-weight Kuwaiti adolescents (aged 10 to 14 years). Five hundred eligible consenting participants were assessed using the Peds QL™ self-reports as well as 374 parent-proxy reports. From the obese group (n= 224), 82 participants agreed to participate in the National Adolescent Treatment Trial for obesity (NATTO) (chapter 6), an assessor-blinded randomised controlled trial, and were randomised to the intervention programme or primary care control over 6 months. The intervention programme aimed to change sedentary behaviour, diet and physical activity in low intensity doses through 6 hours contact over 24 weeks. At baseline, 80 blood samples were collected from 80 out of the 82 participants from the NATTO study, for the assessment of cardiometabolic risk factors namely C-reactive protein, intracellular adhesion molecules, interleukin-6, fasting blood glucose, fasting insulin, alanine aminotransferase, aspartate aminotransferase, gamma glutamyltransferase, total cholesterol, low-density lipoprotein, high-density lipoprotein, triglycerides, and adiponectin. Metabolic syndrome was assessed using two criteria modified for use in younger individuals. Results: From the health related quality of life study, obesity was not associated with impaired health related quality of life in regression analysis. In a structured paired comparison of 98 pairs of obese adolescents vs healthy weight peers, impaired health related quality of life reached significance only for the physical quality of life domain (obese group score = 87.5, healthy weight group score = 93.7, 95% CI for quality of life score = -1.5, -9.4, p 0.007). In a paired comparison between parent-proxy vs self-reports for the obese adolescents, physical quality of life score (parent-proxy score 81.3, self-report score 87.5, 95% CI = -3.2, -11.0, p < 0.001), psychosocial score (parent-proxy score 76.7, self-report score 85.0, 95% CI = -4.2, -10.8, p < 0.001) and total score (parent-proxy score 78.8, self-report score 84.8, 95% CI = -4.9, -10.9, p < 0.001) were all significantly lower in the parent reports. The cardiometabolic risk factors with highest prevalence of abnormal values in the sample (n = 80), described in chapter 5, were; aspartate aminotransferase (89% of samples abnormal), insulin resistance by homeostasis model assessment (HOMA) (67% abnormal ), intracellular adhesion molecule (ICAM) (67% abnormal), fasting insulin (43.5%), C-reactive protein (42.5%), low density lipoprotein (LDL) (35%), total cholesterol (34% abnormal), and systolic blood pressure (30% abnormal). Of all participants (n=80), 77 had at least one impaired cardiometabolic risk factor besides their obesity. Prevalence of Metabolic syndrome was 21.3% using the International Diabetes Federation definition and 30% using the Third Adult Treatment Panel definition. At 6 months outcome in the treatment intervention NATTO, the trial had acceptable retention (n =31 from the intervention group and n =32 from the control group), but engagement with both the intervention and control treatment (as measured by attendance at treatment sessions) was poor. The intervention had no significant effect on BMI Z score relative to control, and no other significant effects of the intervention were observed. Conclusion: In a sample of obese Kuwaiti adolescents, obesity was not associated with marked impairment of health related quality of life; however, marked impairment in multiple cardiometabolic risk factors was present. Conducting the National Adolescent Treatment Trial for Obesity in Kuwait was feasible but not efficacious, and future obesity treatment trials should incorporate a qualitative assessment for better participants’ engagement.

Objectives: To study autism spectrum disorder (ASD) in the Faroe Islands, including prevalence, diagnostic stability and environmental factors that are potentially involved in the aetiology of autism. Method: I. The target group was recruited from the entire population sample of participants with ASD during a two-phase screening and diagnostic process of the entire Faroe Islands population in the relevant school age group born between 1985-1994 (7-16 years, n=7,689) in 2002 and again in 2009 (15-24 years, n= 7,128) using an independent clinical diagnosis and standardised tools. II. The diagnostic stability of ASD from childhood to early adulthood over a period of 7 years compared diagnoses in 2002 and 2009. III. A literature search of vitamin D and ASD covering the period from January 1 1995 to October 31 2011 was carried out. IV. A pilot study involved questioning 20 mothers of young individuals from the target group and 13 mothers of healthy comparisons, regarding mothers’ diet habits, health, life-style and well-being during their pregnancy with an index child. V. 25-hydroxyvitamin D3 (25(OH)D3) levels were examined in a population based cross-sectional study that involved 219 individuals: 40 participants with a diagnosis of ASD from the target group (31 males/9 females), their 62 typically developing siblings (29 brothers/33 sisters), their 77 parents (40 mothers/37 fathers), and 40 healthy comparisons (28 males/12 females). Results: I. The rate of ASD rose significantly from 0.56% (n=43) in 2002 to 0.93% (n=66) in 2009. Although these results were still within the range of typical findings from other studies, of the 24 newly discovered cases in 2009 nearly half were females thus altering the male/female ratio from 6/1 to 2.7/1. II. The stability of clinical ASD diagnosis was perfect for AD, good for “atypical autism”/PDD-NOS, and less than perfect for Asperger syndrome (AS). Stability of the diagnoses made by means of research tools were more variable but still good for AD. Both systems showed excellent stability over the seven-year period for “any ASD” diagnosis, although a number of clear cases (especially in females) had been missed in the original screening in 2002. These results support the notion that a single overarching diagnostic category, ‘autism’ or ASD, would better suit clinical realities as outlined in the new DSM-5. III. The systematic review (in 2010) provided some, albeit very limited, support for the possible role of vitamin D deficiency in the pathogenesis of ASD: there are three main areas of involvement of vitamin D in the human body that could potentially have direct impact on the development of ASD: (1) the brain, (2) gene regulation and (3) the immune system. The prevalence of ASD has been suggested to be raised at higher latitudes. IV. Mothers of individuals with ASD had had during their pregnancy significantly less positive “attitude to sun” (p=0.001), consumed fewer vegetables (p=0.026) and also less fruit (p=0.078). V. The ASD case group had significantly lower 25(OH)D3 levels (24.8 nmol/L) than their typically-developing siblings (42.6 nmol/L, p<0.001) and their parents (44.9 nmol/L, p<0.001), and also significantly lower than healthy age and gender matched comparisons (37.6 nmol/L, p=0.002). There was a trend for males having lower 25(OH)D3 levels than females. There was no association between vitamin D and age, month/season of birth, IQ or subcategories of ASD. Among the ASD group, 60% were severely deficient (<30 nmol/L) and 84.2% of the whole study sample (n=219) had deficient/insufficient levels (<50/<75 nmol/L). Conclusions: I. ASD prevalence in the Faroe Islands increased from 0.56% in 2002 to 0.93% in 2009 mainly due to missed cases in 2002, nearly half of them females. II. There was diagnostic stability for the overall category of ASD over time in the group diagnosed in childhood (7—16) years, but considerable variability with regards to diagnostic sub-groupings. Diagnosing females require novel approach. III. Vitamin D deficiency–either during pregnancy or early childhood–may be an environmental trigger for ASD in individuals genetically predisposed to the broad phenotype of autism. IV. There are some interesting differences in the diet and life-style habits between mothers with a child with ASD and mothers with a healthy child. The ASD-group’s negative “attitude to sun” may indicate some life-style/health differences which may play a role in pathogenesis of ASD, especially in combination with other environmental risk factors. V. The present study, demonstrating an association between low levels of 25(OH)D3 and ASD, is the first to be based in a total population and to use siblings, parents and general population control groups. It adds to similar findings from other regions of the world, indicating vitamin D deficiency in the population and especially in individuals with ASD. As all groups were exposed to low levels of sunlight, the very low 25(OH)D3 in the ASD group suggests that some other underlying pathogenic mechanism may be involved.

This thesis analyses the effects of various structural and organisational characteristics of specialist neonatal units on the clinical and economic outcomes of infants treated within them. Data are utilised from the National Neonatal Research Database (NNRD) which is extracted from the electronic patient records of all infants admitted to the vast majority of neonatal units in England over the period 2006-13 along with national healthcare expenditure and demographic data. Firstly, I examine the effects of neonatal unit volume and designation on infant clinical outcomes. In 2003, neonatal units in England and Wales were re-organised into networks to facilitate access to high level and volume neonatal units for the sickest infants as infants treated in these units had previous been shown to be at less risk of adverse outcomes. No previous studies have examined the effects of neonatal unit volume and designation in such a networked setting. Secondly, I estimate the effect of neonatal healthcare expenditure on the risk of mortality, and in so doing determine the cost-effectiveness of neonatal healthcare. Thirdly, I analyse the effect of nurse to patient ratios in neonatal intensive care on the risk of mortality, recent evidence has demonstrated that neonatal units are often understaffed with respect to clinical guidelines, yet little is known about the consequences of this on infant clinical outcomes. Finally, I explore the effect of local economic conditions at the time of conception on infant health at birth. The number of admissions to neonatal specialist healthcare units has increased in recent years to approximately 10% of all live births. Understanding the mechanisms underlying this increase is important both for healthcare capacity planning and also development of policies aimed at improving infant health at birth. The results in this thesis support policies aimed at increasing the proportion of infants born in hospitals with high volume neonatal units along with an increased provision of resources for neonatal healthcare.

This study presents a mixed methods investigation into the efficacy of an indicated CBT-based intervention for addressing anxiety in a sample of secondary school students within the UK. Phase One of the study employs a quasi-experimental evaluation of a CBT-based intervention. 18 participants (7 male, 11 female, mean age: 12 years 6 months) were allocated to intervention (n=8) or wait-list comparison (n=10) conditions using a matched pairs process. The intervention comprised six sessions of a CBT-based programme, delivered by teaching assistants trained in the principles of CBT; wait-list participants attended their usual lessons. Phase One investigated the effects of intervention participation upon students’ self-reported anxiety and parent-reported perceptions of student anxiety, using the respective versions of the Spence Children’s Anxiety Scale (SCAS and SCAS-P). Results demonstrated that there were no statistically significant effects upon student-reported anxiety or parent-reported perceptions of student anxiety. Parents of participants within the wait-list condition reported increased student anxiety during the intervention phase, albeit this trend did not reach statistical significance. Phase Two represents a qualitative exploration of participants’ perceptions of their post-intervention anxiety regulation abilities and their insight into the programme mechanisms. This phase incorporated Focus Group and Nominal Group Technique approaches, with data reviewed through Thematic Analysis. Findings suggested that participants perceived intervention attendance to have developed their knowledge and understanding of strategies which may either a) actively address the causes of their anxiety or b) enable them to manage the physiological, emotional, cognitive and behavioural implications of anxiety. Participants indicated that intervention participation had increased their understanding of the importance of seeking social support for managing anxieties. Key methodological reflections for this two-phase design are discussed. Findings are compared to the wider literature regarding anxiety and CBT approaches in children and young people. The implications of these findings for future research and the practice of Educational Psychologists are considered.

Background: A substantial increase in the incidence of chronic non-communicable diseases (NCDs) and a decline in communicable diseases and poverty-related diseases are occurring in developing countries (including Nigeria) as a result of an epidemiological transition. Given the burden and poor outcomes of NCDs related to hypertension or high blood pressure (BP) in adulthood, there is an urgent need for the identification of high risk individuals in early life. High BP has already been reported amongst young people worldwide, including Nigeria. High BP in childhood is predictive of high BP in adulthood. There is very little information available on the distribution of blood pressure in children and adolescents, and the factors which determine its distribution in Nigeria. Objectives: To determine the association between: socio-economic characteristics and blood pressure, pubertal maturation status and blood pressure, and anthropometric measures of adiposity and blood pressure in children and adolescents in Nigeria; and also to determine the overall prevalence of hypertension in the population of secondary school aged children and adolescents in Nigeria. Methods: A school-based stratified randomised cross-sectional survey of students aged 11 to 18 years was carried out in the urban area of Lagos, Nigeria. Blood pressure, body weight, height and waist measurements of the participants were obtained. A self-complete validated questionnaire was used to obtain sociodemographic information, health-related information, socio-economic characteristics (including living circumstances and parent/carer education level) and pubertal maturation status of the participants. Data analysis was carried out using descriptive statistics and multiple regression analysis. Results: 1086 students (538 males and 548 females) participated in the study, giving a total response rate of 90.5%. The overall mean systolic and diastolic blood pressure was 105.23±12.63mmHg and 57.87±8.09mmHg, respectively. The overall prevalence of hypertension was 2.5%. Socio-economic characteristics, pubertal maturation status, body mass index and waist circumference were statistically significantly associated with systolic and diastolic blood pressure (p<0.05). Conclusion: This study suggests that the epidemiological transition exists and is having measurable effects in school children in Nigeria. The findings highlight the presence of hypertension, and also the need for investigation of factors associated with blood pressure in children and adolescents so as to guide health policy, public health preventive interventions and health practice for child and adolescent hypertension. This study has long term implications for an extra burden of chronic non-communicable diseases related to hypertension in Nigeria.

Despite the scientific, technological and surgical improvements of the past 50 years organ dysfunction following elective paediatric cardiac surgery utilising cardiopulmonary bypass continues to account for increased complications, often leading to a protracted course in hospital with a longer stay in intensive care and the potential for irreversible organ damage long term. Furthermore, paediatric cardiac surgeons are routinely undertaking more complex operations with a shift from palliation to early correction. This has resulted in younger children being subjected to longer periods on the bypass machine with increased effects on vital organs. This thesis describes two clinical studies designed to further assess and characterise peri-operative cardiac, renal and pulmonary function in children undergoing elective cardiac repair at a tertiary referral centre in Scotland, UK. In the first instance a prospective, observational study was undertaken in forty-five children to examine the use of tissue Doppler imaging in the assessment of peri-operative cardiac function, its relationship to myocardial injury and clinical outcome. Tissue Doppler parameters were obtained using a Vivid 7 ultrasound scanner with a 7-MHz probe pre-operatively, on admission to paediatric intensive care and on day one. Myocardial injury was assessed using Troponin-I on the first post-operative day by a commercially available chemiluminescent immunoassay. In twenty children within this group peri-operative renal function was also investigated using standard estimates of glomerular filtration rate, namely creatinine clearance measured by the kinetic Jaffe method during the first and second twelve hour post-operative periods, in comparison to serum creatinine and the novel biomarker cystatin C. Routine plasma retained pre-operatively and on days 0, 1, 2 and 3 post-operatively was used to measure serum cystatin C and creatinine using a particle-enhanced nephelometric immunoassay and the Roche Creatinine Plus enzymatic assay respectively. The association between cystatin C and recorded perfusion parameters including bypass duration, pump flow, haematocrit, oxygen delivery and Troponin-I was investigated. Peri-operative pulmonary function was evaluated through a phase IV, randomised, double-blind, placebo controlled trial. In total, twenty four children were randomised to receive oral sildenafil or equivalent volume placebo four times the day before surgery. Blood samples were collected peri-operatively to measure serum cyclic guanosine monophosphate with a commercially available competitive enzyme immunoassay. Haemodynamic data and echocardiography were acquired at two and twenty four hours post-operatively including pulmonary vascular resistance index and bi-ventricular contractility. Post-operative oxygenation was also determined at the same time by oxygen delivery and oxygenation index. In Chapter 2, peri-operative cardiac function as assessed by tissue Doppler imaging was examined. The results of this study demonstrated that pre-operatively, bi-ventricular systolic function in the study group was reduced compared with normal controls, displaying a significant step-wise decrease with increasing complexity of lesion. This picture persisted post-operatively predominantly in the right ventricle and was significantly associated with the extent of myocardial injury. Impaired peri-operative left ventricular function correlated with clinical outcomes. In Chapter 3, peri-operative renal function as assessed by cystatin C and its association with parameters of perfusion was examined. The results of this study demonstrated that in comparison to serum creatinine, cystatin C had a superior correlation with glomerular filtration rate in the early post-operative period. An elevated level of this biomarker was significantly associated with bypass duration, minimum pump flow and post-operative myocardial injury. Haematocrit was not directly linked to renal dysfunction in this study although evidence of a critical dysoxic threshold within the kidney was suggested indirectly through oxygen delivery calculations. In Chapter 4, peri-operative pulmonary function and vascular reactivity in association with the pre-operative administration of oral sildenafil (0.5mg/kg, six hourly) was examined. The results of this trial demonstrated that compared to placebo, pre-operative sildenafil resulted in modest elevations of serum cyclic guanosine monophosphate, limited effects on pulmonary vascular resistance index, significant reductions in peri-operative bi-ventricular contractility, significant reductions in post-operative oxygen delivery and a trend for increasing ventilatory support. In summary, the current thesis has demonstrated that in children undergoing corrective cardiac surgery peri-operative bi-ventricular function can be accurately assessed by tissue Doppler imaging which to date has had limited use in this patient group. With regards to renal function, cystatin C was shown to be a better estimate of glomerular filtration rate and a more sensitive marker of early renal dysfunction in children after surgery. Furthermore, cystatin C identified a transient post-operative renal impairment, the magnitude of which was associated with duration of bypass, pump flow and myocardial injury. In relation to pulmonary function, this research identified that pre-operative administration of oral sildenafil to children undergoing cardiac surgery produced limited effects on pulmonary vascular resistance but was associated with reduced ventricular contractility and post-operative oxygenation raising significant concerns over its routine clinical use.

‘FRIENDS for Life’ is a manualised, 10 week, Cognitive Behavioural Therapy (CBT) based programme designed to be run in school and community settings (Barrett, 2010b). The programme has been introduced to schools within the local authority where the researcher is based via the local Targeted Mental Health in Schools (TAMHS) project. The programme is well reviewed and is recommended by the World Health Organisation for the treatment of anxiety disorders in children (World Health Organisation, 2004). Previous research has evaluated the programme when delivered in closely monitored situations with optimal implementation. The aim of this study is to evaluate the impact of FRIENDS for Life as implemented in a mainstream secondary school by school staff trained as part of the TAMHS initiative. This study makes an original contribution to the existing research base by evaluating the programme in a naturalistic, real world setting using an alternative methodology to the majority of published evaluations. Data regarding implementation of the programme was collected and analysed using activity theory. A single case experimental design was used to monitor the impact of the intervention on the emotional distress, anxiety levels and coping strategies of 5 secondary school participants (aged 11-13) who had been identified by school staff as appearing anxious. The findings suggest that participation in FRIENDS did not result in the hypothesised reductions in emotional distress, anxiety and negative coping skills or the hypothesised improvement in active coping skills. These results are discussed with regard to the finding that some aspects of the programme were not delivered. Analysis of the context using activity theory suggested that factors such as lack of time, space for delivery and experience and training impacted upon implementation. Methodological issues contributing to these findings are considered and implications for the local TAMHS project and for Educational Psychologists are discussed.

Background: Epilepsy is a serious chronic neurological disorder that has a higher incidence in children and young people (CYP) than in adults. Epilepsy negatively impacts physical and psychosocial quality of life of CYP. Good outcomes of epilepsy are associated with optimal choice of drug treatment and adequate adherence to the prescribed medicines. Research on the patterns of medication use and adherence to prescribed medicines in CYP remains limited. The long-term clinical outcomes and costs of treating epilepsy have not been extensively studied in CYP in the UK. Aim of the study: This thesis aimed to investigate the pattern of antiepileptic drug (AED) prescribing and the dynamic of medication adherence in CYP with epilepsy. The long-term clinical outcomes and direct costs of treating epilepsy in CYP were estimated at population level. Methods: This study is an observational cohort study of CYP, age 0-17 years, identified from The Health Improvement Network (THIN) primary care database from the UK between January 1988 and December 2004. Four different analyses were carried out on this cohort. First, a cross-sectional design repeated annually was employed to estimate the incidence and prevalence of epilepsy and the pattern of AED prescribing in this population. Secondly, the long-term adherence to prescribed AEDs was calculated using the medication possession ratio (MPR) method. Applying panel data analysis and the Generalised Estimating Equation (GEE) multivariate regression, factors that may have been associated with adherence to the prescribed AEDs were examined. Thirdly, seizure outcomes in terms of seizure frequency and remission of seizures and potential associated factors were assessed using the method of multiple failure survival analysis. Finally, the direct costs of treating epilepsy in CYP in primary care were estimated and stratified by the number of years after the first recording of epilepsy in THIN data. Results: Of total 528,760 CYP born on or after 1st January 1988 and registered in general practices contributed to THIN until 31st December 2004, 2020 CYP were identified who had a diagnosis of epilepsy, from under 1 up to 16.3 years of age (mean=5.6; SD=4.1). The annual incidence of epilepsy in CYP stratified by calendar years ranged from 44.4 (95% CI=31.9-61.8) to 61.2 (95% CI=50.6 -74.1) per 100,000 person-years. Incidence of epilepsy was significantly higher in children with greater socioeconomic deprivation than those with lower deprivation. Around 60% of CYP with epilepsy were prescribed monotherapy each year. Old AEDs such as carbamazepine and sodium valproate were the most frequently prescribed drugs and often prescribed as monotherapy to control epilepsy throughout 1990-2003. Prescribing of lamotrigine, a new AED, increased from 0.07 per person-years in 1992 to 2 per person-years in 2003. The calculated annual adherence to AEDs showed that around 50% of CYP adhered to at least 80% of the prescribed medications each year. Demographic characteristics of CYP were of little significance to affect adherence levels. The incidence of seizures was 0.73 (95% CI=0.71-0.75) per person-years. Incidence of seizures was higher in younger children up to 2 years and decreased with increasing age. A proportion of 94% (95% CI=93%, 96%) of CYP achieved 1 year remission of seizures, 80% (95% CI= 78%, 83%) achieved 2 years and 47% (95% CI=43%, 50%) achieved 5 years remission of seizures. The mean total direct cost associated with treating epilepsy in CYP, according to information in the general practice records that also indicated specialist and hospital care, was estimated at £ 1,153 (SD=1,808) per child in the first year following epilepsy diagnosis and at £459 (SD=1,633) per child for subsequent years. The costs of hospital care and AEDs represented the highest contribution to the total direct costs of epilepsy. The annual direct cost was significantly higher in younger children up to 2 years old. No significant difference in the annual costs was observed between CYP who adhered to at least 80% of medications and those who adhered to less than 80%. Conclusions: The incidence of epilepsy was highest in young children and CYP of higher socioeconomic deprivation. Old AEDs were most often prescribed as first-line drugs and as monotherapy to control epilepsy. Of newer AEDs, there was an increasing trend of prescribing lamotrigine and topiramate as add-on therapy. Long-term adherence to prescribed AEDs was suboptimal in one-half of CYP and positively associated with higher seizure frequency. Inpatient hospital care and drugs were the major contributors to the direct costs of treating epilepsy in CYP. Non-adherence to prescribed medicines was associated with higher hospital care costs but not with total direct costs as the medicines themselves made large contribution to the direct costs

This study presents an evaluation of the FRIENDS for Life program (Barrett, 2010) with an autism spectrum (AS) population. FRIENDS for Life is an intervention program underpinned by the principles of cognitive behavioural therapy (CBT) with a primary aim of reducing participant anxiety levels (Barrett, 2010). Existing research suggests it is an effective intervention in reducing participant anxiety levels (Briesch, Hagermoser Sanetti and Briesch, 2010) and it has been recognised by the World Health Organisation (2004) as the only evidence based program effective in reducing anxiety as a universal and targeted intervention. In recent years an evidence base for the application of CBT with children with AS has emerged, though primarily this research has been conducted in a clinical setting. Therefore this study aims to contribute to both evidence bases through implementing the FRIENDS for Life program within a new population as well as contributing to the broader evidence base evaluating the effectiveness of CBT with children with AS. The study adopted a post positivist epistemology and used a single case experimental design (SCED) to evaluate the effectiveness of the intervention in reducing the anxiety of four participants, aged nine to eleven, accessing special school provision. Anxiety was measured during a baseline, intervention and follow up phase using two weekly measures: the Paediatric Index of Emotional Distress (PI-ED;O'Connor et al, 2010); a short pupil questionnaire, and a weekly observation of participant behaviour. These measures were also triangulated with pre and post measures of anxiety using the Spence Child Anxiety Scale, child (Spence, 1997) and parent (Spence, 1999) version, and the School Anxiety Scale- Teacher Form (Lyneham, Street, Abbott and Rapee, 2008). Outcomes from the SCED showed that for all four pupils there was a significant decrease in anxiety from baseline to follow up on at least one weekly measure of anxiety, indicating a delayed effect on anxiety. The parent, child and teacher report triangulation measures suggested there was no significant change in anxiety post intervention. When considering outcomes, several key limitations to the study's design and implementation were taken into account including threats to construct validity and missing data in the intervention phase for two participants. The study concludes with support for the positive impact on participant anxiety as a result of the FRIENDS for Life intervention and recommendations are made for further investigation of the use of CBT interventions in schools with an AS population.

The work presented in this thesis is the result of 2 years of investigation into pathogenic mechanisms resulting in the development of osteonecrosis in children and young people treated for acute lymphoblastic leukaemia (ALL). This was a study using in vitro methods to investigate the effects of corticosteroids (namely dexamethasone which is used in the treatment of ALL) on osteocyte angiogenesis with particular focus on vascular endothelial growth factor (VEGF) and markers of bone remodelling. Interactions between dexamethasone and vitamin D were investigated in order to identify potential preventative or therapeutic strategies for osteonecrosis that could be studied in vivo. The actions of sex steroids on osteocyte biology and their interactions with dexamethasone were also studied in order to begin to explain the increased susceptibility to osteonecrosis that is exists in both adolescent and female patients. Results demonstrate a number of novel findings including; i) significant interactions between dexamethasone and vitamin D on osteocyte VEGF gene expression and protein secretion as well as the RANKL: OPG ratio which is crucial to bone remodelling, ii) dexamethasone treatment leading to significant alterations in expression levels of an array of genes expressed by osteocytes that are involved in angiogenesis pathways and iii) significant effects of sex steroids on osteocyte VEGF production and modulation of the effects of dexamethasone by oestradiol. Osteonecrosis is an extremely disabling side effect of the treatment for ALL which in the vast majority of cases is now a curable disease. The results of this thesis contribute to the current understanding of the pathogenesis and have identified a number of potential therapeutic pathways to target.