Introduction Randomised controlled trials administering probiotic supplements to preterm infants to prevent sepsis and necrotising enterocolitis are already underway, despite the lack of a robust evidence base of normative values for gut microbiota, bacterial metabolites, and markers of inflammation and immunity. There are increasing calls for observational studies to establish baseline data in these infants. Most of these studies to date have involved the measurement of these analytes individually. In the studies presented in this thesis, we measured a range of stool markers collectively in a cohort of preterm infants in health and disease. Design 56 infants at <32 week gestation and less than 1500g birth weight were sequentially recruited from all three Glasgow Neonatal Units within week one of life after commencement of enteral feeds. Anthropometric, dietary and treatment data were collected. Stool samples were taken once weekly for the first four weeks, testing: short chain fatty acids; calprotectin, secretory immunoglobulin A; and microbial diversity by temporal temperature gel electrophoresis. Results Out of 61 live births meeting the study criteria, 56 infants were enrolled in the study, 62.5% of whom were female. 19.6% were between 24-26 weeks gestation, 28% were 26-28 weeks, 30% were 28-30 weeks, and 21% were 30-32 weeks. 5.3% were between 490-600g in birth weight, 17.8% were 600-800g, 21.4% were 801-1000g, 39.2% 1001-1250g, and 16% were between 1251-1500g. Feed regimen was heterogeneous, comprising 5 combinations of maternal, donor and formula milks. The highest social deprivation level as measured by the Carlisle ‘Depcat’ scoring system of level 7 was significantly higher in the study group than Glasgow or Scotland-wide averages. Sepsis rates were low, with a group median of only 1 per infant. Overall mortality: 7%. 32 with any NEC (56%), 20 with Bells’ ≥2a NEC. 8 (14%) with surgically treated NEC, 5 (8%) underwent ileostomy. SCFAs: (n=56) there were no correlations between gestation, weekly totals, feed type, or NEC and SCFA concentration. Acetate and lactate dominated each sample. Few significant changes were noted with respect to NEC, and these were in the less dominant SCFAs: stage 2a NEC showed higher concentrations of propionate in week 4 than week 3, and lower valerate in week 4 than 2. Stage 3b levels of isobutyrate and heptanoate were significantly lower in week 4 than 3. FC: (n=56) there were no significant differences in FC levels between each week in infants with or without NEC, although the former illustrated a trend to lower levels by week 4. There were no significant differences in NEC before and after clinical signs were apparent, or in those before NEC and after stoma formation for stage 3b NEC. However, significantly lower FC levels were noted in stage 3b NEC requiring ileostomy compared to the immediate pre-operative sample. SIgA: (n=34) Levels rose significantly week on week, and were considerably higher in weeks three and four than week one. There were no significant differences in stool SIgA concentration between infants with and without NEC. A significant increase in mean stool SIgA concentration appeared from week 2 to week 3 in NEC infants, and from week 1 to week 2 for those without. For all breastfed preterm neonates (n=6), the level of milk SIgA was significant higher on week 1 (colostrum) than week 2 and week 3. TTGE: (n=22) There was large variability between number (1-17) and species diversity (25-36 different species). Bacterial composition varied largely between the 2 sample points. No difference in species richness or similarity within the 2 feeding groups was observed. 4 bands were identified in >50% of infants. Intra-individual similarity varied greatly and ranged from a similarity index (Cs) of 0% to 66.8%. There was no statistical difference between the similarity indices of the feeding groups or between those with and without NEC. There were no significant correlations between any of the analytes. Conclusions Only extreme prematurity and extremely low birth weight were associated with NEC, which was at a strikingly high incidence. A limitation was therefore the unexpected onset of severe NEC resulting in prolonged paralytic ileus with low stool production. No correlations were found between analytes, indicating that each set of stool investigations may signify independent physiological, biochemical and immunological gut processes. Despite the severity of NEC, the levels of each analyte were remarkably consistent. High levels of deprivation within the study population may provide the constellation for an as of yet undefined genetic and epigenetic predisposition to NEC in this cohort, similar to that of other illnesses endemic to different geographical areas – notably Multiple Sclerosis in the North East of Scotland – and both follow up of these infants into childhood as well as further analysis of future inborn infants with NEC is planned.

Exclusive breastfeeding (EBF) for 6 months is recommended as the most cost-effective public health intervention to improve child survival particularly in Sub-Saharan Africa and is central to achieving Millennium Development Goal number 4 for child health. However, despite the benefits of EBF to infants and mothers, the rates continue to decrease as the age of the infant increases in an African cultural context including Malawi. There is increasing literature on the effectiveness of community-based peer counselling on EBF promotion in resource-poor settings but its effectiveness in the context of HIV and experiences of HIV positive women with the intervention remains a gap. The purpose of this thesis was to explore determinants of EBF using MaiMwana infant feeding peer-counselling intervention conducted in Mchinji, Malawi as a case study. Specifically, in this study I explored the effectiveness of the intervention to help HIV positive women to overcome the barriers and examine people’s experiences and perceptions towards the intervention with respect to HIV and poverty. I adopted qualitative in-depth interviews with 39 informants, including breastfeeding mothers, peer counsellors and key informants who were purposely selected. The data was analysed using a framework approach. I found that despite having good knowledge, women from rural communities face considerable challenges while practicing EBF. Cultural beliefs, economic constraints, lack of power and support, and fear of transmitting the virus to their infants were cited as major barriers that prevented them from practicing EBF. Overall, the findings from this study suggest that peer counsellors are well accepted by service-users and other community members as they positively viewed their frequent visits as providing additional support, reinforcing infant feeding messages and provide psychological support to women resulting in improved EBF rates. Furthermore, the presence of peer counsellors was viewed as “bringing services at their door step” which reduced time and cost to travel to the health facility. Nevertheless, the findings suggest that voluntary work in resource-poor settings presents considerable challenges such as: poor motivation due to lack of incentives, overworking, lack of knowledge and time to handle HIV positive cases and poor supervision. In order to effectively promote EBF in resource-poor settings, public health programme designers and implementers need to consider these barriers so as to design community-based interventions that suit the local context and create an enabling environment.

Domestic abuse puts children at risk. There is evidence that the health of these children is compromised. This thesis aims to explore whether specific health services to children living in refuges with their mothers who have fled domestic abuse should be targeted at this group. Method The epidemiological, comparative and corporate methods of health care needs assessment were used. Evidence for effective interventions to address the key health issues for this group of children was sought. Few other service models could be found against which to directly benchmark. Guidance for services to children in these circumstances was thus included in the review as a comparator. Professionals and Mothers were interviewed to explore their perspective on the needs of these children. Results Children in refuge have an increased risk of mental health problems and poor access to health services. They are more likely to have suffered maltreatment themselves. Refuges in Cardiff provide assessment and a programme of work and support for children. The specialist health visitor role uncovers unmet health needs in the under 5s. Professionals working with these children and their mothers are concerned about their mental health and are looking for more specialist CAMHS (Child and Adolescent Mental Health Service) help. A number of barriers stand between children and the health services they need. Referral criteria are not clear and timeliness of services and continuity of care is an issue for mobile families. Conclusions A model for health service is suggested for children in refuge using the logic model method. The Primary Mental Health Worker role should provide the advice and expertise Tier 1 workers require and demystify the referral criterion for specialist CAMHS. Timing and continuity of care for appointments requires joint decision making and a flexible service. Health staff requires training to provide an acceptable and accessible service to vulnerable families.

Children with Autism Spectrum Disorder (ASD) have difficulties with social interaction that affect their early learning through play. Systematic reviews were conducted on the effectiveness of Social Stories™ (SS™), Self Video Modelling (SVM) and Peer Video Modelling (PVM) to teach social behaviour to such children. Study 1 compared their effectiveness for teaching three core play skills to 18 young children with ASD: initiating play, turn taking and finishing play; using a counterbalancing design across skills and play materials so that each participant received each intervention. At intake, participants’ ages, Vineland Adaptive Behavior Scale and PLS-3 scores were assessed. The three core skills were observed with good interobserver (97.3%) and procedural (100%) reliability and quantified using a specifically designed scale. The social validity of target skills and interventions was assessed using a Likert scale. All interventions showed evidence of significant improvement. Non-parametric repeated measures ANOVA and post-hoc Wilcoxon tests showed that SVM was superior to SS™ and PVM. Such superiority was evident for initiating play and turn taking but not for finishing play. There was no significant association between the intake variables and either the degree of change between baseline and post-intervention or the post-intervention scores themselves for SS™. Change following SVM was positively related to the Vineland composite score and its motor skills domain score. Post-intervention scores for SVM were positively related to the Vineland composite scores and its communication, daily living and motor skills domain scores as well as all three PLS-3 scores. Change following PVM was related to the Vineland maladaptive score. The target skills and interventions had high social validity. Study 2 showed that more sustained intervention over time resulted in improvement for those who did less well initially. Overall, the research provides encouraging evidence that these interventions are effective in teaching play behaviours to young children with ASD.

The health service provides a Child Health Programme (CHP) to all children to help them attain their health and development potential. Core elements include screening, immunisations, growth and development surveillance, health promotion advice, and parenting support. The surveillance/advice/support components (known as Child Health Surveillance CHS) are delivered through a series of universally offered child health reviews mainly provided by Health Visitors (HVs) supplemented by additional support as required. Scottish policy issued in 2005 led to considerable changes to the CHP. The number of CHS reviews was substantially reduced to enable more intensive support of children who required it. A three category indicator of need was introduced at the same time to facilitate the identification of children requiring enhanced support. This thesis aims to explore the shift to more targeted provision of CHS that occurred from 2005 onwards, and to examine the impact of this on the preventive health care provided to pre-school children. The specific objectives are: · To describe the development of professional guidance on the CHP and how this has been adopted into Scottish policy. · To compare the CHP provided in Scotland to that offered in other high income countries. · To examine the impact of the changes to CHS on the coverage of universally offered child health reviews. · To explore, following the changes to CHS, which factors are associated with children being identified as in need of enhanced CHP support. · To assess the impact of the changes to CHS on the totality of preventive care provided to pre-school children by HVs and General Practitioners (GPs). The key methods used are literature review, policy analysis, and analysis of routine health data. Selected findings include the following: · All the high income countries studied provide the same basic elements as the Scottish CHP but the detail of the different programmes varies considerably. Some of the variation may reflect the different needs of different populations, but much seems to reflect different approaches to evidence interpretation and policy making in different settings. · Not all children offered ‘universal’ child health reviews actually receive them. Children from deprived areas are less likely to receive their reviews. Inequalities in review coverage have remained unchanged after the changes to CHS. · Many factors, including those reflecting infant and maternal health and family social risk, are associated with being identified by HVs as needing enhanced CHP support. The threshold at which children are identified as needing enhanced support varies between areas across Scotland. · GP provision of child health reviews has reduced after the changes to CHS as would be expected. Recorded GP provision of other preventive care consultations is uncommon and has not changed. Currently available routine data do not allow trends in the totality of HV provided care to be examined. In summary, the Child Health Programme makes an important contribution to supporting young children and their families but it is a complex service and considerable uncertainty about aspects of its content and delivery remain.

The World Health Organization estimates that 22 million children worldwide aged <5 years are overweight and highlights tackling childhood obesity as an urgent priority. Childhood obesity is rising to epidemic proportions in the developing world, reflecting changing physical activity levels and dietary intakes, adding a significant public health burden to countries where undernutrition remains common. Interventions to prevent childhood obesity have had disappointing results, because the science and aetiology of obesity is poorly understood and prevention programmes have not targeted appropriate behaviours nor adequately engaged communities being studied. The origins of obesity appear simple, excess energy intake and/or low energy levels expended on physical activity, leading to chronic energy imbalance. However, the problem is more complex with underlying societal, behavioural and genetic causes of energy imbalance remaining unclear. Obesity is driven by individual, household and community factors: research to date has concentrated on individual factors with almost no significant focus on higher level influences on obesity. Findings from studies in developed countries are unlikely to be applicable to rural African settings where there is an increasing transition from a state of undernutrition to that of overnutrition. Few data exist on the prevalence of child and adolescent obesity from low and middle income countries like South Africa. This thesis aimed to determine the prevalence of overweight and obesity in children and adolescents (aged 7-15 years) within this population and to identify possible risk factors. Participants and Methods The study was cross-sectional and involved collecting primary data in local schools. A total of 1,519 subjects were recruited from three age groups (approximately 500 from each age group 7, 11 and 15 years). Participants were recruited from school grades 1, 5 and 9 corresponding to the ages 7, 11 and 15 years respectively. The study comprised two parts, a main cross-sectional study and a further study including a sub-sample of the participants. In the main cross-sectional study anthropometric measurements (height, weight, mid-upper arm circumference and body fat) were performed on all the participants and a lifestyle questionnaire administered (questions related to water collection, travel to school, TV watching and sport participation). The study took place in a demographic surveillance area and data collected from participants was linked with their household/community data to allow analysis of variables associated with overweight/overfat status. 150 participants were randomly selected from the main study (50 from each age group 7, 11 and 15 years) and invited to take part in a sub-sample study which included objective measurement of physical activity (7 days accelerometry) and dietary assessment (2 x 24 hour multiple pass recall assessments) on each participant. Main Findings Prevalence of overweight and obesity was higher in girls than boys and was highest in the oldest age groups for females. Using the Cole/IOTF BMI for age reference combined overweight and obesity was 23% in grade 9 females compared to only 6% in boys in the same grade (p<0.01). The lifestyle questionnaire revealed high levels of water collection, active commuting and TV watching.

Crohn’s disease (CD) is a chronic inflammatory bowel disease. Once considered rare in the paediatric population, it is recognized with increasing frequency among children of all ages. Approximately 20-30% of all patients with CD present when they are younger than 20 years. With its increasing recognition, CD has become one of the most important chronic diseases that affect children and adolescents. In addition to the common gastrointestinal (GI) symptoms (diarrhoea, rectal bleeding, and abdominal pain) children often experience growth retardation, pubertal delay, and bone demineralization. In these children, maintenance of skeletal health is a complex process that is influenced by a number of different mechanisms including steroid therapy, the disease process, nutritional status, endocrine status and the response of the body to inflammatory mediators. The recent introduction of biologic therapy that targets specific mediators of the proinflammatory process is a promising adjunct in the therapeutic management of the child with chronic inflammation. These drugs may also exert beneficial effects on the adverse effects of inflammation on growth and skeletal development. It is unclear whether these beneficial effects are due to improvement in overall disease or due to a direct ‘anti-cytokine’ effect at the level of the target tissue involved in growth and skeletal development. The hypothesis of this study was that the biologic therapy improves linear growth, puberty, bone health, body composition and muscle function in children with CD and this is associated with changes in the IGF-1 axis and markers of bone formation and bone resorption. Chapter 1 is an extensive literature review about the effects of biologic therapy on growth and skeletal development in paediatric patients with chronic inflammatory conditions particularly inflammatory bowel disease (IBD). The main aim of this review was to summarize and evaluate effects of inflammation and biologic therapy on growth and skeletal development in children with chronic inflammatory conditions and to explore the areas of interest for further research. Chapter 2 is the study about the growth in children receiving contemporary disease specific therapy in children with CD. The aim of this study was to assess the frequency of short stature and poor growth and their relationship to disease course and therapy in children with CD. Clinical records of all children with a confirmed diagnosis of CD, who were between 2yrs and 18yrs at the Royal Hospital for Sick Children, Glasgow were examined retrospectively. Data were collected at diagnosis, 1-yr, 2-yr and 3-yr after diagnosis and at maximum follow-up. The relationship of a number of factors including therapeutic modalities to two commonly used anthropometric markers of growth height velocity standard deviation scores (HVSDS) and change in height standard deviation scores (∆HtSDS) was examined. This study suggested that ∆HtSDS may be a more valid method of assessing and reporting longitudinal growth in children with chronic disease, particularly when there is a high prevalence of children of a peri-pubertal age. This study provides clear evidence that despite advances in therapy, short stature and slow growth continue to be encountered in a sub-group of children with CD. Chapter 3 is about the effect of Infliximab therapy on growth, puberty and disease activity in children with CD. The aim of this study was to assess growth, puberty, markers of disease and concomitant therapy over the six months prior to starting Infliximab and for the 6 and 12 months following treatment. Clinical records of all children with IBD who were started on Infliximab therapy between 2003 and 2008 at the Royal Hospital for Sick Children were examined retrospectively. This study has shown an average improvement of approximately 50% in HV in the 6 months after the initiation of Infliximab therapy which was further sustained for a further 6 months. Improvement in growth was found to be better in those children who were responders as compared to non-responders suggests that growth improved as a result of disease control. Improvement in growth was also observed in children who remained pre-pubertal and those who had never been on glucocorticoids (GC) compared to those who had been on GC. This study suggests that increase in height may not be simply due to progress in pubertal status or reduction in glucocorticoid dose. Chapter 4 is about the effect of Adalimumab therapy on growth in paediatric patients with CD. This is the one and only world wide multicentre study that adequately assess the effect of Adalimumab on linear growth in children with CD. The aim of this study was to assess the effect of Adalimumab therapy on growth, puberty and disease activity over the 6 months prior to and 6 months after starting Adalimumab treatment in children with CD. This study provides evidence that Adalimumab is associated with improvement in short term linear growth in children with CD who enter remission but not in those who do not. It is also more likely to happen in children who are on immunosuppression and those in early puberty but seems to be relatively independent of steroid use. These findings suggest that growth improves as a result of several interrelated factors, including improved disease control. It was also interesting to note that the growth response to Adalimumab varied dependent on the reason for discontinuing Infliximab; those who had an allergic reaction to Infliximab fared best. Chapter 5 is Longitudinal observational prospective study of changes in physical growth, IGF-1 axis, bone health, body composition, muscle function and disease activity at baseline (BL), 2 weeks (2wk), 6 weeks (6wk), 6 and 12 months (6M & 12M) following biologic therapy in paediatric patients with CD. The aim of this longitudinal observational prospective study was to assess changes in physical growth, puberty, IGF-1 axis, bone health; body composition and muscle function following biologic therapy in paediatric patients with CD. Patients either newly diagnosed or patients with long-lasting disease in clinical relapse, who started treatment with biologic therapy as part of their standard clinical management, were recruited. A non significant improvement was observed in both ∆HtSDS and HVcms/yr at 12M as compared to BL. Individually, the majority of the children experienced improvement in clinical activity and improvement of the systemic inflammatory markers. A significant increase in biomarker of bone formation bone specific alkaline phosphatase (BALP) and a non-significant increase in a biomarker of bone resorption cross-linked c-terminal telopeptides (CTX-1) was observed from BL to 12M. This observation suggests the beneficial effect of biologic therapy on bone formation. This study showed a significant change in fat mass (FM (kg) in paediatric patients with CD following biologic therapy an effect that has not been reported extensively in previously published studies. A significant change in both fat free mass (FFM (kg) and fat free mass index (FFMI(kg/m²) shows that the treatment with anti-TNF-α therapy also had a significant impact on fat mass accrual. This is the first study that charts the effect of biologic therapy on changes in lower limb muscle function using jumping mechanography in paediatric patients with CD. A non significant change was observed in jump height (m), V-max (m/s), EFI (%), efficiency % from BL to 12M following biologic therapy and a significant increase in both F-max (kN), and P-max (kW) at 12M. Despite the fact that the increase in efficiency % of the movement was not significant but however, the change was likely to be through improvements in jump height and velocity thereby indicating higher muscular flexibility. These data are suggestive of an effect of biologic therapy on lower limb muscle function through improvements in the mechanical efficiency of the muscle.

Introduction Obesity is the most common nutritional disorder in the world and is widely acknowledged as having become a global epidemic.(1) The prevalence of childhood obesity in the United Kingdom (UK) dramatically increased over a short number of years in the 1990s.(2-4) There are well-recognised health consequences of childhood obesity, both during childhood as well as those tracking into adulthood affecting health, psychological and economical welfare.(5;6) However, there is a surprising lack of well conducted published research into effective childhood obesity treatment strategies and few with relevance to the UK National Health Service (NHS).(5;7) This thesis describes (a) the Scottish Childhood Obesity Treatment Trial (SCOTT), a randomised controlled trial (RCT) that compared standard NHS dietetic management of childhood obesity with a novel intensive dietetic approach in Scottish primary school aged (5 – 11 years old) children and (b) reports a complementary qualitative study that explored the parents’ perceptions of the dietetic treatments their child received during the SCOTT project. The SCOTT project was conceived to be an easily reproducible treatment programme within the UK NHS system for primary school aged children. Methodology The SCOTT quantitative study was a single-blind RCT involving 134 obese children of primary school age (5 -11 years), 75 females and 59 males. Inclusion criteria were children with ‘simple’ obesity (body mass index (BMI)  98th centile on the UK 1990 charts) and families that perceived the child’s weight as a problem and were motivated to change. The intervention arm involved an evidence-based novel dietetic treatment over 6-months giving 5 hours of treatment and used client-centred behavioural change techniques to increase motivation for changing diet (using a modified traffic light diet), increasing physical activity and reducing sedentary behaviour. The control arm received 1.5 hours of ‘typical’ dietetic weight management delivered in a traditional (educational) manner. Outcomes recorded at baseline, six and 12 months were BMI standard deviation (SD) score, objectively measured physical activity and sedentary behaviour (using accelerometers) and possible adverse effects of treatment (height growth and quality of life). The primary outcome was change in BMI SD score at six months. The complementary qualitative study used in-depth interviews to explore the thoughts and feeling of parents of the children who had completed the dietetic intervention. All interviews took place after the SCOTT 12 month outcome measurements had been completed. Purposive sampling was used and out of the 79 eligible SCOTT parents 17 were interviewed. The interviews were taped and then transcribed by experienced secretaries. Analysis was carried out using the Framework methodology (8) and aided by Nvivo software. Key Results The novel treatment programme had no significant effect relative to the standard dietetic care on BMI SD score from baseline to six months (-0.10 vs -0.06; 95% CI -0.05 to 0.11) and 12 months (-0.07 vs -0.19; 95% CI -0.17 to 0.07). BMI SD score decreased significantly within both groups from baseline to six and 12 months. There were significant differences between the groups in favour of the novel treatment group for changes in total percentage of time spent in physical activity (95%CI 0.8 to 6.3) and light intensity physical activity (95%CI -4.8 to -0.5). In the qualitative study we found themes and concepts both on our original evaluation and emergent data on the parents’ thoughts and feelings on entering, continuing and leaving treatment. Those parents who had taken part in the behavioural change techniques applauded the process finding it child-friendly and talked of ‘forming a partnership’ with the child and dietitian. Developing a rapport with the dietitian was significant for the parents in their perception of a positive experience. Parents appeared to be characterised as being unaware of their child’s weight problem, in denial, or actively seeking treatment. Parents were consistently motivated to enter treatment due to perceived benefits to their child’s self esteem or quality of life, and weight outcomes were considered less important. During treatment parents expressed a lack of support for lifestyle changes outside the clinic, and noted that members of the extended family often undermined changes. Parents generally felt that treatment should have continued beyond six months, and that it had provided benefits to their child’s well-being, self-esteem, and quality of life, and this is what motivated many of them to remain engaged with treatment. Conclusions The modest magnitude of the benefits observed in the SCOTT study perhap suggest that interventions should be longer term and more intense. The results of the qualitative study suggested that longer term interventions would be acceptable to parents. The qualitative study was an informative addition to the SCOTT quantitative study as it allowed exploration of the subtle differences as perceived by the parents who took part in both arms of the study. It may help inform future treatments for childhood obesity by providing insights into the aspects of treatment and approaches applauded by parents. Future treatments may need to consider providing greater support to lifestyle changes within the extended family, and may need to focus more on psychosocial outcomes. This study highlighted skills and qualities required by dietitians and other health professionals to engage with families of obese children.

Introduction: Insulin Pump Therapy has gained worldwide acceptance for the treatment of Type 1 diabetes mellitus (T1D), offering a new method of insulin delivery, which circumvents the need for Multiple Daily Injections (MDI). It is thought to improve quality of life (QoL) by facilitating an increase in lifestyle flexibility, independence and glycaemic control (Scottish Intercollegiate Guidelines Network, 2010; National Institute for Clinical Excellence, 2008). These benefits have resulted in the National Health Service (NHS) Scotland pledging funding of at least £1million to deliver insulin pumps to under 18s (Scottish Government, 2012). Currently, investigations regarding the impact of Insulin Pump Therapy on QoL have resulted in conflicting findings (Barnard et al., 2007). This study aims to explore the impact of Insulin Pump Therapy on the QoL of children and adolescents, using Interpretative Phenomenological Analysis. Method: Eight participants with T1D, aged between 8 and 13 years and using an insulin pump, were recruited from the Glasgow Royal Hospital for Sick Children Diabetes Clinic. Each participant completed an in-depth interview, which explored their beliefs and attitudes towards Insulin Pump Therapy including its impact on their QoL. Results: Analysis of the transcripts led to the identification of six super-ordinate themes: ‘Physical Impact’, ‘Mood and Behaviour’, ‘Lifestyle Flexibility’, ‘Practicalities’, ‘Peer Reactions’, and ‘Support’. It is suggested that these six factors are not mutually exclusive and together inform the complexity of individuals’ experiences and the impact that the insulin pump has had on many aspects of their lives. These findings suggest a framework to help clinicians understand how young people with T1D perceive and conceptualise their treatment regimes. Conclusions: There was general agreement amongst participants that switching to Insulin Pump Therapy resulted in improvements to their QoL. Additional concerns were outlined but reportedly none of the participants regretted switching to an insulin pump.

In chapter 1, bone structure, bone growth and development, osteoporosis in children and skeletal morbidities in children with acute lymphoblastic leukaemia (ALL) are discussed. After that, the mechanostat and the effect of whole body vibration (WBV) on bone health are considered. Finally, I examine diagnostic approaches to assess the musculoskeletal system. In chapter 2, the incidence and risk factors for skeletal morbidity in ALL children are determined. The medical records of all (n,186, male,110) children presenting with ALL between 1997 and 2007 and treated on UKALL97, UKALL97/01 or UKALL2003 were studied. Skeletal morbidity included musculoskeletal pain (MSP), fractures and osteonecrosis (ON). MSP was classified as any event of limb pain, muscle pain, joint symptoms or back pain that required radiological examination. Fractures and ON were confirmed by X-rays and MRI respectively. We found that skeletal morbidity, presenting as MSP, fractures or ON were reported in 88(47%) children of whom 56(63%) were boys. Of 88 children, 49(55%), 27(30%) and 18(20%) had MSP, fracture(s) or ON, respectively. Six (7%) had both fractures and ON. The median(10th,90thcentiles) age at diagnosis of ALL children without skeletal morbidity was 3.9years(1.4,12), which was lower than in those with skeletal morbidity at 8.2years(2.2,14.3) (p<0.00001,95%CI:1.7,4.4). Children with ALL diagnosed over 8years of age were at increased risk of developing fracture(s) (p=0.01,odds ratio(OR)=2.9,95%CI:1.3,6.5), whereas the risk of ON was higher in those who were diagnosed after 9years of age (p<0.0001,OR=15,95%CI:4.1,54.4). There was no gender-difference in the incidence of skeletal morbidity. Children who received dexamethasone had a higher incidence of skeletal morbidity than those who were treated with prednisolone (p=0.027,OR=2.6,95%CI:1.1,5.9). We concluded that the occurrence of skeletal morbidity in ALL children may be influenced by age and the type of glucocorticoids (GCs). These findings may facilitate the development of effective bone protective intervention. In chapter 3, the aim is to investigate the influence of physical activity, age and mineral homeostasis over the first 12months of chemotherapy on subsequent skeletal morbidity. We reviewed 56 children who presented with ALL between 2003 and 2007 and treated only on iv UKALL2003. The number of in-patient days over the first 12months of chemotherapy was collected and used as a surrogate marker of inactivity and lack of well-being. Data for serum calcium (Ca), phosphate (Pho), magnesium (Mg) and albumin were also collected over this period. Skeletal morbidity was defined as any episode MSP or fractures. We found that the median duration of in-patient days over the first 12months of treatment in children with no skeletal morbidity was 58days(40,100), whereas the median number of in-patient days during the first 12months in those children with any skeletal morbidity, MSP only or fractures only was 83days(54,131), 81days(52,119) and 91days(59,158), respectively (p=0.003). Children with skeletal morbidity and fractures particularly had lower levels of serum Ca, Mg and Pho compared with those without skeletal morbidity over the first 12 months of chemotherapy. There was a higher risk of skeletal morbidity in those who were diagnosed after the age of 8years (p=0.001,OR=16,CI:3,80). Multiple regression analysis showed that the incidence of skeletal morbidity only had a significant independent association with age at diagnosis (p=0.001) and the number of inpatient days (p=0.03) over the first 12months (r=23). All children who were diagnosed after the age of 8years with an inpatient stay of greater than 75 days in the first 12 months of the chemotherapy (n,14) had some form of skeletal morbidity (OR=64). The conclusion was that the incidence of skeletal morbidity in children receiving chemotherapy for UKALL2003 is associated with a higher likelihood of being older and having longer periods of inpatient stay. The close link between age and changes in bone mineral status may be one explanation for the increased bone morbidity in ALL children In chapter 4, the effects of two WBV regimens on endocrine status, muscle function and markers of bone turnover are compared. We recruited 10adult men with a median age of 33years(29,49), who were randomly assigned to stand on the Galileo platform (GP) (frequency (f)=18-22Hz, peak to peak displacement (D)=4mm, peak acceleration (apeak) =2.6-3.8g) or Juvent1000 (f=32-37Hz, 0.085mm,0.3g) platform (JP) three times/week for a period of eight weeks. The measurements were performed at five time points (T0, T1, T2, T3, T4) and performed in a four week period of run-in (No WBV), eight weeks of WBV and a four-week period of washout (No WBV). The measurements included anthropometries, body composition measured by Tanita, muscle function measured by Leonardo mechanography and biochemical markers of endocrine status and bone turnover. The immediate term effect of WBV at 22Hz was associated with an increase in serum growth hormone (GH), increasing v from 0.07μg/l(0.04,0.69) to 0.52μg/l(0.06,2.4) (p=0.06),0.63μg/l(0.1,1.18)(p=0.03) ,0.21μg/l (0.07,0.65) (p=0.2) at 5minutes, 20minutes and 60minutes after WBV, respectively in the GP group. The immediate term effect of GP at 18Hz was associated with a reduction in serum cortisol from 316nmol/l (247,442) at 60minutes pre-WBV to 173nmol/l(123,245)(p=0.01), 165nmol/l(139,276)(p=0.02) and 198nmol/l(106,294)(p=0.04) at 5minutes, 20minutes and 60minutes post-WBV, respectively. At 22 Hz, GP was associated with a reduction in serum cortisol from 269nmol/l(115,323) at 60minutes before WBV to 214nmol/l(139,394)(p=0.5), 200nmol/l(125,337)(p=0.08) and 181nmol/l(104,306)(p=0.04) at 5minutes, 20minutes and 60minutes post-WBV, respectively. Median serum cortisol decreased after eight weeks of WBV from 333nmol/l(242,445) to 270nmol/l(115,323)(p=0.04). Median serum of the carboxy-terminal telopeptide (CTX, bore resorption marker) reduced significantly after eight weeks of WBV from 0.42ng/ml(0.29,0.90) to 0.29ng/ml(0.18,0.44)(p=0.03). None of these changes were observed in the JP group. Therefore, WBV at a certain magnitude can stimulate GH secretion, reduce circulating cortisol and reduce bone resorption. These effects are independent of clear changes in muscle function and depend on the type of WBV that is administered. In chapter 5, the effect of WBV using GP on the bone health of children receiving chemotherapy for ALL was assessed. We recruited 16children with ALL with a median age of 7.8years(5-13.8; 9males), who were randomized either to receive side-alternating WBV (f=16-20Hz,D=2mm, apeak =1-1.6g)(n,9) or to stand on a still platform as a control group (n,7) for 9minutes, once/week for four months. Measurements were performed at baseline, two-month and four-month assessing bone health (DXA and p.QCT), body composition and muscle function by imaging and biochemical assessment. DXA BMC data were corrected for bone area and presented as BMC z-score. We found that the median compliance rate measured as a ratio of actual completed minutes and expected minutes of WBV was 55%(17,100). The median percentage change of total body BMC z score in the WBV group from baseline to four months dropped by 10%(-25,10)(p=0.1), whereas it was 87%(-203,4)(p=0.07) in the control group. The median lumbar spine BMC z-score (L2-L4) in the WBV group was -0.4(-1.3,0.3) and -0.3(-1.4,1.5) at baseline and four months, whereas the respective data in the control group were 0.04(-0.6,2.4) and -0.1(-1.1,1), respectively. The median percentage change in LS-BMC z-score declined from baseline to four-month by19%(-349,365)(p=0.1) vi and 75%(-1016,178)(p=0.1) in the WBV and control groups, respectively. We concluded that WBV is tolerated by children receiving chemotherapy.