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.

Participation in physical activity (PA) of at least moderate intensity may yield important health benefits for children. A popular behavioural tool used to promote increased PA is the pedometer. There is however limited evidence regarding pedometer-based strategies in children. This thesis reports on a series of anthropometric and accelerometer-measurement issue studies which inform the methods used to address the primary aim of this thesis- to determine the effectiveness of goal-setting, selfmonitoring and step-feedback pedometer-based interventions for increasing PA in 10- 11-year-old children. In addition, each study in their own right provides an original contribution to knowledge within their specific area of scholarship. The first objective of this thesis was therefore to determine diurnal variation of height and weight and the combined effect upon body mass index (BMI) weight status in children via a field based study. Next, the reliability of the Actiwatch 4 (AW4) accelerometer was tested in a mechanical laboratory experiment. Following this laboratory trial a second field based study examined the impact of placement site upon AW4 output, and the validity of a regression equation to predict hip-derived AW4 data from wrist-derived data. Finally, a brief intervention mapping approach was used to develop goal-setting, selfmonitoring and step-feedback pedometer-based interventions, the effectiveness of which was evaluated in a small scale controlled trial involving two primary schools. The main findings of this thesis were a) that diurnal variation in height (and in girls alone, weight) impact upon increased BMI and BMI percentile in afternoon versus morning measurements b) AW4 activity counts exhibit acceptable reliability statistics (comparable to other accelerometer models), which improve when raw activity counts are reduced into derived activity intensity variables c) wrist and hip derived AW4 data are not comparable, and the derived regression equation may not be suitable for group level prediction due to inaccurate individual level prediction and the large standard error of the estimate observed d) pilot testing pedometer wear and intervention materials may highlight practical pedometer issues (i.e. pedometer attachment, wearing compliance and acceptability of instruction sheets) that inform intervention implementation and e) pedometer-based goal-setting, self-monitoring and step-feedback interventions did not increase PA in 10-11-year-old children. However, individual-standardised goal setting may be more promising as this appeared to mitigate any decline in moderate-to-vigorous physical activity (MVPA) in moreactive children, and increased MVPA in less-active. To summarise, the findings of this thesis highlight important issues for physical activity scientists to consider when using BMI-determined weight status as a grouping variable and accelerometers as an outcome measure, when evaluating physical activity interventions in children. With regard to the primary aim of this thesis, future researchers should further examine the effectiveness of the individual-standardised against the group-standardised goal type in a longer-duration intervention and using a larger sample of children, which may permit sub-group analyses to be conducted. Of primary importance is future clarification on the effectiveness of goal setting, self-monitoring and step-feedback pedometer-based interventions per se for changing PA in children.

Most mutations in SCN1A-related epilepsies are novel and when an infant presents with febrile seizures (FS) it is uncertain if they will have simple FS, FS+ or develop a severe epilepsy such as Dravet Syndrome. The main aim of this work has been to translate specific genetic findings in SCN1A related epilepsies not only to the phenotype, but to examine the implications this has on treatment and quality of life in children and their families. Clinical and genetic data were collected from 273 individuals with SCN1A mutations identified in our laboratory between November 2005 and February 2010. I examined whether the mutation class, distribution or nature of amino acid substitution correlated with the epilepsy phenotype, using the Grantham Score (GS) as a measure of physicochemical difference between amino acids. From structured referral data I analysed a range of clinical characteristics including epilepsy phenotype, seizure precipitants, EEG data, imaging studies, mutation class and response to medication and determined predictors of developmental outcome. I developed novel ideas on how to characterise mutations in SCN1A related epilepsies, showing that phenotypes are not determined by chance, but are in part determined by defined physico-chemical changes affecting a specific location in the protein structure. I was able to demonstrate that these principles not only apply to the SCN1A gene but also to the wider voltage gated sodium channel family and related diseases. This study has been the largest to date to systematically examine the prognostic, clinical and demographic features of Dravet syndrome. The overall incidence of Dravet syndrome was found to be at least one in every 28,600 UK births. Clinical features predicting a worse developmental outcome included status epilepticus, interictal EEG abnormalities in the first year of life and a motor disorder. No significant effect was seen for seizure precipitants, MRI abnormalities or mutation class (truncating vs. missense). Sodium valproate, benzodiazepines and topiramate were reported the most helpful medications and aggravation of seizures was reported for carbamazepine and lamotrigine. Health related quality of life (HRQOL) has emerged as a widely accepted measure to evaluate how chronic disease impacts on an individual’s well-being and I examined in detail the comorbidities and predictors of health related quality of life in Dravet syndrome. HRQOL was evaluated with two epilepsy-specific instruments, the Impact of Pediatric Epilepsy Scale (IPES) and the Epilepsy & Learning Disabilities Quality of Life Questionnaire (ELDQOL), a generic HRQOL instrument the Pediatric Quality of Life Inventory (PedsQL) and a behavioural screening tool, the Strength and Difficulties Questionnaire (SDQ). 163 individuals with Dravet syndrome and their families participated in the questionnaire study. HRQOL was significantly lower for children with Dravet syndrome compared to normative data. One third of children had conduct problems and two thirds had hyperactive or inattentive behaviour. Regression analysis revealed that behavioural problems were the strongest predictors of poorer HRQOL. Identification of specific comorbidities will help us to better recognise and understand the needs of children and families with Dravet syndrome and facilitate a distinct multi-disciplinary approach to management. Genetic testing in the epilepsies has become an increasingly accessible clinical tool and this is the first study to assess the impact of SCN1A testing on patient management from both carer and physician perspectives. The vast majority of parents whose children tested positive for a mutation reported genetic testing helpful, leading to treatment changes resulting in fewer seizures, and improved access to therapies and respite care. Nearly half of the physicians reported that a positive test facilitated diagnosis earlier than with clinical and EEG data alone. In two thirds it prevented additional investigations and altered the treatment approach; it influenced medication choice in three quarters of cases and through medication change improved seizure control in forty percent. In addition to confirming a clinical diagnosis, a positive SCN1A test enabled early diagnosis, influenced treatment choice and facilitated improvements in clinical management, especially in the very young. Finally I hope that this work will contribute to a better understanding of the causes of SCN1A related epilepsies. Furthermore I hope that it will provide evidence to aid earlier diagnosis and treatment of children with severe infantile epilepsies and that it will offer more information for genetic counselling. These improvements in epilepsy care and seizure control could help prevent or reduce the disability associated with SCN1A related epilepsies such as learning and behaviour problems and would improve the quality of life for children and families.

Background – Physical activity (PA) has been shown to have numerous physical (e.g., reduced risk of cardiovascular disease, type-2 diabetes and obesity) and psychological (e.g., improved mental well-being, and reduction in levels of stress and depression) benefits for childhood health. Despite the known benefits, childhood PA levels are low in Scotland, where less than 20% of children achieve the recommended daily guidelines. Evidence suggests that time spent outside is positively associated with achieving higher PA levels. Understanding what might encourage children to spend time outside in their neighbourhood could inform the development of interventions aimed at encouraging children to be more active. Children from different socio-spatial neighbourhoods may perceive and utilise their neighbourhood differently, influencing how they spend their free time. This PhD thesis examines how children from diverse settings perceive their neighbourhood in relation to their outdoor activity behaviours. Methods – This thesis takes a qualitative, multi-methodological approach, towards understanding 10-11 year old children’s perceptions of their environment in relation to their time spent outside through the lens of Gibson’s theory of affordances. A pilot study (n=15, 5 boys, 10 girls) was conducted to test the feasibility of the methods. For the main study, the children (n=25, 12 boys, 13 girls) were from different levels of area deprivation and from varying levels of urbanicity. Data collection methods included photo voice, drawings, focus groups or interviews. The participants were asked to document features within their environment (via photographs and drawings) that they felt influenced their time outside. They were then asked to participate in either a focus group or a one-to-one interview. The data collection process took place between May and September 2015. Findings – Children’s perceptions of their neighbourhood environments are complex, and numerous differences were found to be dependent on area of residence. Children from rural areas appeared to be influenced more by physical affordances whereas children living in urban settings were influenced more by social affordances, specifically their friends. Children living in more deprived neighbourhoods spoke of needing more PA opportunities in their neighbourhood compared to children living in more affluent neighbourhoods, suggesting that inequalities may still exist between higher and lower area deprivation. Many of the children considered current play equipment too boring, and lacked challenge or risk. The children desired equipment that better suited their perceived capabilities. This thesis found that children were more likely to spend time outside for psychological reasons, such as relaxation. Conclusion – Through the use of novel methodology in this subject area, this thesis adds an original contribution to the literature by exploring children’s environmental perceptions in relation to PA, and by looking at how setting might influence these perceptions. This thesis found that children perceive their environment differently dependent on the context of their lives, suggesting that initiatives to increase childhood PA could differ depending on residential setting. Additionally, policy may emphasize the psychological benefits to children as opposed to the physical benefits. Highlighting benefits such as relaxation, happiness and excitement may be more conducive to increasing PA among this age group than focusing on benefits such as weight management and cardiovascular health.

NHS reforms have sought to ensure that children and young people who are ill receive timely, high quality and effective care as close to home as possible (DH, 2004). This study examined the experience and impact of introducing new, ‘closer to home’ community-based paediatric outpatient clinics from the perspectives of NHS service-users and providers. Twenty-seven interviews conducted with parents and patients (aged 8-16), were analysed using a descriptive phenomenological approach. Thirty-seven interviews conducted with healthcare professionals, were analysed using a thematic framework method. Findings reveal that paediatric outpatient ‘care close to home’ is experienced in ways that go beyond concerns about location and proximity. For families it means care that ‘fits into their lives’ spatially, temporally and emotionally; facilitating a sense of ‘at-homeness’ within the self and within the place, through the creation of a warm and welcoming environment, and by providing timely consultations which attend to aspects of the families’ lifeworld. For service-providers, place and professional identity were closely related, with implicit assumptions made about where high quality of care and clinical expertise were located. Place, time and human relations were thus shown to be meaningful constituents of the experience of paediatric outpatient care. These previously ‘taken-for-granted’ nuances of healthcare delivery have implications for the design and implementation of effective ‘closer to home’ services.

Children are uniquely placed in a context where external influences are likely to determine their food consumption. Evidence regarding the immediate food environment’s influence on dietary quality and/or weight status in children is limited. This thesis uses data from the West Midlands ActiVe lifestyle and healthy Eating in School children (WAVES) study to explore patterns of dietary intake in children aged 5-9 years (n=1467), some of the determinants of children's dietary consumption and their associations with child weight status. Findings suggest that children’s dietary consumption needs to be more healthful, and aspects of children's school and home life may have the potential to influence dietary quality and weight status. Specifically, a healthy home food environment was associated with increased fruit and vegetable intake and a lower weight status. Certain parental feeding practices, such as using food as a reward or to regulate emotion, were also associated with increased energy intake from free sugar and weight status. In conclusion, various environmental and behavioural factors are associated with children’s dietary intake and as such, coordinated efforts in a variety of settings are required to affect the ‘what’, ‘how’ and ‘in what context’ of children’s dietary consumption and consequently childhood obesity prevalence.

The Cognitive Abilities Profile (CAP) (Deutsch and Mohammed, 2010) is a collaborative tool for psychologists and teachers. The CAP is based on principles of Dynamic Assessment (DA) and uses a consultative model for rating pupils' cognitive abilities in various cognitive domains and for planning interventions to facilitate pupils' progress accordingly. The CAP was developed in response to a perceived need for educational psychologists (EPs) to have access to alternative assessments to standardised psychological tests, particularly in the case of learning disadvantaged and ethnic minority pupils. Using DA as one possible approach creates a need for EPs to have access to training and to receive support with the implementation of DA-based intervention methods within local services. However, surveys of EP use of DA indicate limitations in training, inadequate support and difficulties in wider application of DA. In the present work, a quantitative methodology has been used to examine the validity and reliability of the CAP in overcoming the above-noted difficulties in the implementation of DA by EPs. The methodology involved the collection and analysis of data from three groups of EPs, two of which conducted consultations with teachers using the CAP and the third group of EPs used its own choice of consultation methodology and functioned as a control group. The findings of the present work provide evidence of good construct validity of the CAP cognitive domains, adequate inter-rater reliability between CAP users and evidence of advantage for pupils in some areas of functioning between pre- and post-use of the CAP, as validated by independent standardised tests. Analysis of perceptions of EPs of the utility of the CAP, based on the results of feedback questionnaires, addresses issues of user friendliness of the CAP. CAP users agreed on the need for initial training for psychologists and support for practitioners. The findings have implications for adoption of a novel approach in EP and teacher related work.

The effects of androgens reach far and wide and can be physiological as well as pathological. They are not limited to males and involve almost every system in the human body. Their influence on reproductive development and behaviours is well studied, but more recently, attention has turned to the wider reaching consequences of androgen exposure. Disorders of sex development (DSD) are rare conditions in which individuals may be deficient in, or resistant to, the effects of androgens. The long-term health and quality of life for these individuals is not well reported, but where there are reports, there are descriptions of increased depressive like behaviours, anxiety and poor social functioning. Lack of androgens has been linked to poorer neurocognitive outcomes in some studies and there is a concern that more aggressive hormone replacement should be considered in early life for those individuals lacking in androgens. These disorders can be difficult to study for many reasons. Firstly, they are rare conditions. Secondly, adults with DSD do not tend to visit hospital regularly and can therefore be challenging to engage in research. Thirdly, studying the effects of early life exposure to steroid hormones and relating these to later life behaviours is incredibly complex. Animal models have been used for many years to study the hormonal environment. For my first study, I used a model of rodent neonatal androgen blockade by treating pups with the anti-androgen flutamide for the first five days of life. The animals were studied again in adolescence (6 weeks of age) and early adulthood (10 weeks of age). There were no significant differences found in testosterone, dihydrotestosterone and androstenedione levels in either age group, demonstrating that the androgen blockade was transient. The anogenital index (AGI) was significantly shorter in the treated animals when compared to controls at 6 weeks of age and 10 weeks of age. Phallus length was significantly shorter in treated males when compared to the healthy males at 6 weeks of age and at 10 weeks of age. Phallus weight was significantly lower in the treated animals at 10 weeks of age when compared to the healthy animals. This work demonstrated that my rodent model of neonatal androgen blockade was an effective one. My next study used the same rodent model and aimed to link the perinatal hormonal environment with in vivo brain chemistry using a painless, non-invasive technique known as Magnetic Resonance Spectroscopy. Using a mixed effects model, I analysed the effects of sex, gender, treatment with flutamide and age on the metabolite pattern of the rodent brain. Ɣ-aminobutyric acid (GABA), glucose, glutamine, glutamate, phosphocholine and myo-inositol all changed over time. The combined peaks of glutamate and glutamine also demonstrated a significant change over time. GABA, glutamate, phosphocholine and myo-inositol showed significant sex differences as did the combined peaks of glycerophosphocholine and phosphocholine, N-acetylaspartate (NAA) and N-acetylaspartylglutamate (NAAG) and glutamate and glutamine. Aspartate, GABA and myo-inositol were all significantly changed by treatment of the animals with flutamide and GABA and myo-inositol levels in treated males were similar to control females at both 6 and 10 weeks. My final study using the rodent model of androgen blockade looked at the histological changes in the brain. Brains were sectioned and stained for neuronal cell counts and microglial cell counts, and PCR for the Androgen Receptor (AR) was performed. I demonstrated significant, sexually dimorphic changes in neuronal cell counts, microglial cell counts and androgen receptor expression in two clearly defined areas in the rodent brain. In summary, my rodent work demonstrated a link between the neonatal hormonal environment and the sexually dimorphic chemistry and histology of the in vivo brain, and supports the hypothesis that the microglial cell plays a critical role in brain masculinisation. To include a translational aspect to this thesis I extended my work to a population of undermasculinised boys, who were attending hospital for an hCG stimulation test as part of their investigations for 46 XY DSD. The hCG stimulation test is a valuable method for assessing androgen production but there is a need to explore its utility in assessing androgen responsiveness and long-term prognosis. I aimed to assess the effects of the hCG test on the in vivo brain chemistry using MRS, and the peripheral transcriptome using microarray. I reliably demonstrated metabolites in the brains of healthy male infants, healthy female infants and affected male infants. Healthy male infants had significantly lower levels of N-acetylaspartate than affected males in the hypothalamus and lower levels of the phosphocholines in the frontal cortex. In my transcriptomic study of DSD patients, I demonstrated the existence of an androgen responsive group of small RNAs that are measurable in peripheral mononuclear blood cells, and that change over the short duration of an hCG stimulation test, raising the prospect of combining the biochemical assessment of testosterone production with an objective molecular assessment of androgen sufficiency. In summary, in this thesis I have successfully linked the early hormonal environment with later life in vivo brain chemistry, confirmed by histological studies. I have also identified a novel marker, which could potentially be used as an assessment of androgen sufficiency in the future.

Hypoglycaemia is an unavoidable consequence of treatment of Type 1 Diabetes Mellitus (T1DM). Symptoms are often embarrassing and distressing and can lead to the development of fear of hypoglycaemia (FoH). This fear can have a negative impact on diabetes management and can lead to further medical complications. 210 children and young people (CYP), aged 3-17 years and 190 parents from diabetes paediatric clinics across the West Midlands, UK, completed questionnaires exploring the prevalence of hypoglycaemia, FoH and links to hypoglycaemia awareness, self-care, quality of life and anxiety. Demographic information and HbA1c data were also collected. Results indicated that hypoglycaemia and severe hypoglycaemia (SH) are a problem for CYP in the UK. Hypoglycaemia Fear Survey (HFS) scores were higher in parents than in CYP (Total HFS 37.1±14.9 vs. 50.2±17.8 vs. 45.2±18.0, CYP vs. mother vs. father, respectively, p < 0.01). Adolescents with prior experience of severe hypoglycaemia (SH) had higher HFS scores compared to those without (t=-3.61, p < 0.001). Trait anxiety and SH explained 23% of the variance in HFS scores in adolescents. Trait anxiety explained 37% of the variance in HFS scores in under 11 year olds, 18% in mothers of under 11 year olds, 6% in mothers of adolescent and 10% in fathers of adolescents. There was no correlation between HFS and HbA1c. Qualitative analyses identified ‘Burden’ as an overarching theme from CYP and parent interviews. ‘Negative emotions’ and ‘Living with diabetes’ emerged as the key themes of analysis. This research study adds to existing findings on the prevalence of hypoglycaemia, severe hypoglycaemia, FoH and possible related factors, by focusing on the paediatric population and their parents, in the UK, for which there is limited research. Qualitative analyses also provided novel reports of the experience of T1DM for CYP and their mothers. Implications of this research could lead to the development of an FoH and anxiety managementprogramme for CYP and their parents. The findings of this study also help to raise awareness of this very real and current issue in diabetes management.