Eunice Kennedy Shriver National Institute of Child Health and Development

Bethesda, MD, United States

Eunice Kennedy Shriver National Institute of Child Health and Development

Bethesda, MD, United States

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Newth C.J.L.,Childrens Hospital Los Angeles | Meert K.L.,Childrens Hospital of Michigan | Clark A.E.,University of Utah | Moler F.W.,University of Michigan | And 14 more authors.
Journal of Pediatrics | Year: 2012

Objective: To characterize the clinical course, therapies, and outcomes of children with fatal and near-fatal asthma admitted to pediatric intensive care units (PICUs). Study design: This was a retrospective chart abstraction across the 8 tertiary care PICUs of the Collaborative Pediatric Critical Care Research Network (CPCCRN). Inclusion criteria were children (aged 1-18 years) admitted between 2005 and 2009 (inclusive) for asthma who received ventilation (near-fatal) or died (fatal). Data collected included medications, ventilator strategies, concomitant therapies, demographic information, and risk variables. Results: Of the 261 eligible children, 33 (13%) had no previous history of asthma, 218 (84%) survived with no known complications, and 32 (12%) had complications. Eleven (4%) died, 10 of whom had experienced cardiac arrest before admission. Patients intubated outside the PICU had a shorter duration of ventilation (median, 25 hours vs 84 hours; P <.001). African-Americans were disproportionately represented among the intubated children and had a shorter duration of intubation. Barotrauma occurred in 15 children (6%) before admission. Pharmacologic therapy was highly variable, with similar outcomes. Conclusion: Of the children ventilated in the CPCCRN PICUs, 96% survived to hospital discharge. Most of the children who died experienced cardiac arrest before admission. Intubation outside the PICU was correlated with shorter duration of ventilation. Complications of barotrauma and neuromyopathy were uncommon. Practice patterns varied widely among the CPCCRN sites. Copyright © 2012 Mosby Inc.


Anand K.J.S.,University of Tennessee Health Science Center | Clark A.E.,University of Utah | Willson D.F.,University of Virginia | Berger J.,Childrens National Medical Center | And 9 more authors.
Pediatric Critical Care Medicine | Year: 2013

OBJECTIVE:: To examine the clinical factors associated with increased opioid dose among mechanically ventilated children in the pediatric intensive care unit. DESIGN:: Prospective, observational study with 100% accrual of eligible patients. SETTING:: Seven pediatric intensive care units from tertiary-care children's hospitals in the Collaborative Pediatric Critical Care Research Network. PATIENTS:: Four hundred nineteen children treated with morphine or fentanyl infusions. INTERVENTIONS:: None. MEASUREMENTS AND MAIN RESULTS:: Data on opioid use, concomitant therapy, demographic and explanatory variables were collected. Significant variability occurred in clinical practices, with up to 100-fold differences in baseline opioid doses, average daily or total doses, or peak infusion rates. Opioid exposure for 7 or 14 days required doubling of the daily opioid dose in 16% patients (95% confidence interval 12%-19%) and 20% patients (95% confidence interval 16%-24%), respectively. Among patients receiving opioids for longer than 3 days (n = 225), this occurred in 28% (95% confidence interval 22%-33%) and 35% (95% confidence interval 29%-41%) by 7 or 14 days, respectively. Doubling of the opioid dose was more likely to occur following opioid infusions for 7 days or longer (odds ratio 7.9, 95% confidence interval 4.3-14.3; p < 0.001) or co-therapy with midazolam (odds ratio 5.6, 95% confidence interval 2.4-12.9; p < 0.001), and it was less likely to occur if morphine was used as the primary opioid (vs. fentanyl) (odds ratio 0.48, 95% confidence interval 0.25-0.92; p = 0.03), for patients receiving higher initial doses (odds ratio 0.96, 95% confidence interval 0.95-0.98; p < 0.001), or if patients had prior pediatric intensive care unit admissions (odds ratio 0.37, 95% confidence interval 0.15-0.89; p = 0.03). CONCLUSIONS:: Mechanically ventilated children require increasing opioid doses, often associated with prolonged opioid exposure or the need for additional sedation. Efforts to reduce prolonged opioid exposure and clinical practice variation may prevent the complications of opioid therapy. Copyright © 2013 by the Society of Critical Care Medicine and the World.


Zimmerman J.J.,University of Washington | Donaldson A.,University of Utah | Barker R.M.,University of Washington | Meert K.L.,Childrens Hospital of Michigan | And 9 more authors.
Pediatric Critical Care Medicine | Year: 2011

Objectives: Ascertainment of adrenal function assessing free rather that total cortisol may be beneficial for the diagnosis of critical illness-related cortisol insufficiency. We hypothesized that centrifugal ultrafiltration would provide timely free cortisol data that highly correlated with the gold standard, but logistically cumbersome, equilibrium dialysis technique when the free cortisol fractions were identically quantified by chemiluminescence immunoassay. We also hypothesized that free cortisol would correlate with illness severity in a large cohort of critically ill children. Design: Prospective, multi-institutional, observational cohort investigation. Setting: Seven pediatric intensive care units within the Eunice Kennedy Shriver National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network. Patients: One hundred sixty-five critically ill children across the spectrum of illness severity. Interventions: Blood sampling. Measurements and Main Results: Time to derive plasma free cortisol concentrations after centrifugal ultrafiltration or equilibrium dialysis fractionation with chemiluminescence immunoassay was approximately 2 vs. approximately 24 hrs, respectively. Using centrifugal ultrafiltration, mean plasma free cortisol was 4.1 ± 6.7 μg/dL (median, 1.6 μg/dL; range, 0.2- 43.6 μg/L), representing an average of 15.2 ± 9.4% of total cortisol. Nearly 60% of subjects exhibited free cortisol <2 and 30% <0.8 μg/dL, previously suggested threshold concentrations for defining critical illness-related cortisol insufficiency. Plasma-free cortisol concentrations comparing centrifugal ultrafiltration vs. equilibrium dialysis fractionation demonstrated a strong correlation (R 2 = 0.97). For free cortisol <2 μg/dL, Bland-Altman analysis revealed minimal negative bias for the centrifugal ultrafiltration technique. Illness severity assessed by Pediatric Risk of Mortality III correlated moderately with free cortisol and percent total cortisol as free cortisol. Conclusions: Determination of centrifugal ultrafiltration fractionated free cortisol was fast and results correlated highly with equilibrium dialysis fractionated free cortisol. Many children exhibited free cortisol <2 and <0.8 μg/dL but did not demonstrate clinical evidence of critical illness-related cortisol insufficiency. This study ascertains that real-time free cortisol quantification is feasible to potentially help guide clinical decisionmaking for cortisol replacement therapy in the pediatric intensive care unit. Copyright © 2011 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.


PubMed | Eunice Kennedy Shriver National Institute of Child Health and Development and University of Maryland College Park
Type: Journal Article | Journal: Journal of adolescent research | Year: 2016

Family socialization, which includes parental control and support, plays an important role in reducing the likelihood of adolescent involvement in conflict. This study examined the strategies that urban parents living in neighborhoods with high crime rates suggest to help their adolescent children avoid or deescalate conflict. Data come from 48 African American parent/adolescent dyads recruited through the youths middle school. Dyads responded to three video-taped scenarios depicting youth in potential conflict situations. Qualitative methods were used to identify 11 strategies parents suggested to help youth avoid or deescalate conflict. Although the majority of parents advocated for non-violent solutions, these same parents described situations in which their child may need to use violence. These findings have important implications for family-focused violence prevention programs.


Sourbier C.,Urologic | Ricketts C.J.,Urologic | Matsumoto S.,U.S. National Cancer Institute | Crooks D.R.,Urologic | And 16 more authors.
Cancer Cell | Year: 2014

Patients with germline fumarate hydratase (. FH) mutation are predisposed to develop aggressive kidney cancer with few treatment options and poor therapeutic outcomes. Activity of the proto-oncogene ABL1 is upregulated in FH-deficient kidney tumors and drives a metabolic and survival signaling network necessary to cope with impaired mitochondrial function and abnormal accumulation of intracellular fumarate. Excess fumarate indirectly stimulates ABL1 activity, while restoration of wild-type FH abrogates both ABL1 activation and the cytotoxicity caused by ABL1 inhibition or knockdown. ABL1 upregulates aerobic glycolysis via the mTOR/HIF1α pathway and neutralizes fumarate-induced proteotoxic stress by promoting nuclear localization of the antioxidant response transcription factor NRF2. Our findings identify ABL1 as a pharmacologically tractable therapeutic target in glycolytically dependent, oxidatively stressed tumors. © 2014 Elsevier Inc.


Tong W.-H.,Eunice Kennedy Shriver National Institute of Child Health and Development | Sourbier C.,Urologic | Kovtunovych G.,Eunice Kennedy Shriver National Institute of Child Health and Development | Jeong S.,Eunice Kennedy Shriver National Institute of Child Health and Development | And 16 more authors.
Cancer Cell | Year: 2011

Inactivation of the TCA cycle enzyme, fumarate hydratase (FH), drives a metabolic shift to aerobic glycolysis in FH-deficient kidney tumors and cell lines from patients with hereditary leiomyomatosis renal cell cancer (HLRCC), resulting in decreased levels of AMP-activated kinase (AMPK) and p53 tumor suppressor, and activation of the anabolic factors, acetyl-CoA carboxylase and ribosomal protein S6. Reduced AMPK levels lead to diminished expression of the DMT1 iron transporter, and the resulting cytosolic iron deficiency activates the iron regulatory proteins, IRP1 and IRP2, and increases expression of the hypoxia inducible factor HIF-1α, but not HIF-2α. Silencing of HIF-1α or activation of AMPK diminishes invasive activities, indicating that alterations of HIF-1α and AMPK contribute to the oncogenic growth of FH-deficient cells. © 2011 Elsevier Inc.


PubMed | Urologic, Eunice Kennedy Shriver National Institute of Child Health and Development, Duke University and U.S. National Cancer Institute
Type: Journal Article | Journal: Cancer cell | Year: 2014

Patients with germline fumarate hydratase (FH) mutation are predisposed to develop aggressive kidney cancer with few treatment options and poor therapeutic outcomes. Activity of the proto-oncogene ABL1 is upregulated in FH-deficient kidney tumors and drives a metabolic and survival signaling network necessary to cope with impaired mitochondrial function and abnormal accumulation of intracellular fumarate. Excess fumarate indirectly stimulates ABL1 activity, while restoration of wild-type FH abrogates both ABL1 activation and the cytotoxicity caused by ABL1 inhibition or knockdown. ABL1 upregulates aerobic glycolysis via the mTOR/HIF1 pathway and neutralizes fumarate-induced proteotoxic stress by promoting nuclear localization of the antioxidant response transcription factor NRF2. Our findings identify ABL1 as a pharmacologically tractable therapeutic target in glycolytically dependent, oxidatively stressed tumors.


PubMed | Johns Hopkins University, University of Virginia, Eunice Kennedy Shriver National Institute of Child Health and Development and Arizona State University
Type: Journal Article | Journal: Journal of youth and adolescence | Year: 2016

This article examined the role of caregiver messages about violence and exposure to neighborhood violence on adolescent aggression in light of research regarding discrepancies between parents and their children. Drawing upon data from an urban African American sample of 144 caregiver/early adolescent dyads (M=12.99; SD=0.93; 58.7% female) we examined covariates of discrepancies between caregiver and adolescent reports of perceptions of violence as well as their association with adolescent aggression. Analyses suggested that concordance in perceptions of violence was associated with childrens attitudes about violence and caregivers perceptions of family communication. Structural equation modeling indicated a unique role for individual perceptions and suggested that agreement in awareness of neighborhood violence could be protective for early adolescent involvement in aggression.


Davis K.D.,Pennsylvania State University | Lawson K.M.,Ball State University | Almeida D.M.,Pennsylvania State University | Kelly E.L.,University of Minnesota | And 6 more authors.
Pediatrics | Year: 2015

OBJECTIVES: In the context of a group randomized field trial, we evaluated whether parents who participated in a workplace intervention, designed to increase supervisor support for personal and family life and schedule control, reported significantly more daily time with their children at the 12-month follow-up compared with parents assigned to the Usual Practice group. We also tested whether the intervention effect was moderated by parent gender, child gender, or child age. METHODS: The Support-Transform-Achieve-Results Intervention was delivered in an information technology division of a US Fortune 500 company. Participants included 93 parents (45% mothers) of a randomly selected focal child aged 9 to 17 years (49% daughters) who completed daily telephone diaries at baseline and 12 months after intervention. During evening telephone calls on 8 consecutive days, parents reported how much time they spent with their child that day. RESULTS: Parents in the intervention group exhibited a significant increase in parent-child shared time, 39 minutes per day on average, between baseline and the 12-month follow-up. By contrast, parents in the Usual Practice group averaged 24 fewer minutes with their child per day at the 12-month follow-up. Intervention effects were evident for mothers but not for fathers and for daughters but not sons. CONCLUSIONS: The hypothesis that the intervention would improve parents' daily time with their children was supported. Future studies should examine how redesigning work can change the quality of parent-child interactions and activities known to be important for youth health and development. Copyright © 2015 by the American Academy of Pediatrics.


Yang X.,U.S. National Institutes of Health | Yang X.,Eunice Kennedy Shriver National Institute of Child Health and Development | Zhou X.,U.S. National Institutes of Health | Tone P.,University of Richmond | And 2 more authors.
Oncology Letters | Year: 2016

Human hepatocellular carcinoma (HCC) is one of the most common types of cancer and has a very poor prognosis; thus, the development of effective therapies for the treatment of advanced HCC is of high clinical priority. In the present study, the anti-oncogenic effect of combined knockdown of c-Myc expression and ectopic restoration of deleted in liver cancer 1 (DLC1) expression was investigated in human liver cancer cells. Expression of c-Myc in human HCC cells was knocked down by stable transfection with a Myc-specific short hairpin (sh) RNA vector. DLC1 expression in Huh7 cells was restored by adenovirus transduction, and the effects of DLC1 expression and c-Myc knockdown on Ras homolog gene family, member A (RhoA) levels, cell proliferation, soft agar colony formation and cell invasion were measured. Downregulation of c-Myc or re-expression of DLC1 led to a marked reduction in RhoA levels, which was associated with decreases in cell proliferation, soft agar colony formation and invasiveness; this inhibitory effect was augmented with a combination of DLC1 transduction and c-Myc suppression. To determine whether liver cell-specific delivery of DLC1 was able to enhance the inhibitory effect of c-Myc knockdown on tumor growth in vivo, DLC1 vector DNA complexed with galactosylated polyethylene glycol-linear polyethyleneimine was administered by tail vein injection to mice bearing subcutaneous xenografts of Huh7 cells transfected with shMyc or control shRNA. A cooperative inhibitory effect of DLC1 expression and c-Myc knockdown on the growth of Huh7-derived tumors was observed, suggesting that targeted liver cell delivery of DLC1 and c-Myc shRNA may serve as a possible gene therapy modality for the treatment of human HCC. © 2016, Spandidos Publications. All rights reserved.

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