Publications by authors named "Judy L Aschner"

97 Publications

Persistence of symptoms and quality of life at 35 days after hospitalization for COVID-19 infection.

PLoS One 2020 11;15(12):e0243882. Epub 2020 Dec 11.

Department of Pediatrics, Hackensack Meridian School of Medicine, Nutley, New Jersey, United States of America.

Background: Characterizing the prevalence and persistence of symptoms associated with COVID-19 infection following hospitalization and their impact is essential to planning post-acute community-based clinical services. This study seeks to identify persistent COVID-19 symptoms in patients 35 days post-hospitalization and their impact on quality of life, health, physical, mental, and psychosocial function.

Methods And Findings: This prospective cohort study used the PROMIS® Instruments to identify symptoms and quality of life parameters in consecutively enrolled patients between March 22 and April 16, 2020, in New Jersey. The 183 patients (median age 57 years; 61.5% male, 54.1% white) reported persistent symptoms at 35 days, including fatigue (55.0%), dyspnea (45.3%), muscular pain (51%), associated with a lower odds rating general health (41.5%, OR 0.093 [95% CI: 0.026, 0.329], p = 0.0002), quality of life (39.8%; OR 0.116 [95% CI: 0.038, 0.364], p = 0.0002), physical health (38.7%, OR 0.055 [95% CI: 0.016, 0.193], p <0.0001), mental health (43.7%, OR 0.093 [95% CI: 0.021, 0.418], p = 0.0019) and social active role (38.7%, OR 0.095 [95% CI: 0.031, 0.291], p<0.0001), as very good/excellent, particularly adults aged 65 to 75 years (OR 8·666 [95% CI: 2·216, 33·884], p = 0·0019).

Conclusions: COVID-19 symptoms commonly persist to 35 days, impacting quality of life, health, physical and mental function. Early post-acute evaluation of symptoms and their impact on function is necessary to plan community-based services.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243882PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732078PMC
December 2020

Severe Acute Respiratory Syndrome Coronavirus 2 Clinical Syndromes and Predictors of Disease Severity in Hospitalized Children and Youth.

J Pediatr 2021 03 14;230:23-31.e10. Epub 2020 Nov 14.

Department of Pediatrics, Albert Einstein College of Medicine, Children's Hospital at Montefiore, Bronx, NY.

Objective: To characterize the demographic and clinical features of pediatric severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) syndromes and identify admission variables predictive of disease severity.

Study Design: We conducted a multicenter, retrospective, and prospective study of pediatric patients hospitalized with acute SARS-CoV-2 infections and multisystem inflammatory syndrome in children (MIS-C) at 8 sites in New York, New Jersey, and Connecticut.

Results: We identified 281 hospitalized patients with SARS-CoV-2 infections and divided them into 3 groups based on clinical features. Overall, 143 (51%) had respiratory disease, 69 (25%) had MIS-C, and 69 (25%) had other manifestations including gastrointestinal illness or fever. Patients with MIS-C were more likely to identify as non-Hispanic black compared with patients with respiratory disease (35% vs 18%, P = .02). Seven patients (2%) died and 114 (41%) were admitted to the intensive care unit. In multivariable analyses, obesity (OR 3.39, 95% CI 1.26-9.10, P = .02) and hypoxia on admission (OR 4.01; 95% CI 1.14-14.15; P = .03) were predictive of severe respiratory disease. Lower absolute lymphocyte count (OR 8.33 per unit decrease in 10 cells/L, 95% CI 2.32-33.33, P = .001) and greater C-reactive protein (OR 1.06 per unit increase in mg/dL, 95% CI 1.01-1.12, P = .017) were predictive of severe MIS-C. Race/ethnicity or socioeconomic status were not predictive of disease severity.

Conclusions: We identified variables at the time of hospitalization that may help predict the development of severe SARS-CoV-2 disease manifestations in children and youth. These variables may have implications for future prognostic tools that inform hospital admission and clinical management.
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http://dx.doi.org/10.1016/j.jpeds.2020.11.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666535PMC
March 2021

Transcriptional profiling of lung macrophages identifies a predictive signature for inflammatory lung disease in preterm infants.

Commun Biol 2020 May 22;3(1):259. Epub 2020 May 22.

Department of Pediatrics, Rady Children's Hospital, University of California, San Diego, La Jolla, CA, 92093, USA.

Lung macrophages mature after birth, placing newborn infants, particularly those born preterm, within a unique window of susceptibility to disease. We hypothesized that in preterm infants, lung macrophage immaturity contributes to the development of bronchopulmonary dysplasia (BPD), the most common serious complication of prematurity. By measuring changes in lung macrophage gene expression in preterm patients at risk of BPD, we show here that patients eventually developing BPD had higher inflammatory mediator expression even on the first day of life. Surprisingly, the ex vivo response to LPS was similar across all samples. Our analysis did however uncover macrophage signature genes whose expression increased in the first week of life specifically in patients resilient to disease. We propose that these changes describe the dynamics of human lung macrophage differentiation. Our study therefore provides new mechanistic insight into both neonatal lung disease and human developmental immunology.
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http://dx.doi.org/10.1038/s42003-020-0985-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7244484PMC
May 2020

Combined l-citrulline and tetrahydrobiopterin therapy improves NO signaling and ameliorates chronic hypoxia-induced pulmonary hypertension in newborn pigs.

Am J Physiol Lung Cell Mol Physiol 2020 04 19;318(4):L762-L772. Epub 2020 Feb 19.

Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee.

Newborn pigs with chronic hypoxia-induced pulmonary hypertension (PH) have evidence of endothelial nitric oxide synthase (eNOS) uncoupling. In this model, we showed that therapies that promote eNOS coupling, either tetrahydrobiopterin (BH), a NOS cofactor, or l-citrulline, a NO-l-arginine precursor, inhibit PH. We wanted to determine whether cotreatment with l-citrulline and a BH compound, sapropterin dihydrochloride, improves NO signaling and chronic hypoxia-induced PH more markedly than either alone. Normoxic (control) and hypoxic piglets were studied. Some hypoxic piglets received sole treatment with l-citrulline or BH, or were cotreated with l-citrulline and BH, from through of hypoxia. Catheters were placed for hemodynamic measurements, and pulmonary arteries were dissected to assess eNOS dimer-to-monomer ratios and NO production. In untreated hypoxic piglets, pulmonary vascular resistance (PVR) was higher and NO production and eNOS dimer-to-monomer ratios were lower than in normoxic piglets. Compared with the untreated hypoxic group, PVR was lower in hypoxic piglets cotreated with l-citrulline and BH and in those treated with l-citrulline alone but not for those treated solely with BH. NO production and eNOS dimer-to-monomer ratios were greater for all three treated hypoxic groups compared with the untreated group. Notably, greater improvements in PVR, eNOS dimer-to-monomer ratios, and NO production were found in hypoxic piglets cotreated with l-citrulline and BH than in piglets treated with either alone. Cotreatment with l-citrulline and BH more effectively improves NO signaling and inhibits chronic hypoxia-induced PH than either treatment alone. Combination therapies may offer enhanced therapeutic capacity for challenging clinical conditions, such as chronic neonatal PH.
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http://dx.doi.org/10.1152/ajplung.00280.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191483PMC
April 2020

Meningitis, urinary tract, and bloodstream infections in very low birth weight infants enrolled in a heart rate characteristics monitoring trial.

Pediatr Res 2020 06 4;87(7):1226-1230. Epub 2019 Dec 4.

University of Virginia, Charlottesville, VA, USA.

Background: Displaying heart rate characteristic (HRC) scores was associated with lower sepsis-associated mortality in very low birth weight (VLBW) infants in a multicenter randomized controlled trial (HeRO trial). The aim of this study was to test whether HRC indices rise before diagnosis of urinary tract infection (UTI) or meningitis, with and without concomitant BSI.

Methods: Blood, urine, and cerebrospinal fluid (CSF) culture data after 3 days of age and within 120 days of study enrollment were analyzed from 2989 VLBW infants. The HRC index was analyzed 12 h prior to positive cultures compared to 36 h prior, using paired signed-rank tests.

Results: UTI, meningitis, and BSI were diagnosed in 10%, 2%, and 24% of infants, respectively. The mean hourly HRC index was significantly higher 12 h prior to diagnosis of UTI and BSI compared to 36 h prior (UTI 2.07 versus 1.81; BSI 2.62 versus 2.25, both p < 0.0001). The baseline HRC index was higher for meningitis, compared to UTI or BSI, but without a statistically significant rise in the day prior to meningitis diagnosis.

Conclusions: In a large cohort of VLBW infants enrolled in the HeRO trial, the HRC index increased in the 24-h period prior to diagnosis of UTI and BSI but not meningitis.
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http://dx.doi.org/10.1038/s41390-019-0701-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255929PMC
June 2020

Bronchopulmonary dysplasia.

Nat Rev Dis Primers 2019 11 14;5(1):78. Epub 2019 Nov 14.

Cincinnati Children's Hospital Medical Center, Division of Neonatology, Pulmonary Biology, University of Cincinnati, Cincinnati, OH, USA.

In the absence of effective interventions to prevent preterm births, improved survival of infants who are born at the biological limits of viability has relied on advances in perinatal care over the past 50 years. Except for extremely preterm infants with suboptimal perinatal care or major antenatal events that cause severe respiratory failure at birth, most extremely preterm infants now survive, but they often develop chronic lung dysfunction termed bronchopulmonary dysplasia (BPD; also known as chronic lung disease). Despite major efforts to minimize injurious but often life-saving postnatal interventions (such as oxygen, mechanical ventilation and corticosteroids), BPD remains the most frequent complication of extreme preterm birth. BPD is now recognized as the result of an aberrant reparative response to both antenatal injury and repetitive postnatal injury to the developing lungs. Consequently, lung development is markedly impaired, which leads to persistent airway and pulmonary vascular disease that can affect adult lung function. Greater insights into the pathobiology of BPD will provide a better understanding of disease mechanisms and lung repair and regeneration, which will enable the discovery of novel therapeutic targets. In parallel, clinical and translational studies that improve the classification of disease phenotypes and enable early identification of at-risk preterm infants should improve trial design and individualized care to enhance outcomes in preterm infants.
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http://dx.doi.org/10.1038/s41572-019-0127-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6986462PMC
November 2019

Prenatal Opioid Exposure: Neurodevelopmental Consequences and Future Research Priorities.

Pediatrics 2019 09;144(3)

Brown Center for the Study of Children at Risk and Departments of Psychiatry and Human Behavior and Pediatrics, Alpert Medical School, Brown University, Providence, Rhode Island.

Neonatal opioid withdrawal syndrome (NOWS) has risen in prevalence from 1.2 per 1000 births in 2000 to 5.8 per 1000 births in 2012. Symptoms in neonates may include high-pitched cry, tremors, feeding difficulty, hypertonia, watery stools, and breathing problems. However, little is known about the neurodevelopmental consequences of prenatal opioid exposure in infancy, early childhood, and middle childhood. Even less is known about the cognitive, behavioral, and academic outcomes of children who develop NOWS. We review the state of the literature on the neurodevelopmental consequences of prenatal opioid exposure with a particular focus on studies in which NOWS outcomes were examined. Aiming to reduce the incidence of prenatal opioid exposure in the near future, we highlight the need for large studies with prospectively recruited participants and longitudinal designs, taking into account confounding factors such as socioeconomic status, institutional variations in care, and maternal use of other substances, to independently assess the full impact of NOWS. As a more immediate solution, we provide an agenda for future research that leverages the National Institutes of Health Environmental Influences on Child Health Outcomes program to address many of the serious methodologic gaps in the literature, and we answer key questions regarding the short- and long-term neurodevelopmental health of children with prenatal opioid exposure.
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http://dx.doi.org/10.1542/peds.2019-0128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759228PMC
September 2019

Risk of Wrong-Patient Orders Among Multiple vs Singleton Births in the Neonatal Intensive Care Units of 2 Integrated Health Care Systems.

JAMA Pediatr 2019 Aug 26. Epub 2019 Aug 26.

Division of General Internal Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

Importance: Multiple-birth infants in neonatal intensive care units (NICUs) have nearly identical patient identifiers and may be at greater risk of wrong-patient order errors compared with singleton-birth infants.

Objectives: To assess the risk of wrong-patient orders among multiple-birth infants and singletons receiving care in the NICU and to examine the proportion of wrong-patient orders between multiple-birth infants and siblings (intrafamilial errors) and between multiple-birth infants and nonsiblings (extrafamilial errors).

Design, Setting, And Participants: A retrospective cohort study was conducted in 6 NICUs of 2 large, integrated health care systems in New York City that used distinct temporary names for newborns per the requirements of The Joint Commission. Data were collected from 4 NICUs at New York-Presbyterian Hospital from January 1, 2012, to December 31, 2015, and 2 NICUs at Montefiore Health System from July 1, 2013, to June 30, 2015. Data were analyzed from May 1, 2017, to December 31, 2017. All infants in the 6 NICUs for whom electronic orders were placed during the study periods were included.

Main Outcomes And Measures: Wrong-patient electronic orders were identified using the Wrong-Patient Retract-and-Reorder (RAR) Measure. This measure was used to detect RAR events, which are defined as 1 or more orders placed for a patient that are retracted (ie, canceled) by the same clinician within 10 minutes, then reordered by the same clinician for a different patient within the next 10 minutes.

Results: A total of 10 819 infants were included: 85.5% were singleton-birth infants and 14.5% were multiple-birth infants (male, 55.8%; female, 44.2%). The overall wrong-patient order rate was significantly higher among multiple-birth infants than among singleton-birth infants (66.0 vs 41.7 RAR events per 100 000 orders, respectively; adjusted odds ratio, 1.75; 95% CI, 1.39-2.20; P < .001). The rate of extrafamilial RAR events among multiple-birth infants (36.1 per 100 000 orders) was similar to that of singleton-birth infants (41.7 per 100 000 orders). The excess risk among multiple-birth infants (29.9 per 100 000 orders) appears to be owing to intrafamilial RAR events. The risk increased as the number of siblings receiving care in the NICU increased; a wrong-patient order error occurred in 1 in 7 sets of twin births and in 1 in 3 sets of higher-order multiple births.

Conclusions And Relevance: This study suggests that multiple-birth status in the NICU is associated with significantly increased risk of wrong-patient orders compared with singleton-birth status. This excess risk appears to be owing to misidentification between siblings. These results suggest that a distinct naming convention as required by The Joint Commission may provide insufficient protection against identification errors among multiple-birth infants. Strategies to reduce this risk include using given names at birth, changing from temporary to given names when available, and encouraging parents to select names for multiple births before they are born when acceptable to families.
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http://dx.doi.org/10.1001/jamapediatrics.2019.2733DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6714004PMC
August 2019

The 2020 Census and the child undercount: a threat to pediatric research and the health and wellbeing of children.

Pediatr Res 2019 09 22;86(3):289-290. Epub 2019 Jun 22.

Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA.

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http://dx.doi.org/10.1038/s41390-019-0477-6DOI Listing
September 2019

Reactive oxygen species modulate Na-coupled neutral amino acid transporter 1 expression in piglet pulmonary arterial endothelial cells.

Am J Physiol Heart Circ Physiol 2019 04 22;316(4):H911-H919. Epub 2019 Feb 22.

Department of Pediatrics, Vanderbilt University Medical Center , Nashville, Tennessee.

We have previously shown that Na-coupled neutral amino acid transporter 1 (SNAT1) modulates nitric oxide (NO) production in pulmonary arterial endothelial cells (PAECs) from newborn piglets. Specifically, the ability to increase NO production in response to the l-arginine-NO precursor l-citrulline is dependent on SNAT1 expression. Elucidating factors that regulate SNAT1 expression in PAECs could provide new insights and therapeutic targets relevant to NO production. Our major goals were to determine if reactive oxygen species (ROS) modulate SNAT1 expression in PAECs from newborn piglets and to evaluate the role of NADPH oxidase 1 (NOX1) and uncoupled endothelial NO synthase, enzymatic sources of ROS, in hypoxia-induced increases in SNAT1 expression. Treatment with either HO or xanthine plus xanthine oxidase increased SNAT1 expression in PAECs from newborn piglets cultured under normoxic conditions. Hypoxia-induced increases in SNAT1 expression were inhibited by treatments with the ROS-removing agents catalase and superoxide dismutase, NOX1 siRNA, and the NO synthase inhibitor N-nitro-l-arginine methyl ester. Both tetrahydropbiopterin (BH) and l-citrulline, two therapies that decrease ROS by recoupling endothelial NO synthase, reduced the hypoxia-induced increase in SNAT1 expression. BH and l-citrulline treatment improved NO production in hypoxic PAECs despite a reduction in SNAT1 expression. In conclusion, SNAT1 expression is modulated by ROS in PAECs from newborn piglets. However, ROS-mediated decreases in SNAT1 expression per se do not implicate a reduction in NO production. Although SNAT1 may be critical to l-citrulline-induced increases in NO production, therapies designed to alter SNAT1 expression may not lead to a concordant change in NO production. NEW & NOTEWORTHY Na-coupled neutral amino acid transporter 1 (SNAT1) modulates nitric oxide (NO) production in piglet pulmonary arterial endothelial cells. Factors that regulate SNAT1 expression in pulmonary arterial endothelial cells are unclear. Here, we show that ROS-reducing strategies inhibit hypoxia-induced increases in SNAT1 expression. l-Citrulline and tetrahydropbiopterin decrease SNAT1 expression but increase NO production. Although SNAT1 is modulated by ROS, changes in SNAT1 expression may not cause a concordant change in NO production.
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http://dx.doi.org/10.1152/ajpheart.00674.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6483017PMC
April 2019

Neonatal Intensive Care Unit Length of Stay Reduction by Heart Rate Characteristics Monitoring.

J Pediatr 2018 07 24;198:162-167. Epub 2018 Apr 24.

Department of Pediatrics, The University of South Carolina School of Medicine-Greenville, Greenville, SC.

Objective: To examine the effect of heart rate characteristics (HRC) monitoring on length of stay among very low birth weight (VLBW; <1500 g birth weight) neonates in the HeRO randomized controlled trial (RCT).

Study Design: We performed a retrospective analysis of length of stay metrics among 3 subpopulations (all patients, all survivors, and survivors with positive blood or urine cultures) enrolled in a multicenter, RCT of HRC monitoring.

Results: Among all patients in the RCT, infants randomized to receive HRC monitoring were more likely than controls to be discharged alive and prior to day 120 (83.6% vs 80.1%, P = .014). The postmenstrual age at discharge for survivors with positive blood or urine cultures was 3.2 days lower among infants randomized to receive HRC monitoring when compared with controls (P = .026). Although there were trends in other metrics toward reduced length of stay in HRC-monitored patients, none reached statistical significance.

Conclusions: HRC monitoring is associated with reduced mortality in VLBW patients and a reduction in length of stay among infected surviving VLBW infants.

Trial Registration: ClinicalTrials.gov: NCT00307333.
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http://dx.doi.org/10.1016/j.jpeds.2018.02.045DOI Listing
July 2018

Update on Vitamin E and Its Potential Role in Preventing or Treating Bronchopulmonary Dysplasia.

Neonatology 2018 7;113(4):366-378. Epub 2018 Mar 7.

Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

Vitamin E is obtained only through the diet and has a number of important biological activities, including functioning as an antioxidant. Evidence that free radicals may contribute to pathological processes such as bronchopulmonary dysplasia (BPD), a disease of prematurity associated with increased lung injury, inflammation and oxidative stress, led to trials of the antioxidant vitamin E (α-tocopherol) to prevent BPD with variable results. These trials were all conducted at supraphysiologic doses and 2 of these trials utilized a formulation containing a potentially harmful excipient. Since 1991, when the last of these trials was conducted, both neonatal management strategies for minimizing oxygen and ventilator-related lung injury and our understanding of vitamin E isoforms in respiratory health have advanced substantially. It is now known that there are differences between the effects of vitamin E isoforms α-tocopherol and γ-tocopherol on the development of respiratory morbidity and inflammation. What is not known is whether improvements in physiologic concentrations of individual or combinations of vitamin E isoforms during pregnancy or following preterm birth might prevent or reduce BPD development. The answers to these questions require adequately powered studies targeting pregnant women at risk of preterm birth or their premature infants immediately following birth, especially in certain subgroups that are at increased risk of vitamin E deficiency (e.g., smokers). The objective of this review is to compile, update, and interpret what is known about vitamin E isoforms and BPD since these first studies were conducted, and suggest future research directions.
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http://dx.doi.org/10.1159/000487388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5980725PMC
September 2019

Effect of Maternal Smoking on Plasma and Urinary Measures of Vitamin E Isoforms in the First Month after Extreme Preterm Birth.

J Pediatr 2018 06 2;197:280-285.e3. Epub 2018 Feb 2.

Division of Neonatology, Department of Pediatrics, Albert Einstein College of Medicine and the Children's Hospital at Montefiore, Bronx, NY.

We examined the effect of maternal smoking on plasma and urinary levels of vitamin E isoforms in preterm infants. Maternal smoking during pregnancy decreased infant plasma alpha- and gamma-tocopherol concentrations at 1 week and 4 weeks, with 45% of infants of smokers deficient in alpha-tocopherol at 1 month after birth.
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http://dx.doi.org/10.1016/j.jpeds.2017.12.062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5971015PMC
June 2018

Pulmonary hypertension in the premature infant population: Analysis of echocardiographic findings and biomarkers.

Pediatr Pulmonol 2018 03 23;53(3):302-309. Epub 2017 Nov 23.

Division of Pediatric Pulmonary, Allergy, and Immunology, Vanderbilt University, Nashville, Tennessee.

Objective: Extremely low gestational age neonates (ELGANs) are at risk for pulmonary hypertension (PH). We hypothesized that PH, defined by echocardiogram at 36 weeks gestational age (GA), would associate with respiratory morbidity, increased oxidant stress, and reduced nitric oxide production.

Study Design: ELGANs in the Vanderbilt fraction of the Prematurity and Respiratory Outcomes Program (PROP) who had echocardiograms at 36 ± 1 weeks GA were studied. Echocardiogram features of PH were compared with clinical characteristics as well as markers of oxidant stress and components of the nitric oxide pathway. Biomarkers were obtained at enrollment (median day 3), 7, 14, and 28 days of life.

Results: Sixty of 172 infants had an echocardiogram at 36 weeks; 11 had evidence of PH. Infants did not differ by PH status in regards to demographics, respiratory morbidity, or oxidant stress. However, odds of more severe PH were significantly higher in infants with higher nitric oxide metabolites (NOx) at enrollment and with a lower citrulline level at day 7.

Conclusions: Respiratory morbidity may not always associate with PH at 36 weeks among ELGANs. However, components of nitric oxide metabolism are potential biologic markers of PH in need of further study.
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http://dx.doi.org/10.1002/ppul.23913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5815883PMC
March 2018

The Value of Preterm Infant Environmental Health Cohorts: The Canary in the Coal Mine.

JAMA Pediatr 2017 12;171(12):1139-1140

Department of Pediatrics, Albert Einstein College of Medicine and the Children's Hospital at Montefiore, Bronx, New York.

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http://dx.doi.org/10.1001/jamapediatrics.2017.3230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6143135PMC
December 2017

Can We Prevent Bronchopulmonary Dysplasia?

J Pediatr 2017 10;189:26-30

Department of Pediatrics, Oregon Health & Science University, Portland, OR.

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http://dx.doi.org/10.1016/j.jpeds.2017.08.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5657541PMC
October 2017

Endothelial specific SIRT3 deletion impairs glycolysis and angiogenesis and causes diastolic dysfunction.

J Mol Cell Cardiol 2017 11 19;112:104-113. Epub 2017 Sep 19.

Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS, USA. Electronic address:

Endothelial glycolysis plays a critical role in the regulation of angiogenesis. We investigated the role of Sirtuin 3 (SIRT3) on endothelial cell (EC) glycolytic metabolism, angiogenesis, and diastolic function. Our aim was to test the hypothesis that loss of SIRT3 in ECs impairs endothelial glycolytic metabolism and angiogenesis and contributes to myocardial capillary rarefaction and the development of diastolic dysfunction. Using SIRT3 deficient ECs, SIRT3 was found to regulate a metabolic switch between mitochondrial respiration and glycolysis. SIRT3 knockout (KO)-ECs exhibited higher mitochondrial respiration and reactive oxygen species (ROS) formation. SIRT3 knockout (KO)-ECs exhibited a reduction in the expression of glycolytic enzyme, PFKFB3, and a fall in glycolysis and angiogenesis. Blockade of PFKFB3 reduced glycolysis and downregulated expression of VEGF and Angiopoietin-1 (Ang-1) in ECs. Deletion of SIRT3 in ECs also impaired hypoxia-induced expression of HIF-2α, VEGF, and Ang-1, as well as reduced angiogenesis. In vivo, endothelial-specific SIRT3 KO (ECKO) mice exhibited a myocardial capillary rarefaction together with a reduced coronary flow reserve (CFR) and diastolic dysfunction. Histologic study further demonstrated that knockout of SIRT3 in ECs significantly increased perivascular fibrosis in the coronary artery. These results implicate a role of SIRT3 in modulating endothelial function and cardiac function. Ablation of SIRT3 leads to impairment of EC glycolytic metabolism and angiogenic signaling, which may contribute to coronary microvascular rarefaction and diastolic dysfunction in SIRT3 ECKO mice.
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http://dx.doi.org/10.1016/j.yjmcc.2017.09.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5647246PMC
November 2017

Evaluating Serial Strategies for Preventing Wrong-Patient Orders in the NICU.

Pediatrics 2017 May;139(5)

Division of Hospital Medicine.

Background: NICU patients have characteristics believed to increase their risk for wrong-patient errors; however, little is known about the frequency of wrong-patient errors in the NICU or about effective interventions for preventing these errors. We conducted a quality improvement study to evaluate the frequency of wrong-patient orders in the NICU and to assess the effectiveness of an ID reentry intervention and a distinct naming convention (eg, "Wendysgirl") for reducing these errors, using non-NICU pediatric units as a comparator.

Methods: Using a validated measure, we examined the rate of wrong-patient orders in NICU and non-NICU pediatric units during 3 periods: baseline (before implementing interventions), ID reentry intervention (reentry of patient identifiers before placing orders), and combined intervention (addition of a distinct naming convention for newborns).

Results: We reviewed >850 000 NICU orders and >3.5 million non-NICU pediatric orders during the 7-year study period. At baseline, wrong-patient orders were more frequent in NICU than in non-NICU pediatric units (117.2 vs 74.9 per 100 000 orders, respectively; odds ratio 1.56; 95% confidence interval, 1.34-1.82). The ID reentry intervention reduced the frequency of errors in the NICU to 60.2 per 100 000 (48.7% reduction; < .001). The combined ID reentry and distinct naming interventions yielded an additional decrease to 45.6 per 100 000 (61.1% reduction from baseline; < .001).

Conclusions: The risk of wrong-patient orders in the NICU was significantly higher than in non-NICU pediatric units. Implementation of a combined ID reentry intervention and distinct naming convention greatly reduced this risk.
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http://dx.doi.org/10.1542/peds.2016-2863DOI Listing
May 2017

Persistent pulmonary hypertension of the newborn.

Semin Fetal Neonatal Med 2017 08 23;22(4):220-226. Epub 2017 Mar 23.

Departments of Pediatrics and Obstetrics, Gynecology and Women's Health, Albert Einstein College of Medicine and the Children's Hospital at Montefiore, Bronx, NY, USA. Electronic address:

Failure of the normal circulatory adaptation to extrauterine life results in persistent pulmonary hypertension of the newborn (PPHN). Although this condition is most often secondary to parenchymal lung disease or lung hypoplasia, it may also be idiopathic. PPHN is characterized by elevated pulmonary vascular resistance with resultant right-to-left shunting of blood and hypoxemia. Although the preliminary diagnosis of PPHN is often based on differential cyanosis and labile hypoxemia, the diagnosis is confirmed by echocardiography. Management strategies include optimal lung recruitment and use of surfactant in patients with parenchymal lung disease, maintaining optimal oxygenation and stable blood pressures, avoidance of respiratory and metabolic acidosis and alkalosis, and pulmonary vasodilator therapy. Extracorporeal membrane oxygenation is considered when medical management fails. Although mortality associated with PPHN has decreased significantly with improvements in medical care, there remains the potential risk for neurodevelopmental disability which warrants close follow-up of affected infants after discharge.
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http://dx.doi.org/10.1016/j.siny.2017.03.004DOI Listing
August 2017

Effect of perinatal glucocorticoids on vascular health and disease.

Pediatr Res 2017 01 22;81(1-1):4-10. Epub 2016 Sep 22.

Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee.

The benefits of antenatal glucocorticoids are now firmly established in the perinatal management of threatened preterm birth. Postnatal glucocorticoid therapy, however, remains controversial in neonatal medicine, with the need to balance short-term physiological benefits against the potential for long-term adverse consequences. This review focuses on the vascular effects of prenatal and postnatal glucocorticoids, synthesizing data from both experimental animal models and human infants with the goal of better appreciation of the short and long-term effects of these commonly used drugs. Due to their widespread and varied use, improved understanding of the cellular and molecular impact of glucocorticoids is important in guiding current practice and future research.
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http://dx.doi.org/10.1038/pr.2016.188DOI Listing
January 2017

Loss of prolyl hydroxylase domain protein 2 in vascular endothelium increases pericyte coverage and promotes pulmonary arterial remodeling.

Oncotarget 2016 Sep;7(37):58848-58861

Department of Pharmacology and Toxicology, University of Mississippi Medical Center, School of Medicine, Jackson, MS, USA.

Pulmonary arterial hypertension (PAH) is a leading cause of heart failure. Although pulmonary endothelial dysfunction plays a crucial role in the progression of the PAH, the underlying mechanisms are poorly understood. The HIF-α hydroxylase system is a key player in the regulation of vascular remodeling. Knockout of HIF-2α has been reported to cause pulmonary hypertension. The present study examined the role of endothelial cell specific prolyl hydroxylase-2 (PHD2) in the development of PAH and pulmonary vascular remodeling. The PHD2f/f mouse was crossbred with VE-Cadherin-Cre promoter mouse to generate an endothelial specific PHD2 knockout (Cdh5-Cre-PHD2ECKO) mouse. Pulmonary arterial pressure and the size of the right ventricle was significantly elevated in the PHD2ECKO mice relative to the PHD2f/f controls. Knockout of PHD2 in EC was associated with vascular remodeling, as evidenced by an increase in pulmonary arterial media to lumen ratio and number of muscularized arterioles. The pericyte coverage and vascular smooth muscle cells were also significantly increased in the PA. The increase in vascular pericytes was associated with elevated expression of fibroblast specific protein-1 (FSP-1). Moreover, perivascular interstitial fibrosis of pulmonary arteries was significantly increased in the PHD2ECKO mice. Mechanistically, knockout of PHD2 in EC increased the expression of Notch3 and transforming growth factor (TGF-β) in the lung tissue. We conclude that the expression of PHD2 in endothelial cells plays a critical role in preventing pulmonary arterial remodeling in mice. Increased Notch3/TGF-β signaling and excessive pericyte coverage may be contributing to the development of PAH following deletion of endothelial PHD2.
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http://dx.doi.org/10.18632/oncotarget.11585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5312280PMC
September 2016

Tetrahydrobiopterin oral therapy recouples eNOS and ameliorates chronic hypoxia-induced pulmonary hypertension in newborn pigs.

Am J Physiol Lung Cell Mol Physiol 2016 Oct 19;311(4):L743-L753. Epub 2016 Aug 19.

Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Pediatrics, the University of Utah School of Medicine, Salt Lake City, Utah; and

We previously showed that newborn piglets who develop pulmonary hypertension during exposure to chronic hypoxia have diminished pulmonary vascular nitric oxide (NO) production and evidence of endothelial NO synthase (eNOS) uncoupling (Fike CD, Dikalova A, Kaplowitz MR, Cunningham G, Summar M, Aschner JL. Am J Respir Cell Mol Biol 53: 255-264, 2015). Tetrahydrobiopterin (BH) is a cofactor that promotes eNOS coupling. Current clinical strategies typically invoke initiating treatment after the diagnosis of pulmonary hypertension, rather than prophylactically. The major purpose of this study was to determine whether starting treatment with an oral BH compound, sapropterin dihydrochloride (sapropterin), after the onset of pulmonary hypertension would recouple eNOS in the pulmonary vasculature and ameliorate disease progression in chronically hypoxic piglets. Normoxic (control) and hypoxic piglets were studied. Some hypoxic piglets received oral sapropterin starting on day 3 of hypoxia and continued throughout an additional 7 days of hypoxic exposure. Catheters were placed for hemodynamic measurements, and pulmonary arteries were dissected to assess eNOS dimer-to-monomer ratios (a measure of eNOS coupling), NO production, and superoxide (O) generation. Although higher than in normoxic controls, pulmonary vascular resistance was lower in sapropterin-treated hypoxic piglets than in untreated hypoxic piglets. Consistent with eNOS recoupling, eNOS dimer-to-monomer ratios and NO production were greater and O generation was less in pulmonary arteries from sapropterin-treated than untreated hypoxic animals. When started after disease onset, oral sapropterin treatment inhibits chronic hypoxia-induced pulmonary hypertension at least in part by recoupling eNOS in the pulmonary vasculature of newborn piglets. Rescue treatment with sapropterin may be an effective strategy to inhibit further development of pulmonary hypertension in newborn infants suffering from chronic cardiopulmonary conditions associated with episodes of prolonged hypoxia.
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http://dx.doi.org/10.1152/ajplung.00238.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5142125PMC
October 2016

The Natural History of Bronchopulmonary Dysplasia: The Case for Primary Prevention.

Clin Perinatol 2015 Dec 1;42(4):911-31. Epub 2015 Oct 1.

Department of Pediatrics, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Rosenthal Pavilion, Room 402, 111 East 210th Street, Bronx, NY 10467, USA; Department of Obstetrics & Gynecology and Women's Health, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Rosenthal Pavilion, Room 402, 111 East 210th Street, Bronx, NY 10467, USA.

Brochopulmonary dysplasia (BPD) is the most common form of chronic lung disease in infancy. At present, BPD primarily occurs in extremely premature infants (23-28 weeks of gestation) born during the late canalicular/early saccular stage of lung development. This article summarizes the current knowledge of the life course of BPD by emphasizing recent or key articles notating its natural history from the newborn period through adulthood and building the case for a continued focus on its primary prevention.
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http://dx.doi.org/10.1016/j.clp.2015.08.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4662069PMC
December 2015

Neuroimaging identifies increased manganese deposition in infants receiving parenteral nutrition.

Am J Clin Nutr 2015 Dec 11;102(6):1482-9. Epub 2015 Nov 11.

Departments of Pediatrics, Physical Medicine and Rehabilitation, Center for Molecular Toxicology, and Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University School of Medicine, Nashville, TN; Department of Pediatrics and the Research Institute at Nationwide Children's Hospital, Columbus, OH.

Background: Manganese, an essential metal for normal growth and development, is neurotoxic on excessive exposure. Standard trace element-supplemented neonatal parenteral nutrition (PN) has a high manganese content and bypasses normal gastrointestinal absorptive control mechanisms, which places infants at risk of manganese neurotoxicity. Magnetic resonance (MR) relaxometry demonstrating short T1 relaxation time (T1R) in the basal ganglia reflects excessive brain manganese accumulation.

Objective: This study tested the hypothesis that infants with greater parenteral manganese exposure have higher brain manganese accumulation, as measured by MR imaging, than do infants with lower parenteral manganese exposure.

Design: Infants exposed to parenteral manganese were enrolled in a prospective cohort study. Infants classified as having high manganese exposure received >75% of their nutrition in the preceding 4 wk as PN. All others were classified as having low exposure. Daily parenteral and enteral manganese intakes were calculated. Whole-blood manganese was measured by high-resolution inductively coupled plasma mass spectrometry. Brain MR relaxometry was interpreted by a masked reviewer. Linear regression models, adjusted for gestational age (GA) at birth, estimated the association of relaxometry indexes with total and parenteral manganese exposures.

Results: Seventy-three infants were enrolled. High-quality MR images were available for 58 infants, 39 with high and 19 with low manganese exposure. Four infants with a high exposure had blood manganese concentrations >30 μg/L. After controlling for GA, higher parenteral and total manganese intakes were associated with a lower T1R (P = 0.01) in the globus pallidus and putamen but were not associated with whole-blood manganese (range: 3.6-56.6 μg/L). Elevated conjugated bilirubin magnified the association between parenteral manganese and decreasing T1R.

Conclusion: A short T1R for GA identifies infants at risk of increased brain manganese deposition associated with PN solutions commonly used to nourish critically ill infants. These trials were registered at clinicaltrials.gov as NCT00392977 and NCT00392730.
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http://dx.doi.org/10.3945/ajcn.115.116285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4658463PMC
December 2015

Comparisons and Limitations of Current Definitions of Bronchopulmonary Dysplasia for the Prematurity and Respiratory Outcomes Program.

Ann Am Thorac Soc 2015 Dec;12(12):1822-30

1 Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.

Rationale: Bronchopulmonary dysplasia is the most common morbidity of prematurity, but the validity and utility of commonly used definitions have been questioned.

Objectives: To compare three commonly used definitions of bronchopulmonary dysplasia in a contemporary prospective, multicenter observational cohort of extremely preterm infants.

Methods: At 36 weeks postmenstrual age, the following definitions of bronchopulmonary dysplasia were applied to surviving infants with and without imputation: need for supplemental oxygen (Shennan definition), National Institutes of Health Workshop definition, and "physiologic" definition after a room-air challenge.

Measurements And Main Results: Of 765 survivors assessed at 36 weeks, bronchopulmonary dysplasia was diagnosed in 40.8, 58.6, and 32.0% of infants, respectively, with the Shennan, workshop and physiologic definitions. The number of unclassified infants was lowest with the workshop definition (2.1%) and highest with the physiologic definition (16.1%). After assigning infants discharged home in room air before 36 weeks as no bronchopulmonary dysplasia, the modified Shennan definition compared favorably to the workshop definition, with 2.9% unclassified infants. Newer management strategies with nasal cannula flows up to 4 L/min or more and 0.21 FiO2 at 36 weeks obscured classification of bronchopulmonary dysplasia status in 12.4% of infants.

Conclusions: Existing definitions of bronchopulmonary dysplasia differ with respect to ease of data collection and number of unclassifiable cases. Contemporary changes in management of infants, such as use of high-flow nasal cannula, limit application of existing definitions and may result in misclassification. A contemporary definition of bronchopulmonary dysplasia that correlates with respiratory morbidity in childhood is needed. Clinical trial registered with www.clinicaltrials.gov (NCT01435187).
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http://dx.doi.org/10.1513/AnnalsATS.201504-218OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4722827PMC
December 2015

Understanding the Short- and Long-Term Respiratory Outcomes of Prematurity and Bronchopulmonary Dysplasia.

Am J Respir Crit Care Med 2015 Jul;192(2):134-56

1 Center for Asthma Research, Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, and.

Bronchopulmonary dysplasia (BPD) is a chronic respiratory disease associated with premature birth that primarily affects infants born at less than 28 weeks' gestational age. BPD is the most common serious complication experienced by premature infants, with more than 8,000 newly diagnosed infants annually in the United States alone. In light of the increasing numbers of preterm survivors with BPD, improving the current state of knowledge of long-term respiratory morbidity for infants with BPD is a priority. We undertook a comprehensive review of the published literature to analyze and consolidate current knowledge of the effects of BPD that are recognized at specific stages of life, including infancy, childhood, and adulthood. In this review, we discuss both the short-term and long-term respiratory outcomes of individuals diagnosed as infants with the disease and highlight the gaps in knowledge needed to improve early and lifelong management of these patients.
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http://dx.doi.org/10.1164/rccm.201412-2142PPDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4532824PMC
July 2015

Rescue Treatment with L-Citrulline Inhibits Hypoxia-Induced Pulmonary Hypertension in Newborn Pigs.

Am J Respir Cell Mol Biol 2015 Aug;53(2):255-64

4 Department of Pediatrics, Albert Einstein College of Medicine and the Children's Hospital at Montefiore, New York, New York.

Infants with cardiopulmonary disorders associated with hypoxia develop pulmonary hypertension. We previously showed that initiation of oral L-citrulline before and continued throughout hypoxic exposure improves nitric oxide (NO) production and ameliorates pulmonary hypertension in newborn piglets. Rescue treatments, initiated after the onset of pulmonary hypertension, better approximate clinical strategies. Mechanisms by which L-citrulline improves NO production merit elucidation. The objective of this study was to determine whether starting L-citrulline after the onset of pulmonary hypertension inhibits disease progression and improves NO production by recoupling endothelial NO synthase (eNOS). Hypoxic and normoxic (control) piglets were studied. Some hypoxic piglets received oral L-citrulline starting on Day 3 of hypoxia and continuing throughout the remaining 7 days of hypoxic exposure. Catheters were placed for hemodynamic measurements, and pulmonary arteries were dissected to assess NO production and eNOS dimer-to-monomer ratios (a measure of eNOS coupling). Pulmonary vascular resistance was lower in L-citrulline-treated hypoxic piglets than in untreated hypoxic piglets but was higher than in normoxic controls. NO production and eNOS dimer-to-monomer ratios were greater in pulmonary arteries from L-citrulline-treated than from untreated hypoxic animals but were lower than in normoxic controls. When started after disease onset, oral L-citrulline treatment improves NO production by recoupling eNOS and inhibits the further development of chronic hypoxia-induced pulmonary hypertension in newborn piglets. Oral L-citrulline may be a novel strategy to halt or reverse pulmonary hypertension in infants suffering from cardiopulmonary conditions associated with hypoxia.
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http://dx.doi.org/10.1165/rcmb.2014-0351OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4566047PMC
August 2015

Plasma asymmetric dimethylarginine in infants with bronchopulmonary dysplasia: a promising biomarker despite uncertain pathogenic significance.

J Pediatr 2015 Feb 21;166(2):222-4. Epub 2014 Nov 21.

Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee.

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http://dx.doi.org/10.1016/j.jpeds.2014.10.039DOI Listing
February 2015