Changes in Signal Intensity of the Dentate Nucleus and Globus Pallidus in Pediatric Patients: Impact of Brain Irradiation and Presence of Primary Brain Tumors Independent of Linear Gadolinium-based Contrast Agent Administration.

Purpose To determine whether whole-brain irradiation, chemotherapy, and primary brain pathologic conditions affect magnetic resonance (MR) imaging signal changes in pediatric patients independent of the administration of gadolinium-based contrast agents (GBCAs). Materials and Methods This institutional review board-approved, HIPAA-compliant study included 144 pediatric patients who underwent intravenous GBCA-enhanced MR imaging examinations (55 patients with primary brain tumors and whole-brain irradiation, 19 with primary brain tumors and chemotherapy only, 52 with primary brain tumors without any treatment, and 18 with neuroblastoma without brain metastatic disease). The signal intensities (SIs) in the globus pallidus (GP), thalamus (T), dentate nucleus (DN), and pons (P) were measured on unenhanced T1-weighted images. GP:T and DN:P SI ratios were compared between groups by using the analysis of variance and were analyzed relative to group, total cumulative number of doses of GBCA, age, and sex by using multivariable linear models. Results DN:P ratio for the radiation therapy group was greater than that for the other groups except for the group of brain tumors treated with chemotherapy (P < .05). The number of GBCA doses was correlated with the DN:P ratio for the nontreated brain tumor group (P < .0001). The radiation therapy-treated brain tumor group demonstrated higher DN:P ratios than the nontreated brain tumor group for number of doses less than or equal to 10 (P < .0001), whereas ratios in the nontreated brain tumor group were higher than those in the radiation therapy-treated brain tumor group for doses greater than 20 (P = .05). The GP:T ratios for the brain tumor groups were greater than that for the neuroblastoma group (P = .01). Conclusion Changes in SI of the DN and GP that are independent of the administration of GBCA occur in patients with brain tumors undergoing brain irradiation, as well as in patients with untreated primary brain tumors. © RSNA, 2017.

Analysis of surgical interruption of the enterohepatic circulation as a treatment for pediatric cholestasis.

To evaluate the efficacy of nontransplant surgery for pediatric cholestasis, 58 clinically diagnosed children, including 20 with Alagille syndrome (ALGS), 16 with familial intrahepatic cholestasis-1 (FIC1), 18 with bile salt export pump (BSEP) disease, and 4 others with low γ-glutamyl transpeptidase disease (levels <100 U/L), were identified across 14 Childhood Liver Disease Research Network (ChiLDReN) centers. Data were collected retrospectively from individuals who collectively had 39 partial external biliary diversions (PEBDs), 11 ileal exclusions (IEs), and seven gallbladder-to-colon (GBC) diversions. Serum total bilirubin decreased after PEBD in FIC1 (8.1 ± 4.0 vs. 2.9 ± 4.1 mg/dL, preoperatively vs. 12-24 months postoperatively, respectively; P = 0.02), but not in ALGS or BSEP. Total serum cholesterol decreased after PEBD in ALGS patients (695 ± 465 vs. 457 ± 319 mg/dL, preoperatively vs. 12-24 months postoperatively, respectively; P = 0.0001). Alanine aminotransferase levels increased in ALGS after PEBD (182 ± 70 vs. 260 ± 73 IU/L, preoperatively vs. 24 months; P = 0.03), but not in FIC1 or BSEP. ALGS, FIC1, and BSEP patients experienced less severely scored pruritus after PEBD (ALGS, 100% vs. 9% severe; FIC1, 64% vs. 10%; BSEP, 50% vs. 20%, preoperatively vs. >24 months postoperatively, respectively; P < 0.001). ALGS patients experienced a trend toward greater freedom from xanthomata after PEBD. There was a trend toward decreased pruritus in FIC1 after IE and GBC. Vitamin K supplementation increased in ALGS after PEBD (33% vs. 77%; P = 0.03). Overall, there were 15 major complications after surgery. Twelve patients (3 ALGS, 3 FIC1, and 6 BSEP) subsequently underwent liver transplantation. CONCLUSION: This was a multicenter analysis of nontransplant surgical approaches to intrahepatic cholestasis. Approaches vary, are well tolerated, and generally, although not uniformly, result in improvement of pruritus and cholestasis. (Hepatology 2017;65:1645-1654).

Effects of vitamin D repletion on glycemic control and inflammatory cytokines in adolescents with type 1 diabetes.

OBJECTIVE: Little is known about the relationship between vitamin D deficiency and adolescents with type 1 diabetes. On the basis of adult studies showing that vitamin D improves insulin sensitivity and decreases inflammatory cytokines linked to microvascular complications, we hypothesized that treating vitamin D deficiency in adolescents with type 1 diabetes would improve glycemia and reduce inflammatory markers. RESEARCH DESIGN AND METHODS: This was a randomized, prospective, crossover study of 25 adolescents with type 1 diabetes for at least a year (aged: 13-21 yr; 62% female; 62% Hispanic) and vitamin D deficiency (25-OH vitamin D ≤30 ng/mL). Subjects received vitamin D3 (20 000 IU/week) for 6 months, either immediately or after 6 months of observation. RESULTS: At baseline, 63% of subjects screened were vitamin D deficient and randomized. Interleukin-6 (IL-6) was significantly higher in the vitamin D deficient group compared with the sufficient group (medians: 0.36 vs. 0.18) (p = 0.026), whereas neither C-reactive protein (CRP) nor tumor necrosis factor-α (TNF-α) differed. Vitamin D treatment increased serum levels of 25-OH vitamin D from 22 ± 5.3 to 34.3 ± 12.1 ng/mL (p < 0.01). However, treatment did not affect glycated hemoglobin (HbA1c), insulin dosage, CRP, interleukin-6 (IL-6), or TNF-α. CONCLUSIONS: Vitamin D deficiency is prevalent in the adolescent type 1 diabetes population, and could be associated with changes in inflammatory markers. However, vitamin D repletion over 6 months did not affect glycemia or markers of inflammation in our study, highlighting the need for additional research to validate these findings.

Cerebral Oxygenation and Acceleration in Pediatric and Neonatal Interfacility Transport.

OBJECTIVE: The purpose of this study is to measure peak acceleration forces during interfacility transport; examine whether drops in cerebral oxygenation occurred; and test the associations between cerebral oxygenation, acceleration, and patient positioning. METHODS: A cerebral oximeter (INVOS-5100C; Somanetics, Minneapolis, MN) monitored regional saturation of oxygen (rSO2 [cerebral oxygenation]) in pediatric and neonatal patients (N = 24) transported between facilities by ground ambulance, helicopter, or fixed wing aircraft. An accelerometer (GP1; SENSR, Georgetown, TX) bolted to the isolette or gurney recorded z-axis (aligned with the spine) accelerations. RESULTS: The z-axis peak accelerations (absolute values of g) by transport type were as follows: ground ambulance takeoff mean = 0.16 and landing mean = 0.08, helicopter takeoff mean = 0.16 and landing mean = 0.05, fixed wing aircraft takeoff mean = 0.14 and landing mean = 0.20. During takeoff, 2 of 7 patients in the head-to-front of vehicle position experienced rSO2 drop. During landing, 4 of 13 patients in the head-to-back of vehicle position experienced rSO2 drop. There were no significant associations of rSO2 drop during takeoff and landing with patient positioning or with z-axis peak acceleration. CONCLUSION: Acceleration forces of pediatric and neonatal interfacility transport are small and comparable in magnitude. The relationship between rSO2 drop and patient positioning was not significant in this pilot study.

Pilot study to evaluate the effects of tetrahydrobiopterin on adult individuals with phenylketonuria with measurable maladaptive behaviors.

OBJECTIVES: To evaluate the effects of tetrahydrobiopterin (BH4) on maladaptive behavior in patients with phenylketonuria (PKU). METHODS: In an effort to determine if BH4 has any effects on the central nervous system, we studied 10 individuals with PKU and measurable maladaptive behaviors for 1 year. Behavioral assessments using the Vineland Adaptive Behavior Scales-Second Edition and a PKU Behavior Checklist were obtained at baseline, 6 months, and at the end of the study. Biochemical measures including plasma amino acids were obtained quarterly, and phenylalanine (Phe) and tyrosine (Tyr) were obtained monthly. RESULTS: Out of the 10 subjects, 2 were responders to BH4, as determined by a blood Phe reduction >30%. While blood Phe in the 8 nonresponders did not change significantly throughout the study, their Tyr levels were significantly higher at 6 months (p=0.012), but not at 12 months (p=0.23). By the end of the study, 8 subjects exhibited fewer maladaptive behaviors on the components of the Vineland Maladaptive Behavior Index, and all 10 had lower total scores on the PKU Behavior Checklist. CONCLUSION: These findings suggest that there may be direct effects of BH4 on the central nervous system, independent of lowering blood Phe.

Congenital heart disease in low-birth-weight infants: effects of small for gestational age (SGA) status and maturity on postoperative outcomes.

Few studies have examined the role that small for gestational age (SGA) status plays in postoperative outcomes for low-birth-weight (LBW) infants with congenital heart disease (CHD). This study aimed to examine the effect of SGA status, gestational and chronologic age, and weight on differences in morbidities and mortalities during the immediate postoperative hospitalization period. The charts of infants with CHD weighing less than 2.5 kg who underwent operative repair during the neonatal period between 2004 and 2011 were reviewed. Infants with an isolated patent ductus arteriosus were excluded from the study. Data on hospital morbidities and mortality before discharge were collected. The study identified 136 LBW infants with a diagnosis of CHD. Among the 74 infants who underwent surgery and had complete chart records, the SGA infants had a higher gestational age at birth (36.8 vs. 32.3 weeks; p < 0.0001). The SGA and non-SGA infants did not differ in terms of survival to discharge or immediate postoperative outcomes. A lower weight at surgery was significantly associated with an increased risk of postoperative infection. In contradistinction, an older postnatal age at surgery was associated with an increased risk of preoperative infection (p < 0.0001). Additionally, lower gestational age at birth was associated with home oxygen use, higher tracheostomy rates, and discharge with a gastrostomy tube. Small for gestational age status played no protective role in the outcome for LBW infants after primary surgery for CHD. A weight of 2.4 kg or greater at the time of surgery was associated with lower rates of postoperative infections. Greater duration of time between birth and surgery was associated with a greater risk of preoperative infection. A gestational age of 32 weeks or more at birth was associated with decreased morbidities, which could influence obstetric management.

Melatonin and dopamine as biomarkers to optimize treatment in phenylketonuria: effects of tryptophan and tyrosine supplementation.

OBJECTIVE: To determine whether additional supplementation of tryptophan (Trp) and tyrosine (Tyr) improve serotonin and dopamine metabolism in individuals with phenylketonuria treated with large neutral amino acid (LNAA) tablets. STUDY DESIGN: Ten adult individuals with phenylketonuria participated in a randomized, double-blind, placebo-controlled cross-over study consisting of three 3-week phases: washout, treatment with LNAA tablets plus supplementation with either Trp and Tyr tablets or placebo, and LNAA tablets plus the alternate supplementation. An overnight protocol to measure blood melatonin, a serotonin metabolite in the pinealocytes, and urine 6-sulfatoxymelatonin and dopamine in first-void urine specimens was conducted after each phase. RESULTS: Serum melatonin and urine 6-sulfatoxymelatonin and dopamine levels were increased in the LNAA phase (LNAA plus placebo) compared with the washout phase. Serum melatonin and urine 6-sulfatoxymelatonin were not increased in the active phase (LNAA plus Trp + Tyr) compared with the LNAA phase, although plasma Trp:LNAA was increased compared with the LNAA phase. Among 7 subjects with a plasma Trp/LNAA >0.03, a negative correlation between urine 6-sulfatoxymelatonin and plasma phenylalanine levels was observed (r = -0.072). Urine dopamine levels and plasma Tyr:LNAA were increased in the active phase compared with the LNAA phase. CONCLUSION: Melatonin levels were not increased with the higher dose of Trp supplementation, but dopamine levels were increased with the higher dose of Tyr supplementation. Serotonin synthesis appears to be suppressed by high phenylalanine levels at the Trp hydroxylase level.

Maternal Phenylketonuria International Collaborative Study revisited: evaluation of maternal nutritional risk factors besides phenylalanine for fetal congenital heart defects.

Maternal phenylketonuria (MPKU) is known to affect fetal outcome, often being associated with microcephaly and congenital heart defects (CHD) if the maternal diet is not appropriately managed. We hypothesized that other nutrients aside from phenylalanine (Phe) may have significant effects on fetal outcome in MPKU pregnancies. The 416 pregnancies that resulted in live births reported in the Maternal PKU Collaborative Study (MPKUCS) were grouped according to whether or not the offspring were diagnosed with CHD. The groups were compared on first-trimester values of maternal data, including weight gain, plasma amino acids, protein and Phe intake, and red blood cell (RBC) folate. Patients were also grouped by first-trimester average blood Phe (≤910 µmol/L and >910 µmol/L) and then divided by total natural protein and medical food intake. The CHD group of 28 offspring had significantly higher blood Phe and lower proline, valine, methionine, isoleucine, leucine, lysine, arginine, and RBC folate. A significantly higher risk for CHD was found in the groups with lower natural protein and medical food intake, regardless of blood Phe levels. Insufficient natural protein and medical food product intake appears to be a risk factor for CHD independent of first-trimester plasma Phe levels. Low RBC folate and plasma methionine levels in the CHD group may suggest involvement of global DNA hypomethylation.

Glycosaminoglycan metabolism defects and atherosclerosis: frequent association of endothelial dysfunction in patients with Mucopolysaccharidosis.

Cardiovascular lesions, including coronary artery stenosis, are frequently associated and can cause sudden death in patients with genetic defects of glycosaminoglycan (GAG) metabolism. Early diagnosis of coronary artery lesions is difficult, although potentially lifesaving. Histopathological similarities between atherosclerotic changes in adults and in patients with genetic GAG metabolism defects have been known. Atherosclerosis is the result of a complex process involving metabolism of GAGs and proteoglycans preceded by endothelial dysfunction as a key event. Decreased nitric oxide (NO) bioavailability is considered the hallmark of endothelial dysfunction. Reduced NO synthase (NOS) has been reported in atherosclerotic arteries. Impairment in reactive hyperemia-digital peripheral arterial tonometry (RH-PAT) with EndoPAT has been validated to correlate coronary microvascular function in patients with atherosclerosis. RH-PAT is thought to reflect endothelial NO production. Immunohistological staining of endothelial NOS was performed in the stenotic lesions in the coronary artery of a 3-year-old patient with Mucopolysaccharidosis-I, showing decreased activities. This prompted a study to measure endothelial function in patients with GAG metabolism defects for early diagnosis of endothelial dysfunction in the coronary arteries as an early sign of coronary artery changes. Evaluation by RH-PAT in 30 patients with variable genetic defects in GAG metabolism revealed significantly decreased Reactive Hyperemia Indexes compared with 12 controls. Evaluation of endothelial function with RH-PAT in patients with GAG metabolism defects may detect coronary artery lesions that can be underdiagnosed by the other measures such as coronary angiography. Use of this method may prove vital in the management of patients with GAG metabolism defects.

Large neutral amino acid supplementation increases melatonin synthesis in phenylketonuria: a new biomarker.

OBJECTIVE: To determine whether levels of melatonin in blood and urine can serve as a peripheral biomarker to reflect brain serotonin synthesis in individuals with phenylketonuria (PKU). STUDY DESIGN: We measured the levels of melatonin, a serotonin metabolite in the pinealocytes, in the blood and urine of individuals with PKU in a randomized double-blind placebo controlled crossover study consisting of three 3-week phases in 10 adults with PKU: phase 1 (washout), phase 2 (supplementation of large neutral amino acid [LNAA] tablets or placebo), and phase 3 (alternate supplementation). An overnight protocol to measure blood melatonin and urine 6-sulfatoxymelatonin and dopamine in first void urine specimens was conducted after each phase for subjects with PKU and once in 10 controls. RESULTS: Significantly lower concentrations of these neurotransmitter metabolites were observed in subjects with PKU after phase 1 compared with controls (serum melatonin P = .008, urine melatonin P = .0043, urine dopamine P < .0001), with significant increases after LNAA supplementation compared with the placebo phase (serum melatonin P = .0008, urine melatonin P = .0008, urine dopamine P = .0005). The mean tryptophan/LNAA and tyrosine/LNAA ratios were markedly lower in subjects with PKU compared with controls, and these ratios were significantly increased in the LNAA phase compared with the placebo phase (P = .016, P = .0003, respectively). Blood phenylalanine levels in subjects with PKU were not significantly different between placebo and LNAA phases (P = .74). CONCLUSION: Blood and urine melatonin levels may serve as biomarkers reflecting brain serotonin synthesis in subjects with PKU. Because this cannot be evaluated using blood phenylalanine levels, it may provide information on neurotransmitter metabolism for optimal dietary management.

Percutaneous liver biopsy: pathologic diagnosis and complications in children.

OBJECTIVE: The aim of this study was to determine patient factors that predict diagnostic failure or increased risk of bleeding complications following percutaneous liver biopsy in children. METHODS: A retrospective review of all children undergoing percutaneous liver biopsy at a single institution between July 2008 and July 2011 was performed. Demographics, comorbid conditions, preprocedural diagnoses/indications, procedural details, laboratory data, pathologic diagnosis, and complications were recorded. Continuous data were analyzed by Wilcoxon test and categorical data by Fisher exact test to determine statistical significance. RESULTS: Two hundred thirteen children (104 girls) with a median age of 7 years (range 1 week-22 years) underwent 328 percutaneous liver biopsies. Nine (4.2%) experienced a decrease in hemoglobin >2 g/dL, 7 required transfusion (3.3%), and 1 patient died (0.5%). Younger age (1.8 vs 84 months, P = 0.05) and lower preprocedural hematocrit (29.3 vs 34.3, P = 0.05) predicted bleeding complications, whereas the number of biopsies, comorbid conditions, and coagulopathy did not. Sixty-three (19.2%) biopsies were insufficient for definitive histologic evaluation on initial biopsy in 57 patients. Twenty-one of 57 patients (37%) underwent repeat percutaneous biopsy and 3 of 57 (8%) underwent surgical biopsy. Biopsy provided definitive diagnosis in 86% of cases when repeat biopsy was performed. Shorter specimen length (1.4 vs 1.7 cm, P < 0.01) and biopsies performed for unexplained elevation of liver function tests (34.9% vs 16.7%, P < 0.01) were predictive of nondiagnosis. CONCLUSIONS: Percutaneous liver biopsy is safe with a low rate of bleeding-related complications. Ensuring adequate sample length and careful patient selection may further increase the diagnostic yield.

Pediatric rheumatic disease in the intensive care unit: lessons learned from 15 years of experience in a tertiary care pediatric hospital.

OBJECTIVE: This study describes the 15-yr experience of a large urban tertiary care children's hospital in treating critically ill patients with pediatric rheumatic diseases. DESIGN: Retrospective case series. SETTING: Children's Hospital Los Angeles, a large urban tertiary care children's hospital. PATIENTS: All patients with pediatric rheumatic diseases admitted to the Children's Hospital Los Angeles pediatric intensive care unit from January 1995 to July 2009. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: An internal database and medical records were reviewed for demographics, diagnoses, treatments, organ dysfunction, interventions, infections, and outcomes. Standardized mortality ratio was calculated based on Pediatric Risk of Mortality III estimated mortality. Factors associated with mortality were identified by univariate analyses.Ninety patients with 122 total admissions were identified. The majority of patients were Hispanic (63%), female (73%), and had systemic lupus erythematosus (62%). Pediatric rheumatic disease-related complications (50%) were the most common reason for admission; 32% of admissions involved multiorgan dysfunction. Eighteen admissions (15%) resulted in mortality. Deaths were most commonly attributed to combined infection and active rheumatic disease (50%), infection only (22%), rheumatic disease only (11%), or other causes (17%). In 30 (25%) admissions, a new rheumatologic diagnosis was established. Standardized mortality ratio was 0.72 (95% confidence interval 0.38-1.25) for pediatric rheumatic disease patients compared to 0.87 (95% confidence interval 0.79-0.96) for all pediatric intensive care unit patients. Factors associated with mortality included use of mechanical ventilation, vasopressors, and renal replacement (continuous venovenous hemodialysis) (all p < .05). CONCLUSIONS: Pediatric rheumatic disease-related complications were the principal cause of pediatric intensive care unit admission. Deaths occurred most often from severe infections in patients with active rheumatic disease. Pediatric rheumatology patients admitted to the pediatric intensive care unit had outcomes similar to the global pediatric intensive care unit population when adjusted for severity of illness.

Winter Air Pollution from Domestic Coal Fired Heating in Ulaanbaatar, Mongolia, Is Strongly Associated with a Major Seasonal Cyclic Decrease in Successful Fecundity.

Pollution of the environment is increasing and threatens the health and wellbeing of adults and children around the globe. The impact of air pollution on pulmonary and cardiovascular disease has been well documented, but it also has a deleterious effect on reproductive health. Ulaanbaatar, the capital city of Mongolia, has one of the highest levels of air pollution in the world. During the extreme winters when temperatures routinely fall below -20 °C the level of air pollution can reach 80 times the WHO recommended safe levels. Heating mainly comes from coal, which is burned both in power stations, and in stoves in the traditional Ger housing. We studied the impact of air pollution on conception rates and birth outcomes in Ulaanbaatar using a retrospective analysis of health data collected from the Urguu Maternity hospital in Ulaanbaatar, Mongolia. Daily levels of SO2, NO2, PM10, and PM2.5 were collected from the government Air Quality Monitoring Stations in Ulaanbaatar for the same period as the study. In January, the month of highest pollution, there is a 3.2-fold decrease in conceptions that lead to the successfully delivered infants compared to October. The seasonal variations in conceptions resulting in live births in this study in Ulaanbaatar are shown to be 2.03 ± 0.20 (10-sigma) times greater than those in the Denmark/North America study of Wesselink et al., 2020. The two obvious differences between Ulaanbaatar and Europe/North America are pollution and temperature both of which are extreme in Ulaanbaatar. The extreme low temperature is mitigated by burning coal, which is the main source of domestic heat especially in the ger districts. This drives the level of pollution so the two are inextricably linked. Infants conceived in the months of June-October had the greatest cumulative PM2.5 pollution exposure over total gestation, yet these were also the pregnancies with the lowest PM2.5 exposure for the month of conception and three months prior to conception. The delivered-infant conception rate shows a markedly negative association with exposure to PM2.5 prior to and during the first month of pregnancy. This overall reduction in fecundity of the population of Ulaanbaatar is therefore a preventable health risk. It is of great consequence that the air pollution in Ulaanbaatar affects health over an entire lifespan including reproductive health. This could be remedied with a clean source of heating.

Racial and Ethnic Differences in Behavioral Problems and Medication Use Among Children With Autism Spectrum Disorders.

We examined racial and ethnic differences in the prevalence of behavioral problems measured by the Child Behavioral Checklist (CBCL), sleep disturbances measured by the Child Sleep Habits Questionnaire (CSHQ), and medication use among children with Autism Spectrum Disorders (ASD). We analyzed data from the Autism Treatment Network (ATN) dataset for 2,576 children ages 6 to 18 years of age diagnosed with ASD. Multivariable logistic regression accounting for age, gender, Diagnostic and Statistical Manual of Mental Disorders (4th Edition - Text Revision), diagnosis (Autistic Disorder, PDD-NOS, Asperger's Disorder), and parents' education did not show any racial or ethnic differences in behavioral challenges, conduct problems, or sleep disturbances for any of the groups, but Black children had lower odds of Total Problem Behaviors and Asian children had lower odds of Hyperactivity compared to White children. As a group, children from racial and ethnic minorities had lower odds of Total Problem Behaviors and Conduct Problems compared to White children. Hispanic children had lower odds of medication use for Behavioral Challenges, Total Problem Behaviors, Hyperactivity, and Conduct Problems. Asian children had lower odds of medication use for Behavioral Challenges, Total Problem Behaviors, and Hyperactivity; and had close to lower odds in medication use for Conduct Problems. Black children had lower odds for medication use for Total Problem Behaviors only. As a group, children from racial and ethnic minorities had lower odds for medication use for Behavioral Challenges, Total Problem Behaviors, Hyperactivity, and Conduct problems, but not for Sleep Disturbances. While these results are consistent with previous studies showing that White children are significantly more likely to receive psychotropic medication compared to children from racial and ethnic minority groups, we found no such differences for sleep challenges, suggesting that they are more consistently identified and equitably treated than other behavioral problems associated with ASD. We draw upon Andersen's (1995) Behavioral Model of Healthcare Use to suggest predisposing, enabling, and needs factors that may contribute to this pattern of racial and ethnic differences in the use of medications among children ASD.

Long-term neurocognitive function of pediatric patients with severe combined immune deficiency (SCID): pre- and post-hematopoietic stem cell transplant (HSCT).

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is the only cure for patients with severe combined immunodeficiency (SCID). The purpose of this study was to evaluate long-term neurodevelopment of patients with SCID following myeloablative chemotherapy and HSCT. MATERIALS AND METHODS: Sixteen pediatric patients diagnosed with SCID were tested using the Bayley Scales of Infant Development and the validated Vineland Adaptive Behavior Scales (VABS) pre- and 1-year post-HSCT. Three years post-HSCT, there were 11 patients available for testing and four patients available 5 years post-HSCT. Patients greater than 3 years of age were administered the Wechsler Preschool and Primary Scale of Intelligence. Both raw scores and scaled scores were analyzed. RESULTS: There was a significant decrease 1 year post-HSCT in the Bayley Mental Developmental Index (MDI) [92.5 (pre) vs. 70.81 (1 year post), p < 0.0001] and the VABS [99.73 (pre) vs. 79.87 (1 year post), p = <0.0001]. There was a significant decrease over time in the MDI [95.00 (pre) vs. 72.64 (1 year post) vs. 71.82 (3 years post), p < 0.0001], but no significant change between 1 and 3 years post-HSCT. There was no change in the Bayley Psychomotor Development Scale (PDI) [82.4 (pre) vs. 84.8 (1 year post), p = 0.68]. The PDI scores decreased over time [86.29 (pre) vs. 86 (1 year post) vs. 74.14 (3 years post), p = 0.045]. Although there was a decrease in scaled scores, there was not a loss of skills. Analysis of raw scores showed that there was an increase in the raw test scores, which indicated that these children acquired developmental skills, but at a slower rate than normal infants and toddlers. Younger children had a more significant decrease in adaptive scores compared with older children. CONCLUSIONS: These findings may reflect the effects of the isolation and prolonged hospitalization that characterizes the immediate post-transplant period. Patients miss out on social interactions and learning opportunities that normally occur at their respective stages of development. These restrictions keep patients from acquiring developmentally appropriate cognitive skills as well as gross and fine motor developmental milestones. Longitudinal follow-up will be important to quantify acquisition of skills.

Determination of estradiol and progesterone content in capsules and creams from compounding pharmacies.

OBJECTIVES: To analytically characterize the doses of estradiol and progesterone found in compounded combined forms of oral capsule and transdermal cream formulations, and determine the consistency of the hormone formulations within a batch. METHODS: Prescriptions for combined estradiol/progesterone capsules (0.5 and 100 mg, respectively) and creams (0.5 and 100 mg/g, respectively) were sent to 15 custom-compounding pharmacies. Estradiol and progesterone levels were measured by radioimmunoassays. Hormone levels were measured in 2 capsules and 2 creams from each pharmacy; 10 capsules from 3 pharmacies; and top/middle/bottom layer of cream containers to assess consistency. The magnitude and sources of variation for the measurements were examined by analysis of variance models. RESULTS: Thirteen pharmacies filled the prescriptions. Measured estradiol levels were 0.365 to 0.551 mg for capsules and 0.433 to 0.55 mg/g for creams, and progesterone levels were 90.8 to 135 mg for capsules and 93 to 118 mg/g for creams. Greater variations in estradiol levels were observed between pharmacies for estradiol in capsules than in creams; however, measured estradiol levels within pharmacies were more consistent in the capsules than the creams. Similar results were obtained for progesterone levels. CONCLUSION: The variations in estradiol and progesterone levels observed in compounded hormone therapy formulations justify concerns regarding risks as a result of variability, which have been outlined by The North American Menopause Society, the American College of Obstetricians and Gynecologists, and the US Food and Drug Administration (FDA) in their statements regarding compounded hormone use. These data support the need for an US FDA-approved bioidentical hormone therapy. : Video Summary: Supplemental Digital Content 1, http://links.lww.com/MENO/A425.

Symptomatic catheter-associated thrombosis in pediatric trauma patients: Choose your access wisely.

BACKGROUND: Traumatic injury and the presence of a central venous catheter are 2 of the strongest risk factors for venous thromboembolism in children. The purpose of this study was to determine the incidence of symptomatic, catheter-associated thrombosis in critically injured children. We hypothesized that femoral venous catheters are associated with a greater rate of thrombotic complications when compared with all other central venous access points. METHODS: We reviewed a retrospective cohort (2006-2016) of injured children (≤18 years) admitted to a pediatric intensive care unit with central access placed ≤7 days from admission. Symptomatic, catheter-associated thrombosis was determined by radiographic evidence. Poisson regression was used to compare the incidence of catheter-associated thrombosis per 1,000 catheter days between femoral and nonfemoral catheters. All comparisons were 2-tailed with α = 0.05. RESULTS: We examined 209 pediatric trauma patients with central access (65% femoral, 19% subclavian, 11% arm vein, and 5% internal jugular). Femoral catheters were removed earlier (median [interquartile range] 4 [2-7] vs 8 [3-12] days, P < .001) and were larger in diameter (5 Fr [4-7] vs 4 Fr [4-4], P < .001) when compared with all other catheters. Catheter-associated thrombosis was more frequent in femoral versus nonfemoral catheters (18.4 vs 3.5 per 1,000 catheter days, P = .01). CONCLUSION: Femoral venous catheters are associated with a greater incidence of symptomatic, catheter-associated thrombosis in pediatric trauma patients. When central venous access is indicated for injured children, the femoral site should be avoided. If a femoral venous catheter is necessary, use of a smaller catheter should be considered.

Low Beta-Adrenergic Sweat Responses in Cystic Fibrosis and Cystic Fibrosis Transmembrane Conductance Regulator-Related Metabolic Syndrome Children.

ß-adrenergically stimulated sweat secretion depends on the function of the cystic fibrosis transmembrane conductance regulator (CFTR) and discriminates between cystic fibrosis (CF) patients and healthy controls. Therefore, we sought to determine the feasibility, safety, and efficacy of assaying ß-adrenergic sweating in children identified by CF newborn screening to help determine prognoses for individuals with CFTR-related metabolic syndrome (CRMS). Preschool age children with a positive newborn screening test for CF participated in this cross-sectional study. Sweat rates were measured by evaporimetery (cyberDERM, inc.) as transepidermal water losses (g H2O/m2/h) before and after selectively stimulating sweat glands either cholinergically or ß-adrenergically. Net peak sweat responses assayed as evaporation rates were compared between CF and CRMS cohorts. After a pilot test in adults, children between 4 and 6 years of age were evaluated (CF, n = 16; CRMS, n = 10). The test protocol was well tolerated; electrocardiograms and vital signs were within normal range for all subjects. The mean evaporative sweat rates in both groups in response to cholinergic stimulation were similar (CF, 60.3 ± 23.8; CRMS, 57.7 ± 13.9; p = 0.72) as well as to ß-adrenergic stimulation (CF, 1.1 ± 1.7; CRMS, 2.0 ± 2.0; p = 0.14). The ß-adrenergic sweat test is safe and well tolerated by young children. However, the ß-adrenergic sweat secretion rates as measured by evaporimetery did not discriminate between CF and CRMS cohorts.

Evaluation of Tetrahydrobiopterin Therapy with Large Neutral Amino Acid Supplementation in Phenylketonuria: Effects on Potential Peripheral Biomarkers, Melatonin and Dopamine, for Brain Monoamine Neurotransmitters.

BACKGROUND: Phenylketonuria (PKU) is due to a defective hepatic enzyme, phenylalanine (Phe) hydroxylase. Transport of the precursor amino acids from blood into the brain for serotonin and dopamine synthesis is reported to be inhibited by high blood Phe concentrations. Deficiencies of serotonin and dopamine are involved in neurocognitive dysfunction in PKU. OBJECTIVE: (1) To evaluate the effects of sapropterin (BH4) and concurrent use of large neutral amino acids (LNAA) on the peripheral biomarkers, melatonin and dopamine with the hypothesis they reflect brain serotonin and dopamine metabolism. (2) To evaluate synergistic effects with BH4 and LNAA. (3) To determine the effects of blood Phe concentrations on the peripheral biomarkers concentrations. METHODS: Nine adults with PKU completed our study consisting of four 4-week phases: (1) LNAA supplementation, (2) Washout, (3) BH4 therapy, and (4) LNAA with BH4 therapy. An overnight protocol measured plasma amino acids, serum melatonin, and 6-sulfatoxymelatonin and dopamine in first void urine after each phase. RESULTS: (1) Three out of nine subjects responded to BH4. A significant increase of serum melatonin levels was observed in BH4 responders with decreased blood Phe concentration. No significant change in melatonin, dopamine or Phe levels was observed with BH4 in the subjects as a whole. (2) Synergistic effects with BH4 and LNAA were observed in serum melatonin in BH4 responders. (3) The relationship between serum melatonin and Phe showed a significant negative slope (p = 0.0005) with a trend toward differing slopes among individual subjects (p = 0.066). There was also a negative association overall between blood Phe and urine 6-sulfatoxymelatonin and dopamine (P = 0.040 and 0.047). CONCLUSION: Blood Phe concentrations affected peripheral monoamine neurotransmitter biomarker concentrations differently in each individual with PKU. Melatonin levels increased with BH4 therapy only when blood Phe decreased. Monitoring peripheral neurotransmitter metabolites may assist in optimizing individualized treatment in PKU.

Phenotypes of California CF Newborn Screen-Positive Children with CFTR 5T Allele by TG Repeat Length.

BACKGROUND: At the cystic fibrosis transmembrane conductance regulator (CFTR) gene (IVS8)-(TG)m(T)n locus, a lower number of thymidines (legacy names 9T vs. 7T vs. 5T) and a higher number of (TG) repeats (TG-11 vs. 12 vs. 13) are associated with decreasing translation of functional CFTR protein in vitro. METHODS: Retrospective cohort study comparing phenotypes of California CF newborn screen-positive children (followed 2-8 years) who had two CF-causing mutations (diagnosed as CF) with those who had one mutation from a panel of 40 CF-causing mutations (CF40mut) and one (IVS8)-(TG)11, 12, or 13-5T mutation detected by sequencing (diagnosed as CFTR-related metabolic syndrome [cRMS]). RESULTS: The study included 428 children, of which 234 had two CF-causing mutations, and were used to compare with the other 194 children with one CF-causing mutation and one isolated 5T allele [CF40mut/(TG)13-5T = 21, CF40mut/(TG)12-5T = 85, and CF40mut/(TG)11-5T = 88]. Among children with CF40mut/(TG)13-5T, 38% were diagnosed with CF by 8 years, based on sweat chloride results and clinical presentation. Six percent of those with CF40mut/(TG)12-5T, and none with CF40mut/(TG)11-5T, reached diagnostic criteria. CONCLUSIONS: CFTR (IVS8)-(TG)m-5T allele (TG) tract length determination provides valuable information in predicting the risk of developing a CF phenotype. Of the three types of 5T alleles evaluated, screen-positive children with genotype CF40mut/(TG)13-5T progressed from CRMS to CF at a high rate, while there was little evidence of clinical disease in those with CF40mut/(TG)11-5T. Additional data from longer follow-up intervals are needed to fully understand the natural history of individuals with a CF40mut/(TG)m-5T genotype.