Thesis (M.S.)--Boston University

Over the last two decades, obesity has become a major public health concern. Evidence suggests that obesity can be programmed by nutrition in early life. A way to treat/prevent obesity would be a major breakthrough for public health and brown adipose tissue (BAT) has been identified as a potential target for this, due to its propensity to utilise stored energy to produce heat, a process mediated by the uncoupling protein (UCP) 1 gene. In humans and sheep, UCP1 decreases with age. Diet during lactation and subsequent alterations in milk fatty acid profile have not been studied in relation to effects on offspring BAT function. There is evidence from in vitro and rodent studies to suggest the potential for some fatty acids, such as conjugated linoleic acid (CLA), to increase UCP1 expression. The aim of this thesis is to use sheep as a model to investigate the potential to alter the milk fatty acid profile by supplementing ewes’ diet with canola or sunflower oil, as previous research has found these to be effective in increasing milk CLA. I then investigated the effects on offspring in early life, with a particular focus on their BAT and its UCP1 abundance. The perirenal adipose depot was studied due to it being the largest depot in young sheep, which is known to transition from brown to white adipose tissue in the first month of life. In addition to this, I set out to investigate the CLA concentrations of infant formula milk and how they compare to those reported for human breast milk. From the day of delivery, ewes raising two lambs each were supplemented with 3% canola or sunflower oil or fed a control diet. Milk samples and ewe and lamb weights were taken at 7 and 28 days and offspring were tissue and blood sampled at either 7 or 28 days. The mRNA expression several of genes associated with thermogenesis was measured. Results showed that supplementation of ewe’s diet with canola, and to a lesser extent, sunflower oil, resulted in decreases in milk medium-chain saturated fatty acids (SFAs). Both supplements increased milk monounsaturated fatty acids (MUFAs) by ~50%, and total and cis-9, trans-11 CLA by ~80%. In addition, sunflower supplementation increased omega-6 PUFAs by 25% and the trans-10, cis-12 CLA isomer by 177% at 28 days of lactation compared to controls. Female lambs fed by sunflower oil supplemented ewes showed a 50% increase in adipose tissue weights compared with controls. Male and, to a lesser extent, female lambs fed by canola oil supplemented ewes showed increased UCP1 abundance at 28 days of age compared with controls. There was an increase in mRNA expression of other thermogenic genes in the canola females at 7 but not 28 days, however, not in males, so this unlikely to be the main cause of the increases seen in UCP1. Results from my investigation into infant formula showed that CLA was present in 67% of the infant formula milks tested but at lower concentrations to those reported in human breast milk. In conclusion, it is possible to induce changes in ewes’ milk fatty acid profile with dietary supplementation and I have shown that the fatty acid profile of milk received in early life has the potential to affect adipose tissue development and UCP1 gene expression. If in the prevention of the normal decline in UCP1 were to be maintained into adulthood it could improve long-term health by helping to maintain body weight. Further research is now necessary to establish whether this increase in UCP1 is maintained beyond the sampling time points of my investigation.

Studies that evaluate the use of ultrasound-guided continuous paravertebral nerve blocks in pediatric patients are scarce, although the use of peripheral nerve blocks has indeed increased in popularity in the adult demographic. The present study aims to describe the epidemiology, safety and efficacy of ultrasound-guided continuous thoracic paravertebral nerve blocks as an everyday practice on a large scale in pediatric patients at a busy, academic, tertiary-care hospital. In all patients studied, a linear ultrasound transducer was used via the transverse in-line technique for catheter placement. Transducer configuration (frequency of oscillation and probe length) was varied based on individual patient factors, such as age, weight and body mass index. A descriptive, retrospective chart review of all patients who received a continuous paravertebral nerve block within a two-year time frame, from 10/2012 to 10/2014, was conducted, resulting in a sample size of 238 paravertebral catheters placed in 214 patients. In regards to patient demographics, the median age was 2 years (IQR 0.8 years - 12 years), with a range of 1 day to 18 years; and the average weight was 25.3 kg ± 23.6 kg, with a range of 1.8 kg to 113.7 kg. The median catheter duration was 3 days (IQR 2 days - 5 days), with 88.8% of catheters placed unilaterally, and 11.2% placed bilaterally. Median postoperative pain scores, intubation time, morphine equivalent consumption, and midazolam consumption were measured for all patients. The overall complication rate was 16.8% (n = 36 patients) with a minor catheter complication rate of 16.4% (n = 35). 6.1% (n = 13) of complications were due to catheter leakage, 4.7% (n = 10) due to catheter dislodgement, 2.8% (n = 6) due to skin irritation, 1.9% (n = 4) due to catheter occlusion and 0.9% (n = 2) due to minor bleeding at the site of catheter insertion. Only one patient experienced a major complication (0.5% of total patients), manifested as a self-resolving, 30-second seizure after a bolus administration of 2% chloroprocaine to manage postoperative pain. The patient was bag-mask ventilated for 60 seconds and the catheter was discontinued. No long-term sequelae were present in this case. Lastly, 98.1% (n = 210) of patients experienced sufficient pain coverage, yielding a failed block rate of 1.9% (n = 4). These results demonstrate safety and efficacy of ultrasound-guided transverse in-line continuous, thoracic paravertebral nerve block in pediatric patients, especially small infants and children. This technique provides an analgesic alternative to the thoracic epidural for postoperative pain treatment in pediatric patients.

OBJECTIVE: To determine risk factors and examination findings that are predictive of orbital fractures in pediatric patients, in the hope of using the findings to develop a rule for when to obtain a Computerized Tomography Scan (CT). Additionally, we will examine the treatments underwent by patients with confirmed orbital fractures. METHODS: A retrospective cohort study was conducted on patients below the age of 22 who were seen in the Emergency Department (ED) at Boston Children's Hospital (BCH) between January 2009 and May 2013, and underwent Computerized Tomography Scan (CT) for evaluation of orbital fracture. 326 cases were selected for inclusion in analysis. Electronic medical records (EMR) of cases were reviewed and data was collected about mechanism of injury, symptoms, physical exam (PE) findings, diagnosis of orbital fracture, and treatment. Data collected was analyzed using SPSS Statistical Software v.21. Frequency of variables was determined, and chi-square analysis was performed comparing frequencies for patients with orbital fractures to patients without orbital fractures. RESULTS: Of the 326 cases undergoing CT, 133 (40.8%) had radiographic evidence of an orbital fracture. Nausea/vomiting, orbital tenderness, orbital swelling, orbital ecchymosis, and limitation of extraocular movement (EOM) were all identified as statistically significant clinical indicators of orbital fractures. 22 (16.5%) of patients with confirmed orbital fractures underwent surgery, with an average time to surgery of 4.5 days. CONCLUSION: We found that 16.5% of cases with orbital fractures, and only 6.7% of all cases, underwent surgery. We have identified 5 factors that can be used for the development of an evidence-based algorithm for determining when to obtain a CT to rule out an orbital fracture in a pediatric population. We believe that we can use this to improve the evaluation of orbital fractures ED, which in turn will improve the utilization of ED resources, and reduce the exposure of pediatric patients to the risks associated with CT.

Development of the human brain occurs in a number of complex pre- and postnatal stages which are governed by both genetic and environmental factors. Aberrant brain development due to inherited defects may result in a wide spectrum of neurological disorders which are commonly encountered in the clinical field of paediatric neurology. In the work for this thesis, I have investigated the molecular basis and defined the clinical features of three autosomal recessive neurological syndromes. I studied a cohort of children with early onset epileptic encephalopathy and, in one family, identified a novel homozygous pathogenic mutation of PLCB1. I have also utilised autozygosity mapping techniques to study consanguineous families with a complex motor disorder, infantile parkinsonism-dystonia, and identified loss-of function mutations in the gene encoding the dopamine transporter (SLC6A3). Subsequent acquisition of a cohort of similarly affected children allowed detailed clinical and molecular characterisation of this novel disorder, dopamine transporter deficiency syndrome. Finally I have delineated the clinical and genetic features of PLA2G6-associated neurodegeneration. The identification of disease-causing genes contributes greatly to understanding the disease mechanisms underlying such early-onset disorders, and also provides novel insights into normal human neurodevelopment.

Paper partition chromatography has been used extensively to study the aminoacid excretion in the urine of healthy children, of newborn infants and of patients suffering from eight different metabolic disorders. The purpose of this investigation was to discover the aminoacid pattern in the urine and the extent to which it is characteristic of each condition, and to establish the differences between the various aminoacid patterns. In order to gain some insight into the mechanism of the various forms of aminoaciduria a comparison was made between the aminoacid pattern of the plasma and that of the urine. In some cases microbiological assay has been used to establish the plasma level of certain aminoacids more exactly than was possible by paper chromatography. [From p92, Summary and conclusions] The main diseases investigated were: Lignac-Fanconi disease Cystine-lysinuria Phenylpyruvic oligophrenia Liver cirrhosis and hepatitis Steatorrhoea Galactosaemia Wilson's disease [From p4, Introduction]

Introduction: Early-life differences in cardiovascular risk factors could contribute to ethnic differences in cardiometabolic disease in adulthood. The aim of this thesis was to investigate ethnic differences in lifestyle factors, adiposity and blood pressure among 5-6 year old children in the UK. Methods: Cross-sectional data on blood pressure, anthropometric measures, sociodemographics, dietary intake, ethnicity, and objectively-measured physical activity, were analysed (n=1470 consented children; 45% White British, 30% South Asian, 8% Black African/Caribbean). Results: Compared with White British children, South Asian children had higher, and Black African/Caribbean children had similar or lower, levels of total and central adiposity. Pakistani and Black African/Caribbean boys did more moderate-vigorous physical activity, whereas South Asian girls did less compared with their White British peers. South Asian and Black African/Caribbean children had lower or similar blood pressure compared with White British children. Sodium intake was highest among Black African children. Sugar intake was lower among all minority ethnic groups compared with White British children. Conclusions: The findings highlight several early-life ethnic differences which could plausibly contribute to cardiovascular health inequalities in adulthood. Early childhood might offer a key opportunity to prevent or reduce ethnic differences in cardiovascular and metabolic disease later in life.

Twins often show signs of physical and cognitive developmental delays compared with singletons at school age, but tend to catch up by young adulthood. Many previous studies focused on early childhood and beyond, and twins with health issues. In this thesis, I investigated the infancy period of healthy twins in the Birmingham Registry for Twin and Heritability Studies. More specifically, I explored twins’ developmental trajectories compared with singleton standards; ante-, peri-, and postnatal factors related to developmental skills; and the association of maternal occupation with twin pregnancy outcomes. Additionally, I studied the heritability of body mass index (BMI) over a lifespan in a meta-analysis of twin studies. Twins had worse developmental skills and were small for their age compared with singleton standards. Birth weight was not strongly associated with developmental skills as in previous studies; however, larger antenatal head circumference was negatively associated with postnatal development. Higher occupational psychological strain was related to shorter gestations. Finally, heritability of BMI remained high over a lifespan. Results were discussed in light of current clinical and health and safety guidelines. Suggestions for further research and dissemination of findings to parents of multiples were also discussed in the final chapter of this thesis.

The overarching aim of this thesis is to further understanding and knowledge of risk factors relevant to children who runaway. More specifically to; identify risk factors most relevant to children running away; establish whether risk factors can be used to distinguish between those children reported missing once versus those reported on multiple occasions; and evaluate assessment methods currently being used with this group. The systematic review explores risk factors associated with children who runaway. Successful identification of risk factors can be used to inform risk assessment which in turn inform intervention strategies. Through an electronic search 573 references were identified since 2002. However, only 15 references were included in the final review once inclusion and exclusion criteria were applied. Through this review it was identified that runaways are a heterogeneous group. Risk factors most consistently identified to be associated with running away spanned multiple levels including; gender, socioeconomic status, family structure, history of abuse/neglect, substance use and school attachment/engagement. Implications for intervention are discussed. The empirical study utilised data collected by the Gwent Missing Children’s Team collected over a one year period (N= 523) to explore risk factors associated with repeat missing reports. The aim of this study was to develop a model that could be utilised in practice to identify those most at risk of repeat missing incidences in order to direct resources effectively. Through logistic regression analyses it was found that five risk factors can be used to distinguish between those children reported missing once (low risk, N= 275) versus those reported missing on multiple occasions (high risk, N= 248). This provided a simple summation checklist that can correctly classify 70.4% of missing cases. This checklist can be used to inform resource allocation with those children identified as high risk warranting more comprehensive intervention and support. The case study presented the assessment and intervention of an adolescent reported missing to Gwent Police. The aim of this study was to provide an in-depth analysis of a missing child case making links to relevant psychological theory and highlighting implications on practice. This case study demonstrated the cross over between running away and sexual exploitation and highlighted the importance in providing specialist intervention services in order to reduce risk of harm through repeat running away. Finally, a critique of a risk assessment tool widely used in Wales with runaways who are suspected to be at risk of sexual exploitation is presented. Within this critique it was found that the Sexual Exploitation Risk Assessment Framework (SERAF) combines consistency in approach with ease and efficiency of identification and intervention for children at risk of, or abused through, sexual exploitation. However, the tool requires empirical validation and reliability analyses before it can be considered a scientific assessment of risk. Overall, this thesis provides evidence for the use of risk factors in identifying children who are likely to be reported missing or runaway. It suggests that this group is heterogeneous and that risk factors relevant to predicting running away span multiple levels. This suggests that intervention should be holistic and target identified risk factors. Risk assessments currently utilised in respect of this group require validation. Further research to inform such risk assessments is also recommended.

To date, no research has explored the relationship between UK school experience and self-identity for young people with Autism Spectrum Disorder (ASD). Within this study, it is argued that identity is an adaptive process that utilises experience of the sociocultural context to generate a 'self'. Reviewed literature additionally suggests that school may be an important domain of identity development. Using a Narrative Orientated Inquiry (NOI) methodology, this research examines identity constructs within school experience narratives produced by young people who have a diagnosis of ASD. Participants were five mainstream secondary school (MSS) students (four males and one female) with a diagnosis of ASD (including Asperger Syndrome), sound expressive language skills and no additional diagnoses. Narrative Interviews (Mishler 1986a, 1986b) were conducted. Three interpretive perspectives, in accordance with NOI, were used to analyse transcripts: Separation of 'fabula' from 'sjuzet' (Hiles and Čermák, 2008); The Holistic-Content interpretive perspective (Lieblich, Tuval-Mashiach and Zilber, 1998); and Critical Narrative Analysis (Emerson and Frosh, 2004). Member checks were carried out. The stories imply that being a young person with ASD at an MSS can be restrictive and disempowering. Findings can be seen to support the proposed theory of identity, suggesting the relationship between school experience and self-identity for young people with a diagnosis of ASD may be an adaptive one, where school experience is the material subject to the process of identity. Findings appear to show that school experience may hinder, through restrictive systems and structures, or help the development of self-identity for young people with ASD. Where young people with ASD can experience free choice and receive support, not least through school staff empathy and understanding, findings suggest they may be aided in developing self-identity. Peer friendships may also potentially afford the opportunity for young people with ASD to learn about themselves, although further research is required in this area.