Pharmacometrics is a quantitative science that is rapidly changing the landscape of drug development, and particularly so for the pediatric population. The motivation behind the research underlying this dissertation is to contribute towards the improvement of pediatric drug development by the astute application of pharmacometric methods. Two distinct research areas have been focused upon: 1- improving pediatric pharmacokinetic (PK) trial design and 2- improving pediatric dosing of warfarin by using a genetics-based dosing regimen. The first project examined in detail the feasibility of and simulation-based methodology for implementing a recent regulatory PK quality standard. The focus was on designing pediatric PK trials that employ sparse sampling and population analysis methods, using a simulation-estimation platform. The research provided clarity on the impact of various trial design elements, such as PK sampling, adult data inclusion, PK variability and analysis method on sample size adequacy to honor the standard. The PK quality standard was found to be practically feasible in terms of sample size adequacy. Informative sampling schedule for a given number of PK samples per subject is assumed during trial design. Recommendations are made to: 1- use prior adult or pediatric data for trial design and analysis, wherever possible and 2 - use one-stage population analysis methods and biologically feasible covariate models for designing pediatric PK studies. The second project involved derivation of the first ever pediatric warfarin dosing regimen, including starting dose and titration scheme, based on pharmacogenetics (Cyp2c9 *1/*2/*3 and VKORc1 -1629 G>A polymorphisms). While extensive research and several dosing models for warfarin use in adults exist, there is paucity of data in pediatrics. A validated adult warfarin population PKPD model was bridged using physiological principles and limited pediatric data to arrive at a pediatric PKPD model and dosing regimen. Pediatric data (n=26) from an observational study conducted at the Children’s Hospital Los Angeles (CHLA) was used to qualify the pediatric model. A 2-step pediatric starting dose based on body weight (<20 kg and ≥20 kg) for each of 18 (6 Cyp2c9 x 3 VKORC1) genotype categories is proposed. The titration scheme involves percentage changes relative to previous dose, based on latest patient INR. The dosing regimen targets a major (≥ 60%) proportion of INRs within therapeutic range of 2.0-3.0, by the second week into warfarin therapy. Simulataneously, bleeding and thromboembolic risks are minimized via minimal proportions (≤ 10% and ≤ 20%) of INRs > 3.5 and INRs < 2.0, respectively. In simulations, the proposed dosing regimen performed better on target INR outcomes than the standard-of-care dosing used in the CHLA patients. Given the challeneges in and low likelihood of conducting pediatric warfarin clinical studies, the proposed dosing regimen is believed to be an important advance in pediatric warfarin therapy. Prospective warfarin studies in pediatrics using the proposed dosing regimen are recommended to refine and validate the suggested dosing strategy.

Tonic arterial smooth muscle can produce strong contractions indefinitely by formation of slowly cycling crossbridges (latchbridges) that maintain force at a high energy economy. To fully understand the uniqueness of mechanisms regulating tonic arterial contraction, comparisons have been made to phasic visceral smooth muscles that do not sustain high forces. This study explored mechanisms of force maintenance in a phasic artery by comparing KCl-induced contractions in the tonic, femoral artery (FA) and its primary branch, the phasic saphenous artery (SA). KCl rapidly (5 N/m2) and [ca2+]i (250 nM) in FA and SA. By 10 min, [ca2+]i declined to 175 nM in both tissues but stress was sustained in FA (1.3 x 105N/m2) and reduced by 40% in SA (0.8 x l05 N/m2). Reduced tonic stress correlated with reduced myosin light chain (MLC) phosphorylation in SA (28% vs. 42% in FA). SA expressed more MLC phosphatase than FA, and permeabilized (β-escin) SA relaxed more rapidly than FA in the presence of MLC kinase blockade, suggesting that MLC phosphatase activity in SA was greater than that in FA. The reduction in MLC phosphorylation in SA was insufficient to account for reduced tonic force (latchbridge model), and SA expressed more "fast" myosin isoforms than did FA. Cytochalasin-D reduced force-maintenance more in FA than SA. These data support the hypothesis that strong force-maintenance is absent in SA because expressed motor proteins do not support latchbridge formation, and because actin polymerization is not stimulated.

Purpose: The purpose of this study was to examine the knowledge, attitudes, and experiences related to infant oral health for both dental and medical providers.Methods: A survey of infant oral health care was sent to 300 randomly selected general dentists, 300 randomly selected pediatricians, and all pediatric dentists in Virginia. The survey contained questions regarding the providers' routine infant oral health care regimen. In addition demographic data from the provider was collected. Responses to the questionnaire were tabulated and percent frequency distributions for responses to each item computed. Percents for all items were based on the total number of respondents in each of the three practitioner groups.Results: The response rate of the survey was 48%. While 100% of pediatricians treat the infant population, only 5% refer for the first dental visit by age one. In addition compared to dentists fewer pediatricians examine for dental decay or give oral hygiene instructions. Less than half of general dentists surveyed treat the infant population and only 12% refer for the first dental visit by age one. Compared to pediatricians and pediatric dentists general dentists were less likely to discuss the first dental visit or nutritional counseling. Amongst the three practitioner types, pediatric dentists provide the most thorough dental exam, however only 25% actually treat infants by one year of age. Access to dental care remains a significant factor in early childhood caries.Conclusion: Results from this research suggest that the majority of pediatricians and general dentists are not advising patients to see the dentist by one year of age. Concurrently the majority of dentists are not treating patients at one year of age, resulting in a critical problem with access to care. There is a need for increased infant oral health care education in the medical and dental communities to appropriately handle this infant population.

Background: Involuntary exposure to secondhand smoke (SHSe) is an important cause of morbidity in children who present to the pediatric emergency department (PED) and urgent care (UC). SHSe interventions delivered in the PED and UC would benefit both the smoker and child, but there have been no large trials testing the efficacy of such interventions. The Healthy Families program is the first randomized controlled trial to test whether a screening, brief intervention, and referral to treatment (SBIRT) intervention delivered in the PED and UC will be effective in decreasing SHSe in children and increasing cessation in smokers. Methods/design: This trial uses a randomized, two-group design in which caregiver-smokers of children 0-17 years old are recruited from the PED and UC. Eligible caregiver-smokers are randomized to either the: 1) SBIRT Condition with face-to-face, tailored counseling that focuses on the child's illness, the importance of reducing child SHSe, caregiver smoking cessation, and the option to receive nicotine replacement therapy; or 2) Healthy Habits Control Condition which includes face-to-face, tailored attention control "5-2-1-0" counseling that focuses on improving the child's health. Dyadic assessments are conducted in-person at baseline, and via email, phone, or in-person at 6-weeks and 6-months. The primary outcomes are biochemically-verified, 7-day point prevalence and prolonged smoking abstinence. Secondary outcomes are cigarettes smoked per week, 24 h quit attempts, and biochemically validated child SHSe at each time point. The costs of this intervention will also be analyzed. Discussion: This study will test an innovative, multilevel intervention designed to reduce child SHSe and increase smoking cessation in caregivers. If effective and routinely used, this SBIRT model could reach at least one million smokers a year in the U.S., resulting in significant reductions in caregivers' tobacco use, SHSe-related pediatric illness, and healthcare costs in this population of children.

The use of antiretroviral therapy (ART) during pregnancy and lactation has significantly reduced the rate of mother-to-child transmission (MTCT) of HIV. However, pregnancy is known to affect the pharmacokinetics of many drugs, including key antiretroviral (ARV) drugs. In addition, ARV use during lactation raises questions about unintended exposure of breastfed infants to maternal drugs through breast milk. For drugs with significant genetic contribution to observed pharmacokinetic variability, we hypothesised that polymorphisms in drug disposition genes may accentuate or attenuate pregnancy-induced changes and/or breastfed infants’ exposure. HIV positive pregnant women and nursing mothers taking efavirenz (EFV)- or nevirapine (NVP)-based ART were recruited from three hospitals in Benue State, Nigeria. A novel strategy involving a preliminary pharmacogenetic association study was used to investigate the magnitude of pregnancy-induced changes in EFV and NVP pharmacokinetics in women stratified by single nucleotide polymorphisms (SNPs) in disposition genes. EFV apparent clearance (CL/F) was higher and AUC0-24, Cmax and Cmin were significantly lower in pregnant compared with postpartum women. When stratified based on the SNP with the highest predictive power, pregnant women with CYP2B6 516GG genotype were especially at risk. In the NVP cohort, exposure was also significantly lower in pregnant compared with postpartum women. When stratified based on composite CYP2B6 516G > T and 983T > C genotypes, Cmin was below target in most patients with combined CYP2B6 516GG and 983TT during pregnancy and postpartum. Cmin was below target in at least 50% of pregnant women with one or two variant alleles, compared with 0% in postpartum women. The intensive pharmacokinetics of EFV and NVP in breast milk and pharmacogenetic predictors were described for the first time. Breast milk pharmacokinetic parameters of EFV in breast milk differed significantly between patient groups stratified by CYP2B6 516G > T. The median time averaged milk-to-plasma concentration (M/P) ratio was 1.10 (range: 0.57-1.71) and the paediatric dose weight-adjusted exposure index was 4.05% (1.08-13.8). The resulting infant plasma concentration was influenced by CYP2B6 516G > T, highest up to 8 days of age at 1590 ng/mL (190-4631) and decreased by about 90% in the age stratum 9 days to 3 months. NVP AUC0-12, Cmax and Cmin in breast milk were significantly lower in patients with composite CYP2B6 516GG/983TT than those with at least one variant allele. The M/P ratio was 0.88 (0.74-1.2) and paediatric dose weight-adjusted exposure index was 3.64% (1.99-9.88). Infant plasma concentration differed significantly based on CYP2B6 516G > T/983T > C and CYP3A4 20230G > A (*1G), highest in those exposed through both breast milk and post-exposure prophylaxis compared with either alone. A breastfeeding physiologically-based pharmacokinetic (PBPK) model to predict infant exposure to maternal drugs through breast milk was developed and validated, with over 90% of all individual observed data points within the predictive interval. This thesis presents details about five different studies where these findings were observed. Their clinical implications in the context of current knowledge and practice were also explored.

Bakgrund: Att föräldrar är med i vården av sitt sjuka barn har många fördelar och är något att sträva efter. Samtidigt kan föräldrar känna sig stressade och osäkra och har ofta ett behov av att rådfråga en sjuksköterska. Syfte: Syftet var att beskriva föräldrars förväntningar på och upplevelse av sjuksköterskans bemötande i omvårdnad av barn med sjukdomar. Metod: Studien genomfördes som en litteraturstudie och artikelsökning gjordes i Cinahl. Resultat: Tre domäner utformades efter resultatet. Föräldrars förväntningar, upplevelser samt deras syn på gott bemötande. Resultatet visade att föräldrar har stort informationsbehov och önskar en nära relation med sjuksköterskan. De är oroliga över att bli dömda av sjuksköterskan och önskar att bli stärkta i sin föräldraroll. Slutsats: För att föräldrar skall känna sig inkluderade i vården av sitt barn krävs god kommunikation med mycket information samt ett starkt partnerskap. / Background: Involving parents in the healthcare of their sick child has many advantages and is something to strive for. Parents may feel stressed and insecure and they often have a need to consult a nurse. Purpose: The aim of the study was to describe parents’ expectations and experiences of the nurse’s attitudes in the care of their sick child. Methods: The study was conducted as a literature review and article search was made in Cinahl Results: Three domains were formed for the results. Parents expectations, experiences and their views on good treatment. The results showed that parents have a great need for information and they desire a close relationship with the nurse. They are worried about being judged by the nurse and want to be empowered in their parental role. Conclusion: Good communication with a lot of information and a strong partnership is what is needed for parents to feel included in the care of their sick children.

Introduction: Maintaining good oral health may be more important for children with disabilities than others, since problems with oral health may increase the impact of a disability, or the medical condition may increase the risk for poor oral health. In addition, the risk for oral health problems may be influenced by the functioning of the child. Functioning can also affect the child’s ability to cooperate in the dental setting, and how dental treatment is performed. A medical diagnosis alone does not provide enough information about a child’s functioning, nor oral health. Thus, there is a need for a holistic perspective of oral health and dental health care in children with disabilities. The International Classification of Functioning, Disability and Health - Children and Youth (ICF-CY) enables a structured assessment of the biopsychosocial consequences of a health condition. Aim: The overall aim of this thesis was to investigate how biopsychosocial factors relate to oral health and specialist dental health care in children with disabilities in a Swedish, and an international context, with special focus on the experience of dental treatment under general anaesthesia (DGA). Material and methods: The research was conducted using a quantitative, cross-sectional, comparative and descriptive design. An ICF-CY Checklist for Oral Health was completed with data from a structured interview with children 0-16 years old, referred for specialist dental health care, and their parents/carers. Additional information was retrieved from dental and medical records. Three groups were included in data analyses: one large international group of 218 children from Argentina, France, Ireland and Sweden; one large Swedish group with 99 children with complex disabilities; and one international group of children with disabilities and manifest dental caries from Argentina, France and Sweden. Results: The ICF-CY Checklist for Oral Health identified both common and varying functional, social and environmental aspects relevant for oral health and oral health care in children who had been referred to specialist dental clinics in four countries. Swedish children with caries experience had been referred to a paediatric dental specialist clinic at a significantly older age than caries-free children. The medical diagnoses were not significantly related to dental caries or child functioning in the large Swedish group with complex disabilities and low caries prevalence, nor was there a significant relationship between dental caries and child functioning. Collinearity between dental caries and problems in the functioning factor ’Interpersonal interactions andrelationships’ was observed in the international group of children with disabilities and manifest dental caries. DGA sessions with combined medical and dental treatment were common in the large Swedish study group. Children with experience of DGA had more severe problems in intellectual functions than those without experience of DGA. Problems in interpersonal interactions and relationships increased, while problems with mobility decreased, the likelihood for children having had experience of DGA. On international group level, dmft/DMFT was significantly higher in children with the experience of DGA than in those without DGA experience, but looking at Argentina, France and Sweden separately, this was not true for the Swedish children. There were significant, international differences between the prevalence of dmft/DMFT, DGA and environmental barriers. Conclusion: The biopsychosocial perspective, operationalised by the ICF-CY, contributes a holistic view on oral health and specialist dental health care in children with disabilities. In addition to certain differences, children with different health status from different countries share many functional and environmental aspects, important for oral health and dental health care. Early referral to a paediatric specialist dental clinic seemed favourable for oral health. The medical diagnosis was not related to child functioning or dental caries. Child functioning had a significant impact on DGA, and in children with disabilities and manifest dental caries, child functioning also had a correlation with caries. The dental caries burden was a stronger factor than functioning for the experience of DGA, however, dental health organisation and country context seemed to matter the most. Combining dental and medical procedures during the same GA session is good use of resources for both the individual and the society. To ensure children with complex disabilities to have the possibility of achieving equivalent good oral health as other children, DGA is one important factor.

Submitted in partial compliance with the requirements for the Master's Degree in Technology: Chiropractic at the Durban University of Technology, 2013. / Background: Paediatric visits to complementary and alternative medicine (CAM) practitioners results from a wide range of childhood disorders. As there are significant anatomical differences between children and adults, scientific evidence for the effectiveness of chiropractic care for adults is not applicable to paediatrics, leaving a paucity of information supporting the management of paediatric conditions by chiropractors. Most studies regarding paediatrics have been performed in first world countries, leaving a paucity of information about third world countries, where the health care milieu differs. Therefore, this research aimed to determine the practice characteristics regarding paediatric care in chiropractic practices in KwaZulu-Natal. Objectives: This prospective, quantitative, descriptive, cross-sectional study based on a focus group refined and piloted questionnaire, determined the practice characteristics with regards to paediatric practice amongst chiropractors in KwaZulu-Natal. The total sample population was n=118, with each practitioner receiving a Letter of Information and Informed Consent Form and a Questionnaire. Data was analysed using the data analysis tools of Microsoft Office Excel and a p value of <0.05 was considered as statistically significant. Results: A response rate of 36% was obtained. Most of the respondents were middle-aged, female chiropractors who had been practicing for less than a decade. Very few of the chiropractors held paediatric qualifications (18.6%). In terms of paediatric care, most of the respondents used a variety of conservative approaches as evidenced by the type and number of assessments, treatment and management procedures used in practice. Conclusions: The results showed that few chiropractors in KwaZulu-Natal see paediatric patients in their practices; however the chiropractors that managed paediatric conditions were predominantly conservative. This is positive for the chiropractic profession, as it shows diligent and responsible decision making within a vulnerable population group. Future research must assist with facilitating inter-professional relations with other health care professionals and public relations need to be aimed at creating more awareness generally regarding chiropractic paediatric care. / M

Orientador: Nilton Carlos Machado / Resumo: Introdução. O câncer pediátrico é a principal causa de morte por doença em crianças menores de 19 anos. Os tratamentos utilizados afetam negativamente o organismo e aumentam o risco de comprometimento do estado nutricional. Algum grau de desnutrição é observado em 8% a 50% das crianças com câncer ao diagnóstico e pode estar relacionada ao aumento da extensão da doença, atraso no diagnóstico e tratamento. Por outro lado, a obesidade infantil é hoje uma grande questão de saúde pública e um dos desfechos adversos mais comuns em sobreviventes de câncer infantil. Então, é essencial avaliar o estado nutricional destes pacientes, tanto ao diagnóstico, como durante e após a terapia. Objetivos. Avaliar o estado nutricional, de crianças e adolescentes com câncer, através de indicadores antropométricos, características clínicas e demográficas, em três estudos longitudinais: ao diagnóstico, durante e após o tratamento. Propor um manual para manejo do estado nutricional em crianças com câncer. Métodos. Estudo longitudinal e prospectivo em crianças e adolescentes com câncer, com idades entre 1 a 18 anos, atendidas em centro terciário de tratamento oncológico de agosto/2018 a março/2019. Realizado avaliação em três estudos de crianças com câncer: Estudos1, pacientes recém-diagnosticados, que iniciariam terapia; Estudo 2, pacientes sob terapia há pelo menos 3 meses; e Estudo 3, pacientes fora de terapia. Realizou-se, em 3 momentos: momento 0, 30 dias e 180 dias. Realizado: Revisão de prontuá... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Introduction. Pediatric cancer is the leading cause of death from disease in children under 19 years. The treatments used negatively affect the body and increase the risk of compromised nutritional status. Some degree of malnutrition is observed in 8% to 50% of children with cancer at diagnosis and may be related to increased extent of the disease, delayed diagnosis and treatment. On the other hand, childhood obesity is now a major public health issue and one of the most common adverse outcomes in child cancer survivors. Therefore, it is essential to evaluate the nutritional status of these patients, both at diagnosis, during and after therapy. Aims. To evaluate the nutritional status of children and adolescents with cancer through anthropometric indicators, clinical and demographic characteristics, in three longitudinal studies: at diagnosis, during and after treatment. Propose a manual for nutritional status management in children with cancer. Methods. Longitudinal and prospective study in children and adolescents with cancer, aged 1 to 18 years, attended at a tertiary cancer treatment center from August 2018 to March 2019. Evaluation was performed in three studies of children with cancer: Studies1, newly diagnosed patients, who would start therapy; Study 2, patients on therapy for at least 3 months; and Study 3, patients out of therapy. It took place in 3 moments: moment 0, 30 days and 180 days. Performed: Review of medical records; Application of a questionnaire to collec... (Complete abstract click electronic access below) / Mestre

INTRODUCTION: The techniques currently in practice to diagnose and assess interval disease activity in patients with inflammatory bowel disease (IBD) are costly and invasive. Physicians typically rely on information derived from a combination of endoscopic, radiologic, and histologic studies to diagnose and determine the extent and severity of the two most common forms of IBD, Crohn disease (CD) and ulcerative colitis (UC). The development of noninvasive methods of assessing response to therapy is of increasing importance to pediatric healthcare providers. Previous studies have demonstrated that serum and fecal biomarkers are reliable measures of inflammation in the gastrointestinal tract. However, existing biomarkers are non-specific and their levels can be elevated in the context of either acute and chronic inflammation (IBD) or infection. As such, further studies are required to develop newer and novel biomarkers that have greater specificity for use in the diagnosis and interval assessment in children and adults with IBD. OBJECTIVES: The goal of this study is to further assess the relationship between biomarkers in the stool and serum of patients with IBD that are being treated with the anti-TNF therapy, infliximab (Remicade). To accomplish this, we will assess the changes in serum and fecal biomarker levels over the course of treatment and correlate the changes in fecal and serum biomarker levels with clinical, biochemical, and endoscopic outcome variables. METHODS: We conducted a prospective longitudinal cohort study in pediatric patients with IBD receiving long-term immunosuppressive therapy with Remicade. Pediatric patients diagnosed with either CD or UC who receive Remicade at Boston Children’s Hospital were recruited. Patients were drawn from subsets of patients that were either naïve to Remicade, had received Remicade for less than 6 months, or had received Remicade for more than one year at the time of enrollment. We collected longitudinal data over the course of their first 6 consecutive infusions following enrollment, including blood and stool samples, disease activity indexes, as well as a patient-reported outcome measure (IMPACT-III Questionnaire) at each infusion session. RESULTS: A total of 33 patients with IBD who fit our eligibility criteria and provided informed consent were enrolled to date. Of these, 20 had a CD diagnosis and 13 had a UC diagnosis. We collected baseline serum, fecal, and IMPACT-III score data and followed enrolled patients over the course of subsequent infusions. Mean baseline fecal ASCA levels from 8 CD and 6 UC patients were 0.08±0.021 OD and 0.02±0.0015 OD, respectively. At baseline, serum lactoferrin (p<0.10), calprotectin (p<0.10), ESR (p<0.05), and CRP (p<0.10) were significantly higher among CD patients. CONCLUSION: Our data demonstrate the potential for serum and fecal biomarkers to evaluate therapeutic response to Remicade. Completion of study enrollment and data collection will be necessary to determine if individual or combinations of fecal and serum biomarkers yield the most robust measures for use in the diagnosis and interval assessment of children and adults with IBD.