Core outcomes and definitions for pediatric fever and neutropenia research: a consensus statement from an international panel.

BACKGROUND There are no specific recommendations for the design and reporting of studies of children with fever and neutropenia (FN). As a result, there is marked heterogeneity in the variables and outcomes that are reported and new definitions continue to emerge. These inconsistencies hinder the ability of researchers and clinicians to compare, contrast and combine results. The objective was to achieve expert consensus on a core set of variables and outcomes that should be measured and reported, as a minimum, in pediatric FN studies. PROCEDURE The Delphi method was used to achieve consensus among an international group of clinicians, pharmacists, researchers, and patient representatives. Four surveys focusing on (i) the identification of a core set of variables and outcomes; and (ii) definitions of these variables and outcomes, were administered electronically. Consensus was predefined as more than 80% agreement on any statement. RESULTS There were forty-five survey participants and the response rate ranged between 84 and 96%. There was consensus on eight core variables and 10 core outcomes that should be collected and reported in all studies of children with FN. Consensus definitions were identified for all of the core outcomes. CONCLUSION Using the Delphi method, expert consensus on a set of core variables and outcomes, and their corresponding definitions, was achieved. These core sets represent the minimum that should be collected and reported in all studies of children with FN. This will promote collaboration and ensure consistency and comparability between studies.

Natural history of growth hormone deficiency in a pediatric cohort.

BACKGROUND/AIMS Controversies still exist regarding the evaluation of growth hormone deficiency (GHD) in childhood at the end of growth. The aim of this study was to describe the natural history of GHD in a pediatric cohort. METHODS This is a retrospective study of a cohort of pediatric patients with GHD. Cases of acquired GHD were excluded. Univariate logistic regression was used to identify predictors of GHD persisting into adulthood. RESULTS Among 63 identified patients, 47 (75%) had partial GHD at diagnosis, while 16 (25%) had complete GHD, including 5 with multiple pituitary hormone deficiencies. At final height, 50 patients underwent repeat stimulation testing; 28 (56%) recovered and 22 (44%) remained growth hormone (GH) deficient. Predictors of persisting GHD were: complete GHD at diagnosis (OR 10.1, 95% CI 2.4-42.1), pituitary stalk defect or ectopic pituitary gland on magnetic resonance imaging (OR 6.5, 95% CI 1.1-37.1), greater height gain during GH treatment (OR 1.8, 95% CI 1.0-3.3), and IGF-1 level <-2 standard deviation scores (SDS) following treatment cessation (OR 19.3, 95% CI 3.6-103.1). In the multivariate analysis, only IGF-1 level <-2 SDS (OR 13.3, 95% CI 2.3-77.3) and complete GHD (OR 6.3, 95% CI 1.2-32.8) were associated with the outcome. CONCLUSION At final height, 56% of adolescents with GHD had recovered. Complete GHD at diagnosis, low IGF-1 levels following retesting, and pituitary malformation were strong predictors of persistence of GHD.

Inflammatory markers in pediatric stroke: An attempt to better understanding the pathophysiology

BACKGROUND The mechanisms of childhood and perinatal arterial ischemic stroke (AIS) are poorly understood. Multiple risk factors include cerebral arteriopathy, congenital cardiac disease, infection, sickle cell disease, and maternal-fetal conditions in neonates. For infections and parainfectious conditions being the most important a possible inflammatory pathophysiology has long been suspected. This pilot study aims to detect, whether there are any abnormalities of inflammatory markers associated with childhood and neonatal stroke. METHODS The concentration of 23 different metalloproteinases (MMPs), tissue inhibitors of MMPs (TIMPs), endothelial factors, vascular cell adhesion proteins, and cytokines in plasma were measured in 12 children with AIS, 7 healthy age matched controls and 6 full term neonates with perinatal AIS. RESULTS At the time of the acute event children with AIS had significantly elevated levels of MMP-9, TIMP4, IL-6, IL-8 and CRP compared to controls (p < 0.05). Except for lower IL-6 and CRP levels the pattern of children with a history of varizella-zoster virus (VZV) and other viral infections did not differ to the non-infectious group. Median levels of MMP-1, MMP-2, TIMP-1, TIMP-2, sE-selectin, sICAM-1, sVCAM-1, IL-8, IL-10, TNF-alpha, VEGF, Fetuin A were found to be higher in the neonatal group when compared with older children. CONCLUSION This pilot study supports the assumption of an inflammatory process and up-regulation of metalloproteinases and their inhibitors, and altered pattern of circulating pro-inflammatory cytokines, CRP and vWF levels in pediatric and neonatal AIS. It highlights the feasibility but also difficulties for similar larger future studies that should aim to clarify childhood stroke etiopathogenesis and consecutive further therapeutic options.

Lung clearance index in cystic fibrosis subjects treated for pulmonary exacerbations.

Pulmonary exacerbations are important clinical events for cystic fibrosis (CF) patients. Studies assessing the ability of the lung clearance index (LCI) to detect treatment response for pulmonary exacerbations have yielded heterogeneous results. Here, we conduct a retrospective analysis of pooled LCI data to assess treatment with intravenous antibiotics for pulmonary exacerbations and to understand factors explaining the heterogeneous response.A systematic literature search was performed to identify prospective observational studies. Factors predicting the relative change in LCI and spirometry were evaluated while adjusting for within-study clustering.Six previously reported studies and one unpublished study, which included 176 pulmonary exacerbations in both paediatric and adult patients, were included. Overall, LCI significantly decreased by 0.40 units (95% CI -0.60- -0.19, p=0.004) or 2.5% following treatment. The relative change in LCI was significantly correlated with the relative change in forced expiratory volume in 1 s (FEV1), but results were discordant in 42.5% of subjects (80 out of 188). Higher (worse) baseline LCI was associated with a greater improvement in LCI (slope: -0.9%, 95% CI -1.0- -0.4%).LCI response to therapy for pulmonary exacerbations is heterogeneous in CF patients; the overall effect size is small and results are often discordant with FEV1.

Pregnancy Outcomes in Subjects Exposed to Certolizumab Pegol.

OBJECTIVE To provide information on pregnancy outcomes in women receiving certolizumab pegol (CZP). METHODS The UCB Pharma safety database was searched for pregnancies through to September 1, 2014. Reports for maternal and paternal CZP exposure were included and outcomes examined, and data on CZP exposure, pregnancy, comorbidities, and infant events were extracted by 2 independent reviewers. Concomitant medications and disease activity were reviewed for clinical trial patients. RESULTS Of 625 reported pregnancies, 372 (59.5%) had known outcomes. Paternal exposure pregnancies (n = 33) reported 27 live births, 4 miscarriages, 1 induced abortion, and 1 stillbirth. Maternal exposure pregnancies (n = 339) reported 254 live births, 52 miscarriages, 32 induced abortions, and 1 stillbirth. Almost all reported pregnancies had exposure to CZP in the first trimester, when organogenesis takes place, and a third of them continued the drug into the second and/or third trimesters. The most frequent indications for maternal CZP use were Crohn disease (192/339) and rheumatic diseases (118/339). Twelve cases of congenital malformation and a single neonatal death were reported. CONCLUSION Analysis of pregnancy outcomes after exposure to CZP supports previous reports, suggesting a lack of harmful effect of maternal CZP exposure on pregnancy outcomes. However, additional data from a larger number of outcomes after exposure and studies including an unexposed comparison group are required to fully evaluate CZP safety and tolerability in pregnancy.

Racial Disparities in Access to and Outcomes of Kidney Transplantation in Children, Adolescents, and Young Adults: Results From the ESPN/ERA-EDTA (European Society of Pediatric Nephrology/European Renal Association-European Dialysis and Transplant Association) Registry.

BACKGROUND Racial disparities in kidney transplantation in children have been found in the United States, but have not been studied before in Europe. STUDY DESIGN Cohort study. SETTING & PARTICIPANTS Data were derived from the ESPN/ERA-EDTA Registry, an international pediatric renal registry collecting data from 36 European countries. This analysis included 1,134 young patients (aged ≤19 years) from 8 medium- to high-income countries who initiated renal replacement therapy (RRT) in 2006 to 2012. FACTOR Racial background. OUTCOMES & MEASUREMENTS Differences between racial groups in access to kidney transplantation, transplant survival, and overall survival on RRT were examined using Cox regression analysis while adjusting for age at RRT initiation, sex, and country of residence. RESULTS 868 (76.5%) patients were white; 59 (5.2%), black; 116 (10.2%), Asian; and 91 (8.0%), from other racial groups. After a median follow-up of 2.8 (range, 0.1-3.0) years, we found that black (HR, 0.49; 95% CI, 0.34-0.72) and Asian (HR, 0.54; 95% CI, 0.41-0.71) patients were less likely to receive a kidney transplant than white patients. These disparities persisted after adjustment for primary renal disease. Transplant survival rates were similar across racial groups. Asian patients had higher overall mortality risk on RRT compared with white patients (HR, 2.50; 95% CI, 1.14-5.49). Adjustment for primary kidney disease reduced the effect of Asian background, suggesting that part of the association may be explained by differences in the underlying kidney disease between racial groups. LIMITATIONS No data for socioeconomic status, blood group, and HLA profile. CONCLUSIONS We believe this is the first study examining racial differences in access to and outcomes of kidney transplantation in a large European population. We found important differences with less favorable outcomes for black and Asian patients. Further research is required to address the barriers to optimal treatment among racial minority groups.

The Association Between Triglyceride and Leptin Levels in Obese Subjects Following a Low-Carbohydrate or Low-Fat Diet

Obesity has been cited as the second leading preventable cause of death in the United States. Studies have determined that at risk overweight and obese individuals have high circulating levels of leptin indicative of leptin resistance as well as elevated levels of plasma triglycerides. Postulates have been formed that link elevated levels of triglycerides with the inhibition of leptin across the blood-brain barrier. If a method of lowering triglycerides is achieved, leptin should be able to cross the blood-brain barrier and reach the ypothalamus, thus regulating body weight through a decrease in appetite and increase in energy expenditure. The primary aim of this study was to compare the effects of both carbohydrate and fat restricted diets on plasma triglycerides and leptin concentrations in overweight and obese subjects with hypertriglyceridemia. Forty subjects were randomly assigned to either the low carbohydrate or low fat diet group for a 12 wk period. Plasma triglyceride and leptin concentrations in the blood were analyzed before and after the 12 wk period to assess diet-induced changes. Both groups had a significant reduction in body weight, though the effect was much greater in the carbohydrate restricted diet group. Fasting and postprandial plasma triglycerides also decreased to a greater extent in the low carbohydrate diet group. Similarly, leptin levels decreased to a greater extent in the carbohydrate restricted diet group. The changes in leptin levels were directly related to the changes in both fasting and postprandial triglyceride levels. The results from this study provide preliminary evidence of diet-induced triglyceride reductions as an underlying mechanism in lowering plasma leptin and improving leptin sensitivity. Further, they provide evidence that an increase in triglyceride levels is at least partially responsible for leptin resistance and reduced leptin sensitivity in obese hypertriglyceridemic individuals. This novel discovery is important as it raises the possibility that other methods of lowering triglycerides may improve the efficiency of leptin transport and ultimately improve fat metabolism in overweight and obese individuals.

Clinical factors associated with growth and mortality of pediatric patients on HAART at Mulago PIDC, Uganda, 2003--2006

The global social and economic burden of HIV/AIDS is great, with over forty million people reported to be living with HIV/AIDS at the end of 2005; two million of these are children from birth to 15 years of age. Antiretroviral therapy has been shown to improve growth and survival of HIV-infected individuals. The purpose of this study is to describe a cohort of HIV-infected pediatric patients and assess the association between clinical factors, with growth and mortality outcomes. ^ This was a historical cohort study. Medical records of infants and children receiving HIV care at Mulago Pediatric Infectious Disease Clinic (PIDC) in Uganda between July 2003 and March 2006 were analyzed. Height and weight measurements were age and sex standardized to Centers for Disease Control and prevention (CDC) 2000 reference. Descriptive and logistic regression analyses were performed to identify covariates associated with risk of stunting or being underweight, and mortality. Longitudinal regression analysis with a mixed model using autoregressive covariance structure was used to compare change in height and weight before and after initiation of highly active antiretroviral therapy (HAART). ^ The study population was comprised of 1059 patients 0-20 years of age, the majority of whom were aged thirteen years and below (74.6%). Mean height-for-age before initiation of HAART was in the 10th percentile, mean weight-for-age was in the 8th percentile, and the mean weight-for-height was in the 23rd percentile. Initiation of HAART resulted in improvement in both the mean standardized weight-for-age Z score and weight-for-age percentiles (p <0.001). Baseline age, and weight-for-age Z score were associated with stunting (p <0.001). A negative weight-for-age Z score was associated with stunting (OR 4.60, CI 3.04-5.49). Risk of death decreased from 84% in the >2-8 years age category to 21% in the >13 years age category respectively, compared to the 0-2 years of age (p <0.05). ^ This pediatric population gained weight significantly more rapidly than height after starting HAART. A low weight-for-age Z score was associated with poor survival in children. These findings suggest that age, weight, and height measurements be monitored closely at Mulago PIDC. ^

Pediatric antiretroviral adherence and child disclosure in Botswana

The scale-up of antiretrovirals (ARVs) to treat HIV/AIDS in Africa has been rapid over the last five years. Botswana was the first African nation to roll out a comprehensive ARV program, where ARVs are available to all citizens who qualify. Excellent adherence to these ARVs is necessary to maintain HIV suppression and on-going health of all individuals taking them. Children rely almost entirely on their caregivers for the administration of these medications, and very little research has been done to examine the factors which affect both adherence and disclosure to the child of their HIV status. ^ Methods. This cross-sectional study used multiple methods to examine adherence, disclosure, and stigma across various dimensions of the child and caregiver's lives, including 30 caregiver questionnaires, interviewer-administered 3-day adherence recalls, pharmacy pill counts, and chart reviews. Fifty in-depth interviews were conducted with caregivers, male caregivers, teenagers, and health care providers. ^ Results. Perceived family stigma was found to be a predictor of excellent adherence. After controlling for age, children who live with their mothers were significantly less likely to know their HIV status than children living with any other relative (OR=0.403, p=0.014). Children who have a grandmother living in the household or taking care of them each day are significantly more likely to have optimal adherence than children who don't have grandmother involvement in their daily lives. ^ Discussion. Visible illness plays an intermediary role between adherence and perceived family stigma: Caregivers know that ARVs suppress physical manifestations of HIV, and in an effort to avoid unnecessary disclosure of the child's status to family members, therefore have children with excellent adherence. Grandmothers play a vital role in supporting the care and treatment of children in Botswana. ^

A process evaluation of a health literacy intervention targeting pediatric providers' communication skills at the Texas Children's Health Plan

Background. Health literacy is an important determinant for quality health care, and affects communication between patients and physicians. Poor communication may result in negative effects in health. Improved communication between patients and physicians could positively affect health outcomes. Communication skills are teachable.^ Objectives. (1) to evaluate the process involved in the design and implementation of a health literacy intervention targeting pediatric providers’ communication skills at the Texas Children’s Health Plan in Houston, Texas; and (2) to describe lessons learned from this process that may be used in future attempts to address the issue of health literacy and health communication. ^ Design/methods. The process evaluation of the implementation of a health literacy strategy at the Texas Children’s Health Plan (TCHP) consisted of a critical analysis of all documents and minutes from meetings of the team of investigators. It also involved a secondary analysis of data collected between December 2006 and June 2007. Descriptive statistics, paired t-test and Wilcoxon-signed-rank test were employed in analyzing the data. This information was complemented with a limited review of existing literature on communication skills training programs. ^ Results. The design of the educational intervention followed recommendations from experts in the field of health literacy. The delivery of the intervention was possible and benefited from existing resources and logistics within the TCHP. Very few targeted providers participated in two offerings of the workshop (6.6% and 1.7% respectively). After the educational intervention, providers showed increased knowledge of health literacy facts and its effects in health (p=0.001); increased awareness of the low health literacy problem (p=0.003); increased expectations for change in practice (p=0.002), and intent to use health literacy strategies for communication immediately following the intervention (p=0.001). Low participation indicated the need for further investigation of barriers to, and means for successful implementation of programs aimed to improving health communication. ^ Conclusions. A short, focused intervention utilizing health literacy strategies for communication appeared effective in increasing knowledge and intentions for change in a small group of pediatric providers. ^

Pre-employment drug testing among job applicants at a Texas tertiary level pediatric hospital: 1992--2006

This study is a retrospective longitudinal study at Texas Children's Hospital, a 350-bed tertiary level pediatric teaching hospital in Houston, Texas, for the period 1990 to 2006. It measured the incidence and trends of positive pre-employment drug tests among new job applicants At TCH. ^ Over the study period, 16,219 job applicants underwent pre-employment drug screening at TCH. Of these, 330 applicants (2%) tested positive on both the EMIT and GC/MS. After review by the medical review officer, the number of true drug test positive applicants decreased to 126 (0.78%). ^ According to the overall annual positive drug test incidence rates, the highest overall incidence was in 2002 (14.71 per 1000 tests) and the lowest in 2004 (3.17 per 1000 tests). Despite a marked increase in 2002, over the 15-year study period the overall incidence tended to decrease. Incidence rates and trends of other illegal drugs are further discussed in the study. And in general, these incidence rates also decline in the study period. In addition to that, we found the overall, positive drug tests were more common in females than in males (55.5% versus 44.4%). ^

An assessment of differences in pediatric dental services provided for a Medicaid population when compared to a federally subsidized (military) clinic

Reimbursement for dental services performed for children receiving Medicaid is reimbursed per service while dental treatment for military dependents provided at a military installation is neither directly reimbursable to those providing the care nor billed to those receiving the care. The purpose of this study was to compare pediatric dental services provided for a Medicaid population to a federally subsidized military facility to compare treatment choices and subsequent costs of care. It was hypothesized that differences in dental procedures for Medicaid and military dependent children would exist based upon treatment philosophy and payment method. A total of 240 records were reviewed for this study, consisting of 120 Medicaid patients at the University of Texas Health Science Center at San Antonio (UTHSCSA) and 120 military dependents at Wilford Hall Medical Center (WHMC), Lackland Air Force Base, San Antonio. Demographic data and treatment information were abstracted for children receiving dental treatment under general anesthesia between 2002 and 2006. Data was analyzed using the Wilcoxon rank sum test, Kruskal-Wallis test, and Fisher's exact test. The Medicaid recipients treated at UTHSCSA were younger than patients at WHMC (40.2 vs. 49.8 months, p<.001). The university also treated significantly more Hispanic children than WHMC (78.3% vs. 30.0%, p<.001). Children at UTHSCSA had a mean of 9.5 decayed teeth and were treated with 2.3 composite fillings, 0 amalgam fillings, 5.6 stainless steel crowns, 1.1 pulp therapies, 1.6 extractions, and 1.0 sealant. Children at WHMC had a mean of 8.7 decayed teeth and were treated with 1.4 composite fillings, 0.9 amalgam fillings, 5.6 stainless steel crowns, 1.7 pulp therapies, 0.9 extractions, and 2.1 sealants. The means of decayed teeth, total fillings, and stainless steel crowns were not statistically different. UTHSCSA provided more composite fillings (p<.001), fewer amalgam fillings (p<.001), fewer pulp therapies (p <.001), more extractions (p=.01), and fewer sealants (p<.001) when compared to WHMC. Age and gender did not effect decay rates, but those of Hispanic ethnicity did experience more decay than non-Hispanics (9.5 vs. 8.6, p=.02). Based upon Texas Medicaid reimbursement rates from 2006, the cost for dental treatment at both sites was approximately $650 per child. The results of this study do not support the hypothesis that Medicaid providers provide less conservative therapies, which would be more costly, care when compared to a military treatment center. ^