Severe infection due to Gram-negative bacteraemia increases mortality and long term consequences of morbidity. In Liverpool Women’s NHS FT neonatal unit mortality increased from 20% for the more premature babies to 44%. Ciprofloxacin is a synthetic fluoroquinolone prescribed for suspected or proven Gram-negative infection in many neonatal units throughout Europe (25%). At present this drug is not authorised for this population and is prescribed off label. The optimal drug regimen is unknown resulting in a wide range of regimens (5 to 60 mg/kg/day) prescribed internationally. The TINN Consortium ‘Treat Infection in Neonates’ were funded by a European Union FP7 grant to develop a Paediatric Investigation Plan in line with the EU Paediatric Regulations and European Medicines Agency requirements. This thesis describes a prospective population PK clinical trial as part of the work of TINN, a retrospective clinical outcome study in neonates and infants with late onset Gram-negative sepsis and a framework to facilitate PK-PD research. The pharmacokinetic (PK) clinical trial of ciprofloxacin recruited 64 babies including a minimum of seven recruits representing every four weeks of development. The median post menstrual age in weeks was 35.7 (6.5) (range 24.9 - 47.9). Blood samples (n = 265) were collected at pre-defined informative time points in addition to 165 samples scavenged from clinically indicated blood tests, in total 430. A two compartment model with first-order elimination fitted the data. PK parameters included maximum concentration, clearance, area under the curve (0-tau), apparent volume of distribution and half-life and selected covariates with their inter-individual variability (CV%). Based on adult PD targets the minimum area under the curve /minimum inhibitory concentration (AUC/MIC) ratio 125 was achieved by 85% of this population. Higher AUC24 hour/MIC targets >250 may be required for serious infections yet few (42%) of this population achieved this. The optimal AUC/MIC ratio for neonates is unknown. Clearance increased with post-natal age yet the combined effect of PMA at birth and corrected gestational age had a greater effect on clearance. Clearance reduced by 29% with co-administration of inotropes associated with underlying renal compromise. Monte Carlo simulation demonstrated that the AUC24/MIC 125 was achieved by 90% of neonates < 34 weeks PMA administered 7.5 mg/kg/day and 84% of those ≥34 PMA administered 12.5 mg/kg/day. Ciprofloxacin is lipophilic and has good tissue penetration. CSF concentrations achieved a ratio of 0.33 of the serum plasma concentrations. Pharmacodynamic data included a retrospective cohort study over a six year period of neonates with confirmed Gram-negative organisms in blood cultures. Organisms retrieved from the clinical laboratory (n=88) were re-cultured and the MIC ciprofloxacin determined using an E Test. A sub-group were administered ciprofloxacin (n=33); each organism’s MIC was compared with the same neonate’s clinical outcome. Relatively higher MICs within the susceptible range were associated with a greater risk of treatment failure. These data were not statistically significant due to the low incidence of confirmed Gram-negative bacteraemia (1.3%). The clinical implications are that more intensive dosage regimens may be required or a lower clinical breakpoint subject to further PD and safety data. Too few organisms were available to determine if the MIC increased annually but the incidence of ciprofloxacin resistance in surveillance surface swabs was no higher than for gentamicin. To prepare for a future pharmacogenomic study, DNA scavenged from clinical blood samples were compared to a buccal scrape to evaluate whether this less invasive method is reliable. A substantially larger quantity and higher quality of DNA was obtained from scavenged blood. A sub-group were transfused with leukocyte depleted products for their clinical care prior to DNA sampling. The genotyping of allelic polymorphisms were not affected by the donor’s blood sufficiently to affect the genetic fingerprint. This indicates that prior blood transfusions should not be a contra-indication to scavenging blood for pharmacogenetic purposes. The challenges of PK/PD trials in this vulnerable population were explored. The majority were recruited in intensive care and had comorbidity and extreme prematurity. Due to the complexity of critical illness there are limitations to interpreting clinical outcome or safety data from a PK clinical trial design. There were no suspected unexpected serious adverse reactions. Arthralgia was not reported but is difficult to assess in non-weight bearing non-vocal neonates and young infants. A proportionate regulatory model of neonatal PK clinical trials was developed with the Medicines and Health Care Products Regulatory Agency. A framework for pharmacovigilance reporting during critical illness which avoided nuisance reporting was developed. The impact was assessed by an observational case study and review of discharge letters to illustrate the challenge of attributing causality. Individualised therapy may be required in critical illness. The correct dose of an antimicrobial may change daily during the sepsis episode. The inter- and intra-individual variability in parameters is associated with dynamic changes during neonatal development and the effects of critical illness. Further outcome and safety data are required to determine the optimal AUC24/MIC ratio. Paediatric clinical breakpoints specific to each sub-age group of children are required. Individualised therapy may be required to optimise clinical outcome and minimise resistance.

Assessing the quality of health services remains a major challenge for the less industrialized nations of the world. Hospitals consume high proportions of national health budgets but approaches to examining their capacities and performance are still rudimentary. Better assessment strategies are essential for understanding what investments in hospital care and health systems are achieving and whether resources are being equitably distributed. Assessing hospital care for children is a particular challenge given the multiplicity of steps to be correctly undertaken in examining patients, diagnosing disease and giving appropriate treatment. This thesis describes the development of a measure of quality of care for children admitted to hospital, which can be routinely deployed to form part of future nation-wide health system assessments. The measure is based on standards of paediatric care described by national clinical practice guidelines for Kenya adapted from WHO guidelines. It is constructed using data from a trial of a new intervention to improve quality of care in first-level referral hospitals in Kenya. The proposed measure is subsequently validated using data from observations of routine hospital care for children admitted to a different set of hospitals over a period not covered by the primary data. A number of statistical techniques are used in this regard: these include factor analysis to explore the dimensions of process of care, logistic regression to study the association between the new measure and mortality, and multilevel modelling to explore the amount of variability in the data lost through modification of the structure of the measure. These analyses show that the items making up the measure are consistent with three conceptual domains of clinical process described in guidelines. They also provide evidence that the measure is associated with other exposures and outcomes in ways that strengthen its validity and suitability of purpose. Specifically, there is strong evidence that adherence to each of six generic recommendations of how care should be provided is associated with a reduction in odds of death by a fifth. This thesis thus demonstrates the usefulness of a generic approach to measuring quality of care, and highlights key issues to be addressed when extending this approach to other settings.

This study aimed to provide a comprehensive assessment of hospital utilisation among children and young people (CYP), addressing recommendations emerging from the Children and Young People’s Health Outcomes Forum that emphasised the importance of improving the health of young people. The burden of care for CYP with cancer on local and national healthcare systems is unknown and lack of data limits the ability to inform and improve service delivery. Therefore, I used a specialist population-based cancer register in CYP from Yorkshire, linked to hospital admissions data, to analyse healthcare utilisation after diagnosis and treatment for cancer. Additionally, clinical and sociodemographic factors that contributed to hospital utilisations during and after treatment were identified and discussed. The study included 3,151 cases of cancer aged 0-29 years diagnosed in Yorkshire during 1996-2009, and admitted to hospital during 1997-2011. The study observed a steady increase in admissions over the period. Children had higher median number of admissions (median=25, Interquartile range (IQR): 8-44) than teenagers and young adults (TYA) (median=10, IQR: 3-20), and spent longer in hospital on average with median duration of three and one days per 100 person-days respectively. However, TYA with leukaemia experienced longer stays in hospital on average than children, with a median duration of eight and four days, respectively. Factors that influenced the pattern of admissions varied by cancer type, however relapse status, type of initial treatment and year of diagnosis were significantly related to hospitalisation independently. Cancer survivors had a significantly higher risk of morbidity compared with the general population after treatment completion (standardised hospitalisation rate (SHR) = 2.37, 95% CI:2.26-2.49). Findings from this work demonstrate the variation in hospital activity by cancer type and age group, as well as the independent predictors of hospitalisation. This aids the continued development of high-quality cancer services to meet the needs of young people with regard to short-term and long-term care.

Childhood malnutrition is a real-life and a chronic problem and one of the global major public health challenges, especially in developing countries like Ghana. Several attempts from governmental and non-governmental organizations to address the problem have fallen below expectation. It is recognised that the existing studies and nutrition intervention strategies are inadequate and hence not working to expectation. This thesis examines childhood malnutrition in Ghana using appropriate and advanced statistical methods to help improve the understanding of childhood nutrition and to better inform targeted public health nutrition interventions in the country. In this thesis, we provided solutions to five main problems: (1) investigated the major risk factors for malnutrition; (2) investigated household level variations in nutritional outcomes of children; (3) explored, modelled and illustrated spatial variations in the risk of childhood malnutrition over Ghana; (4) explored, modelled, forecasted and illustrated spatio-temporal variations in the risk of childhood malnutrition over Ghana; (5) jointly modelled weight-for-age Z-score (WAZ) and height-for-age Z-score (HAZ) to improve accuracy and reliability in estimates. To answer the first and the second problems, multilevel models were considered. The results showed strong residual household-level variations in under-fives nutritional outcomes and that child’s age, type of birth, child’s experience of diarrhoeal episodes, size of child at birth and months of breast feeding, mother’s education, current age, BMI and national health insurance status, household toilet facility ownership and wealth status were predictive of under-fives nutrition. To answer the third problem, spatial models were employed. The study found substantial spatial variation in the predicted risk of under-fives malnutrition over Ghana and also showed that Normalised Difference Vegetation Index (a marker for vegetation cover), elevation and rural/urban residence status were predictive of under-fives nutritional outcomes. The study considered spatio-temporal models to answer the fourth problem. The results showed substantial spatio-temporal variation in the risk of under-fives chronic malnutrition over Ghana. Our forecasted map of chronic malnutrition showed substantial spatial variation with children from parts of Northern and Western regions being at the highest risk of malnutrition compared to children from other regions of the country. In our forecast maps, the effect of increasing the level of maternal education was shown to reduce the prevalence of malnutrition throughout Ghana. To answer the fifth problem, multivariate response multilevel models were considered. The study found that the residual household effects for WAZ and HAZ are very strongly correlated and that the correlation was stronger for the residual household effects than the residual child effects. This also suggests that after adjusting for risk factors in our model, it is the same as-yet unidentified factors at household level that influence both WAZ and HAZ. The results also showed that there was more accuracy and reliability in estimates from the multivariate response multilevel model over separate multilevel models and showed that the effect of some important risk factors differed substantially across WAZ and HAZ. The findings from this thesis are intended to help policymakers responsible for the health and nutrition of children to design efficient public health policies and targeted nutrition interventions amidst scarce public health resources available in Ghana to better understand, target and to reduce childhood malnutrition prevalence closer to the level expected in a healthy, well-fed population of children under-fives.

Objectives: The aim of this study is to inform the design and development of an online surveillance intervention, which could have a role in improving the management of paediatric respiratory tract infections (RTI) in primary care, including aiding antimicrobial stewardship. The specific objectives are to assess the perceived utility of the intervention in principle, the potential impact in practice, and clinician preferences for the design, content and mode of delivery, identifying barriers and facilitators to intervention use. Methods: Semi-structured one-to-one interviews were conducted with 21 clinicians (18 GPs; 3 Nurse Practitioners) representing a range of clinical experience from a range of Bristol GP surgeries (deprivation deciles 1 to 9). Interviews explored clinicians’ current approaches to managing paediatric RTIs, knowledge of circulating infections, and views of a mock-up example of local viral and syndromic surveillance information. Interviews were audio recorded, transcribed verbatim and analysed using the framework method. Results: Clinicians agreed there is currently no formal primary care system for identifying circulating infections, and the surveillance information was novel and potentially useful. While symptom duration was perceived as useful, there were mixed responses regarding the use and relevance of knowing community viral microbiology. Barriers identified include time pressures, information overload and lack of fit with clinicians’ perceived role as assessing each child as an individual and looking for risk. Clinicians tended to see a role for the intervention to aid patient explanations. Conclusions: Whilst clinicians viewed the information as potentially beneficial for supporting consultations with parents, there were mixed responses to how knowledge of viral microbiology could or should inform their practice of treating each patient individually, with fear of missing the sick child as a key consideration. While some saw a use for the intervention in aiding decision-making, many only wanted information about risks to look for. There was a sense that current practice does not need to change, and that epidemiological information is not used as a starting point for decision-making in this context. The findings have implications for intervention development (which will draw closely on the results), and more broadly for the field of medical decision-making.

Children with Autistic Spectrum Conditions (ASC) experience difficulties in critical areas of social communication and facial emotion recognition (FER) deficits are argued to underlie these social impairments. Currently available interventions to teach FER to ASC children see gains that are often limited to improved recognition of emotions from taught stimuli only (faces used in the interventions). These interventions fail to resolve the problem of enabling distant generalisation (the transference of acquired skills to real life situations) in ASC. This thesis enabled the design and evaluation of an innovative serious game, Emotiquest, to improve the basic FER abilities of young ASC children. Emotiquest uniquely capitalises on three known preferences and strengths of people with ASCs (i.e., the synthetic (cartoon) face advantage, hyper-discrimination ability and hyper-systemising cognitive style) in order to remove a potential barrier to learning (training solely with human faces) and apply a potential facilitator to learning by incorporating discrimination and categorisation training strategies. The pre-post intervention evaluation study investigated the effect of using Emotiquest for 12 weeks by comparing the FER scores of ASC children who played the game with ASC children who did not. Results demonstrated improved FER for children who played the game compared to the ASC control group. Furthermore, generalisation of acquired FER skills to faces not included in the game was evident. Results suggest that the combination of discrimination training strategies and a tri-stimulus approach (training with synthetic and human faces) via a serious game, collectively improves FER in ASC children. The study’s limitations are discussed along with suggestions for future work.

Background: Much of the preventable child mortality and morbidity in the world occurs in Sub-Saharan Africa. Preventive interventions exist but coverage is low. This thesis examines sociocultural perspectives for delivery and uptake of preventive child health interventions, focussing on constraints and facilitating factors, the role of village health workers and the flow of informatioo relating to child health interventions in rural Southern Tanzania. Methods: Between 2004 and 2007, three linked qualitative studies were conducted in two districts of rural southern Tanzania. These included a rapid qualitative study, a longitudinal acceptability study of intermittert treatment for the prevention of malaria in infants, and an in-depth ethnographic study. The respondents include parents of young children, pregnant women, community leaders, service providers, programme implementers and decision makers at district, regional and national levels. The qualitative findings in this thesis are discussed in connection with quantitative data from household and health facility surveys that took place simultaneously in the study area. Results: Health system, socio-cultural, political and managerial factors all played a role in both facilitating and constraining service delivery and uptake. Constraints included mistrust among council health management teams, service providers, village leaders and community members, logistic and technical failures, absenteeism, delays in service provision, shortage of qualified service providers, provider attitudes, and user charges on supposedly free services. Village health workers had no clear management guidelines, leading to questionable roles, unrealistic expectations, and poor retention, despite being locally accepted. Flow of information about health interventions was inefficient, and client-friendly health education sessions were rare. Conclusions: Most constraints could be addressed through improved communication within and between health managemert teams and the community through district and health facility boards and service providers. Village health workers have the potential to deliver services to the unreached. The Ministry of Health guidelines on the recruitment arxI management ofVHWs would be a valuable first step towards this goal.

Background Case fatality in African children with severe acute malnutrition (SAM) remains high despite implementation of WHO management guidelines. Many deaths occur suddenly and unexpectedly leading to speculation about sudden cardiac death. Fluid therapy remains controversial since SAM children are thought to be at high risk of cardiac failure. The evidence base for these recommendations is limited. We conducted a systematic review of the literature on cardiac function in severe malnutrition, and a comprehensive prospective observational study of Cardiac Physiology in Malnutrition (The CAPMAL Study). Methods Eighty-eight hospitalised Kenyan children with SAM were prospectively recruited and a detailed cardiovascular profiling including clinical, biochemical, echocardiographic and electrocardiographic assessment at admission, during nutritional rehabilitation, and at 28-day follow-up was undertaken. The findings were compared with a group of non- malnourished hospital controls (n=22), frequency matched by age, gender and presenting clinical syndrome. Results Little evidence was found of clinically significant cardiac failure among children with SAM, including those who received intravenous fluids. Echocardiography indicated that cardiac dysfunction was common but typically associated with underlying comorbidities such as sepsis and HIV. We also found increased SVRI, which was negatively correlated with the severity of malnutrition. We did not find strong evidence that children with SAM were more likely to have cardiac dysfunction or arrhythmias than matched controls, or that the cardiovascular profile of marasmus differed from kwashiorkor. Conclusions Clinical cardiac failure and sudden death from arrhythmias were not common among children in our study. The appropriate physiological response observed to IV fluids suggests they may be better tolerated than current guidelines suggest. Further studies are urgently needed to define optimal IV fluid regimens for children with SAM and shock and to investigate the role of increased systemic vascular resistance on gut perfusion and myocardial wall stress.

Background: The prevalence of diabetes in the Middle East is amongst the highest worldwide, Bahrain ranks amongst the top 10 countries. In particular, increasing number of children are being diagnosed with type 1 diabetes mellitus (T1DM) posing a significant public health concern. Objective: The aim of this thesis was to characterize the population by exploring lifestyle, dietary and health risk factors associated with pediatric T1DM and to undertake a local needs assessment to inform the development of management strategies. Methodology: An observational case-control study of children with T1DM and healthy controls (n=59 and 53; mean age 9.66±1.72 and 9.02±1.88 years respectively) was conducted to ascertain baseline characteristics of children with T1DM as compared to healthy children with a subsequent more detailed prospective investigation (n=20) of the T1DM population, which included a focus on vitamin D intake and status. A systematic review of the effectiveness of interventions that seek to improve the management of children and adolescents with T1DM and a qualitative study using focus groups with service-users and healthcare workers were undertaken to inform the development of a specific educational package targeting the needs of Bahraini children with diabetes and their families. The findings of all phases were amalgamated to inform the design of an education package and associated feasibility study. Results: Children with T1DM appeared to be more likely to have suffered from an illness before diagnosis of T1DM than their healthy counterparts. Dietary inadequacies were common in Bahraini children irrespective of diabetes diagnosis, particularly excessive sodium intakes, whilst children with T1DM consumed significantly more calories than controls and more protein relative to their RDA. Serum vitamin D as measured by CLIA assay method (standard practice) and by UPLC/MSMS (gold standard) classified 72% and 50% respectively of the children as having suboptimal vitamin D levels. It appears that dietary intake, sunlight exposure and physical activity may to some extent impact the vitamin D status of children with T1DM. The systematic review identified facilitators of successful interventions aimed at children and adolescents with T1DM such as theoretical based interventions. It also highlighted barriers to the real-life integration of such interventions. These factors and the themes identified by the focus groups such as a need to focus on adolescents prior to transitioning were incorporated into the educational package. Conclusion: Children with diabetes do appear to differ from age matched controls with respect to health factors and socio-demographic characteristics. Larger confirmatory studies are urgently needed. The feasibility and acceptability testing of the proposed educational package is currently ongoing with a planned pilot test of the program within the coming year.

Rett syndrome is a profoundly handicapping neurological disorder with an incidence of approximately 1 in 10,000 live female births. The recently acknowledged syndrome has neither known cause nor cure. The nature of the syndrome is particularly distressing for parents, since regression occurs in infants after apparently normal early development. Rapid therapeutic intervention after diagnosis is considered vital in order to ameliorate detrimental stereotypical behaviours and to limit painful physical deterioration. However, there is little published research dealing with the effects of therapies or the manner which they are delivered in schools. The National Curriculum in Britain aims to ensure that pupils have access to a broad and balanced education, regardless of ability. The rights of children are recognised in legislation, and it is accepted that some pupils will need specialist support. Recent trends are towards greater involvement of parents in educational issues and towards encouraging the development of partnerships in education. This research examines therapy provision for girls with Rett syndrome aged between 7 and 12 years, investigates parental opinions regarding effectiveness of therapies in key skill areas of communication, hand function, motor ability and learning ability, and touches upon the broader issues of how essential needs can be considered alongside the rights of children in the classroom environment. The study shows that the roles of teachers and therapists are complementary, and suggests that enhanced professional interaction may be a future objective. Music therapy, physiotherapy, hydrotherapy and speech therapy are the most common forms of intervention, and the perceived values of each are reported. Inconsistency in provision is apparent, and whilst all therapies are considered beneficial, no single therapy is identified as significantly more beneficial than others.