This thesis deals with the quantitative analysis of multiple drugs in the neonate, in blood and in meconium as an alternative biological specimen in forensic toxicology and is also concerned with the dangers of transmission of drugs used and abused by the mother to the foetus and neonate. The aims of the work were to investigate methods for performing a full drug screen on small amounts of biological specimen and to carry out a survey of illicit drug use during pregnancy in the Glasgow area. Following brief overviews of toxicology and the main problems facing the paediatric toxicologist, the development of analytical toxicology procedures to help to overcome them is summarised along with a more detailed examination of solid phase extraction (SPE) - theory, advantages and applications to biological samples. The initial experimental work established the feasibility of performing a full drug screen on small samples of blood such as those obtained from neonates, having a volume of 1-2ml. This used a single SPE cartridge for the extraction of a mixture of acidic and basic drugs followed by end-step analysis with enzyme immunoassay (ELA) and gas chromatography-mass spectrometry (GC/MS). Representative drugs from each group were selected for evaluation purposes: butobarbitone, amylobarbitone, methaqualone, primidone, and phenytoin drugs for the acidic drug group and cocaine, ecgonine methyl ester, morphine, diazepam, and desmethyldiazepam for the basic drug group. These were chosen as examples of drugs commonly used in the UK. Four analytes (morphine, methadone, cocaine and benzoylecgonine) were used to compare two different SPE cartridges, Bond Elut Certify® and Abselut®, which can be used to extract both acidic and basic drugs. The comparison involved four parameters: analyte recovery, lower limits of detection, presence of interferences in the extracts and analysis time required by each. Recoveries were in the range 60-100% and lower limits of detection were in the range 1-25 ng/ml and it was assessed that Bond Elut columns were better than Abselut columns.

This thesis consists of a series of studies utilising quantitative ultrasound (Sunlight Omnisense 7000P) to assess bone health of infants. Preterm infants are at risk of osteopenia of prematurity (OP) which can result in fractures in the short term and may have an impact on growth in infancy and childhood. OP has a multifactorial aetiology including factors such as poor mineral intake and immobility. There is an increasing number of ex-preterm survivors therefore morbidity becomes more important. There is also increasing evidence from epidemiological studies that growth in infancy can have an effect on adult diseases such as osteoporosis. The first study was a cross-sectional study of bone quantitative ultrasound measurements in 110 term and preterm infants shortly after birth. Speed of sound (SOS) was measured at the tibial and the radius. This validated the technique showing reproducible measurements with low inter and intra-observer error, and also showed no benefit to measuring multiple sites. Preterm infants were found to have a significantly lower SOS than term infants. There was a positive correlation between tibial SOS and gestation, with birthweight being a less significant factor than gestation. The second study followed 18 preterm infants longitudinally from birth to hospital discharge or term corrected gestational age (CGA). SOS fell significantly with time in all infants. The most preterm infants had the greatest fall in SOS. SOS at the end of the study period was negatively associated with peak serum alkaline phosphatase and severity of illness score. SOS was significantly lower in the infants who required total parenteral nutrition for longer than 3 weeks. These results show that the neonatal course has a significant impact on SOS trajectory. When preterm infants were followed up in the out-patient clinic over the first two years of life the SOS measurements taken as the next part of this study showed a catch up phenomenon. In the majority of infants, but not all infants, SOS moved into the normal range by 6 months CGA. In the subgroup of infants followed longitudinally those with the lowest SOS at hospital discharge/term corrected age had the greatest increase in SOS over time. An interventional study of passive exercise was performed to explore its role in influencing the bone health of preterm infants. Thirty one infants born at less than 33 weeks gestation were randomised to receive range of motion flexion and extension exercises once daily for 5 days each week starting ‘early’(n=15) or ‘late’ (when on 100kcal/kg/day enteral feeds, n=16) and continuing until term corrected gestational age (CGA) or discharge from hospital. Tibial SOS declined significantly from birth to end of physical activity in both ‘early’ and ‘late’ groups, and this was similar to the decrease seen in a group of historical controls from the earlier longitudinal study. Weight gain and head growth did not show a significant difference between groups or between study infants and controls. No infant was reported to have sustained a fracture, and length of hospital stay was not significantly different between groups. There was no significant increase in sepsis rate, retinopathy of prematurity or chronic lung disease in study infants but numbers were small. On longer term follow-up the intervention was not associated with any adverse effects. To investigate the possibility that the maternal environment plays an important role in influencing infants’ bone health we also studied SOS changes in 188 pregnant women and their offspring. Most women had SOS in the normal range antenatally, and there was no significant change in SOS across pregnancy in the group as a whole. There was a significant negative correlation with SOS SDS and BMI in early pregnancy. Women who smoked cigarettes had lower SOS throughout pregnancy and so did their infants. Serum bone biochemistry was measured in the women antenatally and after delivery, and umbilical cord blood was also taken where possible. Vitamin D deficiency was found to be common at the end of pregnancy. Women of Asian origin had significantly lower vitamin D levels at all stages of pregnancy. There was no significant relationship between maternal and infant SOS, or between maternal vitamin D status and infant SOS. The work of this thesis establishes quantitative ultrasound as a useful technique in the assessment of infant bone health. It is a radiation free tool which provides precise and reproducible measurements in both term and preterm infants. In agreement with a small number of other studies we found that preterm infants have a lower speed of sound at birth compared to term infants; speed of sound increases with increasing gestation while in utero. By including infants who were both appropriately grown and small for gestational age we found maturity to be a more important factor in bone strength than birthweight. Despite the apparent self limiting nature of osteopenia of prematurity an intervention to improve neonatal bone health is still desirable, to prevent fractures. Our results do not substantiate conclusions from previous studies that physical activity alone can improve neonatal bone health. .Findings are however limited by the small sample size. Further studies are needed which investigate alternative exercise regimens, taking into account mineral and nutrient supply. Vitamin D deficiency, smoking and obesity may adversely affect bone health of women and their offspring. In the west of Scotland vitamin D deficiency is common in pregnancy: women of south asian origin are at particularly high risk, and should be supplemented with Vitamin D.

The bacteria located within the human gastrointestinal tract (the gut microbiota) perform numerous protective, immunological and metabolic functions for the host. They are increasingly implicated in the pathogenesis of acquired inflammatory diseases of the gut in childhood, namely: necrotising enterocolitis (NEC) and inflammatory bowel disease (Crohn’s disease (CD) and ulcerative colitis (UC)). Study of the role that the microbiota may play in the development of such diseases may lead to new therapies to modulate or even cure them. However many current techniques depend on the ability to study such bacteria outwith their natural ecosystem. Although molecular techniques can identify species independent of standard cultures they can enlighten little on the metabolic activity of identified bacterial species, which may be important in the propagation of inflammatory responses. Little is known about the potential of novel therapeutic strategies, such as probiotics, to modulate diseases such as NEC. In addition inadequate scientific rigour has been applied to the science of probiotics. The aims of the study described in this dissertation were to test the following hypotheses. Hypotheses: 1. Probiotics prevent NEC in at risk infants of very low birth weight (VLBW). 2. The human gut microbiota can be labelled by stable isotope probing (SIP) to measure metabolic activity. 3. Quantitative measurement of the metabolic activity of the unculturable gut microbiota is a useful way of studying changes in the microbiota, compared with measures of bacterial diversity, and may enlighten our understanding of bacterially mediated inflammatory stimuli in inflammatory gut diseases of childhood.

This study aimed to investigate the effectiveness of Social Stories utilising either photograph or symbol illustrations to address the target behaviours of children with a diagnosis of Autism Spectrum Disorder (ASD). Multiple single-case experiments were conducted utilising an ABA design with 10 participants, all of whom were boys attending mainstream primary schools within a West Midlands Local Authority. The children ranged in age from 5-11 and all of them had a diagnosis and a primary need in relation to ASD. Personalised Social Stories were composed for each of the participants to address a specific target behaviour that had been identified by the child and members of teaching staff. The stories were written by the researcher alongside a member of staff from the Local Authority's Autism Outreach Service and all adhered to the criteria and guidelines for construction outlined by Carol Gray (2004). The format for each of the stories was identical but for the manipulation of the illustrations. The effectiveness of the intervention was monitored using a variety of measures including a Behaviour Log recording the frequency of the target behaviour across each of the experimental phases; the Strengths & Difficulties Questionnaire (Goodman, 1997); and a Teacher / Teaching Assistant Questionnaire that had been designed by the researcher and was based on items contained within the Behaviour Intervention Rating Scale (BIBS) (Elliot & Treuting, 1991). The data obtained from these measures was analysed through the visual inspection of graphical data and the calculation of effect sizes. Discussion is provided about the suitability, reliability and validity of each of the measures and the methods of data analysis. Overall the study provides evidence of the utility and effectiveness of Social Stories for addressing the target behaviours of children with a diagnosis of ASD. Furthermore it offers an original contribution to the existing literature by exploring the impact of different forms of illustration on story efficacy.

Perimetry is essential to identify visual field defects in disorders of the visual pathways. In compliant adults, automated static perimetry (ASP) is the preferred method of visual field assessment. However, children under 10 years have difficulty with the visuo-motor task and constant fixation required. Manual kinetic perimetry is often used for children as it can be adapted to a child’s age. However, it suffers from many of the problems inherent to ASP. In infants perimetry is limited to the “confrontation” technique which can be imprecise and does not generate quantitative data. The lack of reliable ASP in children and quantitative perimetry in infants is a longstanding clinical problem. The aims of this research were to (i) develop, and (ii) clinically evaluate, a technique for ASP in children which utilises “eye tracking”. The first part of this research was concerned with the development of the technique, termed “Saccadic Vector Optokinetic Perimetry” (SVOP). The system comprises a personal computer, display screen, and an X50 eye tracker (Tobii Technology, Sweden). The eye tracker is noncontact and provides data on (i) eye position in 3D space, and (ii) the point of gaze. This allows the screen position of “test stimuli” to be calculated, and eye gaze responses to the “test stimuli” to be assessed in “real time”. A software algorithm was developed to determine if “test stimuli” have been perceived based on the direction, amplitude and latency of a subject’s gaze response. A feasibility study was conducted with 29 subjects comprising 4 groups: (i) healthy adults, (ii) healthy children, (iii) adult patients with visual field defects, and (iv) child patients with visual field defects. Subjects performed SVOP tests which replicated the Humphrey Field Analyser (HFA) C-40 screening test with a stimulus size of Goldmann III and intensity of 14dB. Subjects able to do so also performed equivalent HFA C-40 tests for comparison. In healthy subjects 99.1% of SVOP test points were in agreement with a healthy visual field. In patients with visual field defects, 89.8% of test points were in agreement with HFA equivalent tests. The visual field defects identified using SVOP in the child patients were consistent with their clinical findings. A clinical evaluation of SVOP was undertaken in the second stage of this research with 122 subjects comprising the same four subject groups as in the feasibility trial. An “ideal” test protocol resulted in 8 uniocular visual field tests for each subject comprising 4 SVOP tests and 4 HFA tests. In children where uniocular testing was not tolerable, two binocular SVOP tests were performed. The sensitivity and specificity of the SVOP tests were computed using a direct comparison with reliable HFA tests, and repeatability of SVOP and HFA tests were assessed using Cohen’s kappa coefficient. In child patients unable to provide a reliable HFA test, their clinical history, other clinical findings and the repeatability of their SVOP tests were used to assess the SVOP results. The overall sensitivity and specificity of the SVOP testing was 72.7% and 96.8% respectively. The sensitivity had a greater variation than the specificity amongst the different subject groups. The repeatability of SVOP tests was slightly reduced as compared to the HFA tests across all groups with kappa coefficient’s of 0.65 and 0.74 for SVOP and HFA respectively. In child patients without reliable HFA equivalent tests the SVOP results could commonly be associated with other clinical findings and repeatable testing added to the confidence in the reliability of these cases. The developed SVOP technique performs well with accurate eye tracking data and an attentive child. It has proved extremely useful in identifying and monitoring visual field defects in several child patients who required regular visual field assessment.

Class of 2017 Abstract / Objectives: To assess the perceived confidence level of community pharmacists in utilizing weight-based dosing, dispensing prescriptions, counseling, and recommending over-the-counter medications for the pediatric population in rural and non-rural settings. Methods: A 33-item questionnaire generated through REDCap was distributed to 11,280 pharmacists registered with the Arizona State Board of Pharmacy via email from March 14 to April 4 of 2017. The survey collected information on the participants’ experiences in managing pediatric prescriptions and demographics. Results: Of the 11,280 surveys distributed, a total of 857 responses were submitted by the end of the survey period (7.6%) and 482 responses were included in the analysis; 49 (10.2%) were practicing in rural areas and 433 (89.8%) were practicing in non-rural areas (including urban and suburban) in Arizona. There was no significant difference in the rural group compared to the non-rural group regarding experiences with dispensing pediatric medications. In regards to the confidence level, there was a significant difference between the two groups in calculating and recommending weight-based dosing for prescription and OTC pediatric medications (p = 0.022 and 0.031, respectively) and identifying a dosing error in pediatric prescriptions (p = 0.016). Conclusions: Community pharmacists practicing in rural and non-rural settings in Arizona had similar experiences with dispensing pediatric medications and confidence levels in managing medications for pediatric patients.

The selection of outcomes is a critically important decision when designing randomised controlled trials (RCTs). Informed clinical decisions can only be based on the results of RCTs that have measured outcomes of importance to both clinicians and patients. It can be difficult to know which outcomes should be measured in RCTs. Some groups advocate core outcome sets, which are a minimum set of outcomes that should be measured, and reported, in all clinical trials in a given condition. These increase the likelihood that important outcomes are measured, reduce nonuniformity between studies, and reduce the risk of outcome reporting bias. We systematically reviewed studies that determined which outcomes to measure in clinical trials in children, and found that such work had been conducted in only few conditions, and the quality of existing work was variable. Few studies used structured consensus techniques to reach agreement about which outcomes to measure in trials, and parents were seldom involved. No studies included children. One condition in which there were no robust recommendations about which outcomes to measurein RCTs was childhood asthma, which is a condition of considerable global importance. We subsequently aimed to assess whether the absence of a core outcome set for RCTs of children with asthma meant that certain outcome domains were measured less frequently than others, and whether there was nonuniformity between studies in terms of outcomes selected. We conducted a systematic review of RCTs of children with asthma, published between January 1988 and December 2007, and found that the included studies focussed on short-term disease activity, but quality of life, functional status, and long-term outcomes were infrequently measured. Certain outcomes were measured and reported in various ways. We recommended that a core outcome set should be developed for childhood asthma, using structured consensus techniques, such as the Delphi process. In order to aid the development of such a core set, we first systematically reviewed studies that used the Delphi process to determine which outcomes to measure in clinical trials. We observed variations in the methodology used, identified potential sources of bias, and provided recommendations about how such studies could be conducted and reported. In order to develop a core outcome set for childhood asthma, we used a Delphi process to ascertain the views of 46 clinicians, and around 100 parents and young people, about which outcomes are most important and relevant from their perspective, when making shared decisions about regular therapies which control asthma. The most important outcomes were symptoms, exacerbations, and quality of life. Although consensus still needs to be reached amongst other groups of individuals involved in clinical trials, we conclude that these outcomes should be measured, and reported, in all RCTs that aim to evaluate the effectiveness of regular therapies for children and young people with asthma.

INTRODUCTION: In April 2010 tenofovir and abacavir replaced stavudine in public-sector first-line antiretroviral therapy (ART) for children under 20 years old in South Africa. The association of both abacavir and tenofovir with fewer side-effects and toxicities compared to stavudine could translate to increased durability of tenofovir or abacavir-based regimens. We evaluated changes over time in regimen durability for pediatric patients 3 to 19 years of age at 8 public sector clinics in Johannesburg, South Africa. METHODS: Cohort analysis of treatment naïve, non-pregnant pediatric patients from 3 to 19 years old initiated on ART between April 2004-December 2013. First-line ART regimens before April 2010 consisted of stavudine or zidovudine with lamivudine and either efavirenz or nevirapine. Tenofovir and/or abacavir was substituted for stavudine after April 2010 in first-line ART. We evaluated the frequency and type of single-drug substitutions, treatment interruptions, and switches to second-line therapy. Fine and Gray competing risk regression models were used to evaluate the association of antiretroviral drug type with single-drug substitutions, treatment interruptions, and second-line switches in the first 24-months on treatment. RESULTS: 398 (15.3%) single-drug substitutions, 187 (7.2%) treatment interruptions and 86 (3.3%) switches to second-line therapy occurred among 2602 pediatric patients over 24-months on ART. Overall, the rate of single-drug substitutions started to increase in 2009, peaked in 2011 at 25%, then declined to 10% in 2013, well after the integration of tenofovir into pediatric regimens; no patients over the age of 3 were initiated on abacavir for first-line therapy. Competing risk regression models showed patients on zidovudine or stavudine had upwards of a 5-fold increase in single-drug substitution vs. patients initiated on tenofovir in the first 24-months on ART. Older adolescents also had a 2-3-fold increase in treatment interruptions and switches to second-line therapy compared to younger patients in the first 24-months on ART. CONCLUSIONS: The decline in single-drug substitutions is associated with introduction of tenofovir. Tenofovir use could improve regimen durability and treatment outcomes in resource-limited settings.

Thesis advisor: Eva Garroutte / Thesis advisor: David Karp / In an age in which diversity and healthcare inequalities are prominent issues, culturally competent care has emerged as a popular response. However, there seems to be a gap between this academic interest and the attempts to implement cultural competency in the American healthcare system. The aim of this qualitative research was to explore the link between culture and health and to uncover what cultural competency might mean on a practical level through a case study of the pediatric in-patient units of an urban hospital in Boston, Massachusetts. Through participant observation over the span of two months, as well as 20 semi-structured interviews with 14 healthcare providers and 6 bilingual Latino parents of pediatric patients, I investigated the challenges that these groups face in providing and seeking care, respectively. The results of this project attempt to give voice to the families and their providers, as well as suggest how the hospital can better accommodate the needs of the Latino population. Overall, this project has revealed the complexity of the links between culture and health, and indicated that there is no single model of cultural competence that can adequately capture this complexity. Ultimately, relationships and good communication are at the core of the cross-cultural medical encounter, and may serve to create a more culturally welcoming atmosphere for patients of all backgrounds. / Thesis (BA) — Boston College, 2012. / Submitted to: Boston College. College of Arts and Sciences. / Discipline: Sociology Honors Program. / Discipline: Sociology.

Thesis advisor: Judith A. Vessey / Purpose: The purpose of this study was to elucidate changes in parents' perceptions of health related quality of life (HRQOL), functional status, and caregiver burden in children with severe cerebral palsy (CP) following extensive orthopedic surgery and to determine the amount of nonmedical out-of-pocket expenses (NOOPEs) incurred during hospitalization. Background: CP is the most common cause of childhood physical disability. Children with severe non-ambulatory CP have multiple complex medical problems and frequently develop hip dislocations and neuromuscular scoliosis; these require extensive orthopaedic surgical interventions to prevent progression. The surgical trajectory is costly, resource intensive, and complications are common. Decision-making needs to extend beyond anticipated physical and radiographic improvements to include patient-centered outcomes including HRQOL, functional status, caregiver impact, and financial burden. Currently, research on this second group of outcomes does not exist. Methods: A single group prospective cohort study (N=48) design was used to measure changes pre- and post- surgery. NOOPEs were collected on a daily basis from parents during their child's hospitalization. A linear mixed-model regression analysis for longitudinal data, incorporating serial patient measurements over one year, was used to assess changes in HRQOL, functional status, and caregiver impact using measures normed for this population (i.e., CPCHILD, ACEND). NOOPEs were calculated using descriptive statistics. Results: Significant declines in HRQOL and functional status were noted at six weeks post-operative with return to baseline at three months. Long-term significant (p = .005) improvements, however, were noted beginning at six months. Caregiver impact did not change significantly over time. The total NOOPEs for the inpatient ranged from $59.00-$6977.50 (Median = $479.30) with 1971.5 missed hours from work. Conclusion: Children with severe CP who undergo extensive orthopaedic surgery and their families experience improvements across a variety of patient-centered outcomes in the long-term following surgery. Nursing has a critical role in assisting families in decision-making around surgery and providing anticipatory guidance and support. / Thesis (PhD) — Boston College, 2013. / Submitted to: Boston College. Connell School of Nursing. / Discipline: Nursing.