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.

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.

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

Background: Caring for a child with a chronic health condition is often associated with high levels of anxiety, depression and stress (Burton et al., 2003). Demanding caring duties, a lack of time and social isolation create barriers for carers accessing mental health support. The internet may be useful way for carers to access psychological supports but to date no research has explored this. Aims: To identify common difficulties which carers face and adapt a pre-existing computerised CBT (cCBT) based course to reduce carer stress. To determine the feasibility of providing mental health support to carers through an online course and assess its potential effectiveness and accessibility. Methods: Focus groups and questionnaires completed by hospice staff provided information regarding common stressors encountered by carers. Thematic analysis (Braun and Clarke, 2006) was used to identify topics which were then used to adapt a pre-existing cCBT course which consisted of 6 primary modules and additional online materials/modules plus the offer of weekly email support for 6 weeks from a support worker to encourage use. A single arm feasibility trial of the tailored cCBT was conducted using carers of children with chronic conditions recruited through advertisements and local hospice staff. Participants were provided with access to the cCBT course for 6 weeks and received weekly personalised support emails. Self-report measures of anxiety, depression and daily functioning were measures at baseline and at post-treatment. Questionnaires administered online explored participant satisfaction and course use which were then analysed. Results: 19 hospice workers were recruited to complete questionnaires regarding common difficulties faced by carers. Several themes emerged from thematic analysis of the data including: physical and interpersonal difficulties, external pressures, time constraints, limited support, responding to the child’s illness and difficulties accessing appropriate care for their child. 29 carers were recruited to trial the online course, with 55.6% recruited through social media. 12 (30.8%) carers logged onto the course and 6 (15.4%) completed follow-up measures at 8 weeks post intervention. Of the participants that started the course only 2 (18.2%) completed all 6 course modules. Exploratory analyses showed no statistically significant differences in depression, anxiety or functional impairment. However, results indicated a general reduction in clinically significant anxiety symptoms and functional impairment. Satisfaction questionnaires completed by carers post-intervention indicated a high level of satisfaction with the course. Qualitative results showed that participants valued the email support they received and the flexibility that an online approach provided. Some carers still struggled to find time to complete the course and suggestions were made to amend the course to enable it to be accessed offline and on portable devices. Conclusion: Computerised courses may be an acceptable way of offering mental health support to some carers. Difficulties in retention and recruiting suggest that further adaptations to the course are needed to improve engagement (i.e. delivering the course via apps, or moving to stand alone course topics rather than a recommended course). Alternative methods of delivering psychological support should be explored to avoid excluding those who do not have internet access.

Background: This thesis sits within the arena of weight status during and after childhood acute lymphoblastic leukaemia (ALL), with a particular focus on the prevalence of unhealthy weight status amongst (ALL), Saudi and UK populations. Each chapter in the thesis explores different aspects of unhealthy weight status in ALL which had been highlighted as gaps in the literature at a conference in Puebla, Mexico, at the end of 2006. A summary of each study is given below. Study 1: Background: This study estimated prevalence of unhealthy weight status and metabolic syndrome (MS) amongst Saudi survivors of standard risk ALL. Methods: We recruited 56 survivors, mean age 13.4 years (SD 4.1), a mean of 9.1 years (SD 4.1) post-diagnosis. The BMI for age was used to define weight status relative to national (Saudi) and international (Cole et al., International Obesity Task Force (IOTF), World Health Organisation (WHO), and Centre for Disease Control and Prevention (CDC)) reference data. We measured body composition by dual energy X-ray absorptiometry (DXA), waist circumference, blood pressure, lipid profile (HDL-C, Triglycerides), fasting glucose and insulin. Results: According to international definitions based on BMI for age, around half of the sample had unhealthy weight status. All of the approaches based on BMI for age underestimated over-fatness, present in 27/51 (53%) of the sample according to DXA. Prevalence of MS was 7.1% (3/42 of those over 9-years old) and 5.4% (3/56) by applying the International Diabetes Federation (IDF) definition and National Cholesterol Education Program Third Adult Treatment panel Guidelines (NCEP III), respectively. However, MS by the NCEP III definition was present in 19% of the overweight and obese survivors and 7.1% of the sample had at least two of the components of MS. Conclusions: Unhealthy body weight and over-fatness may be common amongst adolescent Saudi survivors of standard risk ALL, though overweight and obesity may be no more common than in the general Saudi adolescent population. Defining weight status using BMI underestimates over-fatness in this population, as in other populations. Study 2: Background: Underweight, overweight, and obesity at diagnosis may all worsen prognosis in childhood ALL, but no studies have estimated prevalence of unhealthy weight status at diagnosis in large representative samples using contemporary definitions of weight status based on BMI for age. Methods: Retrospective study which aimed to estimate prevalence of underweight, overweight, and obesity at diagnosis for patients with childhood ALL on three successive UK treatment trials: UKALL X (1985-1990, n 1033), UKALL XI (1990- 1997, n 2031), UKALL 97/97-99 (1997-2002, n 898) .The BMI for age was used to define weight status with both UK 1990 BMI for age reference data and the IOTF definitions. Results: Prevalence of underweight was 6% in the most recent trial for which data were available. Prevalence of overweight and obesity was 35% in the most recent trial when expressed using IOTF definitions; 41% when expressed relative to UK 1990 reference data. Conclusions: Even with highly conservative estimates >40% of all UK patients with ALL were underweight, overweight, or obese at diagnosis in the most recent trial for which UK data are available (UKALL 97/99, 1997-2002). Study 3: Background: This study tested the hypothesis that overweight/obesity at diagnosis of childhood ALL was related to risk of relapse. Methods and results: In a national cohort of 1033 patients from the UK there was no evidence that weight status at diagnosis was related significantly to risk of relapse: log ranks test (p value= 0.90) with overweight and obesity as the exposure (n 917); individual (p value= 0.42) and stepwise (p value= 0.96) proportional hazards models, with BMI z score as the exposure (n 1033). Conclusion: The study does not support the hypothesis that overweight/obesity at diagnosis impairs prognosis in childhood ALL in the UK. Study 4: Background: In the sample of Saudi patients recruited to study 1 we compared DXA whole body and lumbar spine bone mineral density (BMD) using manufacturers software with a body size correction which derived bone mineral content (BMC) for bone area and Apparent bone mineral density of lumbar spine (BMADLS). Methods and results: The survivors of ALL were from Saudi Arabia (n 51, mean age 13.5 years). With no corrections, 29 patients (57%) had lumbar spine BMD z score < -1.0 and 21 (41%) had whole body BMD z score < -2. After correction, by using BMC for bone area method only 6 (12%) had lumbar spine BMC z score <-1.0 and 4 (8%) had whole body BMC z score <-2. By using BMADLS method, 18 (35%) had BMC <-1.0 and 6 (11%) had BMC Z score <-2. Conclusions: Correction for body size seems essential to accurate interpretation of DXA bone health data in adolescent survivors of ALL. The three correction methods provided different conclusions, but bone health remains a concern after treatment for ALL.

This research project sets out to explore the lived experience of Being and caring for a child with a Life Limiting Condition. This research uses van Manen’s (1990) conceptualisation of hermeneutic phenomenology that is both a research methodology and a method. The first empirical work is a preliminary study using focus groups with professionals. The findings of this work acts as a backdrop to the further two studies that involve interviewing, in-depth, twenty eight parents and five children. The second study details the parents’ lived experiences and the final study looks at five parent-child dyads and their combined lifeworlds. In keeping with the phenomenological methodology, data was analysed using Template Analysis (King, 2004). It is a rare opportunity to observe and speak with children with Life Limiting Conditions and so gain insight into their lives. Their vulnerability is often characterised by rare and difficult-to-diagnose conditions, significantly shortened life spans with compromised quality of life. For the participants, the experience of Life Limiting illness was not only personal, but was also transactional, communicative and profoundly social. The challenge is one of Being thrown into an abnormal unready world which compels one to consider the paradoxical temporality of the here and now. This brings recognition of being the same as others in a lived space, but also being different in a fundamental way that has a significant impact. The challenge is met by adapting to the environment to find new ways of Being. This research encourages readers to thoughtfully reflect on what is it like for these families and those involved in their care, and to consider practice improvements that address the triadic experience (of child, parent and professional). The full significance of such reflection will ideally promote further questioning and inquiry, in keeping with the always provisional nature of phenomenological inquiry.

In the absence of readily available physiological models of human growth, the effects of oestradiol on the human C28/I2 chondrocyte cell line were studied. The classical oestrogen receptors, ERα and ERβ, were shown to be expressed in both murine and human chondrocyte cell lines. Oestradiol and related chemicals, which alter the function of the oestrogen receptors (ER), were exploited to tease out the different functions of each ER in the growth plate. In the absence of foetal bovine serum, oestradiol had no effect on proliferation, differentiation or apoptosis of chondrocyte cells in monolayer culture or on the growth of the foetal metatarsal culture system. In addition, oestradiol did not convey a protective effect on chondrocytes exposed to the pro-inflammatory cytokines, tumour necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in monolayer culture. However, endogenous oestrogen appears to play an important role in maintaining chondrocyte proliferation in monolayer culture and mineralisation in metatarsal culture as reflected by the inhibitory effects of Faslodex, the non-specific ER antagonist, on chondrocytes and metatarsals in culture. In the presence of methyl-piperidino-pyrazole (MPP), a selective ERα antagonist, and raloxifene, a selective oestrogen receptor modulator with higher ERβ binding affinity, a reduction in chondrocyte proliferation and increase in apoptosis was observed in murine and human chondrocytes. Similarly, a marked reduction in linear growth occurred when foetal murine metatarsals were exposed to MPP and raloxifene in combination. A less marked reduction in growth was observed in MPP-treated metatarsals. These findings suggest that the oestrogen receptors may have opposing actions in the growth plate with ERβ acting like a brake on chondrocyte growth and ERα promoting growth. ERβ may regulate cell proliferation through control of cell cycle modulators affecting G1/S phase transition as MPP and raloxifene in combination reduced cyclin E and p53 levels on Western blot analysis. The aim of the second part of my thesis was to investigate the effect of oral oestrogen on linear growth in girls with primary ovarian insufficiency (POI). A retrospective review of girls with POI treated at a tertiary endocrinology clinic over an 11 year period was performed. As expected the majority of girls with POI had Turner syndrome (TS; 83.7%). Non-TS associated POI was rare and the leading cause was iatrogenic secondary to the effects of total body irradiation for bone marrow transplantation (12.8%). A significant proportion of these girls developed POI after full pubertal development so few cases were available to investigate the effect of oestrogen on growth. The oral oestrogen regime followed in individual patients with TS was highly variable so it was not possible to assess the effects of dose on height velocity or bone maturation in this retrospective audit. However, the second clinical study examined in detail the effect of oestrogen on growth in TS girls who received a standardised course of oral ethinylestradiol for pubertal induction and a standard dose of growth hormone (10 mg/m2/week). These girls participated in a prospective randomised double-blind placebo-controlled multi-centre study of growth promoting treatment in TS. The girls were initially randomised to oxandrolone or placebo at 9 years of age and further randomised to oral ethinylestradiol at 12 or 14 years of age. The results of this study are embargoed until published. The laboratory effects of oestradiol found in this thesis suggest that ERα may stimulate or maintain growth, and ERβ may inhibit growth. The obvious question is how these observations might be involved in the complex relationship between puberty, oestrogen and height velocity in humans. As affinity studies show that the half maximal effective concentration (EC50) of ERα is achieved at slightly lower concentrations of oestradiol than ERβ it is conceivable that the ERα effect could predominate at lower systemic oestradiol concentrations and that ERβ could become more important at higher concentrations for example in later puberty. Alternatively, it is possible that the expression of ERα reduces or ERβ increases in the growth plate after reaching peak height velocity.

Profiles of sleep disturbance and sleep quality of children with the specific neurodevelopmental disorders of Smith-Magenis syndrome (SMS), Angelman syndrome (AS), autism spectrum disorder (ASD) and tuberous sclerosis complex (TSC) and the relationships between behavioural and health characteristics, age and sleep were described in these groups. Interview data demonstrated that children with AS's sleep disturbance had a negative impact on both parents and children. A homogeneous sleep disturbance profile of severe night waking and early morning waking affected over 70% of children with SMS but more heterogeneous profiles were found for children with AS, TSC and ASD using cross-group questionnaire data comparisons and when compared to typically developing (TD) children. A heightened risk of sleep-related breathing disorders was identified for children with AS and SMS. Compared to TD children, children with SMS had significantly earlier morning wake times and children with AS and SMS had significantly earlier bedtimes according to actigraphy and sleep diary data. Increased daytime sleepiness in children with SMS was associated with increased overactivity and impulsivity. This thesis includes the largest samples of actigraphy data for children with SMS and AS to date. The importance of aetiology of intellectual disability in the profiling of sleep disturbance was evidenced. Areas for further assessment and intervention include sleep-related breathing disorders for children with AS and SMS and individualized assessment of circadian rhythm disorders for both groups.