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2.  Depressive symptoms in children with chronic kidney disease 
The Journal of pediatrics  2015;168:164-70.e1.
Objective
To assess depression in children with chronic kidney disease (CKD) and to determine associations with patient characteristics, intellectual and educational levels, and health related quality of life (HRQoL).
Study design
Subjects aged 6–17 years from the Chronic Kidney Disease in Children cohort study completed the Children’s Depression Inventory (CDI), Wechsler’s Abbreviated Scales of Intelligence, Wechsler Individual Achievement Test-II-Abbreviated, and the Pediatric Inventory of Quality of Life Core Scales 4.0. Regression analyses determined associations of CDI score and depression status with subject characteristics, intellectual and educational levels, and HRQoL. A joint linear mixed model and Weibull model were used to determine the effects of CDI score on longitudinal changes in glomerular filtration rate (GFR) and time to renal replacement therapy.
Results
344 subjects completed the CDI. Eighteen (5%) had elevated depressive symptoms and another 7 (2%) were being treated for depression. In adjusted analyses, maternal education beyond high school was associated with 5% lower CDI scores (estimate 0.95; 95% CI 0.92, 0.99). Depression status was associated with lower IQ (99 versus 88, P= 0.053), lower achievement (95 versus 77.5, P<0.05), and lower HRQoL by parent and child reports (effect estimates −15.48; 95% CI −28.71, −2.24 and −18.39; 95% CI −27.81, −8.96, respectively). CDI score was not related to change in GFR.
Conclusion
Children with depression had lower psychoeducational skills and worse HRQoL. Identifying and treating depression should be evaluated as a means to improve the academic performance and HRQoL of children with CKD.
doi:10.1016/j.jpeds.2015.09.040
PMCID: PMC4854431  PMID: 26505290
Child Depression Inventory; adolescents; children; mental health; quality of life; chronic renal insufficiency
3.  Weight Gain and Height Growth during Infancy, Childhood, and Adolescence as Predictors of Adult Cardiovascular Risk 
The Journal of Pediatrics  2017;180:53-61.e3.
Objectives
To investigate independent relationships of childhood linear growth (height gain) and relative weight gain to adult cardiovascular disease (CVD) risk traits in Asian Indians.
Study design
Data from 2218 adults from the Vellore Birth Cohort were examined for associations of cross-sectional height and body mass index (BMI) and longitudinal growth (independent conditional measures of height and weight gain) in infancy, childhood, adolescence, and adulthood with adult waist circumference (WC), blood pressure (BP), insulin resistance (homeostatic model assessment-insulin resistance [HOMA-IR]), and plasma glucose and lipid concentrations.
Results
Higher BMI/greater conditional relative weight gain at all ages was associated with higher adult WC, after 3 months with higher adult BP, HOMA-IR, and lipids, and after 15 years with higher glucose concentrations. Taller adult height was associated with higher WC (men β = 2.32 cm per SD, women β = 1.63, both P < .001), BP (men β = 2.10 mm Hg per SD, women β = 1.21, both P ≤ .001), and HOMA-IR (men β = 0.08 log units per SD, women β = 0.12, both P ≤ .05) but lower glucose concentrations (women β = −0.03 log mmol/L per SD P = .003). Greater height or height gain at all earlier ages were associated with higher adult CVD risk traits. These positive associations were attenuated when adjusted for adult BMI and height. Shorter length and lower BMI at birth were associated with higher glucose concentration in women.
Conclusions
Greater height or weight gain relative to height during childhood or adolescence was associated with a more adverse adult CVD risk marker profile, and this was mostly attributable to larger adult size.
doi:10.1016/j.jpeds.2016.09.059
PMCID: PMC5179199  PMID: 27823768
children; weight gain; height gain; conditional growth analysis; cardiovascular risk markers; Asian Indians; BMI, Body mass index; BP, Blood pressure; CVD, Cardiovascular disease; DBP, Diastolic blood pressure; HOMA-IR, Homeostatic model assessment-insulin resistance; LMIC, Low and middle income countries; SBP, Systolic blood pressure; T2DM, Type 2 diabetes mellitus; WC, Waist circumference
5.  Ways to Identify Children with Medical Complexity and the Importance of Why 
The Journal of pediatrics  2015;167(2):229-237.
doi:10.1016/j.jpeds.2015.04.068
PMCID: PMC5164919  PMID: 26028285
6.  The Triple Aim for Neonatal Abstinence Syndrome 
The Journal of pediatrics  2015;167(6):1189-1191.
For decades, the diagnosis of neonatal abstinence syndrome (NAS) was relatively rare in the US; however, the recent epidemic of prescription and nonprescription opioid use across the country has made this once novel diagnosis common.1 The number of infants diagnosed with NAS in the US has grown nearly 5-fold since 2000. Today, one infant with NAS is born every 25 minutes, accounting for an estimated $1.5 billion in hospital charges.2 The rapid rise of NAS in our nurseries and neonatal intensive care units demands that improvements in research and care delivery systems keep pace.
doi:10.1016/j.jpeds.2015.09.047
PMCID: PMC5161030  PMID: 26454574
7.  Neurodevelopmental Profile, Growth, and Psychosocial Environment of Preterm Infants with Difficult Feeding Behavior at Two Years of Age 
The Journal of pediatrics  2015;167(6):1347-1353.
Objectives
To examine the association of difficult feeding behaviors in very preterm infants at two years of age with growth and neurodevelopmental outcomes and family factors and functioning.
Study design
Eighty children born ≤30 weeks gestation were studied from birth until two years of age. Feeding difficulties were assessed using the Eating Subscale of the Infant-Toddler Social Emotional Assessment at age two years alongside growth and developmental testing. Maternal mental health and family factors were assessed using standardized questionnaires. ANOVA and chi-square analyses were used to determine associations between feeding difficulties and growth, neurodevelopmental outcomes, and family characteristics.
Results
Twenty-one (26%) of the cohort were at risk for feeding difficulties, and an additional 18 (23%) had definite feeding difficulties at age two years. Those with feeding difficulties were more likely to be subject to a range of neurodevelopmental problems including impaired cognition (p=0.02), language (p=0.04), motor (p=0.01) and socio-emotional (p<0.007) skills. Parents of very preterm born children with feeding difficulties had higher parenting stress (p=0.02) and reported more difficulty managing their child’s behavior (p=0.002) and more frequent parent-child interaction problems (p=0.002) than parents of children with fewer feeding difficulties. No associations were found between difficult feeding behaviors and growth, maternal mental health, and family factors.
Conclusions
Difficult feeding behaviors in children born very preterm appear to be highly comorbid with other developmental and family challenges, including neurodevelopmental impairment and parent-child interaction difficulties. Focusing on improving feeding skills, in conjunction with supporting positive parent-child interactions, may be beneficial for improving outcomes.
doi:10.1016/j.jpeds.2015.09.022
PMCID: PMC4662882  PMID: 26490123
Neonatal intensive care unit; outcome; parenting; family functioning
8.  Children with Chronic Hepatitis B in the US and Canada 
The Journal of pediatrics  2015;167(6):1287-1294.e2.
Objectives
To test the hypothesis that children with chronic hepatitis B (CHB) living in the US and Canada would also have international origins and characteristic hepatitis B virus (HBV) genotypes and laboratory profiles.
Study design
Clinical characteristics of children enrolled in the HBRN were collected from 7 US and Canadian centers.
Results
Children (n=343) with an age range of 1.0 – 17.8 years were enrolled; 78% of the children were Asian, 55% were adopted and 97% had international origins with either the child or a parent born in one of 31 countries. The majority had hepatitis B virus (HBV) genotype B (43%) or C (32%), and the remainder had genotype A (5%), D (16%), E (4%), or multiple (<1%). Children with genotype B or C were Asian (98% and 96%), more consistently hepatitis B e antigen (HBeAg) positive (95% and 82%), had higher median HBV DNA levels (8.2 and 8.3 log10 IU/mL), and less frequently had elevated alanine aminotransferase values (43% and 57%) compared with children with other genotypes. The percentage of HBeAg positivity and of those with HBV DNA ≥6 log10 IU/mL declined with age.
Conclusions
The majority of children in the HBRN have HBV genotypes which reflect their international origins. Clinical and laboratory data differ substantially by patient age and HBV genotype. Use of these data can help drive the development of optimal strategies to manage and treat children with CHB.
doi:10.1016/j.jpeds.2015.08.021
PMCID: PMC4662884  PMID: 26364985
hepatitis B DNA; hepatitis B E antigen; viral genotype; international adoptees
9.  Association between Hospital Volume and Within-Hospital Intensive Care Unit Transfer for Sickle Cell Disease in Children’s Hospitals 
The Journal of pediatrics  2015;167(6):1306-1313.
Objective
To assess the relationship between hospital volume and intensive care unit (ICU) transfer among hospitalized children with sickle cell disease (SCD).
Study design
We conducted a retrospective cohort study of 83477 SCD-related hospitalizations at children’s hospitals (2009–2012) using the Pediatric Health Information System database. Hospital-level all-cause and SCD-specific volumes were dichotomized (low versus high). Outcomes were within-hospital ICU transfer (primary) and length of stay (LOS) total (secondary). Multivariable logistic/linear regressions assessed the association of hospital volumes with ICU transfer and LOS.
Results
Of 83477 eligible hospitalizations, 1741 (2.1%) involving 1432 unique children were complicated by ICU transfer. High SCD-specific volume (OR 0.77, 95% CI 0.64–0.91) was associated with lower odds of ICU transfer while high all-cause hospital volume was not (OR 0.87, 95% CI 0.73–1.04). A statistically significant interaction was found between all-cause and SCD-specific volumes. When results were stratified according to all-cause volume, high SCD-specific volume was associated with lower odds of ICU transfer at low all-cause volume (OR 0.46, 95% CI 0.38–0.55). High hospital volumes, both all-cause (OR 0.94, 95% CI 0.92–0.97) and SCD-specific (OR 0.86, 95% CI 0.84–0.88), were associated with shorter LOS.
Conclusions
Children’s hospitals vary substantially in their transfer of children with SCD to the ICU according to hospital volumes. Understanding the practices utilized by different institutions may help explain the variability in ICU transfer among hospitals caring for children with SCD.
doi:10.1016/j.jpeds.2015.09.007
PMCID: PMC4662890  PMID: 26470686
anemia; sickle cell; quality of health care; hospital medicine
10.  A Cost-Effectiveness Analysis of a Pilot Neonatal Screening Program for Sickle Cell Anemia in the Republic of Angola 
The Journal of pediatrics  2015;167(6):1314-1319.
Objective
To assess the cost-effectiveness of a pilot newborn screening (NBS) and treatment program for sickle cell anemia (SCA) in Luanda, Angola.
Study design
In July 2011, a pilot NBS and treatment program was implemented in Luanda, Angola. Infants identified with SCA were enrolled in a specialized SCA clinic in which they received preventive care and sickle cell education. In this analysis, the World Health Organization (WHO) and generalized cost-effectiveness analysis methods were used to estimate gross intervention costs of the NBS and treatment program. To determine healthy life-years (HLYs) gained by screening and treatment, we assumed NBS reduced mortality to that of the Angolan population during the first 5 years based upon WHO and Global Burden of Diseases Study 2010 estimates, but provided no significant survival benefit for children who survive through age 5 years. A secondary sensitivity analysis with more conservative estimates of mortality benefits also was performed. The costs of downstream medical costs, including acute care, were not included.
Results
Based upon the costs of screening 36 453 infants and treating the 236 infants with SCA followed after NBS in the pilot project, NBS and treatment program is projected to result in the gain of 452-1105 HLYs, depending upon the discounting rate and survival assumptions used. The corresponding estimated cost per HLY gained is $1380-$3565, less than the gross domestic product per capita in Angola.
Conclusions
These data demonstrate that NBS and treatment for SCA appear to be highly cost-effective across all scenarios for Angola by the WHO criteria.
doi:10.1016/j.jpeds.2015.08.068
PMCID: PMC4662897  PMID: 26477868
11.  Pharmacokinetics of Oral Methadone in the Treatment of Neonatal Abstinence Syndrome: A Pilot Study 
The Journal of pediatrics  2015;167(6):1214-1220.e3.
Objective
To characterize the population pharmacokinetic (PK) of oral methadone in neonates requiring pharmacologic treatment of neonatal abstinence syndrome (NAS) and to develop a PK model towards an evidence-based treatment protocol.
Study design
Based on a methadone dosing protocol, serum concentrations of methadone and its metabolites were assessed via high performance liquid chromatography-tandem mass spectrometry from dried blood spots. Population PK analysis was performed to determine the volume of distribution and clearance of oral methadone. Methadone plasma concentration-time profiles were simulated from the deduced PK model to optimize the dosing regimen.
Results
There was substantial inter-individual variability in methadone concentrations. Blood concentrations of methadone were best described by a one-compartment model with first-order absorption. The population mean estimates (coefficient of variation percentage) for oral clearance and volume of distribution were 8.94 (103%) L/h/70 kg and 177 (133%) L/70 kg, respectively. Optimized dosing strategies were developed based on the simulated PK profiles. We suggest a starting dose of 0.1 mg/kg per dose every 6 hours for most patients requiring pharmacologic treatment of NAS followed by an expedited weaning phase.
Conclusions
The proposed dosing regimen may reduce the cumulative dose of opioid and shorten the length of hospitalization. Future studies should aim to validate the simulated dosing schemes with clinical data and expand our understanding of the between-patient PK variability.
Trial registration
ClinicalTrials.gov: NCT01754324
doi:10.1016/j.jpeds.2015.08.032
PMCID: PMC4662899  PMID: 26364984
Infant; Methadone; NAS; Neonatal Abstinence Syndrome; Neonate; NONMEM; Opioid; Opiate; Pharmacokinetic; Pregnancy; Withdrawal
12.  Identifying Pediatric Severe Sepsis and Septic Shock: Accuracy of Diagnosis Codes 
The Journal of pediatrics  2015;167(6):1295-1300.e4.
Objectives
To evaluate accuracy of two established administrative methods of identifying children with sepsis using a medical record review reference standard.
Study design
Multicenter retrospective study at six US children’s hospitals. Subjects were children >60 days and <19 years of age were identified in four groups based on ICD9-CM codes: (1) Severe sepsis/septic shock (Sepsis Codes); (2) Infection plus organ dysfunction (Combination Codes); (3) Subjects without codes for infection, organ dysfunction, or severe sepsis; and (4) Infection but not severe sepsis or organ dysfunction. Combination codes were allowed, but not required within the Sepsis Codes group. We determined the presence of reference standard severe sepsis according to consensus criteria. Logistic regression was performed to determine whether addition of codes for sepsis therapies improved case identification.
Results
130 of 432 subjects met reference standard definition of severe sepsis. Sepsis codes had sensitivity 73% (95% CI 70–86), specificity 92% (95% CI 87–95), and positive predictive value (PPV) 79% (95% CI 70–86). Combination codes had sensitivity 15% (95% CI 9–22), specificity 71% (95% CI 65–76), and PPV 18% (95% CI 11–27). Slight improvements in model characteristics were observed when codes for vasoactive medications and endotracheal intubation were added to sepsis codes (c-statistic 0.83 vs. 0.87, p=0.008).
Conclusions
Sepsis specific ICD9-CM codes identify pediatric patients with severe sepsis in administrative data more accurately than a combination of codes for infection plus organ dysfunction.
doi:10.1016/j.jpeds.2015.09.027
PMCID: PMC4662908  PMID: 26470685
Septic Shock; Epidemiology
13.  Impact of fetal-neonatal iron deficiency on recognition memory at two months of age 
The Journal of pediatrics  2015;167(6):1226-1232.
Objective
To assess the effects of fetal-neonatal iron deficiency on recognition memory in early infancy. Perinatal iron deficiency delays or disrupts hippocampal development in animal models and thus may impair related neural functions in human infants, such as recognition memory.
Study design
Event-related potentials were used in an auditory recognition memory task to compare 2-month-old Chinese infants with iron sufficiency or deficiency at birth. Fetal- neonatal iron deficiency was defined two ways: high zinc protoporphyrin/heme ratio (ZPP/H > 118 μmol/mol) or low serum ferritin (< 75 μg/l) in cord blood. Late slow wave (LSW) was used to measure infant recognition of mother’s voice.
Results
ERP patterns differed significantly for fetal-neonatal iron deficiency as defined by high cord ZPP/H but not low ferritin. Comparing 35 infants with iron deficiency (ZPP/H > 118 μmol/mol) to 92 with lower ZPP/H (iron-sufficient), only infants with iron sufficiency showed larger LSW amplitude for stranger’s voice than mother’s voice in frontal-central and parietal-occipital locations, indicating the recognition of mother’s voice.
Conclusions
Infants with iron sufficiency showed electrophysiological evidence of recognizing their mother’s voice, whereas infants with fetal-neonatal iron deficiency did not. Their poorer auditory recognition memory at two months of age is consistent with effects of fetal-neonatal iron deficiency on the developing hippocampus.
doi:10.1016/j.jpeds.2015.08.035
PMCID: PMC4662910  PMID: 26382625
iron deficiency; infant; ERP; recognition memory
14.  Location of usual source of care among children and adolescents in the US, 1997–2013 
The Journal of pediatrics  2015;167(6):1409-1414.
Objectives
To examine national trends in the percentage of children whose usual source of care is at a clinic, health center, or hospital outpatient department (hereafter “clinics”) and whether trends differ by sociodemographic subpopulations. Clinics have a greater percentage of patients from vulnerable populations than do physician’s offices and trends in their use as a usual source of care have not previously been described.
Study design
Analysis of serial, cross-sectional, nationally representative in-person household surveys, the 1997–2013 National Health Interview Surveys, was conducted to identify children with a usual source of care (n=190,571), and the percentage receiving that care in a clinic. We used Joinpoint regression to identify changes in linear trends, and logistic regression with predictive margins to obtain per-year changes in percentages, both unadjusted and adjusted for sociodemographic factors. Interaction terms in logistic regressions were used to assess whether trends varied by sociodemographic subgroups.
Results
Of all children with a usual source of care, the percentage receiving that care in a clinic declined 0.44 percentage points per year (p<0.001) from 22.97% in 1997 to 19.31% in 2002. Thereafter, it increased approximately 0.57 percentage points per year (p<0.001), reaching 26.1% in 2013. Trends for some sociodemographic subgroups varied from these overall trends. No changes were observed between 2003 and 2013 for non-Hispanic black and Medicaid/SCHIP insured children.
Conclusions
This study shows that, although the percentage of children with a usual source of care in a clinic declined between 1997 and 2002, it has steadily increased since that time.
doi:10.1016/j.jpeds.2015.09.026
PMCID: PMC4745654  PMID: 26454575
clinics; safety net; trends
15.  Comparison of Controlled Attenuation Parameter and Liver Biopsy to Assess Hepatic Steatosis in Pediatric Patients 
The Journal of pediatrics  2016;173:160-164.e1.
Objective
To assess whether the degree of steatosis as determined by Controlled Attenuation Parameter (CAP) measurements correlates with that observed on liver biopsies in a single-center pediatric and young adult cohort.
Study design
This was a cross-sectional study in patients undergoing liver biopsy as part of standard clinical care between January 25, 2012, and April 1, 2015 at Boston Children’s Hospital. Eligible patients, with a variety of liver diseases, had CAP measurements within 1 year of biopsy. CAP values were compared across histologic steatosis grades using ANOVA.
Results
Sixty-nine patients (mean age, 16.0 ± 2.9 years; 62% male) were studied. CAP measurements were obtained at a median of 1.3 months (IQR, 0.5–3.2) after biopsy. Of the 69 subjects, 23 had steatosis on biopsy. Mean CAP value (dB/m) for subjects with no steatosis was 198 ± 37 vs 290 ± 47 for subjects with steatosis (P < .0001). There were statistically significant differences between CAP values in individuals with no steatosis vs mild/moderate steatosis (P < .0001), no steatosis vs marked steatosis (P < .0001), and mild/moderate vs marked steatosis (P = .004)
Conclusion
This study demonstrated a difference in CAP between no steatosis and steatosis, and between grades of steatosis. CAP may be a useful non-invasive tool to detect hepatic steatosis in children.
doi:10.1016/j.jpeds.2016.03.021
PMCID: PMC5105890  PMID: 27039224
Non-alcoholic fatty liver disease; NAFLD; liver disease; child; fatty liver; elastography
16.  Corticosteroid Treatment and Growth Patterns in Ambulatory Males with Duchenne Muscular Dystrophy 
The Journal of pediatrics  2016;173:207-213.e3.
Objectives
To evaluate growth patterns of ambulatory males with Duchenne muscular dystrophy (DMD) treated with corticosteroids compared with ambulatory, steroid-naïlve males with DMD and age-matched unaffected general-population males and to test associations between growth and steroid treatment patterns among treated males.
Study design
Using data from the Muscular Dystrophy Surveillance, Tracking, and Research Network, we identified a total of 1768 height, 2246 weight, and 1755 body mass index (BMI) measurements between age 2 and 12 years for 324 ambulatory males who were treated with corticosteroids for at least 6 months. Growth curve comparisons and linear mixed-effects modeling, adjusted for race/ethnicity and birth year, were used to evaluate growth and steroid treatment patterns (age at initiation, dosing interval, duration, cumulative dose).
Results
Growth curves for ambulatory males treated with corticosteroids showed significantly shorter stature, heavier weight, and greater BMI compared with ambulatory, steroid-naïlve males with DMD and general-population US males. Adjusted linear mixed-effects models for ambulatory males treated with corticosteroids showed that earlier initiation, daily dosing, longer duration, and greater dosages predicted shorter stature with prednisone. Longer duration and greater dosages predicted shorter stature for deflazacort. Daily prednisone dosing predicted lighter weight, but longer duration, and greater dosages predicted heavier weight. Early initiation, less than daily dosing, longer duration, and greater doses predicted greater BMIs. Deflazacort predicted shorter stature, but lighter weight, compared with prednisone.
Conclusion
Prolonged steroid use is significantly associated with short stature and heavier weight. Growth alterations associated with steroid treatment should be considered when making treatment decisions for males with DMD.
doi:10.1016/j.jpeds.2016.02.067
PMCID: PMC5100357  PMID: 27039228
17.  Chiari I Malformation in Nephropathic Cystinosis 
The Journal of pediatrics  2015;167(5):1126-1129.
Objective
To determine the relative incidence of Chiari I malformations in children with cystinosis compared with those in the general population.
Study design
Magnetic resonance imaging (MRI) scans were performed on 53 patients with nephropathic cystinosis and 120 controls, age range 3-18 years.
Results
Ten of 53 (18.9%) cystinosis patients had Chiari I or tonsillar ectopia, and only 2 of 120 controls (1.6%) had a similar finding. At least 2 of the patients had symptoms or signs thought to be related to the malformation, and one had surgical decompression. Two had an associated cervical syrinx.
Conclusions
Children with cystinosis have a 12-fold higher prevalence of Chiari I malformations than the general pediatric population. Chiari I malformations should be high on the differential diagnosis when individuals with cystinosis develop neurologic signs and symptoms, and MRI scans should be performed on children with cystinosis who present with new-onset headache, ataxia, incontinence, or other unexplained neurologic symptoms.
doi:10.1016/j.jpeds.2015.07.038
PMCID: PMC4661060  PMID: 26265281
cystinosis; Chiari I; syrinx
18.  Patient Safety Perceptions in Pediatric Out-of-Hospital Emergency Care: Children's Safety Initiative 
The Journal of pediatrics  2015;167(5):1143-1148.e1.
Objective
To characterize emergency medical service (EMS) providers’ perceptions of the factors that contribute to safety events and errors in the out-of-hospital emergency care of children.
Study design
We used a Delphi process to achieve consensus in a national sample of 753 emergency medicine physicians and EMS professionals. Convergence and stability were achieved in 3 rounds and findings were reviewed and interpreted by a national expert panel.
Results
Forty-four (88%) states were represented and 66% of participants were retained through all 3 rounds. From an initial set of 150 potential contributing factors derived from focus groups and literature, participants achieved consensus on the following leading contributors: airway management, heightened anxiety caring for children, lack of pediatric skill proficiency, lack of experience with pediatric equipment, and family members leading to delays or interference with care. Somewhat unexpectedly, medications and communication were low-ranking concerns. After thematic analysis, the overarching domains were ranked by their relative importance: (1) clinical assessment; (2) training; (3) clinical decision-making; (4) equipment; (5) medications; (6) scene characteristics; and (7) EMS cultural norms.
Conclusions
These findings raise considerations for quality improvement and suggest important roles for pediatricians and pediatric emergency physicians in training, medical oversight, and policy development.
doi:10.1016/j.jpeds.2015.07.023
PMCID: PMC4661065  PMID: 26297483
pediatrics; emergency medical services; children; patient safety
19.  Relation of Cardiometabolic Risk Factors Between Parents and Children 
The Journal of pediatrics  2015;167(5):1049-1056.e2.
Objectives
To explore the relations of parent-child cardiometabolic risk factors and assess the influence of adiposity on these associations.
Study design
Associations of adiposity, blood pressure, lipids, fasting insulin and glucose, and a risk factor cluster score were evaluated in a cross-sectional study of 179 parents and their children (6–18 years, N=255). Insulin resistance was assessed by euglycemic clamp in parents and children aged 10 or older. Metabolic syndrome in parents was defined by ATPIII criteria. Cluster scores of the risk factors were created based on age-specific z-scores. Analyses included Pearson correlation and linear regression, adjusted for parent and child age, sex, race, and body mass index (BMI), accounting for within-family correlation.
Results
We found positive parent-child correlations for measures of adiposity (BMI, BMI percentile, waist, subcutaneous fat, and visceral fat; r=0.22–0.34, all p≤0.003), systolic blood pressure (SBP) (r=0.20, p=0.002), total cholesterol (r=0.39, p<0.001), low-density lipoprotein cholesterol (r=0.34, p<0.001), high density lipoprotein cholesterol (r=0.26, p<0.001) triglycerides (r=0.19, p=0.01) and insulin sensitivity (r=0.22, p=0.02) as well as cluster scores (r=0.15, p=0.02). After adjustment for BMI all parent-child correlations, except systolic blood pressure, remained significant.
Conclusions
Although adiposity is strongly correlated between parents and children, many cardiometabolic risk factors correlate independent of parent and child BMI. Adverse parental cardiometabolic profiles may identify at-risk children independent of the child’s adiposity status.
doi:10.1016/j.jpeds.2015.07.053
PMCID: PMC4661075  PMID: 26307644
adiposity; obesity; blood pressure; BMI; cardiovascular; cluster score; correlation; insulin sensitivity; lipid(s)
20.  Comparing the use of CDC and WHO Growth Charts in Children with Cystic Fibrosis through Two Years of Age 
The Journal of pediatrics  2015;167(5):1089-1095.
Objective
To examine differences between use of WHO and CDC growth reference in children with cystic fibrosis (CF) up to 2 years of age.
Study design
Growth from 1–24 months in 2587 children, born 2003–2006 and recorded in the US CF Foundation Registry, was evaluated using WHO and CDC references.
Results
In both boys and girls with CF aged 1–24 months, use of WHO charts resulted in ~8 percentile lower length-for-age (LFA) and ~13% higher short stature rate (LFA<5th percentile). WHO weight-for-age was ~9 percentile lower prior to age 6 months, crossed at 6–7 months, and remained ~14 percentile higher at 8–24 months. WHO Weight-for-Length percentile (WFLp) was similar before 12 months but ~10 percentile higher at 12–24 months compared with CDC. When using WHO charts, 9% of children had underweight (WFLp<50th) classified differently and this rate varied with age: 4% in the first year, 7% at 12, 13% at 15, and 16% at 18 months, respectively. Weight status assessed by WHO BMI charts was different from WHO Weight-for-Length charts. At 24 months when switching back to CDC, 26% of children with normal WFLp on WHO charts appeared underweight on CDC charts. A 70th percentile of WHO BMIp was equivalent to the 50th percentile CDC BMIp.
Conclusion
Growth status in children with CF differed when using WHO and CDC references, particularly during the second year of life. These differences need to be considered for all uses of growth assessment in CF.
doi:10.1016/j.jpeds.2015.07.036
PMCID: PMC4661080  PMID: 26298625
cystic fibrosis; growth; 2000 CDC growth reference; 2006 WHO growth reference; infants; malnutrition
21.  Safety of ROP Examination and imaging in Premature Infants 
The Journal of pediatrics  2015;167(5):994-1000.e2.
Objectives
To describe adverse events (AEs) and noteworthy clinical or ocular findings associated with retinopathy of prematurity (ROP) evaluation procedures.
Study design
Descriptive analysis of pre-defined AEs and noteworthy findings reported in a prospective observational cohort study of infants <1251 g birth weight (BW) who had ROP study visits consisting of both binocular indirect ophthalmoscopy (BIO) and digital retinal imaging. We compared infant characteristics during ROP visits with and without AEs. We compared respiratory support, nutrition, and number of apnea, bradycardia, or hypoxia events 12 hours before and after ROP visits.
Results
1,257 infants, mean BW 802 g, had 4,263 BIO and 4,048 imaging sessions (total 8,311 procedures). No serious AEs were related to ROP visits. Sixty-five AEs were reported among 61 infants for an AE rate of 4.9% infants (61/1257) or 0.8% total procedures (65/8311 BIO + imaging). Most AEs were due to apnea, bradycardia, and/or hypoxia (68%), tachycardia (16%), or emesis (8%). At ROP visit, infants with AEs, compared with those without, were more likely to be on mechanical ventilation (26% versus 12%, p=0.04) even after adjustment for weight and PMA. Noteworthy clinical findings were reported during 8% BIO and 15% imaging exams. Respiratory and nutrition support were not significantly different before and after ROP evaluations.
Conclusions
Retinal imaging by non-physicians combined with BIO was safe. Noteworthy clinical findings occurred during both procedures. Ventilator support was a risk factor for AEs. Monitoring rates of AEs and noteworthy findings are important to the safe implementation of ROP imaging protocols.
Trial registration
Clinicaltrials.gov: NCT01264276
doi:10.1016/j.jpeds.2015.07.050
PMCID: PMC4661087  PMID: 26299381
retinopathy of prematurity; very low birth weight infant; adverse event
22.  Autologous Infant and Allogeneic Adult Red Cells Demonstrate Similar Concurrent Post-Transfusion Survival in Very Low Birth Weight Neonates 
The Journal of pediatrics  2015;167(5):1001-1006.
Objective
Based on the hypothesis that neonatal autologous red blood cell (RBC) survival (RCS) is substantially shorter than adult RBC, we concurrently tracked the survival of transfused biotin-labeled autologous neonatal and allogeneic adult RBC into ventilated, very low birth weight (VLBW) infants.
Study design
RBC aliquots from the first clinically ordered, allogeneic adult RBC transfusion and from autologous infant blood were labeled at separate biotin densities (BioRBC) and transfused. Survival of these BioRBCs populations were concurrently followed over weeks by flow cytometric enumeration using leftover blood. Relative tracking of infant autologous and adult allogeneic BioRBC was analyzed by linear mixed modeling of batched weekly data. When possible, Kidd antigen (Jka and Jkb) mismatches between infant and donor RBCs were also used to track these two populations.
Results
Contrary to our hypothesis, concurrent tracking curves of RCS of neonatal and adult BioRBC in 15 study infants did not differ until week 7, after which neonatal RBC survival became shortened to 59% to 79% of adult enumeration values for uncertain reasons. Analysis of mismatched Kidd antigen RBC showed similar results, thus confirming that BioRBC tracking is not perturbed by biotin RBC labeling.
Conclusions
This study illustrates the utility of multi-density BioRBC labeling for concurrent measurement of RCS of multiple RBC populations in vivo. The similar RCS results observed for neonatal and adult BioRBCs transfused into VLBW infants provides strong evidence that the circulatory environment of the newborn infant—not intrinsic infant-adult RBC differences—is the primary determinant of erythrocyte survival.
Trial registration
Clinicaltrials.gov: NCT 00731588.
doi:10.1016/j.jpeds.2015.08.028
PMCID: PMC4661104  PMID: 26363547
Erythrocyte; kinetics; erythropoiesis
23.  Effects of advancing gestation and non-Caucasian race on ductus arteriosus gene expression 
The Journal of pediatrics  2015;167(5):1033-1041.e2.
Objective
To identify genes affected by advancing gestation and racial/ethnic origin in human ductus arteriosus (DA).
Study design
We collected three sets of DA tissue (n=93, n=89, n=91; total = 273 fetuses) from second trimester pregnancies. We examined four genes, with DNA polymorphisms that distribute along racial lines, to identify "Caucasian" and "Non-Caucasian" DA. We used RT-PCR to measure RNA expression of 48 candidate genes involved in functional closure of the DA, and used multivariable regression analyses to examine the relationships between advancing gestation, "Non-Caucasian" race, and gene expression.
Results
Mature gestation and Non-Caucasian race are significant predictors for identifying infants who will close their patent DA when treated with indomethacin. Advancing gestation consistently altered gene expression in pathways involved with oxygen-induced constriction (e.g., calcium-channels, potassium-channels, and endothelin signaling), contractile protein maturation, tissue remodeling, and prostaglandin and nitric oxide signaling in all three tissue sets. None of the pathways involved with oxygen-induced constriction appeared to be altered in "Non-Caucasian" DA. Two genes, SLCO2A1 and NOS3, (involved with prostaglandin reuptake/metabolism and nitric oxide production, respectively) were consistently decreased in "Non-Caucasian" DA.
Conclusions
Prostaglandins and nitric oxide are the most important vasodilators opposing DA closure. Indomethacin inhibits prostaglandin production, but not nitric oxide production. Because decreased SLCO2A1 and NOS3 expression can lead to increased prostaglandin and decreased nitric oxide concentrations, we speculate that prostaglandin-mediated vasodilation may play a more dominant role in maintaining the "Non-Caucasian" PDA, making it more likely to close when inhibited by indomethacin.
doi:10.1016/j.jpeds.2015.07.011
PMCID: PMC4661123  PMID: 26265282
nitric oxide synthase; Race; Caucasian; Prostaglandin transporter; gene expression; ductus arteriosus
24.  Insulin Sensitivity and β-Cell Function Improve after Gastric Bypass in Severely Obese Adolescents 
The Journal of pediatrics  2015;167(5):1042-8.e1.
Objective
To test the hypothesis that insulin secretion and insulin sensitivity would be improved in adolescents after Roux-en-Y gastric bypass (RYGB).
Study design
A longitudinal study of 22 adolescents and young adults without diabetes undergoing laparoscopic RYGB (mean age 17.1 ± 1.42 years; range 14.5–20.1; male/female 8/14; Non-Hispanic White/African American 17/5) was conducted. Intravenous glucose tolerance tests were done to obtain insulin sensitivity (insulin sensitivity index), insulin secretion (acute insulin response to glucose), and the disposition index as primary outcome variables. These variables were compared over the 1 year of observation using linear mixed modeling.
Results
In the 1-year following surgery, body mass index fell by 38% from a mean of 61 ± 12.3 to 39 ± 8.0 kg/m2 (P < .01). Over the year following surgery, fasting glucose and insulin values declined by 54% and 63%, respectively. Insulin sensitivity index increased 300% (P < .01), acute insulin response to glucose decreased 56% (P < .01), leading to a nearly 2-fold increase in the disposition index (P < .01). Consistent with improved β-cell function, the proinsulin to C-peptide ratio decreased by 21% (P < .01).
Conclusions
RYGB reduced body mass index and improved both insulin sensitivity and β-cell function in severely obese teens and young adults. These findings demonstrate that RYGB is associated with marked metabolic improvements in obese young people even as significant obesity persists.
Trial registration
ClinicalTrials.gov: NCT00360373.
doi:10.1016/j.jpeds.2015.08.020
PMCID: PMC4843108  PMID: 26363548
25.  Early Life Growth Trajectories in Cystic Fibrosis are Associated with Pulmonary Function at Age 6 Years 
The Journal of pediatrics  2015;167(5):1081-8.e1.
Objective
To determine whether severity of lung disease at age 6 years is associated with changes in nutritional status before age 6 within individual children with cystic fibrosis (CF).
Study Design
Children with CF born between 1994 and 2005 and followed in the CF Foundation Patient Registry from age ≤2 through 7 years were assessed according to changes in annualized weight-for-length (WFL) percentiles between ages 0 and 2 and body mass index (BMI) percentiles between ages 2 and 6. The association between growth trajectories before age 6 and forced expiratory volume in one second (FEV1) % predicted at age 6-7 years was evaluated using multivariable linear regression.
Results
A total of 6,805 subjects met inclusion criteria. Children with annualized WFL-BMI always >50th percentile [N=1,323 (19%)] had the highest adjusted mean [95% Confidence Interval (CI)] FEV1 at 6-7 years [101.8 (100.1, 103.5)]. FEV1 at 6-7 years for children whose WFL-BMI increased >10 percentile points by age 6 years was 98.3 (96.6, 100.0). This was statistically significantly higher than FEV1 for children whose WFL-BMI was stable [94.4 (92.6, 96.2)] or decreased >10 percentile points [92.9 (91.1, 94.8)]. Among children whose WFL-BMI increased >10 percentile points, achieving and maintaining WFL-BMI >50th percentile at younger ages was associated with significantly higher FEV1 at 6-7 years.
Conclusions
Within-patient changes in nutritional status in the first 6 years of life are significantly associated with FEV1 at age 6-7 years, suggesting that interventions that improve nutrition in early life may lead to improvements in later lung function.
doi:10.1016/j.jpeds.2015.07.044
PMCID: PMC5017309  PMID: 26340874
CF; FEV1; Forced expiratory volume in 1 second; Weight; BMI; Newborn screening

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