The Development of an Intervention Tool to Address Challenges in the Medical Treatment of Children with Autism .

Challenges in treating children with an autism spectrum disorder (ASD) in medical settings are identified and discussed. Although research supports interventions for children with ASD including positive reinforcement, environmental modification, and visual supports and systems, limited research on the efficacy of these interventions in medical environments and with specific procedures exists. Based on the available intervention literature, this project proposes a picture schedule reinforcement system for use during blood draw procedures for ASD children with diabetes. Future efforts should include increased education for medical providers and health professionals as psychological interventions continue to inform best practices in care for children with ASD in medical settings.

Treatment-seeking behavior and delay in children with severe malaria in Uganda: results of a Markov analysis

Thesis (Master's)--University of Washington, 2016-06

Prophylactic ranitidine treatment in critically ill children - a population pharmacokinetic study

Aims - To characterize the population pharmacokinetics of ranitidine in critically ill children and to determine the influence of various clinical and demographic factors on its disposition. Methods - Data were collected prospectively from 78 paediatric patients (n = 248 plasma samples) who received oral or intravenous ranitidine for prophylaxis against stress ulcers, gastrointestinal bleeding or the treatment of gastro-oesophageal reflux. Plasma samples were analysed using high-performance liquid chromatography, and the data were subjected to population pharmacokinetic analysis using nonlinear mixed-effects modelling. Results - A one-compartment model best described the plasma concentration profile, with an exponential structure for interindividual errors and a proportional structure for intra-individual error. After backward stepwise elimination, the final model showed a significant decrease in objective function value (−12.618; P < 0.001) compared with the weight-corrected base model. Final parameter estimates for the population were 32.1 l h−1 for total clearance and 285 l for volume of distribution, both allometrically modelled for a 70 kg adult. Final estimates for absorption rate constant and bioavailability were 1.31 h−1 and 27.5%, respectively. No significant relationship was found between age and weight-corrected ranitidine pharmacokinetic parameters in the final model, with the covariate for cardiac failure or surgery being shown to reduce clearance significantly by a factor of 0.46. Conclusions - Currently, ranitidine dose recommendations are based on children's weights. However, our findings suggest that a dosing scheme that takes into consideration both weight and cardiac failure/surgery would be more appropriate in order to avoid administration of higher or more frequent doses than necessary.

Parental involvement and group cognitive behavioral treatment for anxiety disorders in children and adolescents: Treatment specificity and mediation effects of parent and peer variables

Phobic and anxiety disorders are one of the most common, if not the most common and debilitating psychopathological conditions found among children and adolescents. As a result, a treatment research literature has accumulated showing the efficacy of cognitive behavioral treatment (CBT) for reducing anxiety disorders in youth. This dissertation study compared a CBT with parent and child (i.e., PCBT) and child group CBT (i.e., GCBT). These two treatment approaches were compared due to the recognition that a child’s context has an effect on the development, course, and outcome of childhood psychopathology and functional status. The specific aims of this dissertation were to examine treatment specificity and mediation effects of parent and peer contextual variables. The sample consisted of 183 youth and their mothers. Research questions were analyzed using analysis of variance for treatment outcome, and structural equation modeling, accounting for clustering effects, for treatment specificity and mediation effects. Results indicated that both PCBT and GCBT produced positive treatment outcomes across all indices of change (i.e., clinically significant improvement, anxiety symptom reduction) and across all informants (i.e., youths and parents) with no significant differences between treatment conditions. Results also showed partial treatment specific effects of positive peer relationships in GCBT. PCBT also showed partial treatment specific effects of parental psychological control. Mediation effects were only observed in GCBT; positive peer interactions mediated treatment response. The results support the use CBT with parents and peers for treating childhood anxiety. The findings’ implications are further discussed in terms of the need to conduct further meditational treatment outcome designs in order to continue to advance theory and research in child and anxiety treatment.

Mediational effects in cognitive behavioral treatment for anxiety disorders in children and adolescents

The current study examined whether variables that have been found to influence treatment outcome serve as mediators of a child and adolescent cognitive behavioral treatment (CBT) anxiety program at multiple time points throughout the intervention. The study also examined mediating variables measured at multiple time points during treatment to determine the time lags necessary for changes in the mediator variable to translate into changes on treatment gains. Participants were 168 youth (ages 6 to 16 years; 54% males) and their mothers who presented to the Child Anxiety and Phobia Program (CAPP) at Florida International University (FIU). Overall, results indicate that the mediators at multiple time points influenced youth anxiety in a fluctuating manner, such that a decrease in skills at one given session caused changes in youth anxiety at a later session. This dynamic between the mediator and outcome may be reflective of the process of therapeutic change and suggests that skills gained from session to session took time to exert their effect on youth anxiety. The methodology employed helps to elucidate how variables mediate treatment outcome in youth anxiety disorders.

Individual child cognitive behavioral treatment versus child-parent cognitive behavioral treatments for anxiety disorders in children and adolescents: Comparative outcomes

Anxiety disorders; such as separation anxiety disorder, generalized anxiety disorder, social phobia and specific phobia, are widespread in children and adolescents. Cognitive behavioral therapy (CBT) has been shown to be effective in reducing excessive fears and anxieties in children and adolescents. Research has produced equivocal findings that involving parents in treatment of child anxiety enhances effects over individual CBT (ICBT). The present dissertation study examined whether parental involvement can enhance individual treatment effect if the parent conditions are streamlined by targeting specific parental variables. The first parent condition, Parent Reinforcement Skills Training (RFST), involved increasing mothers' use of positive reinforcement and decreasing use of negative reinforcement. The second parent condition, Parent Relationship Skill Training (RLST), involved increasing maternal child acceptance and decreasing maternal control (or increasing autonomy granting). Results of the present dissertation findings support the use of all three treatment conditions (ICBT, RLST, RFST) for child anxiety; that is, significant reductions in anxiety were found in each of the three treatment conditions. No significant differences were found between treatment conditions with respect to diagnostic recovery rate, clinician rating, and parent rating of child anxiety. Significant differences between conditions were found on child self rating of anxiety, with some evidence to support the superiority of RLST and RFST to ICBT. These findings support the efficacy of individual, as well as parent involved CBT, and provide mixed evidence with respect to the superiority of parent involved CBT over ICBT. The conceptual, empirical, and clinical implications of the findings are discussed. ^

The Effects of Brominated Flame Retardants on Thyroid Hormone Homeostasis in Human Placenta Tissues and Cell Culture

Polybrominated diphenyl ethers (PBDEs) are a class of brominated flame retardants (BFRs) that have been heavily used in consumer products such as furniture foams, plastics, and textiles since the mid-1970’s. BFRs are added to products in order to meet state flammability standards intended to increase indoor safety in the event of a fire. The three commercial PBDE mixtures, Penta-, Octa-, and DecaBDE, have all been banned in the United States, however, limited use of DecaBDE is still permitted. PBDEs were phased out of production and added to the Stockholm Convention due to concerns over their environmental persistence and toxicity. Human exposure to PBDEs occurs primarily through the inadvertent ingestion of contaminated house dust, as well as though dietary sources. Despite the phase-out and discontinued use of PBDEs, human exposure to this class of chemicals is likely to continue for decades due to the continued use of treated products and existing environmental reservoirs of PBDEs. Extensive research over the years has shown that PBDEs disrupt thyroid hormone (TH) levels and neurodevelopmental endpoints in rodent and fish models. Additionally, there is growing epidemiological evidence linking PBDE exposure in humans to altered TH homeostasis and neurodevelopmental impairments in children. Due to the importance of THs throughout gestation, there is a great need to understand the effects of BFRs on the developing fetus. Specifically, the placenta plays a critical role in the transport, metabolism, and delivery of THs to the fetal compartment during pregnancy and is a likely target for BFR bioaccumulation and endocrine disruption. The central hypothesis of this dissertation research is that BFRs disrupt the activity of TH sulfotransferase (SULT) enzymes, thereby altering TH concentrations in the placenta.

In the first aim of this dissertation research, the concentrations of PBDEs and 2,4,6-TBP were measured in a cohort of 102 placenta tissue samples from an ongoing pregnancy cohort in Durham, NC. Methods were developed for the extraction and analysis of the BFR analytes. It was found that 2,4,6-TBP was significantly correlated with all PBDE analytes, indicating that 2,4,6-TBP may share common product applications with PBDEs or that 2,4,6-TBP is a metabolite of PBDE compounds. Additionally, this was the first study to measure 2,4,6-TBP in human placenta tissues.

In the second aim of this dissertation research, the placenta tissue concentrations of THs, as well as the endogenous activity of deiodinase (DI) and TH SULT enzymes were quantified using the same cohort of 102 placenta tissue samples. Enzyme activity was detected in all samples and this was the first study to measure TH DI and SULT activity in human placenta tissues. Enzyme activities and TH concentrations were compared with BFR concentrations measured in Aim 1. There were few statistically significant associations observed for the combined data, however, upon stratifying the data set based on infant sex, additional significant associations were observed. For example, among males, those with the highest concentrations of BDE-99 in placenta had T3 levels 0.80 times those with the lowest concentration of BDE-99 (95% confidence interval (CI): 0.59, 1.07). Whereas females with the highest concentrations of BDE-99 in placenta had T3 levels 1.50 times those with the lowest concentration of BDE-99 (95% CI: 1.10, 2.04). Additionally, all BFR analyte concentrations were higher in the placenta of males versus females and they were significantly higher for 2,4,6-TBP and BDE-209. 3,3’-T2 SULT activity was significantly higher in female placenta tissues, while type 3 DI activity was significantly higher in male placenta tissues. This research is the first to show sex-specific differences in the bioaccumulation of BFRs in human placenta tissue, as well as differences in TH concentrations and endogenous DI and SULT activity. The underlying mechanisms of these observed sex differences warrant further investigation.

In the third aim of this dissertation research, the effects of BFRs were examined in a human choriocarcinoma placenta cell line, BeWo. Michaelis-Menten parameters and inhibition curves were calculated for 2,4,6-TBP, 3-OH BDE-47, and 6-OH BDE-47. 2,4,6-TBP was shown to be the most potent inhibitor of 3,3’-T2 SULT activity with a calculated IC50 value of 11.6 nM. It was also shown that 2,4,6-TBP and 3-OH BDE-47 exhibit mixed inhibition of 3,3’-T2 sulfation in BeWo cell homogenates. Next, a series of cell culture exposure experiments were performed using 1, 6, 12, and 24 hour exposure durations. Once again, 2,4,6-TBP was shown to be the most potent inhibitor of basal 3,3’-T2 SULT activity by significantly decreasing activity at the high and medium dose (1 M and 0.5 M, respectively) at all measured time points. Interestingly, BDE-99 was also shown to inhibit basal 3,3’-T2 SULT activity in BeWo cells following the 24 hour exposure, despite exhibiting no inhibitory effects in the BeWo cell homogenate experiments. This indicates that BDE-99 must act through a pathway other than direct enzyme inhibition. Following exposures, the TH concentrations in the cell culture growth media and mRNA expression of TH-related genes were also examined. There was no observed effect of BFR treatment on these endpoints. Future work should focus on determining the downstream biological effects of TH SULT disruption in placental cells, as well as the underlying mechanisms of action responsible for reductions in basal TH SULT activity following BFR exposure.

This was one of the first studies to measure BFRs in a cohort of placenta tissue samples from the United States and the first study to measure THs, DI activity, and SULT activity in human placenta tissues. This research provides a novel contribution to our growing understanding of the effects of BFRs on TH homeostasis within the human placenta, and provides further evidence for sex-specific differences within this important organ. Future research should continue to investigate the effects of environmental contaminants on TH homeostasis within the placenta, as this represents the most critical and vulnerable stage of human development.

Effect of vitamin D supplementation on bone status, glucose homeostasis and immune function in children with vitamin D deficiency

Background: Between 1961-1971 vitamin D deficiency was recognized as a public health issue in the UK, because of the lack of effective sunlight and the population mix [1, 2]. In recent years, health care professionals have cited evidence suggesting a re-emergence of the vitamin D deficiency linked to a number of health consequences as a concern [3-6]. Evidence from observational studies has linked low vitamin D status with impairment in glucose homeostasis and immune dysfunction [7-9]. However, interventional studies, particularly those focused on paediatric populations, have been limited and inconsistent. There is a need for detailed studies, to clarify the therapeutic benefits of vitamin D in these important clinical areas. Objective: The aims of this PhD thesis were two-fold. Firstly, to perform preliminary work assessing the association between vitamin D deficiency and bone status, glucose homeostasis and immune function, and to explore any changes in these parameters following short term vitamin D3 replacement therapy. Secondly, to assess the effectiveness of an electronic surveillance system (ScotPSU) as a tool to determine the current incidence of hospital-based presentation of childhood vitamin D deficiency in Scotland. Methods: Active surveillance was performed for a period of two years as a part of an electronic web-based surveillance programme performed by the Scottish Paediatric Surveillance Unit (ScotPSU). The validity of the system was assessed by identifying cases with profound vitamin D deficiency (in Glasgow and Edinburgh) from the regional laboratory. All clinical details were checked against those identified using the surveillance system. Thirty-seven children aged 3 months to 10 years, who had been diagnosed with vitamin D deficiency, were recruited for the bone, glucose and immunity studies over a period of 24 months. Twenty-five samples were analysed for the glucose and bone studies; of these, 18 samples were further analysed for immune study. Treatment consisted of six weeks taking 5000 IU units cholecalciferol orally once a day. At baseline and after completion of treatment, 25 hydroxyvitamin D (25(OH)D), parathyroid hormone (PTH), alkaline phosphatase (ALP), collagen type 1 cross-linked C-telopeptide (CTX), osteocalcin (OCN), calcium, phosphate, insulin, glucose, homeostasis model assessment index, estimated insulin resistance (HOMA IR), glycated hemoglobin (HbA1c), sex hormone binding globulin (SHBG), lipids profiles, T helper 1 (Th1) cytokines (interleukin-2 ( IL-2), tumor necrosis factors-alpha (TNF-α), interferon-gamma (INF-γ)), T helper 2 (Th2) cytokines (interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-6 (IL-6)), T helper 17 (Th17) cytokine (interleukin-17 (IL-17)), Regulatory T (Treg) cytokine (interleukin-10 (IL-10)) and chemokines/cytokines, linked with Th1/Th2 subset balance and/or differentiation (interleukin-8 (IL-8), interleukin-12 (IL-12), eosinophil chemotactic protein ( EOTAXIN), macrophage inflammatory proteins-1beta (MIP-1β), interferon-gamma-induced protein-10 (IP-10), regulated on activation, normal T cell expressed and secreted (RANTES), monocyte chemoattractant protein-1(MCP-1)) were measured. Leukoocyte subset analysis was performed for T cells, B cells and T regulatory cells and a luminex assay was used to measure the cytokiens. Results: Between September 2009 and August 2011, 163 cases of vitamin D deficiency were brought to the attention of the ScotPSU, and the majority of cases (n = 82) were reported in Glasgow. The cross-validation checking in Glasgow and Edinburgh over a one-year period revealed only 3 (11%) cases of clearly symptomatic vitamin D deficiency, which had been missed by the ScotPSU survey in Glasgow. While 16 (67%) symptomatic cases had failed to be reported through the ScotPSU survey in Edinburgh. For the 23 children who are included in bone and glucose studies, 22 (96%) children had basal serum 25(OH)D in the deficiency range (< 50 nmol/l) and one (4%) child had serum 25(OH)D in the insufficiency range (51-75 nmol/l). Following vitamin D3 treatment, 2 (9%) children had final serum 25(OH)D lower than 50 nmol/l, 6 (26%) children had final serum 25(OH)D between >50-75 nmol/l, 12 (52%) children reached a final serum 25(OH)D >75-150 nmol/l and finally 3 (13%) exceeded the normal reference range with a final 25(OH)D >150 nmol/l. Markers for remodelling ALP and PTH had significantly decreased (p = 0.001 and <0.0001 for ALP and PTH respectively). In 17 patients for whom insulin and HOMA IR data were available and enrolled in glucose study, significant improvements in insulin resistance (p = 0.04) with a trend toward a reduction in serum insulin (p = 0.05) was observed. Of those 14 children who had their cytokines profile data analysed and enrolled in the immunity study, insulin and HOMA IR data were missed in one child. A significant increase in the main Th2 secreted cytokine IL-4 (p = 0.001) and a tendency for significant increases in other Th2 secreted cytokines IL-5 (p = 0.05) and IL-6 (p = 0.05) was observed following vitamin D3 supplementation. Conclusion: An electronic surveillance system can provide data for studying the epidemiology of vitamin D deficiency. However, it may underestimate the number of positive cases. Improving vitamin D status in vitamin D deficient otherwise healthy children significantly improved their vitamin D deficient status, and was associated with an improvement in bone profile, improvements in insulin resistance and an alteration in main Th2 secreting cytokines.

Efficacy of Preoperative Chemotherapy in Treatment of Children With Wilms’ Tumor: A Meta-Analysis

Context: To assess the efficacy of preoperative chemotherapy in Wilms’ tumor patients and explore its true value for specific subgroups. Objectives: In the presence of these controversies, a meta-analysis that examines the efficacy of preoperative chemotherapy in Wilms’ tumor patients and specific subgroups is needed to clarify these issues. The objective of this meta-analysis is to assess the efficacy of preoperative chemotherapy in Wilms’ tumor patients and explore its true value for specific subgroups. Data Sources: Computer-based systematic search with “preoperative chemotherapy”, “Neoadjuvant Therapy” and “Wilms’ tumor” as search terms till January 2013 was performed. Study Selection: No language restrictions were applied. Searches were limited to randomized clinical trials (RCTs) or retrospective studies in human participants under 18 years. A manual examination of references in selected articles was also performed. Data Extraction: Relative Risk (RR) and their 95% Confidence Interval (CI) for Tumor Shrinkage (TS), total Tumor Resection (TR), Event-Free Survival (EFS) and details of subgroup analysis were extracted. Meta-analysis was carried out with the help of the software STATA 11.0. Finally, four original Randomized Clinical Trials (RCTs) and 28 retrospective studies with 2375 patients were included. Results: For preoperative chemotherapy vs. up-front surgery (PC vs. SU) group, the pooled RR was 9.109 for TS (95% CI: 5.109 - 16.241; P < 0.001), 1.291 for TR (95% CI: 1.124 - 1.483; P < 0.001) and 1.101 for EFS (95% CI: 0.980 - 1.238; P = 0.106). For subgroup short course vs. long course (SC vs. LC), the pooled RR was 1.097 for TS (95% CI: 0.784 - 1.563; P = 0.587), 1.197 for TR (95% CI: 0.960 - 1.493; P = 0.110) and 1.006 for EFS (95% CI: 0.910 - 1.250; P = 0.430). Conclusions: Short course preoperative chemotherapy is as effective as long course and preoperative chemotherapy only benefits Wilms’ tumor patients in tumor shrinkage and resection but not event-free survival.