July 2018

The publications listed here were found utilizing an affiliation search in CINAHL, PsycINFO, PubMed, and Scopus databases, and should not be considered a complete record of CCHMC affiliated publications for this period.
1. Ahmed Z, Jaworek T, Sarangdhar G, Zheng L, Gul K, Khan S, Friedman T, Sisk R, Bartles J, Riazuddin S. Inframe deletion of human ESPN is associated with deafness, vestibulopathy and vision impairment. J. Med. Genet. 7/1/2018;55(7):jmedgenet-2017-105221-jmedgenet-102017-105221.
2. Andrew M, Liao L, Fujimoto M, Khoury J, Hwa V, Dauber A. PAPPA2 as a Therapeutic Modulator of IGF-I Bioavailability: in Vivo and in Vitro Evidence. Journal of the Endocrine Society. 7/1/2018;2(7):646-656.
3. Barber Foss K, Le Cara E, McCambridge T, Hinton R, Kushner A, Myer G. Epidemiology of Injuries in Women s Lacrosse: Implications for Sport-, Level-, and Sex-Specific Injury Prevention Strategies. Clin. J. Sport Med. 7/1/2018;28(4):406-413.
4. Bevans K, Gardner W, Pajer K, Becker B, Carle A, Tucker C, Forrest C. Psychometric Evaluation of the PROMIS® Pediatric Psychological and Physical Stress Experiences Measures. J. Pediatr. Psychol. 7/1/2018;43(6):678-692.
5. Ferguson A, Fulkerson P. Eosinophilic esophagitis: Time to classify into endotypes? J. Allergy Clin. Immunol. 7/1/2018;142(1):71-72.
6. Hackerson M, Luder H, Beck A, Wedig J, Heaton P, Frede S. Addressing primary nonadherence: A collaboration between a community pharmacy and a large pediatric clinic. Journal of the American Pharmacists Association : JAPhA. 7/1/2018;58(4):S101-S108.e101.
7. Kandil A, Smith G, Mahmoud M, Abruzzo T, Vadivelu S, Subramanyam R. Epidural Blood Patch in Children under Anesthesia: Is There an Indication for Neuromonitoring? J. Neurosurg. Anesthesiol. 7/1/2018;30(3):275-276.
8. Kline-Fath B, Horn P, Yuan W, Merhar S, Venkatesan C, Thomas C, Schapiro M. Conventional MRI scan and DTI imaging show more severe brain injury in neonates with hypoxic-ischemic encephalopathy and seizures. Early Hum. Dev. 7/1/2018;122:8-14.
9. Kruger K, Garman C, Krzak J, Graf A, Hassani S, Tarima S, Sturm P, Hammerberg K, Gupta P, Harris G. Effects of Spinal Fusion for Idiopathic Scoliosis on Lower Body Kinematics During Gait. Spine Deformity. 7/1/2018;6(4):441-447.
10. Macaluso M, Summerville L, Tabangin M, Daraiseh N. Enhancing the detection of injuries and near-misses among patient care staff in a large pediatric hospital. Scand. J. Work Environ. Health. 7/1/2018;44(4):377-384.
11. Moeskops S, Oliver J, Read P, Cronin J, Myer G, Haff G, Lloyd R. Within- and Between-Session Reliability of the Isometric Midthigh Pull in Young Female Athletes. J. Strength Cond. Res. 7/1/2018;32(7):1892-1901.
12. Orscheln E, Dillman J, Towbin A, Denson L, Trout A. Penetrating Crohn disease: does it occur in the absence of stricturing disease? Abdominal Radiology. 7/1/2018;43(7):1583-1589.
13. Sellers Z, Abu-El-Haija M, Husain S, Morinville V. New Management Guidelines for Both Children and Adults With Acute Pancreatitis. Gastroenterology. 7/1/2018;155(1):234-235.
14. Tomoshige K, Guo M, Tsuchiya T, Fukazawa T, Fink-Baldauf I, Stuart W, Naomoto Y, Nagayasu T, Maeda Y. An EGFR ligand promotes EGFR-mutant but not KRAS-mutant lung cancer in vivo. Oncogene: Including Oncogene Reviews. 7/1/2018;37(28):3894-3908.
15. Van Dyk T, Krietsch K, Saelens B, Whitacre C, McAlister S, Beebe D. Inducing more sleep on school nights reduces sedentary behavior without affecting physical activity in short-sleeping adolescents. Sleep Med. 7/1/2018;47:7-10.
16. Mouzaki M, Trout A, Arce-Clachar A, Bramlage K, Kuhnell P, Dillman J, Xanthakos S. Assessment of Nonalcoholic Fatty Liver Disease Progression in Children Using Magnetic Resonance Imaging. The Journal of Pediatrics. 7/2/2018;198:1-330.
17. Read P, Oliver J, Myer G, De Ste Croix M, Belshaw A, Lloyd R. Altered landing mechanics are shown by male youth soccer players at different stages of maturation. Phys. Ther. Sport. 7/7/2018;33:48-53.
18. Alam S, Abdullah C, Aishwarya R, Miriyala S, Panchatcharam M, Peretik J, Orr A, James J, Robbins J, Bhuiyan M. Aberrant Mitochondrial Fission Is Maladaptive in Desmin Mutation-Induced Cardiac Proteotoxicity. Journal of the American Heart Association : Cardiovascular and Cerebrovascular Disease. 7/9/2018;7(14).
19. Trout A, Serai S, Fei L, Sun Q, Abu-El-Haija M. Prospective Assessment of Normal Pancreatic Secretory Function Measured by MRI in a Cohort of Healthy Children. The American Journal of Gastroenterology (Elsevier). 7/10/2018;Epub ahead of print:1-8.
20. Bracey D, Seyler T, Jinnah A, Lively M, Willey J, Smith T, Van Dyke M, Whitlock P. A Decellularized Porcine Xenograft-Derived Bone Scaffold for Clinical Use as a Bone Graft Substitute: A Critical Evaluation of Processing and Structure. Journal of Functional Biomaterials. 7/12/2018;9(3).
21. Huusko J, Karjalainen M, Graham B, Zhang G, Farrow E, Miller N, Jacobsson B, Eidem H, Murray J, Bedell B, Breheny P, Brown N, Bødker F, Litterman N, Jiang P, Russell L, Hinds D, Hu Y, 23andMe Research Team, Rokas A, Teramo K, Christensen K, Williams S, Rämet M, Kingsmore S, Ryckman K, Hallman M, Muglia L. Whole exome sequencing reveals HSPA1L as a genetic risk factor for spontaneous preterm birth. PLoS Genet. 7/12/2018;14(7).
22. Armenian S, Armstrong G, Aune G, Chow E, Ehrhardt M, Ky B, Moslehi J, Mulrooney D, Nathan P, Ryan T, van der Pal H, van Dalen E, Kremer L. Cardiovascular Disease in Survivors of Childhood Cancer: Insights Into Epidemiology, Pathophysiology, and Prevention. J. Clin. Oncol. 7/20/2018;36(21):JCO2017763920-2017762144.
23. Brady R, Jackson L, Frey S, Shane A, Walter E, Swamy G, Schlaudecker E, Szefer E, Wolff M, McNeal M, Bernstein D, Steinhoff M. Randomized trial comparing the safety and antibody responses to live attenuated versus inactivated influenza vaccine when administered to breastfeeding women. Vaccine. 7/25/2018;36(31):4663-4671.
24. Abu-El-Haija M, Lin TK, Khan S, Fei L, Thompson T, Nathan JD. Predictive biomarkers for acute gallstone pancreatitis in the pediatric population. Pancreatology. Jul 2018;18(5):482-485.
Background: Early biomarkers for diagnosis of gallstone pancreatitis (GP) in pediatrics have not been well studied. Reliably differentiating GP from other causes of acute pancreatitis (AP) would allow for early diagnosis and prompt management. We sought to assess biomarkers and clinical variables for early GP diagnosis from a prospectively-enrolled registry of pediatric patients presenting with first AP episode.
Methods: Cross-sectional analysis of a prospective acute pancreatitis registry of children enrolled from March 2013 through October 2016 was performed. Fisher's exact test and Wilcoxon rank sum test were used to compare demographic and clinical variables between GP and non-GP groups. A multivariable logistic regression model was derived, and receiver operating characteristic (ROC) curve was built using stepwise selection.
Results: 114 subjects were enrolled (21 with GP, 93 as non-GP). Median was statistically higher for GP patients in lipase values X upper limit of normal (ULN) on admission, weight percentile for age, alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transferase. By multivariable analysis, significant predictors were ALT and Lipase xULN. A model built using these two variables for prediction of GP identified an AUROC of 0.85. At a predictive probability of 0.35, the model had an 80% sensitivity, 93% specificity, 76% positive predictive value and 95% negative predictive value.
Conclusions' We have developed a model for predicting GP in children that could help guide clinical management of AP patients. Future studies are needed to validate use of laboratory findings and clinical variables in evaluation of gallstone etiology in pediatric AP patients. (C) 2018 IAP and EPC. Published by Elsevier B.V. All rights reserved.
25. Abu-El-Haija M, Uc A, Werlin SL, Freeman AJ, Georgieva M, Jojkic-Pavkov D, Kalnins D, Kochavi B, Koot BGP, Van Biervliet S, Walkowiak J, Wilschanski M, Morinville VD. Nutritional Considerations in Pediatric Pancreatitis: A Position Paper from the NASPHAN Pancreas Committee and ESPHAN Cystic Fibrosis/Pancreas Working Group. J. Pediatr. Gastroenterol. Nutr. Jul 2018;67(1):131-143.
OBJECTIVES: Wide variations exist in how physicians manage the nutritional aspects of children affected by acute pancreatitis (AP), acute recurrent pancreatitis (ARP), and chronic (CP) pancreatitis. Better consensus for optimal management is needed. METHODS: This consensus statement on nutrition in pediatric pancreatic diseases was developed through a joint ESPGHAN-NASPGHAN working group that performed an evidence-based search of the literature on nutrition in AP, ARP, and CP with a focus on pediatrics. The literature was summarized, quality of evidence reviewed, and expert recommendations developed. The authorship met to discuss the evidence and statements. Voting on recommendations occurred over 2 rounds based on feedback. A consensus of at least 75% was required to approve a recommendation. Areas requiring further research were identified. RESULTS AND DISCUSSION: The literature on nutrition in pediatric pancreatitis is limited. Children with mild AP benefit from starting an early nutritional regimen in the course of the attack. Early nutrition should be attempted in severe AP when possible; enteral nutrition is preferred over parenteral nutrition. Children with ARP are likely to tolerate and benefit from a regular diet. Children with CP need ongoing assessment for growth and nutritional deficiencies, exocrine and endocrine insufficiencies. CONCLUSIONS: This document presents the first authoritative recommendations on nutritional considerations in pediatric pancreatitis. Future research should address the gaps in knowledge particularly relating to optimal nutrition for AP in children, role of diet or dietary supplements on recurrent attacks of pancreatitis and pain episodes, monitoring practices to detect early growth and nutritional deficiencies in CP and identifying risk factors that predispose children to these deficiencies.
26. Aceves SS, King E, Collins MH, Yang GY, Capocelli KE, Abonia JP, Atkins D, Bonis PA, Carpenter CL, Dellon ES, Eby MD, Falk GW, Gonsalves N, Gupta SK, Hirano I, Kocher K, Krischer JP, Leung J, Lipscomb J, Menard-Katcher P, Mukkada VA, Pan Z, Spergel JM, Sun Q, Wershil BK, Rothenberg ME, Furuta GT, Consortium of Eosinophilic Gastrointestinal Disease R. Alignment of parent- and child-reported outcomes and histology in eosinophilic esophagitis across multiple CEGIR sites. J. Allergy Clin. Immunol. Jul 2018;142(1):130-138 e131.
BACKGROUND: Patient-reported outcome metrics for eosinophilic esophagitis (EoE) have been developed and validated but not used in a multicenter pediatric population or systematically aligned with histology. OBJECTIVE: We sought to understand (1) the potential of caregiver report to predict patient self-reported symptoms and (2) the correlation of patient-reported outcome domains with histology. METHODS: Patients with EoE (n = 310) and their parents participating in the Consortium of Gastrointestinal Eosinophilic Disease Researchers (CEGIR) observational clinical trial were queried for baseline patient symptoms and quality of life (QOL) by using the Pediatric Eosinophilic Esophagitis Symptom Score, version 2 (PEESSv2.0), and the Pediatric QOL EoE module (PedsQL-EoE), and biopsy specimens were analyzed by using the EoE Histology Scoring System. RESULTS: PEESSv2.0 parental and child reports aligned across all domains (r = 0.68-0.73, P < .001). PedsQL-EoE reports correlated between parents and children across ages and multiple domains (r = 0.48-0.79, P < .001). There was a tight correlation between symptoms on PEESSv2.0 and their effects on QOL both on self-report and parental report (P < .001). Self-reported symptoms on PEESSv2.0 (positively) and PedsQL-EoE (inversely) showed a weak correlation with proximal, but not distal, peak eosinophil counts and features and architectural tissue changes on the EoE Histology Scoring System (P < .05). CONCLUSIONS: Parents of children with EoE aged 3 to 18 years accurately reflected their children's disease symptoms and QOL. Self- and parent-reported symptoms correlate with proximal esophageal histology. Our data suggest that parental report in young children can function as an adequate marker for self-reported symptoms and that self-reported symptoms can reflect changes in tissue histology in the proximal esophagus. These findings should be considered during clinical trials for drug development.
27. Ao YY, Cong X, Jin M, Sun XM, Wei XM, Wang JJ, Zhang Q, Song J, Yu JM, Cui J, Qi JX, Tan M, Duan ZJ. Genetic Analysis of Reemerging GII.P16-GII.2 Noroviruses in 2016-2017 in China. J. Infect. Dis. Jul 1 2018;218(1):133-143.
Background. During 2016-2017, the previously rare GII.P16-GII.2 norovirus suddenly emerged as the predominant genotype causing gastroenteritis outbreaks in China and other countries. Its origin, phylodynamics, and mechanism behind the predominance remain unclear.
Methods. Bayesian phylogenetic analyses were performed on 180 full capsid and 150 polymerase sequences of 2016-2017 GII.P16-GII.2 noroviruses in China, and those for all publicly available GII.P16andGII.2 sequences. Saliva-based histo-blood group antigen (HBGA) binding assays and crystal structural analysis were conducted by using the P proteins of 2016-2017 GII.P16-GII.2 noroviruses.
Results. The reemerging GII.P16-GII.2 norovirus showed a rapid genetic diversification after its emergence in 2012-2013. The antigenicity and HBGA binding profile of the early 2016-2017 and pre-2016 GII.2 noroviruses were similar. A further variant with a single Val256Ile mutation and the conventionally orientated Asp382 in the VP1 protein showed an expanded HBGA-binding spectrum. Mutations on the surface of polymerase that could alter its function were seen, which may help to accelerate the VP1 gene evolution to 5.5 x 10(-3) substitutions per site per year. This virus can be traced back to Pearl River Delta, China.
Conclusions. Our findings provide new insights into GII.2 norovirus epidemics and highlight the necessity of enhanced global surveillance for potential epidemics of rare-genotype noroviruses.
28. Aronson PL, Wang ME, Nigrovic LE, Shah SS, Desai S, Pruitt CM, Balamuth F, Sartori L, Marble RD, Rooholamini SN, Leazer RC, Woll C, DePorre AG, Neuman MI, Febrile Young Infant Research C. Time to Pathogen Detection for Non-ill Versus Ill-Appearing Infants </=60 Days Old With Bacteremia and Meningitis. Hosp Pediatr. Jul 2018;8(7):379-384.
OBJECTIVES: We sought to determine the time to pathogen detection in blood and cerebrospinal fluid (CSF) for infants </=60 days old with bacteremia and/or bacterial meningitis and to explore whether time to pathogen detection differed for non-ill-appearing and ill-appearing infants. METHODS: We included infants </=60 days old with bacteremia and/or bacterial meningitis evaluated in the emergency departments of 10 children's hospitals between July 1, 2011, and June 30, 2016. The microbiology laboratories at each site were queried to identify infants in whom a bacterial pathogen was isolated from blood and/or CSF. Medical records were then reviewed to confirm the presence of a pathogen and to extract demographic characteristics, clinical appearance, and the time to pathogen detection. RESULTS: Among 360 infants with bacteremia, 316 (87.8%) pathogens were detected within 24 hours and 343 (95.3%) within 36 hours. A lower proportion of non-ill-appearing infants with bacteremia had a pathogen detected on blood culture within 24 hours compared with ill-appearing infants (85.0% vs 92.9%, respectively; P = .03). Among 62 infants with bacterial meningitis, 55 (88.7%) pathogens were detected within 24 hours and 59 (95.2%) were detected within 36 hours, with no difference based on ill appearance. CONCLUSIONS: Among infants </=60 days old with bacteremia and/or bacterial meningitis, pathogens were commonly identified from blood or CSF within 24 and 36 hours. However, clinicians must weigh the potential for missed bacteremia in non-ill-appearing infants discharged within 24 hours against the overall low prevalence of infection.
29. Auger KA, Simmons JM, Tubbs-Cooley HL, Sucharew HJ, Statile AM, Pickler RH, Sauers-Ford HS, Gold JM, Khoury JC, Beck AF, Wade-Murphy S, Kuhnell P, Shah SS, group HOTs. Postdischarge Nurse Home Visits and Reuse: The Hospital to Home Outcomes (H2O) Trial. Pediatrics. Jul 2018;142(1).
BACKGROUND: Hospital discharge is stressful for children and families. Poor transitional care is linked to unplanned health care reuse. We evaluated the effects of a pediatric transition intervention, specifically a single nurse home visit, on postdischarge outcomes in a randomized controlled trial. METHODS: We randomly assigned 1500 children hospitalized on hospital medicine, neurology services, or neurosurgery services to receive either a single postdischarge nurse-led home visit or no visit. We excluded children discharged with skilled home nursing services. Primary outcomes included 30-day unplanned, urgent health care reuse (composite measure of unplanned readmission, emergency department, or urgent care visit). Secondary outcomes, measured at 14 days, included postdischarge parental coping, number of days until parent-reported return to normal routine, and number of "red flags" or clinical warning signs a parent or caregiver could recall. RESULTS: The 30-day reuse rate was 17.8% in the intervention group and 14.0% in the control group. In the intention-to-treat analysis, children randomly assigned to the intervention group had higher odds of 30-day health care use (odds ratio: 1.33; 95% confidence interval: 1.003-1.76). In the per protocol analysis, there were no differences in 30-day health care use (odds ratio: 1.14; confidence interval: 0.84-1.55). Postdischarge coping scores and number of days until returning to a normal routine were similar between groups. Parents in the intervention group recalled more red flags at 14 days (mean: 1.9 vs 1.6; P < .01). CONCLUSIONS: Children randomly assigned to the intervention had higher rates of 30-day postdischarge unplanned health care reuse. Parents in the intervention group recalled more clinical warning signs 2 weeks after discharge.
30. Baer RJ, Yang J, Berghella V, Chambers CD, Coker TR, Kuppermann M, Oltman SP, Rand L, Ryckman KK, Muglia LJ, Chung PJ, Jetliffe-Pawlowski LL. Risk of preterm birth by maternal age at first and second pregnancy and race/ethnicity. J. Perinat. Med. Jul 2018;46(5):539-546.
We examined the risk of preterm birth (PTB, <37 weeks' gestation) in a second pregnancy and analyzed the extent to which this risk varies by maternal age and race/ethnicity. The sample included nulligravida mothers in California who delivered two singletons between 2005 and 2011. Logistic regression was used to calculate the odds of PTB in the second pregnancy. Within each race/ethnicity stratum, women delivering term infants in their first pregnancy and between 25 and 34 years old for both pregnancies served as the referent group. There were 2,90,834 women included in the study. Among women who delivered their first infant at term, the odds of delivering their second infant early differed by race and age. Hispanic, Black and Asian non-Hispanic women who were <18 years for both pregnancies were at higher odds of having a PTB in their second pregnancy (adjusted odds ratios 1.7, 3.3 and 2.9, respectively). Asian non-Hispanic women who were <18 years for their first delivery at term and between 18 and 24 years for their second delivery, or were >34 years for both, were also at higher odds of delivering their second baby prematurely (adjusted odds ratios 1.9 and 1.3, respectively). Women who deliver their first infant at <37 weeks of gestation are at 3 to 7 times higher odds of delivering their second infant preterm. Providers should consider including information about these risks in counseling their patients.
31. Beckwith TJ, Dietrich KN, Wright JP, Altaye M, Cecil KM. Reduced regional volumes associated with total psychopathy scores in an adult population with childhood lead exposure. Neurotoxicology. Jul 2018;67:1-26.
Childhood lead exposure has been correlated to acts of delinquency and criminal behavior; however, little research has been conducted to examine its potential long term influence on behavioral factors such as personality, specifically psychopathic personality. Neuroimaging studies have demonstrated that the effects of childhood lead exposure persist into adulthood, with structural abnormalities found in gray and white matter regions involved in behavioral decision making. The current study examined whether measurements of adult psychopathy were associated with neuroanatomical differences in structural brain volumes for a longitudinal cohort with measured childhood lead exposure. We hypothesized that increased total psychopathy scores and increased blood lead concentration at 78 months of age (PbB78) would be inversely associated with volumetric measures of gray and white matter brain structures responsible for executive and emotional processing. Analyses did not display a direct effect between total psychopathy score and gray matter volume; however, reduced white matter volume in the cerebellum and brain stem in relation to increased total psychopathy scores was observed. An interaction between sex and total psychopathy score was also detected. Females displayed increased gray matter volume in the frontal, temporal, and parietal lobes associated with increased total psychopathy score, but did not display any white matter volume differences. Males primarily displayed reductions in frontal gray and white matter brain volume in relation to increased total psychopathy scores. Additionally, reduced gray and white matter volume was associated with increased blood lead levels in the frontal lobes; reduced white matter volume was also observed in the parietal and temporal lobes. Females demonstrated gray and white matter volume loss associated with increased PbB78 values in the right temporal lobe, as well as reduced gray matter volume in the frontal lobe. Males displayed reduced white matter volumes associated with increased PbB78 values in the frontal, temporal, and parietal lobes. Comparison of the two primary models revealed a volumetric decrease in the white matter of the left prefrontal cortex associated with increased total psychopathy scores and increased blood lead concentration in males. The results of this study suggested that increased psychopathy scores in this cohort may be attributable to the neuroanatomical abnormalities observed and that childhood lead exposure may be influential to these outcomes.
32. Beebe DW, Powers SW, Slattery EW, Gubanich PJ. Short Sleep and Adolescents' Performance on a Concussion Assessment Battery: An Experimental Sleep Manipulation Study. Clin. J. Sport Med. Jul 2018;28(4):395-397.
OBJECTIVE: Correlational studies have linked short sleep to adolescents' report of postconcussion symptoms and cognitive performance during concussion assessments. This study tested whether those are cause-effect relationships. DESIGN: Three-week randomly counterbalanced, within-subjects, crossover experiment. SETTING: Adolescents slept at home with weekly visits to an outpatient clinic for sleep monitor uploads and outcome assessments. PARTICIPANTS: Twenty-four healthy 14- to 17.9-year-olds. CONDITIONS: After an initial sleep-stabilization period, adolescents experienced 5-night spans of short sleep (SS; 6.5 hours/night in bed) versus Healthy Sleep Opportunity (HS; 9.5 hours/night in bed). MAIN OUTCOME MEASURES: Cognitive indexes and the postconcussion symptom scale (PCSS) from the Immediate PostConcussion Assessment and Cognitive Testing. RESULTS: Adolescents reported significantly worse symptoms on the PCSS after SS than HS, even after excluding items manifestly related to sleep. Verbal memory was also worse after SS than HS, though the effect was small. The manipulation did not significantly affect other cognitive indexes. CONCLUSIONS: A realistic "dose" of short sleep, similar to what many adolescents experience regularly on school nights, can cause or contribute to symptom reports during concussion assessments. Consistent with previous sleep research, one-on-one cognitive tests seem to be less sensitive than measures of emotional and behavioral functioning to the effects of short sleep.
33. Bernardo D, Nariai H, Hussain SA, Sankar R, Salamon N, Krueger DA, Sahin M, Northrup H, Bebin EM, Wu JY, Grp UPE, Grp TS. Visual and semi-automatic non-invasive detection of interictal fast ripples: A potential biomarker of epilepsy in children with tuberous sclerosis complex. Clin. Neurophysiol. Jul 2018;129(7):1458-1466.
Objectives: We aim to establish that interictal fast ripples (FR; 250-500 Hz) are detectable on scalp EEG, and to investigate their association to epilepsy.
Methods: Scalp EEG recordings of a subset of children with tuberous sclerosis complex (TSC)-associated epilepsy from two large multicenter observational TSC studies were analyzed and compared to control children without epilepsy or any other brain-based diagnoses. FR were identified both by human visual review and compared with semi-automated review utilizing a deep learning-based FR detector.
Results: Seven out of 7 children with TSC-associated epilepsy had scalp FR compared to 0 out of 4 children in the control group (p = 0.003). The automatic detector has a sensitivity of 98% and false positive rate with average of 11.2 false positives per minute.
Conclusions: Non-invasive detection of interictal scalp FR was feasible, by both visual and semi-automatic detection. Interictal scalp FR occurred exclusively in children with TSC-associated epilepsy and were absent in controls without epilepsy. The proposed detector achieves high sensitivity of FR detection; however, expert review of the results to reduce false positives is advised.
Significance: Interictal FR are detectable on scalp EEG and may potentially serve as a biomarker of epilepsy in children with TSC. (C) 2018 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.Y.
34. Bettenhausen JL, Auger KA, Colvin JD. The Inpatient Blindside: Comorbid Mental Health Conditions and Readmissions among Hospitalized Children. J. Hosp. Med. Jul 2018;13(7):507-508.
35. Block JP, Bailey LC, Gillman MW, Lunsford D, Boone-Heinonen J, Cleveland LP, Finkelstein J, Horgan CE, Jay M, Reynolds JS, Sturtevant JL, Forrest CB, Group PCACGS. PCORnet Antibiotics and Childhood Growth Study: Process for Cohort Creation and Cohort Description. Acad. Pediatr. Jul 2018;18(5):569-576.
OBJECTIVES: The National Patient-Centered Clinical Research Network (PCORnet) supports observational and clinical research using health care data. The PCORnet Antibiotics and Childhood Growth Study is one of PCORnet's inaugural observational studies. We sought to describe the processes used to integrate and analyze data from children across 35 participating institutions, the cohort characteristics, and prevalence of antibiotic use. METHODS: We included children in the cohort if they had at least one same-day height and weight measured in each of 3 age periods: 1) before 12 months, 2) 12 to 30 months, and 3) after 24 months. We distributed statistical queries that each institution ran on its local version of the PCORnet Common Data Model, with aggregate data returned for analysis. We defined overweight or obesity as age- and sex-specific body mass index >/=85th percentile, obesity >/=95th percentile, and severe obesity >/=120% of the 95th percentile. RESULTS: A total of 681,739 children met the cohort inclusion criteria, and participants were racially/ethnically diverse (24.9% black, 17.5% Hispanic). Before 24 months of age, 55.2% of children received at least one antibiotic prescription; 21.3% received a single antibiotic prescription; 14.3% received 4 or more; and 33.3% received a broad-spectrum antibiotic. Overweight and obesity prevalence was 27.6% at age 4 to <6 years (n = 362,044) and 36.2% at 9 to <11 years (n = 58,344). CONCLUSIONS: The PCORnet Antibiotics and Childhood Growth Study is a large national longitudinal observational study in a diverse population that will examine the relationship between early antibiotic use and subsequent growth patterns in children.
36. Brewington JJ, Filbrandt ET, LaRosa FJ, 3rd, Moncivaiz JD, Ostmann AJ, Strecker LM, Clancy JP. Brushed nasal epithelial cells are a surrogate for bronchial epithelial CFTR studies. JCI Insight. Jul 12 2018;3(13).
Recent advances in the management of cystic fibrosis (CF) target underlying defects in the CF transmembrane conductance regulator (CFTR) protein, but efficacy analyses remain limited to specific genotype-based subgroups. Patient-derived model systems may therefore aid in expanding access to these drugs. Brushed human nasal epithelial cells (HNEs) are an attractive tissue source, but it remains unclear how faithfully they recapitulate human bronchial epithelial cell (HBE) CFTR activity. We examined this gap using paired, brushed HNE/HBE samples from pediatric CF subjects with a wide variety of CFTR mutations cultured at the air-liquid interface. Growth and structural characteristics for the two cell types were similar, including differentiation into mature respiratory epithelia. In electrophysiologic analysis, no correlation was identified between nasal and bronchial cultures in baseline resistance or epithelial sodium channel (ENaC) activity. Conversely, robust correlation was demonstrated between nasal and bronchial cultures in both stimulated and inhibited CFTR activity. There was close correlation in modulator-induced change in CFTR activity, and CFTR activity in both cell types correlated with in vivo sweat chloride measurements. These data confirm that brushed HNE cell cultures recapitulate the functional CFTR characteristics of HBEs with fidelity and are therefore an appropriate noninvasive HBE surrogate for individualized CFTR analysis.
37. Brody MJ, Vanhoutte D, Schips TG, Boyer JG, Bakshi CV, Sargent MA, York AJ, Molkentin JD. Defective Flux of Thrombospondin-4 through the Secretory Pathway Impairs Cardiomyocyte Membrane Stability and Causes Cardiomyopathy. Mol. Cell. Biol. Jul 2018;38(14).
Thrombospondins are stress-inducible secreted glycoproteins with critical functions in tissue injury and healing. Thrombospondin-4 (Thbs4) is protective in cardiac and skeletal muscle, where it activates an adaptive endoplasmic reticulum (ER) stress response, induces expansion of the ER, and enhances sarcolemmal stability. However, it is unclear if Thbs4 has these protective functions from within the cell, from the extracellular matrix, or from the secretion process itself. In this study, we generated transgenic mice with cardiac cell-specific overexpression of a secretion-defective mutant of Thbs4 to evaluate its exclusive intracellular and secretion-dependent functions. Like wild-type Thbs4, the secretion-defective mutant upregulates the adaptive ER stress response and expands the ER and intracellular vesicles in cardiomyocytes. However, only the secretion-defective Thbs4 mutant produces cardiomyopathy with sarcolemmal weakness and rupture that is associated with reduced adhesion-forming glycoproteins in the membrane. Similarly, deletion of Thbs4 in the mdx mouse model of Duchenne muscular dystrophy enhances cardiomyocyte membrane instability and cardiomyopathy. Finally, overexpression of the secretion-defective Thbs4 mutant in Drosophila, but not wild-type Thbs4, impaired muscle function and sarcomere alignment. These results suggest that transit through the secretory pathway is required for Thbs4 to augment sarcolemmal stability, while ER stress induction and vesicular expansion mediated by Thbs4 are exclusively intracellular processes.
38. Broomall E, Taylor JM, Peariso K. A 2-Year-Old Boy With Difficulty Waking After Bone Marrow Transplantation. Semin. Pediatr. Neurol. Jul 2018;26:120-123.
We report a 2-year-old boy who was evaluated for difficult waking during prolonged intensive care unit admission associated with bone marrow transplant for Wiskott-Aldrich syndrome. Neurologic examination was found to be abnormal, with nuchal rigidity initially, then decreased extremity movement and areflexia developing over several days. Electromyogram showed length-dependent, axonal, sensorimotor polyneuropathy. Cerebrospinal fluid showed albuminocytologic dissociation suggestive of Guillain-Barre syndrome or acute motor and sensory axonal neuropathy variant. The patient was treated with immunotherapy and slowly showed signs of motor recovery over several months. A review of Wiskott-Aldrich syndrome, Guillain-Barre syndrome, immune-mediated complications of bone marrow transplantation, and acute weakness in the intensive care unit is provided in this case report.
39. Brunner HI, Rider LG, Kingsbury DJ, Co D, Schneider R, Goldmuntz E, Onel KB, Giannini EH, Lovell DJ, Council PA. Pediatric Rheumatology Collaborative Study Group - over four decades of pivotal clinical drug research in pediatric rheumatology. Pediatr. Rheumatol. Online J. Jul 11 2018;16(1):45.
IMPORTANCE: Specialized research networks are essential to achieve drug approvals for rare pediatric diseases. Such networks help realize the potential of global legislation enacted upon the recognition that most children are treated with drugs whose most beneficial dose and regimen have not been established in pediatric patients. The Pediatric Rheumatology Collaborative Study Group (PRCSG) is a North American clinical trials network that is specialized in the performance of clinical trials of new therapies for pediatric populations with rheumatic diseases. This review provides an overview of the strategies employed by this research network to achieve drug and biologic approvals for children with pediatric rheumatic diseases, particularly juvenile idiopathic arthritis. OBSERVATIONS: Clinical trial conduct in rare pediatric diseases has required global recruitment. Supported or led by the PRCSG, highly responsive, validated, composite measures have been established to assess drug efficacy. For pediatric orphan diseases with high disease burdens, specialized investigative sites and study designs are needed to complete adequately powered trials at the high standard necessary to enable drug labeling by regulatory agencies. Novel trial designs have been utilized for more efficient testing of innovative drug candidates. All these have been developed or co-developed by the PRCSG research network. CONCLUSIONS AND RELEVANCE: Specialized research networks in pediatric rheumatology, such as the PRCSG, have changed the landscape of available therapies and improved overall disease outcomes for children with pediatric rheumatic diseases.
40. Brunner HI, Tzaribachev N, Vega-Cornejo G, Louw I, Berman A, Penades IC, Anton J, Avila-Zapata F, Cuttica R, Horneff G, Foeldvari I, Keltsev V, Kingsbury DJ, Viola DO, Joos R, Lauwerys B, Gastanaga MEP, Rama ME, Wouters C, Bohnsack J, Breedt J, Fischbach M, Lutz T, Minden K, Mirava T, Ally MMTM, Rubio-Perez N, Gervais ES, Van Zyl R, Li XH, Nys M, Wong R, Banerjee S, Lovell DJ, Martini A, Ruperto N, Or PRIT, Collaborative PR. Subcutaneous Abatacept in Patients With Polyarticular-Course Juvenile Idiopathic Arthritis Results From a Phase III Open-Label Study. Arthritis & Rheumatology. Jul 2018;70(7):1144-1154.
Objective. To investigate the pharmacokinetics, effectiveness, and safety of subcutaneous (SC) abatacept treatment over 24 months in patients with polyarticular-course juvenile idiopathic arthritis (JIA).
Methods. In this phase III, open-label, international, multicenter, single-arm study, patients with polyarticular JIA (cohort 1, ages 6-17 years and cohort 2, ages 2-5 years) in whom treatment with >= 1 disease-modifying antirheumatic drug was unsuccessful received weight-tiered SC abatacept weekly: 10 to <25 kg (50 mg), 25 to >= 50 kg (87.5 mg), 50 kg (125 mg). Patients who had met the JIA-American College of Rheumatology 30% improvement criteria (achieved a JIA-ACR 30 response) at month 4 were given the option to continue SC abatacept to month 24. The primary end point was the abatacept steady-state serum trough concentration (C-minss) in cohort 1 at month 4. Other outcome measures included JIA-ACR 30, 50, 70, 90, 100, and inactive disease status, the median Juvenile Arthritis Disease Activity Score in 71 joints using the C-reactive protein level (JADAS-71-CRP) over time, safety, and immunogenicity.
Results. The median abatacept C-minss at month 4 (primary end point) and at month 24 was above the target therapeutic exposure (10 g/ml) in both cohorts. The percentage of patients who had achieved JIA-ACR 30, 50, 70, 90, or 100 responses or had inactive disease responses at month 4 (intent-to-treat population) was 83.2%, 72.8%, 52.6%, 28.3%, 14.5%, and 30.1%, respectively, in cohort 1 (n=173) and 89.1%, 84.8%, 73.9%, 58.7%, 41.3%, and 50.0%, respectively, in cohort 2 (n= 46); the responses were maintained to month 24. The median (interquartile range) JADAS-71-CRP improved from baseline to month 4: cohort 1, from 21.0 (13.5, 30.3) to 4.6 (2.1, 9.4); cohort 2, from 18.1 (14.0, 23.1) to 2.1 (0.3, 4.4). Improvements were sustained to month 24, at which time 27 of 173 patients (cohort 1) and 11 of 22 patients (cohort 2) had achieved JADAS-71-CRP remission. No unexpected adverse events were reported; 4 of 172 patients (2.3%) in cohort 1 and 4 of 46 (8.7%) in cohort 2 developed anti-abatacept antibodies, with no clinical effects.
Conclusion. Weight-stratified SC abatacept yielded target therapeutic exposures across age and weight groups, was well tolerated, and improved polyarticular JIA symptoms over 24 months.
41. Chen Y, Wu D, Dong M, Zhu Y, Lu J, Li X, Chen C, Li Z. Population pharmacokinetics of vancomycin and AUC-guided dosing in Chinese neonates and young infants. Eur. J. Clin. Pharmacol. Jul 2018;74(7):921-930.
OBJECTIVES: To develop a population pharmacokinetic (PK) model for vancomycin in Chinese neonates and infants less than 2 months of age (young infants) with a wide gestational age range, in order to determine the appropriate dosing regimen for this population. METHODS: We performed a retrospective chart review of patients from the neonatal intensive care unit (NICU) at Children's Hospital of Fudan University to identify neonates and young infants treated with vancomycin from May 2014 to May 2017. Vancomycin concentrations and covariates were utilized to develop a one-compartment model with first-order elimination. The predictive performance of the final model was assessed by both internal and external evaluation, and the relationship between trough concentration and AUC0-24 was investigated. Monte Carlo simulations were performed to design an initial dosing schedule targeting an AUC0-24 >/= 400. RESULTS: The analysis included a total of 330 concentration-time data points from 213 neonates and young infants with gestational age (GA) and body weight of 25-42 weeks and 0.88-5.1 kg, respectively. Body weight, postmenstrual age (PMA) and serum creatinine level were found to be important factors explaining the between-subject variability in vancomycin PK parameters for this population. Both internal and external evaluation supported the prediction of the final vancomycin PK model. The typical population parameter estimates of clearance and distribution volume for an infant weighing 2.73 kg with a PMA of 39.8 weeks and serum creatinine of 0.28 mg/dL were 0.103 L/h/kg and 0.58 L/kg, respectively. Although vancomycin serum trough concentrations were predictive of the AUC, considerable variability was observed in the achievement of an AUC0-24/MIC of >/=400. For MIC values of </=0.5 mg/L, AUC0-24/MIC >/=400 was achieved for 95% of the newborn infants with vancomycin troughs of 5-10 mg/L. When the MIC increased to 1 mg/L, only 15% of the patients with troughs of 5-10 mg/L achieved AUC0-24/MIC >/=400. For MIC values of 2 mg/L, no infants achieved the target. Simulations predicted that a dose of at least 14 and 15 mg/kg every 12 h was required to attain the target AUC0-24 >/= 400 in 90% of infants with a PMA of 30-32 and 32-34 weeks, respectively. This target was also achieved in 93% of simulated infants in the oldest PMA groups (36-38 and 38-40 weeks, respectively) when the dosing interval was extended to 8 h. For infants with a PMA >/=44 weeks, a dose increase to 18 mg/kg every 8 h was needed. The trough concentrations of 5-15 mg/L were highly predictive of an AUC0-24 of >/=400 when treating invasive MRSA infections with an MIC of </=1 mg/L. CONCLUSIONS: The PK parameters for vancomycin in Chinese infants younger than 2 months of age were estimated using the model developed herein. This model has been used to predict individualized dosing regimens in this vulnerable population in our hospital. A large external evaluation of our model will be conducted in future studies.
42. Chhipa RR, Fan Q, Anderson J, Muraleedharan R, Huang Y, Ciraolo G, Chen X, Waclaw R, Chow LM, Khuchua Z, Kofron M, Weirauch MT, Kendler A, McPherson C, Ratner N, Nakano I, Dasgupta N, Komurov K, Dasgupta B. AMP kinase promotes glioblastoma bioenergetics and tumour growth. Nat. Cell Biol. Jul 2018;20(7):823-835.
Stress is integral to tumour evolution, and cancer cell survival depends on stress management. We found that cancer-associated stress chronically activates the bioenergetic sensor AMP kinase (AMPK) and, to survive, tumour cells hijack an AMPK-regulated stress response pathway conserved in normal cells. Analysis of The Cancer Genome Atlas data revealed that AMPK isoforms are highly expressed in the lethal human cancer glioblastoma (GBM). We show that AMPK inhibition reduces viability of patient-derived GBM stem cells (GSCs) and tumours. In stressed (exercised) skeletal muscle, AMPK is activated to cooperate with CREB1 (cAMP response element binding protein-1) and promote glucose metabolism. We demonstrate that oncogenic stress chronically activates AMPK in GSCs that coopt the AMPK-CREB1 pathway to coordinate tumour bioenergetics through the transcription factors HIF1alpha and GABPA. Finally, we show that adult mice tolerate systemic deletion of AMPK, supporting the use of AMPK pharmacological inhibitors in the treatment of GBM.
43. Chiang SCC, Vergamini SM, Husami A, Neumeier L, Quinn K, Ellerhorst T, Sheppard L, Gifford C, Buchbinder D, Joshi A, Ifversen M, Kleiner GI, Bussel JB, Chandrakasan S, Pesek RD, Pozos TC, Rose MJ, Scurlock AM, Zhang K, Bryceson YT, Bleesing J, Marsh RA. Screening for Wiskott-Aldrich syndrome by flow cytometry. J. Allergy Clin. Immunol. Jul 2018;142(1):333-335 e338.
44. Chonat S, McLemore ML, Bunting ST, Nortman S, Zhang K, Kalfa TA. Congenital dyserythropoietic anaemia type I diagnosed in a young adult with a history of splenectomy in childhood for presumed haemolytic anaemia. Br. J. Haematol. Jul 2018;182(1):10.
45. Cooke AL, Morris J, Melchior JT, Street SE, Jerome WG, Huang R, Herr AB, Smith LE, Segrest JP, Remaley AT, Shah AS, Thompson TB, Davidson WS. A thumbwheel mechanism for APOA1 activation of LCAT activity in HDL. J. Lipid Res. Jul 2018;59(7):1244-1255.
APOA1 is the most abundant protein in HDL. It modulates interactions that affect HDL's cardioprotective functions, in part via its activation of the enzyme, LCAT. On nascent discoidal HDL, APOA1 comprises 10 alpha-helical repeats arranged in an anti-parallel stacked-ring structure that encapsulates a lipid bilayer. Previous chemical cross-linking studies suggested that these APOA1 rings can adopt at least two different orientations, or registries, with respect to each other; however, the functional impact of these structural changes is unknown. Here, we placed cysteine residues at locations predicted to form disulfide bonds in each orientation and then measured APOA1's ability to adopt the two registries during HDL particle formation. We found that most APOA1 oriented with the fifth helix of one molecule across from fifth helix of the other (5/5 helical registry), but a fraction adopted a 5/2 registry. Engineered HDLs that were locked in 5/5 or 5/2 registries by disulfide bonds equally promoted cholesterol efflux from macrophages, indicating functional particles. However, unlike the 5/5 registry or the WT, the 5/2 registry impaired LCAT cholesteryl esterification activity (P < 0.001), despite LCAT binding equally to all particles. Chemical cross-linking studies suggest that full LCAT activity requires a hybrid epitope composed of helices 5-7 on one APOA1 molecule and helices 3-4 on the other. Thus, APOA1 may use a reciprocating thumbwheel-like mechanism to activate HDL-remodeling proteins.
46. Dasgupta R, Renaud E, Goldin AB, Baird R, Cameron DB, Arnold MA, Diefenbach KA, Gosain A, Grabowski J, Guner YS, Jancelewicz T, Kawaguchi A, Lal DR, Oyetunji TA, Ricca RL, Shelton J, Somme S, Williams RF, Downard CD. Ovarian torsion in pediatric and adolescent patients: A systematic review. J. Pediatr. Surg. Jul 2018;53(7):1387-1391.
OBJECTIVE: Ovarian torsion in pediatric patients is a rare event and is primarily managed by pediatric general surgeons. Torsion can be treated with detorsion of the ovary or oopherectomy. Oopherectomy is the most common procedure performed by pediatric general surgeons for ovarian torsion. The purpose of this systematic review by the American Pediatric Surgical Association Outcomes and Evidence Based Practice Committee was to examine evidence from the medical literature and provide recommendations regarding the optimal treatment of ovarian torsion. METHODS: Using PRISMA guidelines, six questions were addressed by searching Medline, Cochrane, Embase Central and National clearing house databases using relevant search terms. Risks of ovarian detorsion including thromboembolism and malignancy, indications for oophoropexy, benefits of detorsion including recovery of function and subsequent fertility, and recommended surveillance after detorsion were evaluated. Consensus recommendations were derived for each question based on the best available evidence. RESULTS: Ninety-six studies were included. Risks of ovarian detorsion such as thromboembolism and malignancy were reviewed, demonstrating minimal evidence for unknowingly leaving a malignancy behind in the salvaged ovary and no evidence in the literature of thromboembolic events after detorsion of a torsed ovary. There is no clear evidence supporting the benefit of oophoropexy after a single episode of ovarian torsion. The gross appearance of the ovary does not correlate with long-term ovarian viability or function. Pregnancies have occurred in patients after detorsion of an ovary both spontaneously and with harvested oocytes from previously torsed ovaries. The consensus recommendation for imaging surveillance following ovarian detorsion is an ultrasound at 3months postprocedure but sooner if there is a concern for malignancy. CONCLUSION: There appears to be overwhelming evidence supporting ovarian detorsion rather than oopherectomy for the management of ovarian torsion in pediatric patients. Ovarian salvage is safe and is the preferred treatment for ovarian torsion. Most salvaged ovaries will maintain viability after detorsion. TYPE OF STUDY: Systematic review of level 3-4 studies. LEVEL OF EVIDENCE: 3-4.
47. Dillman JR, Towbin AJ, Imbus R, Young J, Gates E, Trout AT. Comparison of Two Neutral Oral Contrast Agents in Pediatric Patients: A Prospective Randomized Study. Radiology. Jul 2018;288(1):245-251.
Purpose To prospectively compare small bowel distention provided by, as well as patient acceptance of, two different neutral (negative) oral contrast materials used for cross-sectional enterography in a pediatric population. Materials and Methods In this noninferiority study, 66 pediatric patients undergoing clinical computed tomographic (CT) or magnetic resonance (MR) enterography were randomized to receive either a flavored beverage for neutral abdominal and pelvic imaging (Breeza; Beekley Medical, Bristol, Conn) or a low-density barium sulfate suspension. Patients were blinded to the oral contrast material administered and were asked to rate taste, texture, and their perceived health state (where 0 was very bad and 10 was very good). Ingested volume of the prescribed weight-based oral contrast material preparation was recorded. Maximum small bowel diameter was measured in all four abdominal quadrants. Mean bowel diameter as well as taste, texture, and health state scores were compared between cohorts by using t tests; proportions were compared by using Fisher exact tests. Results Thirty-three patients each received Breeza and barium sulfate suspension, respectively. No difference was found in age (Breeza, 13.5 years +/- 2.6 [standard deviation]; barium sulfate suspension, 13.9 years +/- 2.8; P = .49), sex distribution (15 girls each; P > .99), or health state (P = .21) between cohorts. Twenty-eight of 33 (84.8%) and 17 of 33 (51.5%) patients completed the Breeza and barium sulfate suspension preparations, respectively (P = .007). Breeza received higher scores for taste (6.1 +/- 2.5 vs 2.7 +/- 2.5; P < .0001) and texture (7.3 +/- 2.3 vs 3.6 +/- 2.9; P < .0001). No difference was found in bowel distention between Breeza and barium sulfate suspension (1.63 cm +/- 0.24 vs 1.69 cm +/- 0.25; P = .44). Conclusion The neutral oral contrast materials Breeza and low-density barium sulfate suspension provide similar small bowel distention. Patients receiving Breeza are more likely to ingest the entire prescribed volume.
48. Dimopoulos K, Diller GP, Opotowsky AR, D'Alto M, Gu H, Giannakoulas G, Budts W, Broberg CS, Veldtman G, Swan L, Beghetti M, Gatzoulis MA. Definition and Management of Segmental Pulmonary Hypertension. J Am Heart Assoc. Jul 4 2018;7(14).
49. Dong F, Jin X, Boettler MA, Sciulli H, Abu-Asab M, Del Greco C, Wang S, Hu YC, Campos MM, Jackson SN, Muller L, Woods AS, Combs CA, Zhang J, Nickerson ML, Kruth HS, Weiss JS, Kao WW. A Mouse Model of Schnyder Corneal Dystrophy with the N100S Point Mutation. Sci. Rep. Jul 5 2018;8(1):10219.
Schnyder corneal dystrophy (SCD) is a rare autosomal dominant disease in humans, characterized by abnormal deposition of cholesterol and phospholipids in cornea caused by mutations in the UbiA prenyltransferase domain containing 1 (UBIAD1) gene. In this study, we generated a mouse line carrying Ubiad1 N100S point mutation using the CRISPR/Cas9 technique to investigate the pathogenesis of SCD. In vivo confocal microscopy revealed hyper-reflective dot-like deposits in the anterior cornea in heterozygotes and homozygotes. No significant change was found in corneal epithelial barrier function or wound healing. Electron microscopy revealed abnormal mitochondrial morphology in corneal epithelial, stromal, and endothelial cells. Mitochondrial DNA copy number assay showed 1.27 +/- 0.07 fold change in homozygotes versus 0.98 +/- 0.05 variation in wild type mice (P < 0.05). Lipidomic analysis indicated abnormal metabolism of glycerophosphoglycerols, a lipid class found in mitochondria. Four (34:1, 34:2, 36:2, and 44:8) of the 11 glycerophosphoglycerols species identified by mass spectrometry showed a significant increase in homozygous corneas compared with heterozygous and wild-type mouse corneas. Unexpectedly, we did not find a difference in the corneal cholesterol level between different genotypes by filipin staining or lipidomic analysis. The Ubiad1(N100S) mouse provides a promising animal model of SCD revealing that mitochondrial dysfunction is a prominent component of the disease. The different phenotype in human and mouse may due to difference in cholesterol metabolism between species.
50. Dong M, McGann PT, Mizuno T, Ware RE, Vinks AA. Model-based dosing with concentration feedback as an integral part of personalized hydroxycarbamide management. Br. J. Clin. Pharmacol. Jul 2018;84(7):1410-1412.
51. D'Souza AM, Shah R, Gupta A, Towbin AJ, Alonso M, Nathan JD, Bondoc A, Tiao G, Geller JI. Surgical management of children and adolescents with upfront completely resected hepatocellular carcinoma. Pediatr. Blood Cancer. Jul 3 2018:e27293.
BACKGROUND: Hepatocellular carcinoma (HCC) is an aggressive malignant neoplasm that is often chemoresistant. Complete surgical resection remains the mainstay of therapy. The role of liver transplantation (LT) in pediatric HCC is in evolution, as is the role of adjuvant chemotherapy for stage I disease. METHODS: A retrospective review of patients < 18 years of age with completely resected HCC treated with surgical intervention alone at our institution from 2004 to 2015 was conducted. RESULTS: Twelve patients with a median age of 12 years (range = 1-17; number of females = 7) with upfront resected HCC (Evans stage I) were identified. Four patients had HCC without identifiable risk factors (fibrolamellar-HCC = 2; early HCC arising in focal nodular hyperplasia = 1, well-differentiated [wd] HCC = 1). Four patients had early or wd-HCC in the context of portosystemic shunts (Abernethy = 2; mesocaval shunt and portal vein thrombosis = 2). Four patients had moderate to wd-HCC in the context of pre-existing liver disease with cirrhosis (progressive familial intrahepatic cholestasis type-2 = 2, alpha-1 antitrypsin deficiency = 1, Alagille syndrome = 1). Seven patients underwent LT (multifocal = 5; solitary = 2); five exceeded Milan criteria (MC) by imaging. Five patients underwent complete resection (segmentectomy = 2; hemihepatectomy = 3). Ten patients received no adjuvant chemotherapy. All patients are alive without evidence of disease with a median follow-up of 54.1 months (range = 28.1-157.7 months). CONCLUSIONS: Pediatric and adolescent patients with upfront, completely resected HCC can be effectively treated without chemotherapy. LT should be considered for nonmetastatic HCC, especially in the context of pre-existing chronic liver disease, even when the tumor exceeds MC. Distinct pediatric selection criteria are needed to identify patients most suitable for LT.
52. Dvorak CC, Satwani P, Stieglitz E, Cairo MS, Dang H, Pei Q, Gao Y, Wall D, Mazor T, Olshen AB, Parker JS, Kahwash S, Hirsch B, Raimondi S, Patel N, Skeens M, Cooper T, Mehta PA, Grupp SA, Loh ML. Disease burden and conditioning regimens in ASCT1221, a randomized phase II trial in children with juvenile myelomonocytic leukemia: A Children's Oncology Group study. Pediatr. Blood Cancer. Jul 2018;65(7):e27034.
BACKGROUND: Most patients with juvenile myelomonocytic leukemia (JMML) are curable only with allogeneic hematopoietic cell transplantation (HCT). However, the current standard conditioning regimen, busulfan-cyclophosphamide-melphalan (Bu-Cy-Mel), may be associated with higher risks of morbidity and mortality. ASCT1221 was designed to test whether the potentially less-toxic myeloablative conditioning regimen containing busulfan-fludarabine (Bu-Flu) would be associated with equivalent outcomes. PROCEDURE: Twenty-seven patients were enrolled on ASCT1221 from 2013 to 2015. Pre- and post-HCT (starting Day +30) mutant allele burden was measured in all and pre-HCT therapy was administered according to physician discretion. RESULTS: Fifteen patients were randomized (six to Bu-Cy-Mel and nine to Bu-Flu) after meeting diagnostic criteria for JMML. Pre-HCT low-dose chemotherapy did not appear to reduce pre-HCT disease burden. Two patients, however, received aggressive chemotherapy pre-HCT and achieved low disease-burden state; both are long-term survivors. All four patients with detectable mutant allele burden at Day +30 post-HCT eventually progressed compared to two of nine patients with unmeasurable allele burden (P = 0.04). The 18-month event-free survival of the entire cohort was 47% (95% CI, 21-69%), and was 83% (95% CI, 27-97%) and 22% (95% CI, 03-51%) for Bu-Cy-Mel and Bu-Flu, respectively (P = 0.04). ASCT1221 was terminated early due to concerns that the Bu-Flu arm had inferior outcomes. CONCLUSIONS: The regimen of Bu-Flu is inadequate to provide disease control in patients with JMML who present to HCT with large burdens of disease. Advances in molecular testing may allow better characterization of biologic risk, pre-HCT responses to chemotherapy, and post-HCT management.
53. Elmi-Terander A, Nachabe R, Skulason H, Pedersen K, Soderman M, Racadio J, Babic D, Gerdhem P, Edstrom E. Feasibility and Accuracy of Thoracolumbar Minimally Invasive Pedicle Screw Placement With Augmented Reality Navigation Technology. Spine (Phila Pa 1976). Jul 15 2018;43(14):1018-1023.
STUDY DESIGN: Cadaveric laboratory study. OBJECTIVE: To assess the feasibility and accuracy of minimally invasive thoracolumbar pedicle screw placement using augmented reality (AR) surgical navigation. SUMMARY OF BACKGROUND DATA: Minimally invasive spine (MIS) surgery has increasingly become the method of choice for a wide variety of spine pathologies. Navigation technology based on AR has been shown to be feasible, accurate, and safe in open procedures. AR technology may also be used for MIS surgery. METHODS: The AR surgical navigation was installed in a hybrid operating room (OR). The hybrid OR includes a surgical table, a motorized flat detector C-arm with intraoperative 2D/3D imaging capabilities, integrated optical cameras for AR navigation, and patient motion tracking using optical markers on the skin. Navigation and screw placement was without any x-ray guidance. Two neurosurgeons placed 66 Jamshidi needles (two cadavers) and 18 cannulated pedicle screws (one cadaver) in the thoracolumbar spine. Technical accuracy was evaluated by measuring the distance between the tip of the actual needle position and the corresponding planned path as well as the angles between the needle and the desired path. Time needed for navigation along the virtual planned path was measured. An independent reviewer assessed the postoperative scans for the pedicle screws' clinical accuracy. RESULTS: Navigation time per insertion was 90 +/- 53 seconds with an accuracy of 2.2 +/- 1.3 mm. Accuracy was not dependent on operator. There was no correlation between navigation time and accuracy. The mean error angle between the Jamshidi needles and planned paths was 0.9 degrees +/- 0.8 degrees . No screw was misplaced outside the pedicle. Two screws breached 2 to 4 mm yielding an overall accuracy of 89% (16/18). CONCLUSION: MIS screw placement directed by AR with intraoperative 3D imaging in a hybrid OR is accurate and efficient, without any fluoroscopy or x-ray imaging during the procedure. LEVEL OF EVIDENCE: N/A.
54. Foster BJ, Pai ALH, Zelikovsky N, Amaral S, Bell L, Dharnidharka VR, Hebert D, Holly C, Knauper B, Matsell D, Phan V, Rogers R, Smith JM, Zhao H, Furth SL. A Randomized Trial of a Multicomponent Intervention to Promote Medication Adherence: The Teen Adherence in Kidney Transplant Effectiveness of Intervention Trial (TAKE-IT). Am. J. Kidney Dis. Jul 2018;72(1):30-41.
BACKGROUND: Poor adherence to immunosuppressive medications is a major cause of premature graft loss among children and young adults. Multicomponent interventions have shown promise but have not been fully evaluated. STUDY DESIGN: Unblinded parallel-arm randomized trial to assess the efficacy of a clinic-based adherence-promoting intervention. SETTING & PARTICIPANTS: Prevalent kidney transplant recipients 11 to 24 years of age and 3 or more months posttransplantation at 8 kidney transplantation centers in Canada and the United States (February 2012 to May 2016) were included. INTERVENTION: Adherence was electronically monitored in all participants during a 3-month run-in, followed by a 12-month intervention. Participants assigned to the TAKE-IT intervention could choose to receive text message, e-mail, and/or visual cue dose reminders and met with a coach at 3-month intervals when adherence data from the prior 3 months were reviewed with the participant. "Action-Focused Problem Solving" was used to address adherence barriers selected as important by the participant. Participants assigned to the control group met with coaches at 3-month intervals but received no feedback about adherence data. OUTCOMES: The primary outcomes were electronically measured "taking" adherence (the proportion of prescribed doses of immunosuppressive medications taken) and "timing" adherence (the proportion of doses of immunosuppressive medications taken between 1 hour before and 2 hours after the prescribed time of administration) on each day of observation. Secondary outcomes included the standard deviation of tacrolimus trough concentrations, self-reported adherence, acute rejection, and graft failure. RESULTS: 81 patients were assigned to intervention (median age, 15.5 years; 57% male) and 88 to the control group (median age, 15.8 years; 61% male). Electronic adherence data were available for 64 intervention and 74 control participants. Participants in the intervention group had significantly greater odds of taking prescribed medications (OR, 1.66; 95% CI, 1.15-2.39) and taking medications at or near the prescribed time (OR, 1.74; 95% CI, 1.21-2.50) than controls. LIMITATIONS: Lack of electronic adherence data for some participants may have introduced bias. There was low statistical power for clinical outcomes. CONCLUSIONS: The multicomponent TAKE-IT intervention resulted in significantly better medication adherence than the control condition. Better medication adherence may result in improved graft outcomes, but this will need to be demonstrated in larger studies. TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT01356277.
55. Fulkerson PC. Siglec-8 on murine eosinophils: A new model for an old target. J. Leukoc. Biol. Jul 2018;104(1):7-9.
56. Giambra BK, Mangeot C, Benscoter DT, Britto MT. Identification of hospitalized tracheostomy and ventilator dependent patients in administrative data. Pediatr. Pulmonol. Jul 2018;53(7):973-978.
BACKGROUND: Patients with established tracheostomy and ventilator dependence are hospitalized more frequently and use more healthcare resources than other patients with complex chronic conditions. However, data to compare variation in hospitalization and resource use among patients in this population across the United States is deficient, partly due to the lack of structured methods to query national databases. AIM: Determine the best method for identifying the subset of children with established tracheostomy and ventilator dependence in Pediatric Health Information System (PHIS). HYPOTHESIS: A combination of identifiable characteristics coded in the PHIS database can be used to identify the population of patients with established tracheostomy and ventilator dependence who are admitted to the hospital. METHODS: This cross-sectional, retrospective cohort study used established methods to extract data from PHIS and assessed the sensitivity and specificity of an algorithm to identify patients with established tracheostomy and ventilator dependence as compared with a local registry of ventilator dependent patients. RESULTS: A newly created algorithm identified >90% of the 157 patients with established tracheostomy and ventilator dependence hospitalized at our organization during 2014. The sensitivity and specificity of the algorithm to identify these patients was 91% and 99%, respectively. CONCLUSIONS: This new algorithm can be used to reliably identify and further study healthcare utilization by this population of patients with established tracheostomy and ventilator dependence. In addition, future work can determine the applicability of this algorithm to other administrative datasets.
57. Glenn IC, Abdulhai S, McNinch NL, Lally PA, Ponsky TA, Schlager A, Congenital Diaphragmatic Hernia Study G. Evaluating the utility of the "late ECMO repair": a congenital diaphragmatic hernia study group investigation. Pediatr. Surg. Int. Jul 2018;34(7):721-726.
PURPOSE: Optimal timing of congenital diaphragmatic hernia (CDH) repair in patients requiring extracorporeal membrane oxygenation (ECMO) remains controversial. The "late ECMO repair" is an approach where the patient, once deemed stable for decannulation, is repaired while still on ECMO to enable expeditious return to ECMO if surgery induces instability. The goal of this study was to investigate the potential benefit of this approach by evaluating the rate of return to ECMO after repair. METHODS: The CDH Study Group database was used to analyze CDH patients requiring ECMO support. The primary outcome was return to ECMO within 72 h of CDH repair among those repaired following ECMO decannulation ("post-ECMO" patients). Secondary outcomes were death within 72 h of repair and cumulative death and return to ECMO rate. RESULTS: A total of 668 patients were repaired post-ECMO decannulation. Six patients (0.9%) in the post-ECMO group required return to ECMO within 72 h of surgery and a total of 19 (2.8%) died or returned to ECMO within 72 h of surgery. CONCLUSION: The rate of return to ECMO and death following CDH repair is extremely low and does not justify the risks inherent to "on-ECMO" repair. Patients stable to come off ECMO should undergo repair after decannulation.
58. Goldberg DJ, Zak V, Goldstein BH, McCrindle BW, Menon SC, Schumacher KR, Payne RM, Rhodes J, McHugh KE, Penny DJ, Trachtenberg F, Hamstra MS, Richmond ME, Frommelt PC, Files MD, Yeager JL, Pemberton VL, Stylianou MP, Pearson GD, Paridon SM, Pediatric Heart Network I. Design and rationale of the Fontan Udenafil Exercise Longitudinal (FUEL) trial. Am. Heart J. Jul 2018;201:1-8.
The Fontan operation creates a circulation characterized by elevated central venous pressure and low cardiac output. Over time, these characteristics result in a predictable and persistent decline in exercise performance that is associated with an increase in morbidity and mortality. A medical therapy that targets the abnormalities of the Fontan circulation might, therefore, be associated with improved outcomes. Udenafil, a phosphodiesterase type 5 inhibitor, has undergone phase I/II testing in adolescents who have had the Fontan operation and has been shown to be safe and well tolerated in the short term. However, there are no data regarding the long-term efficacy of udenafil in this population. The Fontan Udenafil Exercise Longitudinal (FUEL) Trial is a randomized, double-blind, placebo-controlled phase III clinical trial being conducted by the Pediatric Heart Network in collaboration with Mezzion Pharma Co, Ltd. This trial is designed to test the hypothesis that treatment with udenafil will lead to an improvement in exercise capacity in adolescents who have undergone the Fontan operation. A safety extension trial, the FUEL Open-Label Extension Trial (FUEL OLE), offers the opportunity for all FUEL subjects to obtain open-label udenafil for an additional 12 months following completion of FUEL, and evaluates the long-term safety and tolerability of this medication. This manuscript describes the rationale and study design for FUEL and FUEL OLE. Together, these trials provide an opportunity to better understand the role of medical management in the care of those who have undergone the Fontan operation.
59. Goyal NK, Folger AT, Sucharew HJ, Brown CM, Hall ES, Van Ginkel JB, Ammerman RT. Primary Care and Home Visiting Utilization Patterns among At-Risk Infants. J. Pediatr. Jul 2018;198:240-+.
Objective To describe well child care (WCC) utilization in the first year of life among at-risk infants, and the relationship to home visiting enrollment.
Study design Retrospective cohort study using linked administrative data for infants >= 34 weeks' gestation from 2010 to 2014, within a regional. academic primary care system. Association between WCC visits and home visiting enrollment was evaluated using bivariate comparisons and multivariable Poisson regression. Latent class analysis further characterized longitudinal patterns of WCC attendance. Multivariable logistic regression tested the association between home visiting and pattern of timeliest adherence to recommended WCC.
Results Of 11 936 infants, mean number of WCC visits was 4.1 in the first 12 months of life. Of 3910 infants eligible for home visiting, 28.5% were enrolled. Among enrolled infants, mean WCC visits was 4.7 vs 4.4 among eligible, nonenrolled infants, P value < .001. After multivariable adjustment, there was no significant association between enrollment and WCC visit count (adjusted incident rate ratio 1.03, 95% CI 0.99, 1.07). Using latent class analysis. 3 WCC classes were identified: infants in class 1 (77.7%) were most adherent to recommended WCC, class 2 (12.5% of cohort) had progressively declining WCC attendance over the first year of life, and class 3 (9.8%) maintained moderate attendance. In multivariable regression, home visiting was associated with class 1 membership, aOR 1.27, 95% CI 1.04, 1.57.
Conclusions A pattern of timely WCC attendance was more likely among infants in home visiting; however, most infants eligible for home visiting were not enrolled.
60. Grace JO, Malik A, Reichman H, Munitz A, Barski A, Fulkerson PC. Reuse of public, genome-wide, murine eosinophil expression data for hypotheses development. J. Leukoc. Biol. Jul 2018;104(1):185-193.
The eosinophil (Eos) surface phenotype and activation state is altered after recruitment into tissues and after exposure to pro-inflammatory cytokines. In addition, distinct Eos functional subsets have been described, suggesting that tissue-specific responses for Eos contribute to organ homeostasis. Understanding the mechanisms by which Eos subsets achieve their tissue-specific identity is currently an unmet goal for the eosinophil research community. Publicly archived expression data can be used to answer original questions, test and generate new hypotheses, and serve as a launching point for experimental design. With these goals in mind, we investigated the effect of genetic background, culture methods, and tissue residency on murine Eos gene expression using publicly available, genome-wide expression data. Eos differentiated from cultures have a gene expression profile that is distinct from that of native homeostatic Eos; thus, researchers can repurpose published expression data to aid in selecting the appropriate culture method to study their gene of interest. In addition, we identified Eos lung- and gastrointestinal-specific transcriptomes, highlighting the profound effect of local tissue environment on gene expression in a terminally differentiated granulocyte even at homeostasis. Expanding the "toolbox" of Eos researchers to include public-data reuse can reduce redundancy, increase research efficiency, and lead to new biological insights.
61. Graef DM, Crabtree VM, Srivastava DK, Li C, Pritchard M, Hinds PS, Mandrell B. Sleep and mood during hospitalization for high-dose chemotherapy and hematopoietic rescue in pediatric medulloblastoma. Psychooncology. Jul 2018;27(7):1847-1853.
OBJECTIVE: Disrupted sleep is common in pediatric cancer, which is associated with psychological distress and may impact neural recovery. Information regarding sleep during pediatric brain tumor treatment is limited. This study aimed to describe objective sleep-wake patterns and examine the sleep-mood relation in youth hospitalized for intensive chemotherapy and stem cell rescue. METHODS: Participants included 37 patients (M age = 9.6 +/- 4.2 years) enrolled on a medulloblastoma protocol (SJMB03) and their parents. Respondents completed a mood disturbance measure on 3 days, and patients wore an actigraph for 5 days as an objective estimate of sleep-wake patterns. General linear mixed models examined the relation between nocturnal sleep and next-day mood, as well as mood and that night's sleep. RESULTS: Sleep duration was deficient, sleep efficiency was poor, and daytime napping was common, with large between-subjects variability. There were minimal mood concerns across all days. The sleep and next-day mood relationship was nonsignificant (P > .05). Greater parent-reported child mood disturbance on day 2 was associated with decreased same-night sleep (P < .001) and greater patient-reported mood disturbance was associated with greater same-night sleep latency (P = .036). CONCLUSIONS: Patients with medulloblastoma are vulnerable to disturbed sleep during hospitalization, and mood may be an important correlate to consider. Sleep and mood are modifiable factors that may be targeted to maximize daytime functioning.
62. Greiner MV, Beal SJ. Developing a Health Care System for Children in Foster Care. Health Promot Pract. Jul 2018;19(4):621-628.
In 2012, the Comprehensive Health Evaluations for Cincinnati's Kids (CHECK) Center was launched at Cincinnati Children's Hospital Medical Center to provide health care for over 1,000 children placed into foster care each year in the Cincinnati community. This consultation model clinical program was developed because children in foster care have been difficult to manage in the traditional health care setting due to unmet health needs, missing medical records, cumbersome state mandates, and transient and impoverished social settings. This case study describes the history and creation of the CHECK Center, demonstrating the development of a successful foster care health delivery system that is inclusive of all community partners, tailored for the needs and resources of the community, and able to adapt and respond to new information and changing systems.
63. Griebel AJ, Schaffer JE, Hopkins TM, Alghalayini A, Mkorombindo T, Ojo KO, Xu Z, Little KJ, Pixley SK. An in vitro and in vivo characterization of fine WE43B magnesium wire with varied thermomechanical processing conditions. J. Biomed. Mater. Res. B Appl. Biomater. Jul 2018;106(5):1987-1997.
Absorbable implants made of magnesium alloys may revolutionize surgical intervention, and fine magnesium wire will be critical to many applications. Functionally, the wires must have sufficient mechanical properties to withstand implantation and in-service loading, have excellent tissue tolerance, and exhibit an appropriate degradation rate for the application. Alloy chemistry and thermomechanical processing conditions will significantly impact the material's functional performance, but the exact translation of these parameters to implant performance is unclear. With this in mind, fine (127 microm) WE43B magnesium alloy wires in five thermomechanical process (TMP) conditions (90% cold work [CW], and 250, 375, 400, and 450 degrees C heat treatments) were investigated for their effect on mechanical and corrosion behavior. The TMP conditions gave clear metallurgical differences: transverse grain dimensions ranged from 200 nm (CW) to 3 microm (450 degrees C), UTS varied from 324 MPa (450 degrees C) to 608 MPa (250 degrees C), and surgical knotting showed some were suitable (CW, 400 degrees C, 450 degrees C) while others were not (250 degrees C, 350 degrees C). In vitro and in vivo corrosion testing yielded interesting and in some cases conflicting results. After 1 month immersion in cell culture medium, wire corrosion was extensive, and TMP conditions altered the macrocorrosion morphology but not the rate or total release of magnesium ions. After 1 month subdermal implantation in mice, all wires were well tolerated and showed very little corrosion (per microCT and histology), but differences in localized corrosion were detected between conditions. This study indicates that WE43B wires treated at 450 degrees C may be most suitable for surgical knotting procedures. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1987-1997, 2018.
64. Hall ES, Lee M, DeFranco EA. Contribution of previable live births to disparity in infant mortality of US-born Puerto Ricans compared with infants of other Hispanic origins. Public Health. Jul 2018;160:77-80.
OBJECTIVES: Although US-born Hispanics experience infant mortality rates (IMRs) which are lower than the national rate, within the Hispanic population, infants of Puerto Rican origin experience higher IMRs than other Hispanics. We aimed to describe the contribution of deaths among previable live-born infants to disparity in IMRs comparing Puerto Rican infants to infants of other Hispanic origins. STUDY DESIGN: Retrospective, descriptive analysis. METHODS: We analyzed data from the Centers for Disease Control and Prevention (CDC) WONDER online database representing linked US live births and infant deaths from 2005 to 2014. Data were stratified by race and ethnicity as well as by Puerto Rican and non-Puerto Rican Hispanic origin. Live births <23 weeks of gestation were classified as previable. Ten-year IMRs were calculated as the number of deaths divided by the number of live births for each group over the entire decade. RESULTS: Puerto Rican IMR of 7.34 (per 1000 live births) was higher than the US rate of 6.34 as well as the non-Puerto Rican Hispanic IMR of 5.15. Approximately 22% of US deaths were attributable to previable live births compared with 27% among Puerto Ricans and 20% among non-Puerto Rican Hispanics. The contribution to IMR of previable births among Puerto Ricans measuring 1.96 per 1000 total live births was 42% higher than the US rate of 1.38 and 90% higher than the non-Puerto Rican Hispanic rate of 1.03. CONCLUSIONS: Further research is needed to develop interventions to reduce disparity in previable birth rates, particularly among infants of Puerto Rican origin.
65. Han L, Zheng R, Richards MR, Tan M, Kitova EN, Jiang X, Klassen JS. Quantifying the binding stoichiometry and affinity of histo-blood group antigen oligosaccharides for human noroviruses. Glycobiology. Jul 1 2018;28(7):488-498.
Human noroviruses (HuNoVs) are a major cause of acute gastroenteritis. Many HuNoVs recognize histo-blood group antigens (HBGAs) as cellular receptors or attachment factors for infection. It was recently proposed that HuNoV recognition of HBGAs involves a cooperative, multistep binding mechanism that exploits both known and previously unknown glycan binding sites. In this study, binding measurements, implemented using electrospray ionization mass spectrometry (ESI-MS) were performed on homodimers of the protruding domain (P dimers) of the capsid protein of three HuNoV strains [Saga (GII.4), Vietnam 026 (GII.10) and VA387 (GII.4)] with the ethyl glycoside of the B trisaccharide (alpha-d-Gal-(1-->3)-[alpha-l-Fuc-(1-->2)]-beta-d-Gal-OC2H5) and free B type 1 tetrasaccharide (alpha-d-Gal-(1-->3)-[alpha-l-Fuc-(1-->2)]-beta-d-Gal-(1-->3)-d-GlcNAc) in an effort to confirm the existence of new HBGA binding sites. After correcting the mass spectra for nonspecific interactions that form in ESI droplets as they evaporate to dryness, all three P dimers were found to bind a maximum of two B trisaccharides at the highest concentrations investigated. The apparent affinities measured for stepwise binding of B trisaccharide suggest positive cooperativity. Similar results were obtained for B type 1 tetrasaccharide binding to Saga P dimer. Based on these results, it is proposed that HuNoV P dimers possess only two HBGA binding sites. It is also shown that nonspecific binding corrections applied to mass spectra acquired using energetic ion source conditions that promote in-source dissociation can lead to apparent HuNoV-HBGA oligosaccharide binding stoichiometries and affinities that are artificially high. Finally, evidence that high concentrations of oligosaccharide can induce conformational changes in HuNoV P dimers is presented.
66. Hanson HR, Babcock L, Byczkowski T, Goldstein SL. Describing pediatric acute kidney injury in children admitted from the emergency department. Pediatr. Nephrol. Jul 2018;33(7):1243-1249.
OBJECTIVE: To define those children who develop acute kidney injury (AKI) within 48 h of admission from the emergency department (ED) and ascertain patient-related factors in the ED associated with AKI. METHODS: Retrospective, cohort study of children, birth to 19 years, admitted to a tertiary pediatric hospital from the ED between January 2010 and December 2013 who had serum creatinine (SCr) drawn as part of clinical care. AKI was defined as a 50% increase in SCr above baseline, as measured within 48 h of hospital presentation. Multivariable logistic regression was performed to determine factors associated with AKI by comparing those with and without kidney injury on hospital presentation. RESULTS: Of all ED admissions, 13,827 subjects (27%) were included; 10% developed AKI. Of kids with AKI, 75% had a measured SCr consistent with AKI while in the ED, 36% were admitted to the intensive care unit, and 2% died (all significantly more than children without AKI). Young age, history of AKI or solid organ transplant, receipt of intravenous fluids or central venous access in the ED, and admission to intensive care were factors independently associated with AKI (AUC = 0.793, 95% CI 0.78-0.81). CONCLUSIONS: One in 10 children who had SCr measured and were admitted to a tertiary pediatric hospital had AKI on or within 48 h of presentation. Inherent characteristics, identifiable in the ED, are associated with an increased risk of AKI. Future research should focus on improving AKI recognition in the ED by the development of a risk stratification tool.
67. Harlow KE, Africa JA, Wells A, Belt PH, Behling CA, Jain AK, Molleston JP, Newton KP, Rosenthal P, Vos MB, Xanthakos SA, Lavine JE, Schwimmer JB, Nonalcoholic Steatohepatitis Clinical Research N. Clinically Actionable Hypercholesterolemia and Hypertriglyceridemia in Children with Nonalcoholic Fatty Liver Disease. J. Pediatr. Jul 2018;198:76-83 e72.
OBJECTIVE: To determine the percentage of children with nonalcoholic fatty liver disease (NAFLD) in whom intervention for low-density lipoprotein cholesterol or triglycerides was indicated based on National Heart, Lung, and Blood Institute guidelines. STUDY DESIGN: This multicenter, longitudinal cohort study included children with NAFLD enrolled in the National Institute of Diabetes and Digestive and Kidney Diseases Nonalcoholic Steatohepatitis Clinical Research Network. Fasting lipid profiles were obtained at diagnosis. Standardized dietary recommendations were provided. After 1 year, lipid profiles were repeated and interpreted according to National Heart, Lung, and Blood Institute Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction. Main outcomes were meeting criteria for clinically actionable dyslipidemia at baseline, and either achieving lipid goal at follow-up or meeting criteria for ongoing intervention. RESULTS: There were 585 participants, with a mean age of 12.8 years. The prevalence of children warranting intervention for low-density lipoprotein cholesterol at baseline was 14%. After 1 year of recommended dietary changes, 51% achieved goal low-density lipoprotein cholesterol, 27% qualified for enhanced dietary and lifestyle modifications, and 22% met criteria for pharmacologic intervention. Elevated triglycerides were more prevalent, with 51% meeting criteria for intervention. At 1 year, 25% achieved goal triglycerides with diet and lifestyle changes, 38% met criteria for advanced dietary modifications, and 37% qualified for antihyperlipidemic medications. CONCLUSIONS: More than one-half of children with NAFLD met intervention thresholds for dyslipidemia. Based on the burden of clinically relevant dyslipidemia, lipid screening in children with NAFLD is warranted. Clinicians caring for children with NAFLD should be familiar with lipid management.
68. Hewett TE, Myer GD. Mapping current research trends on anterior cruciate ligament injury risk against the existing evidence: In vivo biomechanical risk factors - A Letter to the Editor. Clin. Biomech. (Bristol, Avon). Jul 2018;56:92-93.
69. Hintz SR, Vohr BR, Bann CM, Taylor HG, Das A, Gustafson KE, Yolton K, Watson VE, Lowe J, DeAnda ME, Ball MB, Finer NN, Van Meurs KP, Shankaran S, Pappas A, Barnes PD, Bulas D, Newman JE, Wilson-Costello DE, Heyne RJ, Harmon HM, Peralta-Carcelen M, Adams-Chapman I, Duncan AF, Fuller J, Vaucher YE, Colaizy TT, Winter S, McGowan EC, Goldstein RF, Higgins RD, Health SsgotEKSNIoC, Human Development Neonatal Research N. Preterm Neuroimaging and School-Age Cognitive Outcomes. Pediatrics. Jul 2018;142(1).
BACKGROUND AND OBJECTIVES: Children born extremely preterm are at risk for cognitive difficulties and disability. The relative prognostic value of neonatal brain MRI and cranial ultrasound (CUS) for school-age outcomes remains unclear. Our objectives were to relate near-term conventional brain MRI and early and late CUS to cognitive impairment and disability at 6 to 7 years among children born extremely preterm and assess prognostic value. METHODS: A prospective study of adverse early and late CUS and near-term conventional MRI findings to predict outcomes at 6 to 7 years including a full-scale IQ (FSIQ) <70 and disability (FSIQ <70, moderate-to-severe cerebral palsy, or severe vision or hearing impairment) in a subgroup of Surfactant Positive Airway Pressure and Pulse Oximetry Randomized Trial enrollees. Stepwise logistic regression evaluated associations of neuroimaging with outcomes, adjusting for perinatal-neonatal factors. RESULTS: A total of 386 children had follow-up. In unadjusted analyses, severity of white matter abnormality and cerebellar lesions on MRI and adverse CUS findings were associated with outcomes. In full regression models, both adverse late CUS findings (odds ratio [OR] 27.9; 95% confidence interval [CI] 6.0-129) and significant cerebellar lesions on MRI (OR 2.71; 95% CI 1.1-6.7) remained associated with disability, but only adverse late CUS findings (OR 20.1; 95% CI 3.6-111) were associated with FSIQ <70. Predictive accuracy of stepwise models was not substantially improved with the addition of neuroimaging. CONCLUSIONS: Severe but rare adverse late CUS findings were most strongly associated with cognitive impairment and disability at school age, and significant cerebellar lesions on MRI were associated with disability. Near-term conventional MRI did not substantively enhance prediction of severe early school-age outcomes.
70. Hiruma T, Tsuyuzaki H, Uchida K, Trapnell BC, Yamamura Y, Kusakabe Y, Totsu T, Suzuki T, Morita S, Doi K, Noiri E, Nakamura K, Nakajima S, Yahagi N, Morimura N, Chang K, Yamada Y. IFN-beta Improves Sepsis-related Alveolar Macrophage Dysfunction and Postseptic Acute Respiratory Distress Syndrome-related Mortality. Am. J. Respir. Cell Mol. Biol. Jul 2018;59(1):45-55.
IFN-beta is reported to improve survival in patients with acute respiratory distress syndrome (ARDS), possibly by preventing sepsis-induced immunosuppression, but its therapeutic nature in ARDS pathogenesis is poorly understood. We investigated the therapeutic effects of IFN-beta for postseptic ARDS to better understand its pathogenesis in mice. Postseptic ARDS was reproduced in mice by cecal ligation and puncture to induce sepsis, followed 4 days later by intratracheal instillation of Pseudomonas aeruginosa to cause pneumonia with or without subcutaneous administration of IFN-beta 1 day earlier. Sepsis induced prolonged increases in alveolar TNF-alpha and IL-10 concentrations and innate immune reprogramming; specifically, it reduced alveolar macrophage (AM) phagocytosis and KC (CXCL1) secretion. Ex vivo AM exposure to TNF-alpha or IL-10 duplicated cytokine release impairment. Compared with sepsis or pneumonia alone, pneumonia after sepsis was associated with blunted alveolar KC responses and reduced neutrophil recruitment into alveoli despite increased neutrophil burden in lungs (i.e., "incomplete alveolar neutrophil recruitment"), reduced bacterial clearance, increased lung injury, and markedly increased mortality. Importantly, IFN-beta reversed the TNF-alpha/IL-10-mediated impairment of AM cytokine secretion in vitro, restored alveolar innate immune responsiveness in vivo, improved alveolar neutrophil recruitment and bacterial clearance, and consequently reduced the odds ratio for 7-day mortality by 85% (odds ratio, 0.15; 95% confidence interval, 0.03-0.82; P = 0.045). This mouse model of sequential sepsis --> pneumonia infection revealed incomplete alveolar neutrophil recruitment as a novel pathogenic mechanism for postseptic ARDS, and systemic IFN-beta improved survival by restoring the impaired function of AMs, mainly by recruiting neutrophils to alveoli.
71. Hjorten R, Skorecki K. Leveraging Ancestral Heterogeneity to Map Shared Genetic Risk Loci in Pediatric Steroid-Sensitive Nephrotic Syndrome. J. Am. Soc. Nephrol. Jul 2018;29(7):1793-1794.
72. Hoffman LM, Veldhuijzen van Zanten SEM, Colditz N, Baugh J, Chaney B, Hoffmann M, Lane A, Fuller C, Miles L, Hawkins C, Bartels U, Bouffet E, Goldman S, Leary S, Foreman NK, Packer R, Warren KE, Broniscer A, Kieran MW, Minturn J, Comito M, Broxson E, Shih CS, Khatua S, Chintagumpala M, Carret AS, Escorza NY, Hassall T, Ziegler DS, Gottardo N, Dholaria H, Doughman R, Benesch M, Drissi R, Nazarian J, Jabado N, Boddaert N, Varlet P, Giraud G, Castel D, Puget S, Jones C, Hulleman E, Modena P, Giagnacovo M, Antonelli M, Pietsch T, Gielen GH, Jones DTW, Sturm D, Pfister SM, Gerber NU, Grotzer MA, Pfaff E, von Bueren AO, Hargrave D, Solanki GA, Jadrijevic Cvrlje F, Kaspers GJL, Vandertop WP, Grill J, Bailey S, Biassoni V, Massimino M, Calmon R, Sanchez E, Bison B, Warmuth-Metz M, Leach J, Jones B, van Vuurden DG, Kramm CM, Fouladi M. Clinical, Radiologic, Pathologic, and Molecular Characteristics of Long-Term Survivors of Diffuse Intrinsic Pontine Glioma (DIPG): A Collaborative Report From the International and European Society for Pediatric Oncology DIPG Registries. J. Clin. Oncol. Jul 1 2018;36(19):1963-1972.
Purpose Diffuse intrinsic pontine glioma (DIPG) is a brainstem malignancy with a median survival of < 1 year. The International and European Society for Pediatric Oncology DIPG Registries collaborated to compare clinical, radiologic, and histomolecular characteristics between short-term survivors (STSs) and long-term survivors (LTSs). Materials and Methods Data abstracted from registry databases included patients from North America, Australia, Germany, Austria, Switzerland, the Netherlands, Italy, France, the United Kingdom, and Croatia. Results Among 1,130 pediatric and young adults with radiographically confirmed DIPG, 122 (11%) were excluded. Of the 1,008 remaining patients, 101 (10%) were LTSs (survival >/= 2 years). Median survival time was 11 months (interquartile range, 7.5 to 16 months), and 1-, 2-, 3-, 4-, and 5-year survival rates were 42.3% (95% CI, 38.1% to 44.1%), 9.6% (95% CI, 7.8% to 11.3%), 4.3% (95% CI, 3.2% to 5.8%), 3.2% (95% CI, 2.4% to 4.6%), and 2.2% (95% CI, 1.4% to 3.4%), respectively. LTSs, compared with STSs, more commonly presented at age < 3 or > 10 years (11% v 3% and 33% v 23%, respectively; P < .001) and with longer symptom duration ( P < .001). STSs, compared with LTSs, more commonly presented with cranial nerve palsy (83% v 73%, respectively; P = .008), ring enhancement (38% v 23%, respectively; P = .007), necrosis (42% v 26%, respectively; P = .009), and extrapontine extension (92% v 86%, respectively; P = .04). LTSs more commonly received systemic therapy at diagnosis (88% v 75% for STSs; P = .005). Biopsies and autopsies were performed in 299 patients (30%) and 77 patients (10%), respectively; 181 tumors (48%) were molecularly characterized. LTSs were more likely to harbor a HIST1H3B mutation (odds ratio, 1.28; 95% CI, 1.1 to 1.5; P = .002). Conclusion We report clinical, radiologic, and molecular factors that correlate with survival in children and young adults with DIPG, which are important for risk stratification in future clinical trials.
73. Holdaway AS, Becker SP. Children's sleep problems are associated with poorer student-teacher relationship quality. Sleep Med. Jul 2018;47:100-105.
OBJECTIVE: Children's sleep problems are associated with poorer student functioning in the school environment, including impairment in peer relationships; yet, no studies have examined sleep functioning in relation to the student-teacher relationship. The objective of this study was to examine whether child-rated total sleep problems or specific sleep problem domains (bedtime problems, nighttime problems, or daytime sleepiness) were associated with teacher-rated student-teacher closeness and conflict after controlling for student mental health symptoms known to be associated with both greater sleep problems and poorer student-teacher relationship quality. The study also examined whether age moderated the relation between sleep problems and student-teacher relationship quality. PARTICIPANTS: Participants were 175 children (81 boys and 94 girls) in the first to sixth grades (age = 6-13 years) and their teachers. METHODS: Children completed the Sleep Self-Report. Teachers completed a measure of student mental health symptoms (ie, attention-deficit/hyperactivity disorder, oppositional defiant disorder, conduct disorder, and anxiety/depression) and a measure of their relational closeness and conflict with each student. RESULTS: Total sleep problems were associated with greater student-teacher conflict, after controlling for child mental health symptoms and demographic factors. This association was moderated by age such that sleep problems were associated with conflict for younger children but not older children. Notably, daytime sleepiness specifically was associated with less student-teacher closeness. CONCLUSIONS: This is the first study to demonstrate a relation between student sleep functioning and the student-teacher relationship. Results of the study suggest that sleep may be an important component of school-based screening and evaluation efforts, as sleep is an important malleable factor related to school success.
74. Howell DR, Meehan WP, 3rd, Barber Foss KD, Reches A, Weiss M, Myer GD. Reduced dual-task gait speed is associated with visual Go/No-Go brain network activation in children and adolescents with concussion. Brain Inj. 2018;32(9):1129-1134.
OBJECTIVE: To investigate the association between dual-task gait performance and brain network activation (BNA) using an electroencephalography (EEG)-based Go/No-Go paradigm among children and adolescents with concussion. METHODS: Participants with a concussion completed a visual Go/No-Go task with collection of electroencephalogram brain activity. Data were treated with BNA analysis, which involves an algorithmic approach to EEG-ERP activation quantification. Participants also completed a dual-task gait assessment. The relationship between dual-task gait speed and BNA was assessed using multiple linear regression models. RESULTS: Participants (n = 20, 13.9 +/- 2.3 years of age, 50% female) were tested at a mean of 7.0 +/- 2.5 days post-concussion and were symptomatic at the time of testing (post-concussion symptom scale = 40.4 +/- 21.9). Slower dual-task average gait speed (mean = 82.2 +/- 21.0 cm/s) was significantly associated with lower relative time BNA scores (mean = 39.6 +/- 25.8) during the No-Go task (beta = 0.599, 95% CI = 0.214, 0.985, p = 0.005, R(2) = 0.405), while controlling for the effect of age and gender. CONCLUSION: Among children and adolescents with a concussion, slower dual-task gait speed was independently associated with lower BNA relative time scores during a visual Go/No-Go task. The relationship between abnormal gait behaviour and brain activation deficits may be reflective of disruption to multiple functional abilities after concussion.
75. Howell DR, Meehan WP, Foss KDB, Reches A, Weiss M, Myer GD. Reduced dual-task gait speed is associated with visual Go/No-Go brain network activation in children and adolescents with concussion. Brain Inj. 2018;32(9):1129-1134.
Objective: To investigate the association between dual-task gait performance and brain network activation (BNA) using an electroencephalography (EEG)-based Go/No-Go paradigm among children and adolescents with concussion. Methods: Participants with a concussion completed a visual Go/No-Go task with collection of electroencephalogram brain activity. Data were treated with BNA analysis, which involves an algorithmic approach to EEG-ERP activation quantification. Participants also completed a dual-task gait assessment. The relationship between dual-task gait speed and BNA was assessed using multiple linear regression models. Results: Participants (n=20, 13.9 +/- 2.3years of age, 50% female) were tested at a mean of 7.0 +/- 2.5days post-concussion and were symptomatic at the time of testing (post-concussion symptom scale=40.4 +/- 21.9). Slower dual-task average gait speed (mean=82.2 +/- 21.0cm/s) was significantly associated with lower relative time BNA scores (mean=39.6 +/- 25.8) during the No-Go task (=0.599, 95% CI=0.214, 0.985, p=0.005, R-2=0.405), while controlling for the effect of age and gender. Conclusion: Among children and adolescents with a concussion, slower dual-task gait speed was independently associated with lower BNA relative time scores during a visual Go/No-Go task. The relationship between abnormal gait behaviour and brain activation deficits may be reflective of disruption to multiple functional abilities after concussion.
76. Hutton JS, Lin L, Gruber R, Berndsen J, DeWitt T, Van Ginkel JB, Ammerman RT. Shared Reading and Television Across the Perinatal Period in Low-SES Households. Clin. Pediatr. (Phila.). Jul 2018;57(8):904-912.
The American Academy of Pediatrics recommends that shared reading commence as soon as possible after birth and screen-based media be discouraged for those less than 18 months old. Early routines can predict long-term use and health outcomes. This longitudinal study involved low-socioeconomic status mothers (n = 282) enrolled in home visiting. Surveys were administered prenatally and at 2 months old regarding shared reading and infant television viewing, and health literacy was screened prenatally. Planned age to initiate reading decreased from 2.8 to 1.8 months old, 80% reading by 2 months old, averaging 1 to 3 days per week, with "too busy" being the major barrier. Planned age for infant TV decreased from 13.2 to 4.3 months old, 68% viewing by 2 months old and more than half daily. TV was observed in 70% of infant sleep environments. Health literacy was correlated with perceived developmental benefits of shared reading (positively) and TV viewing (negatively), 43% of mothers scoring at risk for inadequate levels. A majority cited the prenatal period as opportune to discuss reading and TV.
77. Ikeda AK, Hong P, Ishman SL, Joe SA, Randolph GW, Shin JJ. Evidence-Based Medicine in Otolaryngology, Part 8: Shared Decision Making-Impact, Incentives, and Instruments. Otolaryngol. Head Neck Surg. Jul 2018;159(1):11-16.
In our previous installment, we introduced shared decision making (SDM) as a collaborative process in which patients, families, and clinicians develop a mutually optimized treatment plan when more than 1 reasonable treatment option exists. In this subsequent installment of our Evidence-Based Medicine in Otolaryngology Series, we expand on the topic of SDM, including the related current state of clinical decision making, the impact of SDM on health care utilization and patient satisfaction, the potential role of system and society changes, the experience with SDM as it relates to race and ethnicity, existing financial incentives, and the validated instruments that assess the extent to which SDM occurs.
78. Jankowski MP, Miller L, Koerber HR. Increased Expression of Transcription Factor SRY-box-Containing Gene 11 (Sox11) Enhances Neurite Growth by Regulating Neurotrophic Factor Responsiveness. Neuroscience. Jul 1 2018;382:93-104.
The peripherally projecting axons of dorsal root ganglion (DRG) neurons readily regenerate after damage while their centrally projecting branches do not regenerate to the same degree after injury. One important reason for this inconsistency is the lack of pro-regeneration gene expression that occurs in DRG neurons after central injury relative to peripheral damage. The transcription factor SRY-box-containing gene 11 (Sox11) may be a crucial player in the regenerative capacity of axons as previous evidence has shown that it is highly upregulated after peripheral axon damage but not after central injury. Studies have also shown that overexpression or inhibition of Sox11 after peripheral nerve damage can promote or block axon regeneration, respectively. To further understand the mechanisms of how Sox11 regulates axon growth, we artificially overexpressed Sox11 in DRG neurons in vitro to determine if increased levels of this transcription factor could enhance neurite growth. We found that Sox11 overexpression significantly enhanced neurite branching in vitro, and specifically induced the expression of glial cell line-derived neurotrophic factor (GDNF) family receptors, GFRalpha1 and GFRalpha3. The upregulation of these receptors by Sox11 overproduction altered the neurite growth patterns of DRG neurons alone and in response to growth factors GDNF and artemin; ligands for GFRalpha1 and GFRalpha3, respectively. These data support the role of Sox11 to promote neurite growth by altering responsiveness of neurotrophic factors and may provide mechanistic insight as to why peripheral axons of sensory neurons readily regenerate after injury, but the central projections do not have an extensive regenerative capacity.
79. Jobe AH, Goldenberg RL. Antenatal corticosteroids: an assessment of anticipated benefits and potential risks. Am. J. Obstet. Gynecol. Jul 2018;219(1):62-74.
Antenatal corticosteroids are standard of care for pregnancies at risk of preterm delivery between 24-34 weeks' gestational age. Recent trials demonstrate modest benefits from antenatal corticosteroids for late preterm and elective cesarean deliveries, and antenatal corticosteroids for periviable deliveries should be considered with family discussion. However, many women with threatened preterm deliveries receive antenatal corticosteroids but do not deliver until >34 weeks or at term. The net effect is that a substantial fraction of the delivery population will be exposed to antenatal corticosteroids. There are gaps in accurate assessments of benefits of antenatal corticosteroids because the randomized controlled trials were performed prior to about 1990 in pregnancies generally >28 weeks. The care practices for the mother and infant survival were different than today. The randomized controlled trial data also do not strongly support the optimal interval from antenatal corticosteroid treatment to delivery of 1-7 days. Epidemiology-based studies using large cohorts with >85% of at-risk pregnancies treated with antenatal corticosteroids probably overestimate the benefits of antenatal corticosteroids. Although most of the prematurity-associated mortality is in low-resource environments, the efficacy and safety of antenatal corticosteroids in those environments remain to be evaluated. The short-term benefits of antenatal corticosteroids for high-risk pregnancies in high-resource environments certainly justify antenatal corticosteroids as few risks have been identified over many years. However, cardiovascular and metabolic abnormalities have been identified in large animal models and cohorts of children exposed to antenatal corticosteroids that are consistent with fetal programming for adult diseases. These late effects of antenatal corticosteroids suggest caution for the expanded use of antenatal corticosteroids beyond at-risk pregnancies at 24-34 weeks. A way forward is to develop noninvasive fetal assessments to identify pregnancies across a wider gestational age that could benefit from antenatal corticosteroids.
80. Khoury P, Akuthota P, Ackerman SJ, Arron JR, Bochner BS, Collins MH, Kahn JE, Fulkerson PC, Gleich GJ, Gopal-Srivastava R, Jacobsen EA, Leiferman KM, Francesca LS, Mathur SK, Minnicozzi M, Prussin C, Rothenberg ME, Roufosse F, Sable K, Simon D, Simon HU, Spencer LA, Steinfeld J, Wardlaw AJ, Wechsler ME, Weller PF, Klion AD. Revisiting the NIH Taskforce on the Research needs of Eosinophil-Associated Diseases (RE-TREAD). J. Leukoc. Biol. Jul 2018;104(1):69-83.
Eosinophil-associated diseases (EADs) are rare, heterogeneous disorders characterized by the presence of eosinophils in tissues and/or peripheral blood resulting in immunopathology. The heterogeneity of tissue involvement, lack of sufficient animal models, technical challenges in working with eosinophils, and lack of standardized histopathologic approaches have hampered progress in basic research. Additionally, clinical trials and drug development for rare EADs are limited by the lack of primary and surrogate endpoints, biomarkers, and validated patient-reported outcomes. Researchers with expertise in eosinophil biology and eosinophil-related diseases reviewed the state of current eosinophil research, resources, progress, and unmet needs in the field since the 2012 meeting of the NIH Taskforce on the Research of Eosinophil-Associated Diseases (TREAD). RE-TREAD focused on gaps in basic science, translational, and clinical research on eosinophils and eosinophil-related pathogenesis. Improved recapitulation of human eosinophil biology and pathogenesis in murine models was felt to be of importance. Characterization of eosinophil phenotypes, the role of eosinophil subsets in tissues, identification of biomarkers of eosinophil activation and tissue load, and a better understanding of the role of eosinophils in human disease were prioritized. Finally, an unmet need for tools for use in clinical trials was emphasized. Histopathologic scoring, patient- and clinician-reported outcomes, and appropriate coding were deemed of paramount importance for research collaborations, drug development, and approval by regulatory agencies. Further exploration of the eosinophil genome, epigenome, and proteome was also encouraged. Although progress has been made since 2012, unmet needs in eosinophil research remain a priority.
81. Kline-Fath BM, Merrow AC, Jr., Calvo-Garcia MA, Nagaraj UD, Saal HM. Fowler syndrome and fetal MRI findings: a genetic disorder mimicking hydranencephaly/hydrocephalus. Pediatr. Radiol. Jul 2018;48(7):1032-1034.
Fetal ventriculomegaly is a common referral for prenatal MRI, with possible etiologies being hydrocephalus and hydranencephaly. The underlying cause of hydranencephaly is unknown, but many have suggested that the characteristic supratentorial injury is related to idiopathic bilateral occlusions of the internal carotid arteries from an acquired or destructive event. Fowler syndrome is a rare genetic disorder that causes fetal akinesia and a proliferative vasculopathy that can result in an apparent hydranencephaly-hydrocephaly complex. On prenatal imaging, the presence of significant parenchymal loss in the supratentorial and infratentorial brain is a clue to the diagnosis, which should prompt early genetic testing.
82. Lal DR, Gadepalli SK, Downard CD, Ostlie DJ, Minneci PC, Swedler RM, Chelius TH, Cassidy L, Rapp CT, Billmire D, Bruch S, Burns RC, Deans KJ, Fallat ME, Fraser JD, Grabowski J, Hebel F, Helmrath MA, Hirschl RB, Kabre R, Kohler J, Landman MP, Leys CM, Mak GZ, Raque J, Rymeski B, Saito JM, St Peter SD, von Allmen D, Warner BW, Sato TT, Midwest Pediatric Surgery C. Challenging surgical dogma in the management of proximal esophageal atresia with distal tracheoesophageal fistula: Outcomes from the Midwest Pediatric Surgery Consortium. J. Pediatr. Surg. Jul 2018;53(7):1267-1272.
PURPOSE: Perioperative management of infants with esophageal atresia and tracheoesophageal fistula (EA/TEF) is frequently based on surgeon experience and dogma rather than evidence-based guidelines. This study examines whether commonly perceived important aspects of practice affect outcome in a contemporary multi-institutional cohort of patients undergoing primary repair for the most common type of esophageal atresia anomaly, proximal EA with distal TEF. METHODS: The Midwest Pediatric Surgery Consortium conducted a multicenter, retrospective study examining selected outcomes on infants diagnosed with proximal EA with distal TEF who underwent primary repair over a 5-year period (2009-2014), with a minimum 1-year follow up, across 11 centers. RESULTS: 292 patients with proximal EA and distal TEF who underwent primary repair were reviewed. The overall mortality was 6% and was significantly associated with the presence of congenital heart disease (OR 4.82, p=0.005). Postoperative complications occurred in 181 (62%) infants, including: anastomotic stricture requiring intervention (n=127; 43%); anastomotic leak (n=54; 18%); recurrent fistula (n=15; 5%); vocal cord paralysis/paresis (n=14; 5%); and esophageal dehiscence (n=5; 2%). Placement of a transanastomotic tube was associated with an increase in esophageal stricture formation (OR 2.2, p=0.01). Acid suppression was not associated with altered rates of stricture, leak or pneumonia (all p>0.1). Placement of interposing prosthetic material between the esophageal and tracheal suture lines was associated with an increased leak rate (OR 4.7, p<0.001), but no difference in the incidence of recurrent fistula (p=0.3). Empiric postoperative antibiotics for >24h were used in 193 patients (66%) with no difference in rates of infection, shock or death when compared to antibiotic use </=24h (all p>0.3). Hospital volume was not associated with postoperative complication rates (p>0.08). Routine postoperative esophagram obtained on day 5 resulted in no delayed/missed anastomotic leaks or a difference in anastomotic leak rate as compared to esophagrams obtained on day 7. CONCLUSION: Morbidity after primary repair of proximal EA and distal TEF patients is substantial, and many common practices do not appear to reduce complications. Specifically, this large retrospective series does not support the use of prophylactic antibiotics beyond 24h and empiric acid suppression may not prevent complications. Use of a transanastomotic tube was associated with higher rates of stricture, and interposition of prosthetic material was associated with higher leak rates. Routine postoperative esophagram can be safely obtained on day 5 resulting in earlier initiation of oral feeds. STUDY TYPE: Treatment study. LEVEL OF EVIDENCE: III.
83. Lee B, Carmolli M, Dickson DM, Colgate ER, Diehl SA, Uddin MI, Islam S, Hossain M, Rafique TA, Bhuiyan TR, Alam M, Nayak U, Mychaleckyj JC, McNeal MM, Petri WA, Qadri F, Haque R, Kirkpatrick BD. Rotavirus-Specific Immunoglobulin A Responses Are Impaired and Serve as a Suboptimal Correlate of Protection Among Infants in Bangladesh. Clin. Infect. Dis. Jul 15 2018;67(2):186-192.
Background. Rotavirus (RV)-specific immunoglobulin A (IgA) responses following oral RV vaccination are impaired in low-income countries, where the utility of RV-IgA as a correlate of protection (CoP) remains unclear. In a monovalent oral RV vaccine (Rotarix) efficacy trial among infants in Dhaka, Bangladesh, we identified factors associated with poor RV-IgA responses and explored the utility of RV-IgA as a CoP.
Methods. Infants were randomized to receive Rotarix or no Rotarix at 10 and 17 weeks of life and followed with active diarrheal surveillance. RV-IgA concentration, seroconversion, and seropositivity were determined at 18 weeks of life and analyzed for correlation(s) with rotavirus diarrhea (RVD) and for contribution to Rotarix vaccine effect.
Results. Among vaccinated infants, overall RV-IgA geometric mean concentration was 21 U/mL; only 27% seroconverted and 32% were seropositive after vaccination. Increased RV-specific maternal antibodies significantly impaired immunogenicity. Seroconversion was associated with reduced risk of RVD through 1 year of life, but RV-IgA seropositivity only explained 7.8% of the vaccine effect demonstrated by the clinical endpoint (RVD).
Conclusions. RV-IgA responses were low among infants in Bangladesh and were significantly impaired by maternal antibodies. RV-IgA is a suboptimal CoP in this setting; an improved CoP for RV in low-income countries is needed.
84. Lennon A, Hugentobler JA, Sroka MC, Nissen KS, Kurowski BG, Gagnon I, Quatman-Yates CC. An Exploration of the Impact of Initial Timing of Physical Therapy on Safety and Outcomes After Concussion in Adolescents. J. Neurol. Phys. Ther. Jul 2018;42(3):123-131.
BACKGROUND AND PURPOSE: Physical therapy (PT) is a management strategy increasingly recognized to facilitate recovery after concussion. The purpose of this study was to investigate the safety and outcomes of multimodal impairment-based PT at varying time points after injury in youth diagnosed with concussion. METHODS: Data were extracted retrospectively from medical records for patients who received PT for concussion-related impairments. Patient records were categorized into 3 cohorts on the basis of the timing of PT implementation: 0-20 days following injury (early intervention), 21 to 41 days following injury (middle intervention), and 42 or more days following injury (late intervention). The primary outcome measure was Post-Concussion Symptom Inventory score from the beginning to the end of the PT episode of care. Additional outcome measures included number of PT sessions, duration of PT episode of care (days), and occurrence of unplanned visits to a health care provider. RESULTS: A total of 120 patient records (mean age of 14.77 years) were analyzed. Thirty-three, 39, and 48 individuals were categorized into the early, middle, and late intervention cohorts, respectively. There were no significant differences between intervention cohorts with regard to symptom change on the Post-Concussion Symptom Inventory from the beginning to the end of the PT episode of care, unplanned health care visits, number of PT sessions, or duration of PT episode of care. DISCUSSION AND CONCLUSIONS: Early initiation of PT may be safe and tolerable. Future prospective studies are needed to explore the efficacy of PT services administered early following injury to help characterize an optimal care plan for youth following concussion.Video Abstract available for more insights from the authors (see Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A210).
85. Li JJ, Hong XM, Mesiano S, Muglia LJ, Wang XB, Snyder M, Stevenson DK, Shaw GM. Natural Selection Has Differentiated the Progesterone Receptor among Human Populations. Am. J. Hum. Genet. Jul 5 2018;103(1):45-57.
The progesterone receptor (PGR) plays a central role in maintaining pregnancy and is significantly associated with medical conditions such as preterm birth that affects 12.6% of all the births in U.S. PGR has been evolving rapidly since the common ancestor of human and chimpanzee, and we herein investigated evolutionary dynamics of PGR during recent human migration and population differentiation. Our study revealed substantial population differentiation at the PGR locus driven by natural selection, where very recent positive selection in East Asians has substantially decreased its genetic diversity by nearly fixing evolutionarily novel alleles. On the contrary, in European populations, the PGR locus has been promoted to a highly polymorphic state likely due to balancing selection. Integrating transcriptome data across multiple tissue types together with large-scale genome-wide association data for preterm birth, our study demonstrated the consequence of the selection event in East Asians on remodeling PGR expression specifically in the ovary and determined a significant association of early spontaneous preterm birth with the evolutionarily selected variants. To reconstruct its evolutionary trajectory on the human lineage, we observed substantial differentiation between modern and archaic humans at the PGR locus, including fixation of a deleterious missense allele in the Neanderthal genome that was later introgressed in modern human populations. Taken together, our study revealed substantial evolutionary innovation in PGR even during very recent human evolution, and its different forms among human populations likely result in differential susceptibility to progesterone-associated disease conditions including preterm birth.
86. Lutley AL, Standridge SM. A Case of An Unusual Bell's Palsy Mimic. Semin. Pediatr. Neurol. Jul 2018;26:77-79.
We discuss the case of a 5-year-old boy who presented with an isolated left-sided cranial nerve 7 palsy that was initially magnetic resonance imaging negative. Owing to continued symptoms, repeat magnetic resonance imaging was performed and showed a temporal bone encephalocele. A review of the differential diagnosis of cranial nerve 7 palsy, warning signs signaling the need for additional workup, and a discussion of temporal lobe encephaloceles is provided in this case report. It is important to recognize that structural lesions can closely mimic idiopathic Bell's palsy, despite initial negative imaging.
87. Mahle WT, Hu C, Trachtenberg F, Menteer J, Kindel SJ, Dipchand AI, Richmond ME, Daly KP, Henderson HT, Lin KY, McCulloch M, Lal AK, Schumacher KR, Jacobs JP, Atz AM, Villa CR, Burns KM, Newburger JW, Pediatric Heart Network I. Heart failure after the Norwood procedure: An analysis of the Single Ventricle Reconstruction Trial. J. Heart Lung Transplant. Jul 2018;37(7):879-885.
BACKGROUND: Heart failure results in significant morbidity and mortality in young children with hypoplastic left heart syndrome (HLHS) after the Norwood procedure. METHODS: We studied subjects enrolled in the prospective Single Ventricle Reconstruction (SVR) Trial who survived to hospital discharge after a Norwood operation and were followed up to age 6 years. The primary outcome was heart failure, defined as heart transplant listing after Norwood hospitalization, death attributable to heart failure, or symptomatic heart failure (New York Heart Association [NYHA] Class IV). Multivariate modeling was undertaken using Cox regression methodology to determine variables associated with heart failure. RESULTS: Of the 461 subjects discharged home following a Norwood procedure, 66 (14.3%) met the criteria for heart failure. Among these, 15 died from heart failure, 39 were listed for transplant (22 had a transplant, 12 died after listing, and 5 were alive and not yet transplanted), and 12 had NYHA Class IV heart failure but were never listed. The median age at heart failure identification was 1.28 (interquartile range 0.30 to 4.69) years. Factors associated with early heart failure included post-Norwood lower fractional area change, need for extracorporeal membrane oxygenation, non-Hispanic ethnicity, Norwood perfusion type, and total support time (p < 0.05). CONCLUSIONS: By 6 years of age, heart failure developed in nearly 15% of children after the Norwood procedure. Although transplant listing was common, many patients died from heart failure before receiving a transplant or without being listed. Shunt type did not impact the risk of developing heart failure.
88. Mara CA, Cribbie RA. Equivalence of Population Variances: Synchronizing the Objective and Analysis. Journal of Experimental Education. 2018;86(3):442-457.
Researchers are often interested in establishing equivalence of population variances. Traditional difference-based procedures are appropriate to answer questions about differences in some statistic (e.g., variances, etc.). However, if a researcher is interested in evaluating the equivalence of population variances, it is more appropriate to use a procedure designed to determine equivalence. A simulation study was used to compare novel equivalence-based tests to traditional variance homogeneity tests under common data conditions. Results demonstrated that traditional difference-based tests assess equality of variances from the wrong perspective and that the proposed Levene-Wellek-Welch test for equivalence of group variances the best performing test for detecting equivalence. An R function is provided in order to facilitate use of this test for equivalence of population variances.
89. Marsh RA, Haddad E. How i treat primary haemophagocytic lymphohistiocytosis. Br. J. Haematol. Jul 2018;182(2):185-199.
Primary haemophagocytic lymphohistiocytosis (HLH) diseases are a collection of inherited genetic disorders that cause the syndrome of HLH. Great advances have been made in the last 20years with regard to the discovery of many of the genetic aetiologies of disease. Several advances have also been made on the clinical stage. Accurate screening diagnostics for primary HLH diseases that are superior to traditional Natural Killer cell function testing have been developed and are now available in many countries. There is now grounded clinical experience on which to base routine treatment decisions for patients with HLH. Newer approaches to allogeneic haematopoietic cell transplantation have increased overall patient survival. Despite these advances, however, there is still much work to be done to further improve patient care. This How I Treat' article will focus on summarizing current diagnostic, treatment and transplant strategies for patients with primary HLH diseases.
90. Messer EP, Greiner MV, Beal SJ, Eismann EA, Cassedy A, Gurwitch RH, Boat BW, Bensman H, Bemerer J, Hennigan M, Greenwell S, Eiler-Sims P. Child adult relationship enhancement (CARE): A brief, skills-building training for foster caregivers to increase positive parenting practices. Children and Youth Services Review. Jul 2018;90:74-82.
Objective: Foster caregivers are tasked with developing good relationships with children and managing child behavior; however, these caregivers often do not have access to evidence-based interventions typically designed for custodial parents and children with behavioral and/or traumatic symptoms in the clinical range. This study examined the feasibility and impact of a novel six-hour training, Child Adult Relationship Enhancement (CARE), on caregiver behavior compared to standard training used by foster care agencies.
Method: Thirty-one foster caregivers (90% female) were randomly assigned to CARE training (n = 15) or standard training (n = 16).
Results: In comparison to the standard training, foster caregivers who received CARE training demonstrated significant improvement in parenting behavior as measured by the Dyadic Parent Child Interactive Coding System one month later and reported fewer anxiety symptoms in their children as measured by the Trauma Symptom Checklist for Young Children three months later. Conclusions
These preliminary findings from this randomized controlled trial suggest that CARE can be delivered in the context of existing mandated foster care training programs, with some evidence that CARE training enhances positive parenting behavior and assists with decreasing anxiety symptoms in youth in the foster care system.
91. Michaelis R, Tang V, Goldstein LH, Reuber M, LaFrance WC, Jr., Lundgren T, Modi AC, Wagner JL. Psychological treatments for adults and children with epilepsy: Evidence-based recommendations by the International League Against Epilepsy Psychology Task Force. Epilepsia. Jul 2018;59(7):1282-1302.
Given the significant impact that psychosocial factors and epilepsy treatments can have on the health-related quality of life (HRQOL) of individuals with epilepsy and their families, there is great clinical interest in the role of psychological evaluation and treatments to improve HRQOL and comorbidities. Therefore, the International League Against Epilepsy (ILAE) charged the Psychology Task Force with the development of recommendations for clinical care based on evaluation of the evidence from their recent Cochrane review of psychological treatments in individuals with epilepsy. The literature search for a recent Cochrane review of randomized controlled trials investigating psychological treatments for individuals with epilepsy constitutes the key source of evidence for this article. To provide practical guidance to service providers, we provide ratings on study research designs based on (1) the American Academy of Neurology's Level of Evidence system and (2) the Grading of Recommendations, Assessment, Development, and Evaluation system. This paper is the culmination of an international collaboration process involving pediatric and adult psychologists, neurologists, psychiatrists, and neuropsychiatrists. The process and conclusions were reviewed and approved by the ILAE Executive Committee. The strongest evidence for psychological interventions was identified for the most common mental health problems, including depression, neurocognitive disturbances, and medication adherence. Psychological interventions targeting the enhancement of HRQOL and adherence and a decrease in comorbidity symptoms (anxiety, depression) should be incorporated into comprehensive epilepsy care. There is a range of psychological strategies (ie, cognitive behavioral therapy and mindfulness-based therapies) that show promise for improving the lives of persons with epilepsy, and clinical recommendations are provided to assist epilepsy health care providers in treating the comorbidities and challenges associated with epilepsy and its treatments.
92. Mikkelsen M, Saleh MG, Near J, Chan KL, Gong T, Harris AD, Oeltzschner G, Puts NAJ, Cecil KM, Wilkinson ID, Edden RAE. Frequency and phase correction for multiplexed edited MRS of GABA and glutathione. Magn. Reson. Med. Jul 2018;80(1):21-28.
PURPOSE: Detection of endogenous metabolites using multiplexed editing substantially improves the efficiency of edited magnetic resonance spectroscopy. Multiplexed editing (i.e., performing more than one edited experiment in a single acquisition) requires a tailored, robust approach for correction of frequency and phase offsets. Here, a novel method for frequency and phase correction (FPC) based on spectral registration is presented and compared against previously presented approaches. METHODS: One simulated dataset and 40 gamma-aminobutyric acid-/glutathione-edited HERMES datasets acquired in vivo at three imaging centers were used to test four FPC approaches: no correction; spectral registration; spectral registration with post hoc choline-creatine alignment; and multistep FPC. The performance of each routine for the simulated dataset was assessed by comparing the estimated frequency/phase offsets against the known values, whereas the performance for the in vivo data was assessed quantitatively by calculation of an alignment quality metric based on choline subtraction artifacts. RESULTS: The multistep FPC approach returned corrections that were closest to the true values for the simulated dataset. Alignment quality scores were on average worst for no correction, and best for multistep FPC in both the gamma-aminobutyric acid- and glutathione-edited spectra in the in vivo data. CONCLUSIONS: Multistep FPC results in improved correction of frequency/phase errors in multiplexed gamma-aminobutyric acid-/glutathione-edited magnetic resonance spectroscopy experiments. The optimal FPC strategy is experiment-specific, and may even be dataset-specific. Magn Reson Med 80:21-28, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine.
93. Miller A, Eismann E, Carr P, Little KJ, Lightdale-Miric N. Response to "Letter Regarding 'Outcomes of Isolated Radial Osteotomy for Volar Distal Radioulnar Joint Instability Following Radial Malunion in Children'". Journal of Hand Surgery-American Volume. Jul 2018;43(7):E9-E10.
94. Moghieb A, Clair G, Mitchell HD, Kitzmiller J, Zink EM, Kim YM, Petyuk V, Shukla A, Moore RJ, Metz TO, Carson J, McDermott JE, Corley RA, Whitsett JA, Ansong C. Time-resolved proteome profiling of normal lung development. Am. J. Physiol. Lung Cell Mol. Physiol. Jul 1 2018;315(1):L11-L24.
Biochemical networks mediating normal lung morphogenesis and function have important implications for ameliorating morbidity and mortality in premature infants. Although several transcript-level studies have examined normal lung development, corresponding protein-level analyses are lacking. Here we performed proteomics analysis of murine lungs from embryonic to early adult ages to identify the molecular networks mediating normal lung development. We identified 8,932 proteins, providing a deep and comprehensive view of the lung proteome. Analysis of the proteomics data revealed discrete modules and the underlying regulatory and signaling network modulating their expression during development. Our data support the cell proliferation that characterizes early lung development and highlight responses of the lung to exposure to a nonsterile oxygen-rich ambient environment and the important role of lipid (surfactant) metabolism in lung development. Comparison of dynamic regulation of proteomic and recent transcriptomic analyses identified biological processes under posttranscriptional control. Our study provides a unique proteomic resource for understanding normal lung formation and function and can be freely accessed at Lungmap.net.
95. Nahman-Averbuch H, Shefi T, Schneider VJ, 2nd, Li D, Ding L, King CD, Coghill RC. Quantitative sensory testing in patients with migraine: a systematic review and meta-analysis. Pain. Jul 2018;159(7):1202-1223.
Quantitative sensory testing (QST) is widely used to assess somatosensory function by application of controlled stimuli across a variety of modalities. The aim of the present meta-analysis is to synthesize QST results across a wide array of studies of patients with migraine to identify the QST parameters that are reliably different between patients with migraine and healthy controls. In addition, we aimed to determine whether such differences vary according to stimulus location. A comprehensive literature search (up to January 2017) was conducted, which included studies comparing QST parameters between patients with migraine and healthy controls. For each QST modality, we calculated up to 3 meta-analyses for combined (combined data from multiple testing locations), local (head and neck), and nonlocal (outside the head or neck) locations. A total of 65 studies were included in the meta-analyses. Lower heat and pressure pain thresholds were observed in patients with migraine compared with healthy controls in the combined locations. Importantly, lower pressure pain threshold in patients with migraine was found in local areas but not in nonlocal areas. In addition, patients with migraine had higher pain ratings to cold suprathreshold stimuli for combined and nonlocal areas, and higher pain ratings to electrical suprathreshold stimuli for nonlocal areas. This meta-analysis indicates that the alterations in nociceptive processing of patients with migraine may be modality, measure, and location specific. These results provide researchers and clinicians the evidence to choose QST parameters optimally suited for differentiating patients with migraine and healthy controls.
96. Neyra JA, Goldstein SL. Optimizing renal replacement therapy deliverables through multidisciplinary work in the intensive care unit. Clin. Nephrol. Jul 2018;90(1):1-5.
97. Oien RA, Vambheim SM, Hart L, Nordahl-Hansen A, Erickson C, Wink L, Eisemann MR, Shic F, Volkmar FR, Grodberg D. Sex-Differences in Children Referred for Assessment: An Exploratory Analysis of the Autism Mental Status Exam (AMSE). J. Autism Dev. Disord. Jul 2018;48(7):2286-2292.
The autism mental status exam is an eight-item observational assessment that structures the way we observe and document signs and symptoms of ASD. Investigations of test performance indicate strong sensitivity and specificity using gold-standard assessment as reference standard. This study aims to explore potential sex differences in AMSE test performance and observations of 123 children referred for autism assessment. Results indicates more language deficits in females with ASD than in males with ASD and less sensory symptoms in females compared to males with ASD. The AMSE performance is similar in identifying ASD and non-ASD in females compared to males. Less disruptive behaviors in females, might cause a need for a bigger hit to other areas of development to raise concern.
98. Olbrecht VA, Ding L, Spruance K, Hossain M, Sadhasivam S, Chidambaran V. Intravenous Acetaminophen Reduces Length of Stay Via Mediation of Postoperative Opioid Consumption After Posterior Spinal Fusion in a Pediatric Cohort. Clin. J. Pain. Jul 2018;34(7):593-599.
OBJECTIVES: Since approval of intravenous acetaminophen (IV APAP), its use has become quite common without strong positive evidence. Our goal was to determine the effect of IV APAP on length of hospital stay (LOS) via mediation of opioid-related side effects in pediatric patients. MATERIALS AND METHODS: After Institutional Review Board approval, 114 adolescents undergoing posterior spinal fusion were prospectively recruited and managed postoperatively with patient-controlled analgesia and adjuvant therapy. Patients were divided into 2 groups based on the use of IV APAP: control (n=70) and treatment (n=44). Association of IV APAP use with opioid outcomes was analyzed using inverse probability of treatment weighting (IPTW)-adjusted propensity scores to balance the 2 groups for all significant covariates except postoperative opioid consumption. Mediation analysis was carried out for LOS with IV APAP as the independent variable and morphine consumption as the mediator. RESULTS: Oral intake was delayed by approximately 1 day (P<0.001) and LOS was 0.6 days longer in the control group (P=0.044). After IPTW, time to oral intake remained significantly longer in the control group (P=0.014). The mediation model with IPTW revealed a significant negative association between IV APAP and morphine consumption (P<0.001), which significantly increased LOS (P<0.003). IV APAP had a significant opioid-sparing effect associated with shorter LOS. DISCUSSION: IV APAP hastens oral intake and is associated with decreased LOS in an adolescent surgery population likely through decreased opioid consumption. Through addition of IV APAP in this population, LOS may be decreased, an important implication in the setting of escalating health care costs.
99. Oria M, Figueira RL, Scorletti F, Sbragia L, Owens K, Li Z, Pathak B, Corona MU, Marotta M, Encinas JL, Peiro JL. CD200-CD200R imbalance correlates with microglia and pro-inflammatory activation in rat spinal cords exposed to amniotic fluid in retinoic acid-induced spina bifida. Sci. Rep. Jul 13 2018;8(1):10638.
Spina bifida aperta is a congenital malformation characterized by the failure of neural tube closure resulting in an unprotected fetal spinal cord. The spinal cord then undergoes progressive damage, likely due to chemical and mechanical factors related to exposure to the intrauterine environment. Astrogliosis in exposed spinal cords has been described in animal models of spina bifida during embryonic life but its relationship with neuroinflammatory processes are completely unknown. Using a retinoic acid-induced rat model of spina bifida we demonstrated that, when exposed to amniotic fluid, fetal spinal cords showed progressive astrogliosis with neuronal loss at mid-gestation (E15) compared to unexposed spinal cords. The number of microglial cells with a reactive phenotype and activation marker expression increased during gestation and exhibited progressive disruption in the inhibitory immune ligand-receptor system. Specifically we demonstrate down-regulation of CD200 expression and up-regulation of CD200R. Exposed spinal cords demonstrated neuroinflammation with increased tissue water content and cytokine production by the end of gestation (E20), which correlated with active Caspase3 expression in the exposed layers. Our findings provide new evidence that microglia activation, including the disruption of the endogenous inhibitory system (CD200-CD200R), may participate in the pathogenesis of spina bifida through late gestation.
100. Parast L, Burkhart Q, Gidengil C, Schneider EC, Mangione-Smith R, Lion C, McGlynn EA, Carle A, Britto MT, Elliott MN. Validation of New Care Coordination Quality Measures for Children with Medical Complexity. Acad. Pediatr. Jul 2018;18(5):581-588.
OBJECTIVES: To validate new caregiver-reported quality measures assessing care coordination services for children with medical complexity (CMC). METHODS: A cross-sectional analysis of the associations between 20 newly developed Family Experiences with Coordination of Care (FECC) quality measures and 3 validation measures among 1209 caregivers who responded to a telephone or mailed survey from August to November 2013 in Minnesota and Washington. Validation measures included an access composite, a provider rating item, and a care coordination outcome measure, all derived from Consumer Assessments of Healthcare Providers and Systems (CAHPS) survey items. Multivariate regression was used to examine associations between the 3 validation measures and each of the 20 FECC quality measures. RESULTS: Nineteen of the 20 FECC quality measures were significantly and positively associated with >/=1 of the validation measures. The components of care coordination demonstrating the strongest positive association with provider ratings included: 1) having a care coordinator who was knowledgeable and supportive and advocated for the child's needs (beta = 26.4; 95% confidence interval [CI], 20.0-32.8, scaled to reflect change associated with a 0-100 change in the FECC measure score); and 2) receiving a written visit summary that was useful and easy to understand (beta = 22.0; 95% CI, 17.1-27.0). CONCLUSIONS: Nineteen newly developed FECC quality measures demonstrated convergent validity with previously validated CAHPS measures. These new measures are valid for assessing the quality of care coordination services provided to CMC and may be useful for evaluating new models of care focused on improving these services.
101. Parikh SN, Rajdev N, Sun Q. The Growth of Trochlear Dysplasia During Adolescence. J. Pediatr. Orthop. Jul 2018;38(6):e318-e324.
BACKGROUND: Femoral trochlear dysplasia is a known risk factor for patellar instability. The growth pattern of the normal trochlea is known, but there have been no studies investigating the growth and development of the dysplastic trochlea. The purpose of this study was to assess the growth pattern of trochlear dysplasia in adolescents. METHODS: In a retrospective analysis, magnetic resonance images of adolescents with patellar instability and trochlear dysplasia were evaluated. These images were measured for lateral and medial condylar height, trochlear height, cartilaginous and bony trochlear bump, and cartilaginous and bony sulcus angle. The type of trochlear dysplasia was classified as per Dejour classification. These measurements were plotted against age, and their growth patterns were evaluated using statistical methods. RESULTS: Of 235 knees with patellar instability, trochlear dysplasia was present in 175 knees (74% knees) and these were further analyzed. With increasing age, the mean lateral and medial condylar heights and mean trochlear height showed statistically significant increase (P<0.01). Cartilaginous trochlear bump (slope=0.15, P=0.013) and bony trochlear bump (slope=0.22, P<0.01) increased with age, with some reaching the pathologic value by age of 15.1 years. After age 11 years, there were no significant changes for cartilaginous and bony sulcus angles (cartilage: slope=0.03, P=0.96; bony: slope=-0.90, P=0.11). The mean cartilaginous sulcus angle was significantly greater than the mean bony sulcus angle (P<0.01). All Dejour types of trochlear dysplasia were present across all age groups. CONCLUSIONS: All linear measurements of trochlear dysplasia (condylar height, trochlear height, trochlear bump) increased with age. However, the shape of trochlear dysplasia, as reflected by sulcus angle and Dejour classification, did not change with increasing age. The shape of trochlear dysplasia is most likely a genetic predisposition and does not necessarily change during skeletal growth. LEVEL OF EVIDENCE: Level II-diagnostic, cross-sectional.
102. Parker DM, Angeles-Han ST, Stanton AL, Holland GN. Chronic Anterior Uveitis in Children: Psychosocial Challenges for Patients and Their Families. Am. J. Ophthalmol. Jul 2018;191:Xvi-Xxiv.
PURPOSE: To describe issues of concern to childrenwith chronic anterior uveitis; to consider the psychological impact of chronic anterior uveitis on children's lives; and to understand the effect of a child's chronic illness on other family members.
DESIGN: Expert commentary.
METHODS: Author experiences were supplemented by a review of pertinent medical literature and by consideration of content from semi-structured, separate patient and parent interviews.
RESULTS: Vision loss and the fear of blindness are not the only stressors for children with chronic anterior uveitis and their families; of additional concern are the burdens of examinations and treatment regimens, as well as drug toxicities. Children with chronic anterior uveitis experience medical, academic, interpersonal, psychological, and developmental challenges. The impact of disease extends to other members of a patient's family as well; parents experience challenges in similar domains. Problems with adherence to medical regimens are common. Both the disease and its treatment affect quality of life, and can interfere with successful management of disease and transition to autonomy in adulthood, as reported for other chronic conditions. Coping processes vary greatly between different families.
CONCLUSIONS: Eye examinations and the rigors of long-term treatment often influence the psychosocial health of patients and families; physicians who are aware of these issues can help patients and families cope with chronic illness and may improve outcomes. Further psychosocial research to understand the experiences of children dealing with chronic anterior uveitis is warranted; this commentary can serve as a foundation for development of age- and disease-specific research questions. (C) 2018 Elsevier Inc. All rights reserved.
103. Patel ZH, Lu XM, Miller D, Forney CR, Lee J, Lynch A, Schroeder C, Parks L, Magnusen AF, Chen XT, Pujato M, Maddox A, Zoller EE, Namjou B, Brunner HI, Henrickson M, Huggins JL, Williams AH, Ziegler JT, Comeau ME, Marion MC, Glenn SB, Adler A, Shen N, Nath SK, Stevens AM, Freedman BI, Pons-Estel BA, Tsao BP, Jacob CO, Kamen DL, Brown EE, Gilkeson GS, Alarcon GS, Martin J, Reveille JD, Anaya JM, James JA, Sivils KL, Criswell LA, Vila LM, Petri M, Scofield RH, Kimberly RP, Edberg JC, Ramsey-Goldman R, Bang SY, Lee HS, Bae SC, Boackle SA, Graham DC, Vyse TJ, Merrill JT, Niewold TB, Ainsworth HC, Silverman ED, Weisman MH, Wallace DJ, Raj P, Guthridge JM, Gaffney PM, Kelly JA, Alarcon-Riquelme ME, Langefeld CD, Wakeland EK, Kaufman KM, Weirauch MT, Harley JB, Kottyan LC. A plausibly causal functional lupus-associated risk variant in the STAT1-STAT4 locus. Hum. Mol. Genet. Jul 1 2018;27(13):2392-2404.
Systemic lupus erythematosus (SLE or lupus) (OMIM: 152700) is a chronic autoimmune disease with debilitating inflammation that affects multiple organ systems. The STAT1-STAT4 locus is one of the first and most highly replicated genetic loci associated with lupus risk. We performed a fine-mapping study to identify plausible causal variants within the STAT1-STAT4 locus associated with increased lupus disease risk. Using complementary frequentist and Bayesian approaches in trans-ancestral Discovery and Replication cohorts, we found one variant whose association with lupus risk is supported across ancestries in both the Discovery and Replication cohorts: rs11889341. In B cell lines from patients with lupus and healthy controls, the lupus risk allele of rs11889341 was associated with increased STAT1 expression. We demonstrated that the transcription factor HMGA1, a member of the HMG transcription factor family with an AT-hook DNA-binding domain, has enriched binding to the risk allele compared with the non-risk allele of rs11889341. We identified a genotype-dependent repressive element in the DNA within the intron of STAT4 surrounding rs11889341. Consistent with expression quantitative trait locus (eQTL) analysis, the lupus risk allele of rs11889341 decreased the activity of this putative repressor. Altogether, we present a plausible molecular mechanism for increased lupus risk at the STAT1-STAT4 locus in which the risk allele of rs11889341, the most probable causal variant, leads to elevated STAT1 expression in B cells due to decreased repressor activity mediated by increased binding of HMGA1.
104. Peinhaupt M, Roula D, Theiler A, Sedej M, Schicho R, Marsche G, Sturm EM, Sabroe I, Rothenberg ME, Heinemann A. DP1 receptor signaling prevents the onset of intrinsic apoptosis in eosinophils and functions as a transcriptional modulator. J. Leukoc. Biol. Jul 2018;104(1):159-171.
Prostaglandin (PG) D-2 is the ligand for the G-protein coupled receptors DP1 (D-type prostanoid receptor 1) and DP2 (also known as chemoattractant receptor homologous molecule, expressed on Th2 cells; CRTH2). Both, DP1 and DP2 are expressed on the cellular surface of eosinophils; although it has become quite clear that PGD(2) induces eosinophil migration mainly via DP2 receptors, the role of DP1 in eosinophil responses has remained elusive. In this study, we addressed how DP1 receptor signaling complements the pro-inflammatory effects of DP2. We found that PGD(2) prolongs the survival of eosinophils via a DP1 receptor-mediated mechanism that inhibits the onset of the intrinsic apoptotic cascade. The DP1 agonist BW245c prevented the activation of effector caspases in eosinophils and protected mitochondrial membranes from depolarization whichas a consequencesustained viability of eosinophils. DP1 activation in eosinophils enhanced the expression of the anti-apoptotic gene BCL-X-L, but also induced pro-inflammatory genes, such as VLA-4 and CCR3. In HEK293 cells that overexpress recombinant DP1 and/or DP2 receptors, activation of DP1, but not DP2, delayed cell death and stimulated proliferation, along with induction of serum response element (SRE), a regulator of anti-apoptotic, early-response genes. We conclude that DP1 receptors promote the survival via SRE induction and induction of pro-inflammatory genes. Therefore, targeting DP1 receptors, along with DP2, may contribute to anti-inflammatory therapy in eosinophilic diseases.
The PGD2-DP1 axis impedes caspase activity, protects mitochondrial function and consequently sustains eosinophil survival by controlling SRE induction and upregulation of pro-inflammatory and anti-apoptotic genes.
105. Peterson CM, Peugh J, Loucks L, Shaffer A. Emotional maltreatment in family of origin and young adult romantic relationship satisfaction: A dyadic data analysis. Journal of Social and Personal Relationships. Jul 2018;35(6):872-888.
The aims of the current study were to use dyadic data analysis to examine the associations of history of childhood emotional maltreatment to current relationship satisfaction among young adult romantic partners as moderated by the effects of hostile behavioral observations within these romantic couples. Our sample included 52 young adult romantic dyads recruited from a large southeastern university. Current relationship satisfaction and history of childhood emotional maltreatment were obtained via self-report; behavioral interactions were rated on a behavioral coding system to determine level of dyadic hostility. Results revealed a significant interaction effect: Females' history of childhood emotional maltreatment significantly predicted relationship satisfaction for women at low or average (but not high) levels of dyadic hostility. Our findings suggest that for young women, romantic relationship satisfaction is compromised by their own history of emotional maltreatment, particularly when the couple's conflict resolution style is characterized by low to average levels of hostility.
106. Phan M, Hickey E, Beck AF, Klein MD, Real FJ. A "Smart" Way of Addressing Food Insecurity in the Digital Age. Pediatrics. Jul 2018;142(1):e20181336-e20181336.
107. Ray S, Tillo D, Assad N, Ufot A, Deppmann C, Durell SR, Porollo A, Vinson C. Replacing C189 in the bZIP domain of Zta with S, T, V, or A changes DNA binding specificity to four types of double-stranded DNA. Biochem. Biophys. Res. Commun. Jul 2 2018;501(4):905-912.
Zta is a bZIP transcription factor (TF) in the Epstein-Barr virus that binds unmethylated and methylated DNA sequences. Substitution of cysteine 189 of Zta to serine (Zta(C189S)) results in a virus that is unable to execute the lytic cycle, which was attributed to a change in binding to methylated DNA sequences. To learn more about the role of this position in defining sequence-specific DNA binding, we mutated cysteine 189 to four other amino acids, producing Zta(C189S), Zta(C189T), Zta(C189A), and Zta(C189V) mutants. Zta and mutants were used in protein binding microarray (PBM) experiments to evaluate sequence-specific DNA binding to four types of double-stranded DNA (dsDNA): 1) with cytosine in both strands (DNA(C|C)), 2) with 5-methylcytosine (5mC) in one strand and cytosine in the second strand (DNA(5mC|C)), 3) with 5-hydroxymethylcytosine (5hmC) in one strand and cytosine in the second strand (DNA(5hmC|C)), and 4) with both cytosines in all CG dinucleotides containing 5mC (DNA(5mCG)). Zta(C189S) and Zta(C189T) bound the TRE (AP-1) motif (TGA(G)/CTCA) more strongly than wild-type Zta, while binding to other sequences, including the C/EBP half site GCAA was reduced. Binding of Zta(C189S) and Zta(C189T) to DNA containing modified cytosines (DNA(5mC|C), DNA(5hmC|C), and DNA(5mCG)) was reduced compared to Zta. Zta(C189A) and Zta(C189V) had higher non-specific binding to all four types of DNA. Our data suggests that position C189 in Zta impacts sequence-specific binding to DNA containing modified and unmodified cytosine.
108. Read PJ, Oliver JL, De Ste Croix MBA, Myer GD, Lloyd RS. An audit of injuries in six english professional soccer academies. J. Sports Sci. 2018;36(13):1542-1548.
Regulations now state that professional academies in the United Kingdom are required to substantially increase the volume of soccer training. This study assessed the current injury occurrence, providing an update to reports published prior to the introduction of the Elite Player Performance Plan (EPPP). 608 soccer players aged 11-18years from six professional soccer clubs were prospectively monitored, recording injuries during the 2014-2015 season. An injury rate of 1.32 injuries per player/season was indicated with a mean time loss of 21.9days per injury. The greatest time loss per injury was in the U14s-U15s, and the highest rate of severe injuries in the U15s. Strains and sprains were the most common injury type, with the knee and ankle the most frequently injured anatomical sites. Seasonal variation indicated two peaks in injury incidence, occurring in September and January. In comparison to a published audit prior to the inception of the EPPP, this study indicates that academy soccer players are three-times more likely to experience an injury. Given that time loss and injury severity also increased during periods that typically follow rapid growth, these players should be considered an important group for training load monitoring and injury prevention strategies.
109. Roberson NP, Dillman JR, O'Hara SM, DeFoor WR, Jr., Reddy PP, Giordano RM, Trout AT. Comparison of ultrasound versus computed tomography for the detection of kidney stones in the pediatric population: a clinical effectiveness study. Pediatr. Radiol. Jul 2018;48(7):962-972.
BACKGROUND: The incidence of pediatric nephrolithiasis in the United States is increasing. There is a paucity of literature comparing the diagnostic performance of computed ultrasound (US) to tomography (CT) in the pediatric population. OBJECTIVE: To determine the diagnostic performance of renal US for nephrolithiasis in children using a clinical effectiveness approach. MATERIALS AND METHODS: Institutional review board approval with a waiver of informed consent was obtained for this retrospective, HIPAA-complaint investigation. Billing records and imaging reports were used to identify children (</=18 years old) evaluated for nephrolithiasis by both US and unenhanced CT within 24 h between March 2012 and March 2017. Imaging reports were reviewed for presence, number, size and location of kidney stones. Diagnostic performance of US (reference standard=CT) was calculated per renal unit (left/right kidney) and per renal sector (four sectors per kidney). For sector analysis, US was considered truly positive if a stone was identified at CT in the same or an adjacent sector. RESULTS: There were 68 renal stones identified by CT in 30/69 patients (43%). Mean patient age was 14.7+/-3.6 years, and 35 were boys. For detecting nephrolithiasis in any kidney, US was 66.7% (48.8-80.8%) sensitive and 97.4% (86.8-99.9%) specific (positive predictive value=95.2% [77.3-99.8%], negative predictive value=79.2% [65.7-88.3%], positive likelihood ratio=26.0). Per renal sector, US was 59.7% (46.7-71.4%) sensitive and 97.4% (95.5-98.5%) specific (positive predictive value=72.3% [58.2-83.1%], negative predictive value=95.4% [93.2-96.9%], positive likelihood ratio=22.5). Of the 30 stones not detected by US, only 3 were >3 mm at CT. CONCLUSION: In clinical practice, US has high specificity for detecting nephrolithiasis in children but only moderate sensitivity and false negatives are common.
110. Roberts P, Trout AT, Dillman JR. Nodular macroregenerative tissue as a pattern of regeneration in cholangiopathic disorders. Pediatr. Radiol. Jul 2018;48(7):932-940.
Published case series have described central hepatic macroregenerative nodules or masses as a common feature of Alagille syndrome. Our experience suggests this regenerative pattern can be seen more generally in cholangiopathic disorders.
To define the frequency of central regenerative tissue in Alagille syndrome and other cholangiopathic disorders and to describe the typical appearance of such regenerative tissue.
We conducted a retrospective study of CT and MR imaging performed in children and young adults with cholangiopathic disorders between January 2000 and June 2016. Two pediatric radiologists reviewed images in consensus for the presence and features of macroregenerative tissue. Tissue histopathology, when available, was retrieved from the medical record.
Of 226 patients with cholangiopathic disorders, 23% (52/226) had macroregenerative tissue, and this tissue was central in 96% (50/52). Tissue was well defined and mass-like in 38% (20/52). Regenerative tissue was most common among the subset of patients with Langerhans cell histiocytosis with hepatic involvement (71%, 5/7) and was identified in 43% (16/37) of patients with Alagille syndrome. Regenerative tissue was iso- to hyperintense on T1-weighted MR sequences in 96% (50/52) of cases and hypointense on T2-weighted MR imaging in 94% (48/51). Arterial phase hyperenhancement was present in only five patients (12% of 43), none of whom showed portal venous phase washout. Histopathology was available for 20 cases, all showing benign regenerative tissue.
Central mass-like regeneration appears to be a common regenerative pattern in cholangiopathic disorders and should not be mistaken for malignancy.
111. Robinson EM, Baker R, Hossain MM. Randomized Trial Evaluating the Effectiveness of Coloring on Decreasing Anxiety Among Parents in a Pediatric Surgical Waiting Area. Journal of Pediatric Nursing-Nursing Care of Children & Families. Jul-Aug 2018;41:80-83.
Anxiety is common among pediatric surgical patients and their parents. Numerous studies have examined interventions to reduce pediatric patients' anxiety; however, less is known about reducing parental anxiety. In other populations, producing art has been shown to significantly reduce anxiety.
Purpose: This study aimed to determine whether parents' anxiety decreased after coloring while their child is in surgery.
Design and Methods: A block randomized controlled trial was conducted with a convenience sample of 106 parents of childrenwhowere having a scheduled surgery. Each day of data collection was randomized where all parents enrolled that day would either color a pre-drawn art template for 30 min or would simply wait in the waiting room for 30 min. The primary outcome measure was anxiety, measured by the 6-item short form of the Spielberger State Trait Anxiety Inventory (STAI).
Results: Parents' average anxiety score decreased fromthe initial measurement to the measurement 30 min later in both the control group and the intervention group. The reduction in anxietywas significantly greater for those parents who participated in coloring during their wait (p < 0.0001).
Conclusions: Coloring is a creative, simple, low cost, and effective activity to reduce anxiety among parents in a pediatric surgical waiting area. Practice Implications: Providing coloring materials and information about the benefits of coloring in pediatric surgery waiting areas is an easy to implement intervention to reduce parental anxiety. (c) 2018 Elsevier Inc. All rights reserved.
112. Rochman M, Azouz NP, Rothenberg ME. Epithelial origin of eosinophilic esophagitis. J. Allergy Clin. Immunol. Jul 2018;142(1):10-23.
Eosinophilic esophagitis (EoE) is a chronic, allergen-driven inflammatory disease of the esophagus characterized predominantly by eosinophilic inflammation, leading to esophageal dysfunction. Converging data have placed the esophageal epithelium at the center of disease pathogenesis. In particular, the main EoE disease susceptibility loci at 2p23 and 5p22 encode for gene products that are produced by the esophageal epithelium: the intracellular protease calpain 14 and thymic stromal lymphopoietin, respectively. Furthermore, genetic and functional data establish a primary role for impaired epithelial barrier function in disease susceptibility and pathoetiology. Additionally, the EoE transcriptome, a set of genes dysregulated in the esophagi of patients with EoE, is enriched in genes that encode for proteins involved in esophageal epithelial cell differentiation. This transcriptome has a high proportion of esophagus-specific epithelial genes that are notable for the unexpected enrichment in genes encoding for proteases and protease inhibitors, as well as in IL-1 family genes, demonstrating a previously unappreciated role for innate immunity responses in the esophagus under homeostatic conditions. Among these pathways, basal production of the serine protease inhibitor, Kazal-type 7 (SPINK7) has been demonstrated to be part of the normal differentiation program of esophageal epithelium. Profound lost expression of SPINK7 occurs in patients with EoE and is sufficient for unleashing increased proteolytic activity (including urokinase plasminogen activator), impaired barrier function, and production of large quantities of proinflammatory and proallergic cytokines, including thymic stromal lymphopoietin. Collectively, we put forth a model in which the esophagus is normally equipped as an anti-inflammatory sensing organ and that defects in this pathway, mediated by epithelial protease/protease inhibitor imbalances, unleash inflammatory responses resulting in disorders, such as EoE.
113. Roy S, Rai P, Mpollo MSEM, Chang KH, Rizvi T, Shanmukhappa SK, VandenHeuvel K, Aronow B, Inagami T, Cancelas JA, Malik P. Angiotensin receptor signaling in sickle cell anemia has a reno-protective effect on urine concentrating ability but results in sickle glomerulopathy. Am. J. Hematol. Jul 2018;93(7):E177-E181.
114. Rudzinski ER, Lockwood CM, Stohr BA, Vargas SO, Sheridan R, Black JO, Rajaram V, Laetsch TW, Davis JL. Pan-Trk Immunohistochemistry Identifies NTRK Rearrangements in Pediatric Mesenchymal Tumors. Am. J. Surg. Pathol. Jul 2018;42(7):927-935.
Activating neurotrophic receptor kinase (NTRK) fusions define certain pediatric mesenchymal tumors, including infantile fibrosarcoma and cellular mesoblastic nephroma. Traditionally, molecular confirmation of these fusions has included either fluorescent in situ hybridization for ETV6 rearrangements or reverse-transcriptase polymerase chain reaction for the classic ETV6-NTRK3 fusion. However, these methods overlook variant NTRK rearrangements, which are increasingly appreciated as recurrent events in a subset of pediatric mesenchymal tumors. New therapeutic agents successfully target these fusions and may prevent morbid surgeries in very young children, making recognition of tumors harboring NTRK rearrangements of increasing importance. We evaluated the performance of immunohistochemical (IHC) staining using pan-Trk and TrkA antibodies in 79 pediatric mesenchymal tumors. Negative controls included pediatric mesenchymal tumors not harboring (n=28) or not expected to harbor (n=22) NTRK fusions. NTRK rearrangements were detected predominantly by DNA-based next-generation sequencing assays, specifically UW OncoPlex and UCSF500 Cancer Gene Panel. Pan-Trk IHC (EPR17341) was 97% sensitive and 98% specific for the presence of an NTRK rearrangement, and TrkA IHC (EP1058Y) was 100% sensitive and 63% specific for the presence of an NTRK rearrangement. Tumors with NTRK1 or NTRK2 rearrangements showed cytoplasmic staining, whereas tumors with NTRK3 rearrangements showed nuclear +/- cytoplasmic staining. We conclude that pan-Trk IHC is a highly sensitive and specific marker for NTRK rearrangements in pediatric mesenchymal tumors.
115. Saarel EV, Granger S, Kaltman JR, Minich LL, Tristani-Firouzi M, Kim JJ, Ash K, Tsao SS, Berul CI, Stephenson EA, Gamboa DG, Trachtenberg F, Fischbach P, Vetter VL, Czosek RJ, Johnson TR, Salerno JC, Cain NB, Pass RH, Zeltser I, Silver ES, Kovach JR, Alexander ME, Pediatric Heart Network I. Electrocardiograms in Healthy North American Children in the Digital Age. Circ Arrhythm Electrophysiol. Jul 2018;11(7):e005808.
BACKGROUND: Interpretation of pediatric ECGs is limited by lack of accurate sex- and race-specific normal reference values obtained with modern technology for all ages. We sought to obtain contemporary digital ECG measurements in healthy children from North America, to evaluate the effects of sex and race, and to compare our results to commonly used published datasets. METHODS: Digital ECGs (12-lead) were retrospectively collected for children </=18 years old with normal echocardiograms at 19 centers in the Pediatric Heart Network. Patients were classified into 36 groups: 6 age, 2 sex, and 3 race (white, black, and other/mixed) categories. Standard intervals and amplitudes were measured; mean+/-SD and 2nd/98th percentiles were determined by age group, sex, and race. For each parameter, multivariable analysis, stratified by age, was conducted using sex and race as predictors. Parameters were compared with 2 large pediatric ECG data sets. RESULTS: Among ECGs from 2400 children, significant differences were found by sex and race categories. The corrected QT interval in lead II was greater for girls compared with boys for age groups >/=3 years (P</=0.03) and for whites compared with blacks for age groups >/=12 years (P<0.05). The R wave amplitude in V6 was greater for boys compared with girls for age groups >/=12 years (P<0.001), for blacks compared with white or other race categories for age groups >/=3 years (P</=0.006), and greater compared with a commonly used public data set for age groups >/=12 years (P<0.0001). CONCLUSIONS: In this large, diverse cohort of healthy children, most ECG intervals and amplitudes varied by sex and race. These differences have important implications for interpreting pediatric ECGs in the modern era when used for diagnosis or screening, including thresholds for left ventricular hypertrophy.
116. Schlaudecker EP, Ambroggio L, McNeal MM, Finkelman FD, Way SS. Declining responsiveness to influenza vaccination with progression of human pregnancy. Vaccine. Jul 25 2018;36(31):4734-4741.
BACKGROUND: Influenza immunization is universally recommended during pregnancy to protect mothers and their offspring. However, pregnancy-induced shifts in vaccine responsiveness remain poorly defined. METHODS: Quantitative and qualitative shifts in the serological response to influenza vaccination were evaluated in healthy women throughout the course of pregnancy. Serum was obtained before and after vaccination among 71 pregnant and 67 non-pregnant women during the 2011-12 and 2012-13 influenza seasons. Serum hemagglutination inhibition (HAI) assay was used to investigate anti-influenza antibody responses by comparing pre-vaccine and post-vaccine geometric mean titers (GMTs) between groups for each antigen. IgG1, IgG2, IgG3, and IgG4 anti-influenza titers were also evaluated by enzyme-linked immunosorbent assay (ELISA). Pregnancy induced shifts in HAI titers and levels of each anti-influenza antibody isotype were evaluated using linear regression models. RESULTS: Post-vaccine GMTs at day 28 were significantly reduced for women vaccinated during pregnancy for A/California (H1N1) in 2011 (p=0.027), A/Perth (H3N2) in 2011 (p=0.037), and B/Wisconsin in 2012 (p=0.039). Vaccine responses progressively declined with the initiation of vaccination later in pregnancy. Anti-H1N1 IgG1, IgG2, and IgG3 titers were reduced in pregnant women compared to non-pregnant controls, and these titers declined with pregnancy progression. The most striking differences were found for anti-H1N1 IgG1, where titers decreased by approximately 7% each week throughout pregnancy. CONCLUSIONS: HAI responses elicited by immunization were significantly reduced during pregnancy for three different influenza vaccine antigens. Anti-H1N1 IgG1 was significantly lower in pregnant women and decreased throughout the course of pregnancy. Waning serological responsiveness to influenza vaccination with the progression of human pregnancy has important translational implications for when immunization should be optimally administered during pregnancy.
117. Schulman PM, Gerstein NS, Merkel MJ, Braner DA, Tegtmeyer K. Ultrasound-Guided Cannulation of the Subclavian Vein. N. Engl. J. Med. Jul 5 2018;379(1):e1.
118. Schumacher DJ, Holmboe ES, van der Vleuten C, Busari JO, Carraccio C. Developing Resident-Sensitive Quality Measures: A Model From Pediatric Emergency Medicine. Acad. Med. Jul 2018;93(7):1071-1078.
PURPOSE: To begin closing the gap with respect to quality measures available for use among residents, the authors sought to identify and develop resident-sensitive quality measures (RSQMs) for use in the pediatric emergency department (PED) setting. METHOD: In May 2016, the authors reviewed National Quality Measures Clearinghouse (NQMC) measures to identify resident-sensitive measures. To create additional measures focused on common, acute illnesses (acute asthma exacerbation, bronchiolitis, closed head injury [CHI]) in the PED, the authors used a nominal group technique (NGT) and Delphi process from September to December 2016. To achieve a local focus for developing these measures, all NGT and Delphi participants were from Cincinnati Children's Hospital Medical Center. Delphi participants rated measures developed through the NGT in two areas: importance of measure to quality care and likelihood that measure represents the work of a resident. RESULTS: The review of NQMC measures identified 28 of 183 as being potentially resident sensitive. The NGT produced 67 measures for asthma, 46 for bronchiolitis, and 48 for CHI. These were used in the first round of the Delphi process. After two rounds, 18 measures for asthma, 21 for bronchiolitis, and 21 for CHI met automatic inclusion criteria. In round three, participants categorized the potential final measures by their top 10 and next 5. CONCLUSIONS: This study describes a template for identifying and developing RSQMs that may promote high-quality care delivery during and following training. Next steps should include implementing and seeking validity evidence for the locally developed measures.
119. Scorletti F, Hammill A, Patel M, Ricci K, Dasgupta R. Malignant tumors misdiagnosed as benign vascular anomalies. Pediatr. Blood Cancer. Jul 2018;65(7).
BackgroundMalignant soft tissue tumors are rare and difficult to diagnose in children. These can initially be misdiagnosed as benign vascular anomalies. Management of these two conditions differs drastically and delay in diagnosis may impact overall survival.
PurposeTo predict qualities that may increase the index of suspicion for malignancy in patients presenting with lesions initially considered vascular anomalies.
MethodsA retrospective review at a quaternary hemangioma and vascular malformation center of all patients who presented between 2008 and 2016 with an initial diagnosis of a benign vascular malformation, which on further work-up was noted to be a malignancy. Demographics, clinical presentation, and laboratory and radiologic studies were analyzed.
ResultsEleven patients were identified; the median age at presentation was 2 months (0-24years). Ten out of 11 lesions had rapid growth, which prompted biopsy. Pain was an inconsistent finding (36%). Tumor markers were positive in only one case. Median follow-up was 3 years (range 6 months to 8 years); seven patients have no evidence of disease, two patients are under treatment for progression or relapse of disease, and two patients have died.
ConclusionAlthough malignant vascular tumors are rare, a clear index of suspicion needs to be maintained particularly with rapid growth or increasing symptoms. Differentiation of malignant tumor from benign lesions relies on the comprehensive evaluation of clinical manifestations, evolution of the lesion, and abnormal clinical behavior, by an experienced multidisciplinary vascular malformation team. There should be a low threshold for biopsy of unclear vascular lesions.
120. Sengupta S, Sobo M, Lee K, Senthil Kumar S, White AR, Mender I, Fuller C, Chow LML, Fouladi M, Shay JW, Drissi R. Induced Telomere Damage to Treat Telomerase Expressing Therapy-Resistant Pediatric Brain Tumors. Mol. Cancer Ther. Jul 2018;17(7):1504-1514.
Brain tumors remain the leading cause of cancer-related deaths in children and often are associated with long-term sequelae among survivors of current therapies. Hence, there is an urgent need to identify actionable targets and to develop more effective therapies. Telomerase and telomeres play important roles in cancer, representing attractive therapeutic targets to treat children with poor-prognosis brain tumors such as diffuse intrinsic pontine glioma (DIPG), high-grade glioma (HGG), and high-risk medulloblastoma. We have previously shown that DIPG, HGG, and medulloblastoma frequently express telomerase activity. Here, we show that the telomerase-dependent incorporation of 6-thio-2'deoxyguanosine (6-thio-dG), a telomerase substrate precursor analogue, into telomeres leads to telomere dysfunction-induced foci (TIF) along with extensive genomic DNA damage, cell growth inhibition, and cell death of primary stem-like cells derived from patients with DIPG, HGG, and medulloblastoma. Importantly, the effect of 6-thio-dG is persistent even after drug withdrawal. Treatment with 6-thio-dG elicits a sequential activation of ATR and ATM pathways and induces G2-M arrest. In vivo treatment of mice bearing medulloblastoma xenografts with 6-thio-dG delays tumor growth and increases in-tumor TIFs and apoptosis. Furthermore, 6-thio-dG crosses the blood-brain barrier and specifically targets tumor cells in an orthotopic mouse model of DIPG. Together, our findings suggest that 6-thio-dG is a promising novel approach to treat therapy-resistant telomerase-positive pediatric brain tumors. Mol Cancer Ther; 17(7); 1504-14. (c)2018 AACR.
121. Shoda T, Wen T, Aceves SS, Abonia JP, Atkins D, Bonis PA, Caldwell JM, Capocelli KE, Carpenter CL, Collins MH, Dellon ES, Eby MD, Gonsalves N, Gupta SK, Falk GW, Hirano I, Menard-Katcher P, Kuhl JT, Krischer JP, Leung J, Mukkada VA, Spergel JM, Trimarchi MP, Yang GY, Zimmermann N, Furuta GT, Rothenberg ME, Consortium of Eosinophilic Gastrointestinal Disease R. Eosinophilic oesophagitis endotype classification by molecular, clinical, and histopathological analyses: a cross-sectional study. Lancet Gastroenterol Hepatol. Jul 2018;3(7):477-488.
BACKGROUND: Eosinophilic oesophagitis is understood in terms of quantifiable histological, endoscopic, and molecular features. Data are scant for inter-relations of these features and their potential to identify distinct disease endotypes. We aimed to identify clinical-pathological correlations between endoscopic and histological disease variables by transcription profiling of the oesophagus of patients with eosinophilic oesophagitis of varying severity and disease activity states. METHODS: We did a cross-sectional study across ten hospital sites in the USA associated with the Consortium of Eosinophilic Gastrointestinal Disease Researchers. We analysed oesophageal biopsy specimens taken from paediatric and adult patients with eosinophilic oesophagitis (discovery cohort), using the eosinophilic oesophagitis diagnostic panel (EDP), a set of 96 informative transcripts. Histological and endoscopic features were assessed by quantification of oesophageal eosinophils and use of the eosinophilic oesophagitis histology scoring system (HSS) and the eosinophilic oesophagitis endoscopic reference score (EREFS). Associations among the various histological, endoscopic, and molecular features were analysed by Spearman correlation. Results were replicated in a biologically independent, single-centre, validation cohort of patients with active eosinophilic oesophagitis. FINDINGS: The discovery cohort contained 185 samples and the validation cohort comprised 100 specimens. In the discovery cohort, EDP showed intersite consistency, significant correlation with oesophageal eosinophils (p<0.0001), and similar findings between paediatric and adult patients. Of eight HSS domains, basal zone hyperplasia correlated with the EDP (median Spearman rho 0.47 [IQR 0.36-0.60]). Of five EREFS features, distal furrows correlated with the EDP (median Spearman rho 0.42 [0.32-0.50]). By analysing active eosinophilic oesophagitis in the discovery cohort, the EDP identified three clusters associated with distinct endotypes (termed EoEe1-3) despite similar eosinophil levels. EoEe1 was associated with a normal-appearing oesophagus (risk ratio [RR] 3.27, 95% CI 1.04-10.27; p=0.0443), an inverse association with a history of oesophageal dilation (0.27, 0.09-0.82; p=0.0105) and showed relatively mild histological, endoscopic, and molecular changes. EoEe2 showed an inflammatory and steroid-refractory phenotype (RR 2.77, 95% CI 1.11-6.95; p=0.0376) and had the highest expression of inflammatory cytokines and steroid-responding genes. EoEe3 was associated with a narrow-calibre oesophagus (RR 7.98, 95% CI 1.84-34.64; p=0.0013) and adult onset (2.22, 1.19-4.12; p=0.0155), and showed the highest degree of endoscopic and histological severity and the lowest expression of epithelial differentiation genes. These endotypes were replicated in the validation cohort by clustering and with an eosinophilic oesophagitis endotype-prediction algorithm. INTERPRETATION: Our new disease classification stratifies patients with eosinophilic oesophagitis into subgroups with potential clinical and therapeutic significance and provides a framework for a precision medicine approach to eosinophilic oesophagitis. FUNDING: National Institutes of Health.
122. Shook LM, Ware RE. Effective screening leads to better outcomes in sickle cell disease. Arch. Dis. Child. Jul 2018;103(7):628-630.
123. Spar DS, Bianco NR, Knilans TK, Czosek RJ, Anderson JB. The US Experience of the Wearable Cardioverter-Defibrillator in Pediatric Patients. Circ Arrhythm Electrophysiol. Jul 2018;11(7):e006163.
BACKGROUND: Certain pediatric patients are at risk for sudden cardiac death. The wearable cardioverter-defibrillator (WCD) can be used in clinical situations in which implantable cardioverter-defibrillator placement is not ideal. The objectives of the study are to examine the effectiveness, safety, and compliance of the WCD in the identification and treatment of life-threatening ventricular arrhythmias in pediatric patients. METHODS: All United States pediatric patients <18 years who wore a WCD, from 2009 to 2016 were retrospectively reviewed. RESULTS: In total, 455 patients were identified. The median age was 15 (3-17) years, median duration of WCD use was 33 (1-999) days and median patient wear time was 20.6 (0.3-23.8) hours per day. The population was divided into 2 groups: (1) patients with implantable cardioverter-defibrillator problem, n=63 and (2) patients with nonimplantable cardioverter-defibrillator problem, n=392. Wear time per day was >20 hours in both groups. Wear duration was shorter in the implantable cardioverter-defibrillator problem group, 26 days versus 35 days, P<0.05. There were 7 deaths (1.5%); all not wearing WCD at time of death. Eight patients (1.8%) received at least 1 WCD shock treatment. Of the 6 patients (1.3%) who had appropriate therapy, there were 7 episodes of either polymorphic ventricular tachycardia or ventricular fibrillation with a total of 13 treatments delivered. All episodes were successfully converted and the patients survived. CONCLUSIONS: The WCD has overall adequate compliance with appropriate wear times and wear durations in pediatric patients. The WCD is safe and effective in treating ventricular arrhythmias that can lead to sudden cardiac death in pediatric patients.
124. Spergel JM, Aceves SS, Kliewer K, Gonsalves N, Chehade M, Wechsler JB, Groetch M, Friedlander J, Dellon ES, Book W, Hirano I, Muir AB, Cianferoni A, Spencer L, Liacouras CA, Cheng E, Kottyan L, Wen T, Platts-Mills T, Rothenberg ME. New developments in patients with eosinophilic gastrointestinal diseases presented at the CEGIR/TIGERS Symposium at the 2018 American Academy of Allergy, Asthma & Immunology Meeting. J. Allergy Clin. Immunol. Jul 2018;142(1):48-53.
The Consortium of Eosinophilic Gastrointestinal Diseases and the International Gastrointestinal Eosinophil Researchers organized a day-long symposium at the recent 2018 Annual Meeting of the American Academy of Allergy, Asthma & Immunology, which was coupled for the first time with the World Allergy Organization meeting to create an international platform. The symposium featured experts in many facets of eosinophilic gastrointestinal diseases, including allergy, immunology, gastroenterology, pathology, and nutrition, and was a well-attended event. The basic science, genetics, cellular immunology, and clinical features of the diseases, with a focus on epithelial, eosinophil, and mast cell responses, as well as current and emerging treatment options, were reviewed. Here we briefly review some of the highlights of the material presented at the meeting.
125. Stagaard R, Flick MJ, Bojko B, Gorynski K, Gorynska PZ, Ley CD, Olsen LH, Knudsen T. Abrogating fibrinolysis does not improve bleeding or rFVIIa/rFVIII treatment in a non-mucosal venous injury model in haemophilic rodents. J. Thromb. Haemost. Jul 2018;16(7):1369-1382.
Background: Fibrinolysis may exacerbate bleeding in patients with hemophilia A (HA). Accordingly, antifibrinolytics have been used to help maintain hemostatic control. Although antifibrinolytic drugs have been proven to be effective in the treatment of mucosal bleeds in the oral cavity, their efficacy in non-mucosal tissues remain an open question of significant clinical interest. Objective: To determine whether inhibiting fibrinolysis improves the outcome in non-mucosal hemophilic tail vein transection (TVT) bleeding models, and to determine whether a standard exvivo clotting/fibrinolysis assay can be used as a predictive surrogate for invivo efficacy. Methods: A highly sensitive TVT model was employed in hemophilic rodents with a suppressed fibrinolytic system to examine the effect of inhibiting fibrinolysis on bleeding in non-mucosal tissue. In mice, induced and congenital hemophilia models were combined with fibrinolytic attenuation achieved either genetically or pharmacologically (tranexamic acid [TXA]). In hemophilic rats, tail bleeding was followed by whole blood rotational thromboelastometry evaluation of the same animals to gauge the predictive value of such assays. Results: The beneficial effect of systemic TXA therapy observed exvivo could not be confirmed invivo in hemophilic rats. Furthermore, neither intravenously administered TXA nor congenital knockout of the fibrinolytic genes encoding plasminogen or tissue-type plasminogen activator markedly improved the TVT bleeding phenotype or response to factor therapy in hemophilic mice. Conclusions: The findings here suggest that inhibition of fibrinolysis is not effective in limiting the TVT bleeding phenotype of HA rodents in non-mucosal tissues.
126. Thomas R, Higgins L, Ding LL, Widdice LE, Chandler E, Kahn JA. Factors Associated With HPV Vaccine Initiation, Vaccine Completion, and Accuracy of Self-Reported Vaccination Status Among 13-to 26-Year-Old Men. American Journal of Mens Health. Jul 2018;12(4):819-827.
Human papillomavirus (HPV) vaccination coverage in young men is suboptimal. The aims of this study were (a) to examine HPV vaccination and factors associated with HPV vaccination in men 13 to 26 years of age and (b) to examine and determine factors associated with accurate self-report of vaccination. Young men (n = 400) recruited from a teen health center and a sexually transmitted disease (STD) clinic completed a survey. Accuracy was defined as correct report of at least one dose and number of doses. Mean age was 21.5 years, 104 (26.0%) received at least one vaccine dose and 49 (12.3%) received all three doses. Factors significantly associated with receipt of at least one dose in multivariable models included recruitment site (teen health center vs. STD clinic, adjusted odds ratio [AOR] = 2.75), public versus other insurance (AOR = 2.12), and age (AOR = 0.68). Most young men accurately reported their vaccination status but accuracy of report differed by age: 50.6% of 14- to 18-year-olds, 75.9% of 19- to 21-year-olds, and 93.2% of 22- to 26-year-olds. Most (293, 73.3%) accurately reported number of doses received. Age was associated with accuracy of self-report of at least one vaccine dose (AOR = 1.42), while recruitment site (STD vs. teen health center, AOR = 2.56) and age (AOR = 1.44) were associated with accuracy of self-report of number of vaccine doses. In conclusion, HPV initiation and completion in this study sample were low. Teen health center attendance, public insurance, and younger age were associated with vaccine initiation; older age and STD clinic setting were associated with accurate vaccination self-report.
127. Udobi KC, Kokenge AN, Hautman ER, Ullio G, Coene J, Williams MT, Vorhees CV, Mabondzo A, Skelton MR. Cognitive deficits and increases in creatine precursors in a brain-specific knockout of the creatine transporter gene Slc6a8. Genes Brain Behav. Jul 2018;17(6):e12461.
Creatine transporter (CrT; SLC6A8) deficiency (CTD) is an X-linked disorder characterized by severe cognitive deficits, impairments in language and an absence of brain creatine (Cr). In a previous study, we generated floxed Slc6a8 (Slc6a8 (flox) ) mice to create ubiquitous Slc6a8 knockout (Slc6a8(-/y) ) mice. Slc6a8(-/y) mice lacked whole body Cr and exhibited cognitive deficits. While Slc6a8(-/y) mice have a similar biochemical phenotype to CTD patients, they also showed a reduction in size and reductions in swim speed that may have contributed to the observed deficits. To address this, we created brain-specific Slc6a8 knockout (bKO) mice by crossing Slc6a8(flox) mice with Nestin-cre mice. bKO mice had reduced cerebral Cr levels while maintaining normal Cr levels in peripheral tissue. Interestingly, brain concentrations of the Cr synthesis precursor guanidinoacetic acid were increased in bKO mice. bKO mice had longer latencies and path lengths in the Morris water maze, without reductions in swim speed. In accordance with data from Slc6a8 (-/y) mice, bKO mice showed deficits in novel object recognition as well as contextual and cued fear conditioning. bKO mice were also hyperactive, in contrast with data from the Slc6a8 (-/y) mice. The results show that the loss of cerebral Cr is responsible for the learning and memory deficits seen in ubiquitous Slc6a8(-/y) mice.
128. Vagnozzi RJ, Molkentin JD, Houser SR. New Myocyte Formation in the Adult Heart: Endogenous Sources and Therapeutic Implications. Circ. Res. Jul 6 2018;123(2):159-176.
Death of adult cardiac myocytes and supportive tissues resulting from cardiovascular diseases such as myocardial infarction is the proximal driver of pathological ventricular remodeling that often culminates in heart failure. Unfortunately, no currently available therapeutic barring heart transplantation can directly replenish myocytes lost from the injured heart. For decades, the field has struggled to define the intrinsic capacity and cellular sources for endogenous myocyte turnover in pursuing more innovative therapeutic strategies aimed at regenerating the injured heart. Although controversy persists to this day as to the best therapeutic regenerative strategy to use, a growing consensus has been reached that the very limited capacity for new myocyte formation in the adult mammalian heart is because of proliferation of existing cardiac myocytes but not because of the activity of an endogenous progenitor cell source of some sort. Hence, future therapeutic approaches should take into consideration the fundamental biology of myocyte renewal in designing strategies to potentially replenish these cells in the injured heart.
129. von Bueren AO, Karremann M, Gielen GH, Benesch M, Fouladi M, van Vuurden DG, van Zanten S, Hoffman LM, Kramm CM. A suggestion to introduce the diagnosis of "diffuse midline glioma of the pons, H3 K27 wildtype (WHO grade IV)". Acta Neuropathol. Jul 2018;136(1):171-173.
130. Walsh KE, Marsolo KA, Davis C, Todd T, Martineau B, Arbaugh C, Verly F, Samson C, Margolis P. Accuracy of the medication list in the electronic health record-implications for care, research, and improvement. J. Am. Med. Inform. Assoc. Jul 1 2018;25(7):909-912.
Objective: Electronic medication lists may be useful in clinical decision support and research, but their accuracy is not well described. Our aim was to assess the completeness of the medication list compared to the clinical narrative in the electronic health record. Methods: We reviewed charts of 30 patients with inflammatory bowel disease (IBD) from each of 6 gastroenterology centers. Centers compared IBD medications from the medication list to the clinical narrative. Results: We reviewed 379 IBD medications among 180 patients. There was variation by center, from 90% patients with complete agreement between the medication list and clinical narrative to 50% agreement. Conclusions: There was a range in the accuracy of the medication list compared to the clinical narrative. This information may be helpful for sites seeking to improve data quality and those seeking to use medication list data for research or clinical decision support.
131. Wasserman H, Backeljauw PF, Khoury JC, Kalkwarf HJ, Gordon CM. Bone fragility in Turner syndrome: Fracture prevalence and risk factors determined by a national patient survey. Clin. Endocrinol. (Oxf.). Jul 2018;89(1):46-55.
OBJECTIVE: Osteoporosis is considered a comorbidity of adult women with Turner syndrome (TS). Limited data are available on fracture prevalence in girls and women with this diagnosis. We aimed to determine the prevalence of fractures in individuals with TS in the United States and identify risk factors for fracture. DESIGN: Girls and women with TS were invited to participate in an anonymous, self-report, national survey from November 2016 to March 2017. Non-TS controls were obtained through direct contacts of TS participants. RESULTS: During childhood (0-12 years), adolescence (13-25 years) and young adulthood (26-45 years), there was no difference between TS and controls in fracture prevalence. Girls and women with TS were more likely to report upper extremity fractures, whereas controls were more likely to report phalangeal fractures. Older women (>45 years) with TS were more likely to fracture than non-TS controls (P = .01). Balance problems were more common in individuals with TS than controls (26.5% vs 14.8%, P = .0006). In TS, those reporting balance problems were 54% more likely to have a prior fracture than those without balance problems (OR=1.54, 95% CI 1.03, 2.30), even after controlling for age. There was no significant association between balance problems and fractures among controls. CONCLUSIONS: In a nationwide survey, there was no difference in fracture prevalence in younger women with TS compared with controls. However, the location of fractures differed. After controlling for age, impaired balance was associated with an increased fracture risk in TS and may be an underrecognized risk factor for fracture in this population.
132. Wei C, Stock L, Schneider-Gold C, Sommer C, Timchenko NA, Timchenko L. Reduction of Cellular Nucleic Acid Binding Protein Encoded by a Myotonic Dystrophy Type 2 Gene Causes Muscle Atrophy. Mol. Cell. Biol. Jul 15 2018;38(14).
Myotonic dystrophy type 2 (DM2) is a neuromuscular disease caused by an expansion of intronic CCTG repeats in the CNBP gene, which encodes a protein regulating translation and transcription. To better understand the role of cellular nucleic acid binding protein (CNBP) in DM2 pathology, we examined skeletal muscle in a new model of Cnbp knockout (KO) mice. This study showed that a loss of Cnbp disturbs myofibrillar sarcomeric organization at birth. Surviving homozygous Cnbp KO mice develop muscle atrophy at a young age. The skeletal muscle phenotype in heterozygous Cnbp KO mice was milder, but they developed severe muscle wasting at an advanced age. Several proteins that control global translation and muscle contraction are altered in muscle of Cnbp KO mice. A search for CNBP binding proteins showed that CNBP interacts with the alpha subunit of the dystroglycan complex, a core component of the multimeric dystrophin-glycoprotein complex, which regulates membrane stability. Whereas CNBP is reduced in cytoplasm of DM2 human fibers, it is a predominantly membrane protein in DM2 fibers, and its interaction with alpha-dystroglycan is increased in DM2. These findings suggest that alterations of CNBP in DM2 might cause muscle atrophy via CNBP-mediated translation and via protein-protein interactions affecting myofiber membrane function.
133. Woods JC, Conradi MS. He-3 diffusion MRI in human lungs. J. Magn. Reson. Jul 2018;292:90-98.
Hyperpolarized He-3 gas allows the air spaces of the lungs to be imaged via MRI. Imaging of restricted diffusion is addressed here, which allows the microstructure of the lung to be characterized through the physical restrictions to gas diffusion presented by airway and alveolar walls in the lung. Measurements of the apparent diffusion coefficient (ADC) of He-3 at time scales of milliseconds and seconds are compared; measurement of acinar airway sizes by determination of the microscopic anisotropy of diffusion is discussed. This is where Dr. JJH Ackerman's influence was greatest in aiding the formation of the Washington University He-3 group, involving early a combination of physicists, radiologists, and surgeons, as the first applications of He-3 ADC were to COPD and its destruction/modification of lung microstructure via emphysema. The sensitivity of the method to early COPD is demonstrated, as is its validation by direct comparison to histology. More recently the method has been used broadly in adult and pediatric obstructive lung diseases, from severe asthma to cystic fibrosis to bronchopulmonary dysplasia, a result of premature birth. These applications of the technique are discussed briefly. (C) 2018 Elsevier Inc. All rights reserved.
134. Zhang Y, Zhang B. Semiparametric spatial model for interval-censored data with time-varying covariate effects. Comput. Stat. Data Anal. Jul 2018;123:146-156.
Cox regression is one of the most commonly used methods in the analysis of interval-censored failure time data. In many practical studies, the covariate effects on the failure time may not be constant over time. Time-varying coefficients are therefore of great interest due to their flexibility in capturing the temporal covariate effects. To analyze spatially correlated interval-censored time-to-event data with time-varying covariate effects, a Bayesian approach with dynamic Cox regression model is proposed. The coefficient is estimated as a piecewise constant function and the number of jump points estimated from the data. A conditional autoregressive distribution is employed to model the spatial dependency. The posterior summaries are obtained via an efficient reversible jump Markov chain Monte Carlo algorithm. The properties of our method are illustrated by simulation studies as well as an application to smoking cessation data in southeast Minnesota. (C) 2018 Elsevier B.V. All rights reserved.
135. Zhou YL, Yan XM, Feng XM, Bu JC, Dong YZ, Lin PP, Hayashi Y, Huang R, Olsson A, Andreassen PR, Grimes HL, Wang QF, Cheng T, Xiao ZJ, Jin J, Huang G. Setd2 regulates quiescence and differentiation of adult hematopoietic stem cells by restricting RNA polymerase II elongation. Haematologica. Jul 3 2018;103(7):1110-1123.
SET domain containing 2 (Setd2), encoding a histone methyltransferase, is associated with many hematopoietic diseases when mutated. By generating a novel exon 6 conditional knockout mouse model, we describe an essential role of Setd2 in maintaining the adult hematopoietic stem cells. Loss of Setd2 results in leukopenia, anemia, and increased platelets accompanied by hypocellularity, erythroid dysplasia, and mild fibrosis in bone marrow. Setd2 knockout mice show significantly decreased hematopoietic stem and progenitor cells except for erythroid progenitors. Setd2 knockout hematopoietic stem cells fail to establish long-term bone marrow reconstitution after transplantation because of the loss of quiescence, increased apoptosis, and reduced multiple-lineage terminal differentiation potential. Bioinformatic analysis revealed that the hematopoietic stem cells exit from quiescence and commit to differentiation, which lead to hematopoietic stem cell exhaustion. Mechanistically, we attribute an important Setd2 function in murine adult hematopoietic stem cells to the inhibition of the Nsd1/2/3 transcriptional complex, which recruits super elongation complex and controls RNA polymerase II elongation on a subset of target genes, including Myc. Our results reveal a critical role of Setd2 in regulating quiescence and differentiation of hematopoietic stem cells through restricting the NSDs/SEC mediated RNA polymerase II elongation.