Background and aims: Leukaemia is a cancer of the blood and is the most common type of childhood cancer with almost 500 new cases every year in the UK. There is a vast amount of research exploring the experiences of parents of children with cancer, however, there is less research focussed on parents whose children are in the maintenance phase of Acute Lymphoblastic Leukaemia (ALL) treatment. This treatment phase usually occurs in the first or second year following diagnosis but can start much earlier. The maintenance phase still involves active treatment but with less visits to and stays in hospital. At this stage, parents have been through the most intense segment of the treatment regimen and may have encountered various Khalighyprotocol may therefore have valuable advice to provide to other parents regarding coping and useful supports. This study aimed to explore the coping style and patterns of accessing support in mothers and fathers who have a child diagnosed with ALL and who are in the maintenance phase of treatment. The aim was also to explore whether there were differences between mothers and fathers with regards to coping and support. Methods: Three mothers and two fathers were interviewed separately using a semi structured interview. These interviews were then transcribed and analysed using interpretative phenomenological analysis (IPA). Results: Four main themes were identified through interviews with parents: the parental role; internal coping strategies; external coping strategies; and looking to the future. Conclusions: Parents were found to use a variety of coping strategies and accessed various sources of support to help them to deal with their child’s ALL diagnosis. These coping strategies could be shared with parents who are new to the haematology service. There were however, significant difficulties with recruitment which means it was not possible to compare mothers and fathers in terms of coping style and types of support accessed. This highlights that the recruitment strategy needs revising if further research is to be conducted in this area.

Background: Reducing neonatal mortality rates [NMR] (deaths/1,000 live births within 28 days of delivery) is a key global health goal. Using comparable data from Ghana (West Africa) and Scotland, I investigated NMR, specific causes of death and risk factors in the two countries. By identifying the main causes of excess mortality in Ghana and where they occur, it is hoped more effective strategies can be developed. Methods: This thesis used a multilevel mixed methods study design. Data on live births were obtained from three Health and Demographic Surveillance Systems (HDSS) in the north, middle and south of Ghana respectively: Navrongo (2004-12; 17,016 live births, 320 deaths); Kintampo (2005-10; 11,207 live births, 140 deaths); Dodowa (2006-14; 21,647 live births, 135 deaths). Comparable Scottish data were obtained from the Information Services Division (1992 to 2015; 1,278,846 live births, 2,783 deaths). Each dataset was analysed by neonatal death (dead/alive), using univariate and multivariable logistic regression. The multivariable analyses adjusted for maternal demographic and obstetric characteristics. Missing data were analysed using multiple imputation techniques. Data analyses were complemented by a researcher-developed questionnaire survey of 71 maternity care providers in the three regions of Ghana followed by face-to-face in-depth interviews with 48 maternity care providers who had experience of prematurity, birth asphyxia, neonatal infection and neonatal death. Results: The NMRs in the three HDSS were: Navrongo: 18.8; Kintampo: 12.5; and Dodowa 6.2 and in Scotland it was 2.2; the NMR in both countries is reducing. More than 99% of the neonatal deaths in Scotland occurred in the first week compared to 74% in Ghana. The leading causes of neonatal deaths (NMR) in Ghana were infection (4.3), asphyxia (3.7) and prematurity (2.2). In Scotland, they were congenital malformations (0.6), asphyxia (0.4) and prematurity (0.3). Only 88 deaths (0.07) of neonatal deaths in Scotland were due to infection. Ninety-eight percent of babies born in Scotland were born in a health facility compared to 60% of babies born in Ghana (hospital: 38.1%; clinic: 21.1%). In Ghana, babies born in hospitals had a higher risk of neonatal mortality compared to those born at home (NMR-hospital: 15.6; clinic: 7.1; home: 11.8). Most of the neonatal deaths in Ghana occurred at home (54%); there were more deaths among babies who were born in a hospital but died at home (hosp/home) compared to those born at home but died in a hospital (home/hosp). Asphyxia was the leading cause of death among hosp/hosp, and infection was the leading cause of death among hosp/home, home/home and home/hosp. Neonatal mortality in Ghana was largely influenced by where mothers sought maternity service, or the type of personnel who provided maternity care service. Mothers and babies who were cared for in hospitals by doctors and midwives received relatively better care and proper management of birth complications. Those who were cared for in clinics received basic delivery services and management of uncomplicated asphyxia. Mothers and babies who were cared for at home by traditional birth attendants (TBA) received poor care and poor management of neonatal illnesses based on traditional approaches which increased the risk of death. Women’s maternity choices were influenced by wider societal factors including prominent cultural values, family hierarchical structures and the cost of maternity services, and individual/ family factors including place of residence and availability of transport and beliefs about the cause of disease. Conclusion: There is considerable opportunity for reducing NMR in Ghana, especially deaths due to asphyxia and infections. Most uncomplicated deliveries should be performed by midwives in community clinics. The number of community maternity clinics should gradually be increased to enable home deliveries by TBAs to be phased out. Facilities should be improved for delivery and postnatal care in hospitals and the proportion of sick babies managed by health care workers trained in their care should be increased. Regular postnatal checks in the community by trained staff should be standard.

Thesis (M.S.)--Brandeis University, 2009. / Title from PDF title page (viewed on May 29, 2009). Includes bibliographical references.

Childhood onset growth hormone deficiency (CO-GHD) may contribute to low bone mass and alterations to body composition. This thesis consists of a series of studies utilising dual-energy X-ray absorptiometry (DXA), peripheral quantitative computerized tomography (pQCT) and biochemical assessment of bone health and body composition of CO-GHD. In addition, metabolic profiles, glucose metabolism as well as quality of life have been studied in these subjects. Furthermore, an interventional study of weight bearing exercise (WBE) was performed to explore its role in influencing the bone health of children and adolescents with CO-GHD. Chapter 1, relevant literature reviews explore: bone structure, growth, development and strength; GH/IGF-1 system and its actions; CO-GHD and its impacts during childhood and transition; and WBE and its mechanism and impacts on bone health. Chapter 2 presents the rationale and specific aims of this thesis. Chapter 3, a retrospective multicentre review of management of young adults with CO-GHD in four paediatric centres in Scotland during transition. Medical records of 130 eligible CO-GHD adolescents (78 males), who attained final height between 2005-2013 were reviewed. Of the 130, 74/130(57%) had GH axis re-evaluation by stimulation tests /IGF-1 measurements. Of those, 61/74(82%) remained GHD with 51/74(69%) restarting adult rhGH. Predictors of persistent GHD included an organic hypothalamic-pituitary disorder and multiple pituitary hormone deficiencies (MPHD). Despite clinical guidelines, there was significant variation in the management of CO-GHD in young adulthood across Scotland. Chapter 4, a cross-sectional control study of bone DXA measurements in (n=21) subjects with CO-GHD treated with rhGH and had attained final height from 2005 to 2013 in a single tertiary paediatric centre compared to (n= 21) heights/age matched healthy controls. By applying different models of DXA adjustment, our analysis revealed lower TB-BMC for bone area in males with CO-GHD and lower LS-BMAD SDS in females with CO-GHD compared to matched controls. In addition, subjects with CO-GHD had lower LM for height and higher FM for height compared to controls, and this was more pronounced in males than females (p=0.04). The time of onset and aetiology of CO-GHD have a larger influence on accrual of bone mass in these patients. These findings indicate that adolescents with CO-GHD have a low bone mass, despite prior long term rhGH replacement therapy. In chapter 5, we investigated bone health of subjects with CO-GHD at time of initial evaluation and retesting at final height. A total of 25 children (first time assessment group) undergoing GH stimulation tests for investigation of short stature (naive GHD-15, normal-10), and 11adolescents with CO-GHD (retesting group) undergoing biochemical re-evaluation at final height after withdrawal of rhGH therapy (persistent GHD-7, GH-sufficient-4) were recruited from Royal Hospital for Children between 2012-2013. By using further bone health assessment methods in addition to DXA (including p.QCT, mechanography, bone profiles and biomarkers), the bone density and body composition did not differ when we compared GHD to matched height but normal GH at initial evaluation and retesting. However, naive GHD had lower muscle force as assessed by mechanography compared to the normal. In addition, bone resorption biomarker CTX was significantly higher in naive GHD vs. normal and that was significantly correlated to PTH levels in both first time assessment and retesting groups. Our results suggest that muscle force and serum PTH may be important determinants of bone health in subjects with CO-GHD. Chapter 6 investigates lipids, adipokines (leptin- adiponectin- resistin) and glucose homeostasis and their relationship with bone and body composition in children and adolescents with CO-GHD at times of initial evaluation and retesting at final height (same population as chapter 5). Lipid profiles, adipokines and glucose homeostasis were not different between those with GHD and those who had normal GH levels across the groups of first time assessment and retesting. In the retesting group, those who were older at the time of diagnosis of CO-GHD with a shorter duration of rhGH therapy were more likely to have higher cholesterol(r=0.9, p<0.001), leptin (r=0.8, p<0.001), and lower osteoclacin (r=-0.7, p=0.01) at final height. Leptin levels correlated positively with osteocalcin at diagnosis (r=0.51, p=0.01) but inversely at retesting (r=-0.91, p<0.01). The conclusion was that the timing and duration of childhood rhGH therapy might influence adiposity parameters and bone metabolism in subjects with CO-GHD. In chapter 7 the study participants of chapter 5 were asked to complete either Short Form-36 (SF-36) or Adult Growth Hormone Deficiency Assessment (AGHDA) quality of life (QoL) questionnaires at the time of assessment of their GH axis. Our analysis showed that the overall QoL was not altered in children with naive GHD with a total score of SF-36 [93 (77, 96) naive GHD vs. 90 (84, 93) normal, P=0.56] (higher scores reflect better QoL). However, naive GHD had less energy and vitality scores compared with normal (75 (65, 100) vs. 95 (65,100) respectively, p=0.04), when the normal scored lower in the subscale of emotional well-being compared to those with naive GHD (78 (55, 84) vs. 90 (68, 96) respectively, p<0.001). In the retesting group, those with persistent GHD scored better in the AGHDA than GH sufficient (6 points (2, 8) vs. 9 points (7, 17) respectively, though not significant (p= 0.10) (higher scores reflect poorer QoL). Unexpectedly, subscale analysis showed that GH-sufficient subjects significantly lacked energy and complained of tiredness compared to those who were confirmed to have persistent GHD (5 points (3, 6) vs. 1 point (0, 1) respectively, p= 0.03). Further studies to validate QoL specific instruments in this population are needed with greater insight to elucidate factors that modify the relationship between GH status and QoL in children and adolescents. Chapter 8 was a prospective intervention, randomised controlled study of 14 subjects among the first time assessment group (GHD-10, normal-4) and five subjects with CO-GHD among retesting group (persistent GHD-4, GH-sufficent-1). Subjects were randomised into either an exercise intervention group (EX) (25 jumps off 25 cm platform step/three days/week for six months) or a control, in addition to rhGH being prescribed. The results of this study were limited by the small sample size and poor compliance. Therefore, there were insufficient data to recommend the use of weight bearing exercise in the absence of rhGH in children and adolescents with CO-GHD. Further studies with adequate sample size that can more rigorously exam the optimal exercise interventions are needed. Chapter 9 discusses the main findings of each chapter in this thesis and outlines potential limitations of the thesis methodology, and some important and interesting areas for future research in children and adolescents with CO-GHD.

The number of babies that require care in the Neonatal Intensive Care Unit continues to rise in the UK and parents who have a baby who is born sick or prematurely find themselves adapting to this stressful and often unexpected event whilst also trying to establish their role as a new parent. With no current large British studies, this study explores the experiences of both mothers and fathers in the NICU in relation to adaptation and parental role development and how their experience changes over time. In total 76 parents were interviewed using semi structured interviews 7-10 days following the birth to capture their early experiences of the NICU and then again beyond 28 days to explore any changes in their views and feelings over time. Interviews were tape recorded, transcribed verbatim into the written word and imported into WINMAX PRO. Data analysis revealed nine major sections. These are preparation prior to birth, labour and delivery, first sight of infant, support from the partner, family, friends and other parents, support from and communication with staff, adaptation to the NICU experience, development of the parental role, changes with time and the experiences of fathers. Findings show differences in what mothers and fathers find stressful about their NICU experience, how they adapt to the birth of a sick or premature infant and in their development of the parental role. With the passage of time the events surrounding the birth became less significant as parents start to look to the future. Their role as a parent continued to develop with feelings that their baby needed and recognised them, but many parents felt that they were unable to influence what happened to their baby in the NICU. Recommendations are made for further research and for changes to NICU practice.

Background: Reactive attachment disorder (RAD) has been described as one of the least researched and most poorly understood psychiatric disorders (Chaffin et al., 2006). Despite this, given what is known about maltreatment and attachment, it is likely that RAD has profound consequences for child development. Very little is known about the prevalence and stability of RAD symptoms over time. Until recently it has been difficult to investigate the presence of RAD due to limited measures for informing a diagnosis. However this study utilised a new observational tool Method: A cross sectional study design with a one-year follow-up explored RAD symptoms in maltreated infants in Scotland (n=55, age range= 16-62 months) and associated mental health and cognitive functioning. The study utilised the Rating of Inhibited Attachment Behavior Scale (Corval, et al., unpublished 2014) that has recently been developed by experts in the field along side The Disturbances of Attachment Interview (Smyke & Zeanah, 1999). Children were recruited as part of the BeST trial, whereby all infants who came in to the care of the local authority in Glasgow due to child protection concerns were invited to participate. The study sample was representative of the larger pool of data in terms of age, gender, mental health and cognitive functioning. Results: The sample was found to be representative of the population of maltreated children from which it was derived. Prevalence of RAD was found to be 7.3% (n=3, 95% CI [0.43 – 14.17]) at T1, when children are first placed in to foster care. At T2, following one year in improved care conditions, 4.3% (n=2, 95% CI [below 0 – 10.16]) met a borderline RAD diagnosis. Levels of observed RAD symptoms decreased significantly at T2 in comparison to T1 but carer reported symptoms of RAD did not. Children whose RAD symptoms did not improve were found to be significantly older and showed less prosocial behaviour. RAD was associated with some mental health and cognitive difficulties. Lower Verbal IQ and unexpectedly, prosocial behaviour were found to predict RAD symptoms. Conclusions: The preliminary findings have added to the developing understanding of RAD symptoms and associated difficulties however further exploration of RAD in larger samples would be invaluable.

Thesis (PhD)--Stellenbosch University, 2013. / Bibliography / ENGLISH ABSTRACT: Introduction: Lipoatrophy is a common adverse effect of stavudine and this effect is strongly dose-dependent. Stavudine remains the most commonly used paediatric antiretroviral drug in sub-Saharan Africa, yet when the current study began in 2009, the prevalence and severity of lipoatrophy in children on antiretroviral therapy in sub-Saharan Africa had never been studied. The development of lipoatrophy may have serious and far-reaching consequences for patients and their families. The off-label stavudine dosing method, prescribed to children whose caregivers do not have access to a refrigerator, in which the contents of an adult capsule is mixed into tap water, has potential for over-dosing or under-dosing. In addition, children on stavudine continue to be exposed to a disproportionately high dose out of line with the reduced adult dose. Aims: 1. a) To investigate the prevalence and risk factors for lipoatrophy in HIV-infected children in Southern Africa b) To identify a simple anthropometric screening tool to detect early lipoatrophy in children 2. To validate the off-label stavudine dosing method prescribed to children whose caregivers do not have access to a refrigerator, with a view to reducing the recommended dose and thereby the side-effects. Methods: 1. a) We recruited pre-pubertal children on antiretroviral therapy from a family HIV clinic in our facility. Lipoatrophy was identified by two experienced paediatric HIV clinicians using a standardized grading scale. A dietician performed dietary assessment and anthropometric measurements. Previous antiretroviral exposures were recorded. A subset of recruits received Dual-Energy X-ray Absorbtiometry scanning. b) Anthropometric measurements in children with and without lipoatrophy were compared using multivariate linear regression adjusting for age and gender. The most discerning anthropometric variables underwent Receiver Operating Characteristic curve analysis to identify the most appropriate diagnostic cut-off. 2. a) Accuracy of the standard off-label stavudine dosing method was investigated using high-performance liquid chromatography to recover active drug from solutions made up using the prescribed method. This was compared to the stated drug content of the capsules. b) Bioavailability was investigated by performing a randomized crossover pharmacokinetic study wherein healthy HIV-seronegative adult volunteers received one of two generic stavudine capsule formulations, either intact or mixed in water using the prescribed method. Plasma stavudine concentrations were assayed by liquid chromatography tandem mass spectrometry. Results: 1. a) Prevalence of lipoatrophy was 36%, and incidence was 12% per person-year. Adjusted odds ratio for developing lipoatrophy was 1.9 (CI: 1.3–2.9) for each additional year of accumulated exposure to standard-dose stavudine. b) Baseline biceps skin-fold thickness correlated well with maximum lipoatrophy grading score at any site, giving a partial correlation coefficient of 0.33 (p=0.0006), and a receiver operating characteristic area-under-curve value of 0.75 (CI: 0.64 – 0.84). Biceps skin-fold thickness <5mm at baseline had a sensitivity of 89% (CI: 67–100%) and a negative predictive value of 97% (CI: 91–100%) for predicting which children would go on to develop lipoatrophy by 15 month follow-up. Specificity was 60% (CI: 46–75%) and positive predictive value was 32% (CI: 14–50%). 2. a) Recovery of active drug from solution was 97.1%, 97.4% and 93.8% for the proprietary and two generic formulations respectively. b) Pharmacokinetic parameters of the off-label dosing method were well within the target range of intact capsule dosing for both generics. Conclusions: 1. a) The prevalence and incidence of lipoatrophy in pre-pubertal children on antiretroviral therapy in South Africa is high. Cumulative exposure to standard-dose stavudine was the greatest risk factor for lipoatrophy. b) Biceps skin-fold thickness provided reasonable sensitivity and specificity to detect and predict lipoatrophy in pre-pubertal children on antiretroviral therapy. 2. The off-label dosing method for stavudine prescribed to children whose caregivers do not have access to a refrigerator is reasonably accurate and is bioequivalent to intact capsule administration. / AFRIKAANSE OPSOMMING: Inleiding: Lipoatrofie is 'n algemene nadelige uitwerking van stavudien en hierdie effek is sterk dosis-afhanklike. Stavudien bly die mees algemeen gebruikte paediatriese antiretrovirale medikasie in sub-Sahara Afrika, maar toe ons studie begin het, was lipoatrofie in kinders op antiretrovirale terapie in sub-Sahara Afrika nog nooit voorheen bestudeer nie. Die ontwikkeling van lipoatrofie kan ernstige en verreikende gevolge vir die pasiënt en hul familie hê. Die af-etiket stavudien dosering metode voorgeskryf aan kinders wie se versorgers nie toegang tot 'n yskas het nie het 'n aansienlike potensiäal vir oor-dosering of onder-dosering. Daarbenewens, is kinders op stavudien blootgestel aan 'n disproporsionele hoë dosis uit-pas met die verminderde volwasse dosis. Doelwitte: 1. a) Om ondersoek in te stel na die voorkoms en risiko faktore vir lipoatrofie in MIV-geïnfekteerde kinders in Suid Afrika b) Om 'n eenvoudige antropometriese instrument te identifiseer om vroeë lipoatrofie op te spoor in kinders op antiretrovirale medikasie 2. Om die af-etiket stavudien dosering metode wat voorgeskryf is aan kinders wie se versorgers nie toegang tot 'n yskas het nie te valideer, met 'n oog op die vermindering van die aanbevole dosis Metodes: 1. a) Ons het 'n groep van onder-puberteitsjarige kinders op antiretrovirale terapie gewerf uit 'n familie MIV kliniek in ons fasiliteit. Lipoatrofie is geïdentifiseer deur twee ervare MIV pediaters deur gebruik van 'n gestandaardiseerde gradering skaal. 'n Diëetkundige het diëet assessering en antropometriese metings uitgevoer. Vorige antiretrovirale blootstellings is aangeteken. In 'n subset was Dual-energie X-straal Absorbtiometry (DXA) skandering uitgevoer. b) Antropometriese metings in kinders met en sonder lipoatrofie is vergelyk met behulp van meerveranderlike lineêre regressie aangepas vir ouderdom en geslag. Die mees kieskeurige antropometriese veranderlikes het Receiver Operating Curve analise ondergaan om die mees geskikte diagnostiese afgesnypunt te identifiseer. 2. a) Akkuraatheid is ondersoek deur gebruik te maak van hoë werkverrigting vloeistofchromatografie om aktiewe medikasie vanuit oplossings te herstel, wat gemeng is soos aangedui deur die voorgeskrewe af-etiket dosering metode. b) Biobeskikbaarheid is ondersoek deur die uitvoering van 'n ewekansige oorgesteekde farmakokinetiese studie waarin gesonde MIV- negatiewe volwasse vrywilligers een van twee generiese stavudien kapsule formulerings ontvang het, óf heel of in water gemeng soos aangedui deur die voorgeskrewe af-etiket dosering metode. Plasma stavudien konsentrasies is gemeet deur vloeistofchromatografie tandem massaspektrometrie. Uitslae: 1. a) Voorkoms van lipoatrofie was 36%, en insidensie was 12% per persoon-jaar. Aangepaste Odds ratio vir die ontwikkeling van lipoatrofie was 1,9 (CI: 1,3-2,9) vir elke addisionele jaar van opgehoopte blootstelling aan standaard dosis stavudien. b) Biceps vel-vou dikte <5mm het 'n sensitiwiteit van 89% (CI: 83-96%) en 'n negatiewe voorspellende waarde van 90% (CI: 84-96%) vir die opsporing en voorspelling van lipoatrofie. 2. a) Herwinning van aktiewe medikasie uit oplossings was 97,1%, 97,4% en 93,8% vir die oorspronklike en twee generiese formulerings onderskeidelik. b) Farmakokinetiese parameters van die af-etiket dosering metode was wel binne die teikenband van ongeskonde kapsule dosering vir beide generiese formulerings. Gevolgtrekkings: 1. a) Die voorkoms van lipoatrofie in onder-puberteitsjarige kinders op antiretrovirale terapie in Suid-Afrika is hoog. Die bedrag stavudien waaraan kinders blootgestel is moet hersien word. Die standaard stavudien dosis vir kinders moet herge-evalueer word. b) Biceps vel-vou dikte het redelike goeie sensitiwiteit en spesifisiteit om lipoatrofie op te spoor en te voorspel. 2. Die af-etiket dosering metode vir stavudien voorgeskryf aan kinders wie se versorgers nie toegang tot 'n yskas het nie is redelik akkuraat en is bio-ekwivalent aan ongeskonde kapsule administrasie.

Introduction: Acute lymphoblastic leukaemia (ALL) is the commonest childhood cancer. In the early trials of ALL treatment, central nervous system (CNS) relapse was a common occurrence - the introduction of CNS-directed therapy in the 1970s was associated with the largest single improvement in outcome for childhood ALL. Today, despite universal intensive CNS-directed therapy - with significant associated toxicity - the CNS is involved in around 50% of ALL relapses, with approximately 50% of these being isolated CNS (iCNS) relapse. Whilst many factors increase risk of CNS relapse, few are specific for CNS relapse. Discovery of specific risk factors for CNS relapse would allow increased therapy for children at high risk, and potentially less CNS-directed therapy for those at low risk. Relatively little is known about the biological differences between systemic and CNS ALL. In the CNS, leukaemic cells form plaques adherent to the leptomeninges, bathed in low-nutrient, low-oxygen cerebrospinal fluid (CSF). It was hypothesised that leukaemic cells adapt metabolically to this nutritionally poor CNS microenvironment, and these metabolic adaptations may be targets for specific therapy and/or specific biomarkers for CNS relapse. Findings: Transcriptional analysis of ALL cell lines from CNS and spleen in a mouse xenograft model, and of ALL cells retrieved from the CSF at CNS relapse of ALL, have shown the upregulation of cholesterol biosynthesis as a key adaptation to the CNS niche. Analysis of transcriptomic data from the bone marrow or peripheral blood from children with ALL at diagnosis have shown the potential for upregulated cholesterol biosynthesis (and, independently, upregulated IL7R) as a significant risk factor for CNS relapse of ALL. To support this finding, metabolomic analysis found evidence of changes in CSF cholesterol in the presence of CNS leukaemia, and of increased mevalonate (a cholesterol precursor) and cholesterol in ALL cells retrieved from the CNS in a xenograft model. Therapeutic targeting of CNS ALL in vivo with statins resulted in a CNS-specific increase ALL disease burden. Untargeted metabolomic analysis of CSF shows differences between children with ALL (either at diagnosis or on maintenance therapy) and non-ALL controls, and between children with ALL at diagnosis and the same children on maintenance therapy. Creatine abundance was significantly different in children with ALL at diagnosis compared with both other groups (1/3 lower at diagnosis than either on maintenance or non-ALL controls). This change in creatine and persisted on analysis of CSF from mice with and without leukaemia. On analysis of CSF from children at CNS relapse with ALL there is evidence of increased reduced creatine at time of CNS relapse in 3 of 4 patients. Conclusions: There is evidence to confirm the hypothesis that ALL cell adapt metabolically to the CNS niche. Cholesterol biosynthesis was identified as a key pathway upregulated in CNS ALL, and upregulated cholesterol biosynthesis in ALL cells at diagnosis was found to be a key risk factor for CNS relapse of ALL. In addition, clear changes in the CSF metabolome related to both ALL and ALL therapy were shown, and a new potential marker for the presence of CNS ALL identified. Prospective analyses in independent cohorts are required to determine the clinical utility of these novel strategies for prediction of CNS relapse risk.