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  • Evaluating preterm care across Europe using the eNewborn European Network database
    Pediatr. Res. (IF 2.880) Pub Date : 2020-01-23
    Dominique Haumont; Neena Modi; Ola D. Saugstad; Rosine Antetere; Cuong NguyenBa; Mark Turner; Kate Costeloe; Willem Aelvoet

    Background The inefficiency of recording data repeatedly limits the number of studies conducted. Here we illustrate the wider use of data captured as part of the European eNewborn benchmarking programme. Methods We extracted data on 39,529 live-births from 22 weeks 0 days to 31 weeks 6 days gestational age (GA) or ≤1500 g birth weight. We explored relationships between delivery room care and Apgar scores on mortality and bronchopulmonary dysplasia (BPD) and calculated the time needed for each country to detect a clinically relevant change in these outcomes following a hypothetical intervention. Results Early neonatal, neonatal, and in-hospital mortality were 3.90% (95% CI 3.71, 4.09), 6.00% (5.77, 6.24) and 7.57% (7.31, 7.83), respectively. The odds of death were greater with decreasing GA, lower Apgar scores, growth restriction, male sex, multiple birth and no antenatal steroids. Relationships for BPD were similar. The time required for participating countries to achieve 80% power to detect a relevant change in outcomes following a hypothetical intervention in 23–25 weeks’ GA infants ranged from 12 years for neonatal mortality and 22 years for BPD compared to 1 year for the whole network. Conclusions The eNewborn platform offers opportunity to drive efficiencies in benchmarking, quality control and research.

    更新日期:2020-01-23
  • Preterm birth and the future risk of orthopedic fracture
    Pediatr. Res. (IF 2.880) Pub Date : 2020-01-22
    Jonathan Michaud; Thuy Mai Luu; John C. LeBlanc; Jessica Healy-Profitós; Aimina Ayoub; Nathalie Auger

    Background Preterm birth occurs during a critical period of bone mineralization. We assessed whether preterm birth increases the risk of childhood fracture. Methods We analyzed a cohort of 788,903 infants born between 2006 and 2016 in Quebec, Canada. The exposure was preterm birth (<37 weeks). The outcome was any future hospitalization for fracture before 2018. We estimated hazard ratios (HR) and 95% confidence intervals (CI) for the association of prematurity with fractures in adjusted Cox regression models. We determined if the risk of facture varied by the child’s age. Results The incidence of fracture hospitalizations was higher in preterm children than in term children (17.9 vs. 15.3 per 10,000 person-years). Compared with term, preterm children had 1.27 times the risk of femur fracture hospitalization (95% CI 1.01–1.60) and 2.27 times the risk of assault-related fractures (95% CI 1.37–3.76). Preterm children had 2.20 times the risk of femur fracture between 6 and 17 months of age (95% CI 1.45–3.35). Conclusions Preterm birth is associated with an increased risk of hospitalization for femur fractures and assault-related fractures. Associations are stronger before 18 months of age. Families of preterm children may benefit from counseling and support for fracture prevention during early childhood.

    更新日期:2020-01-22
  • Antibiotics in early life associate with specific gut microbiota signatures in a prospective longitudinal infant cohort
    Pediatr. Res. (IF 2.880) Pub Date : 2020-01-18
    Katri Korpela; Anne Salonen; Harri Saxen; Anne Nikkonen; Ville Peltola; Tytti Jaakkola; Willem de Vos; Kaija-Leena Kolho

    BACKGROUND The effects of antibiotics on infant gut microbiota are unclear. We hypothesized that the use of common antibiotics results in long-term aberration in gut microbiota. METHODS Antibiotic-naive infants were prospectively recruited when hospitalized because of a respiratory syncytial virus infection. Composition of fecal microbiota was compared between those receiving antibiotics during follow-up (prescribed at clinicians’ discretion because of complications such as otitis media) and those with no antibiotic exposure. Fecal sampling started on day 1, then continued at 2-day intervals during the hospital stay, and at 1, 3 and 6 months at home. RESULTS One hundred and sixty-three fecal samples from 40 patients (median age 2.3 months at baseline; 22 exposed to antibiotics) were available for microbiota analyses. A single course of amoxicillin or macrolide resulted in aberration of infant microbiota characterized by variation in the abundance of bifidobacteria, enterobacteria and clostridia, lasting for several months. Recovery from the antibiotics was associated with an increase in clostridia. Occasionally, antibiotic use resulted in microbiota profiles associated with inflammatory conditions. CONCLUSIONS Antibiotic use in infants modifies especially bifidobacterial levels. Further studies are warranted whether administration of bifidobacteria will provide health benefits by normalizing the microbiota in infants receiving antibiotics.

    更新日期:2020-01-21
  • Enquiring beneath the surface: can a gene expression assay shed light into the heterogeneity among newborns with neonatal encephalopathy?
    Pediatr. Res. (IF 2.880) Pub Date : 2020-01-17
    Rafael Balada; Cristian Tebé; Marisol León; Gemma Arca; Miguel Alsina; Alba-Aina Castells; Soledad Alcántara; Alfredo Garcia-Alix

    Background We aimed to assess whether a gene expression assay provided insights for understanding the heterogeneity among newborns affected by neonatal encephalopathy (NE). Methods Analysis by RT-qPCR of the mRNA expression of candidate genes in whole blood from controls (n = 34) and NE (n = 24) patients at <6, 12, 24, 48, 72 and 96 h of life, followed by determination of differences in gene expression between conditions and correlation with clinical variables. Results During the first 4 days of life, MMP9, PPARG, IL8, HSPA1A and TLR8 were more expressed and CCR5 less expressed in NE patients compared to controls. MMP9 and PPARG increased and CCR5 decreased in moderate/severe NE patients compared to mild. At 6–12 h of life, increased IL8 correlated with severe NE and death, decreased CCR5 correlated with chorioamnionitis and increased HSPA1A correlated with expanded multiorgan dysfunction, severe NE and female sex. Conclusions MMP9, PPARG and CCR5 mRNA expression within first days of life correlates with the severity of NE. At 6–12 h, IL8 and HSPA1A are good reporters of clinical variables in NE patients. HSPA1A may have a role in the sexual dimorphism observed in NE. CCR5 is potentially involved in the link between severe NE and chorioamnionitis.

    更新日期:2020-01-17
  • Sex differences in infant blood metabolite profile in association with weight and adiposity measures
    Pediatr. Res. (IF 2.880) Pub Date : 2020-01-17
    Susan Ellul; Anne-Louise Ponsonby; John B. Carlin; Fiona Collier; Toby Mansell; Peter Vuillermin; David Burgner; Richard Saffery

    BACKGROUND Nuclear magnetic resonance (NMR) metabolic profiling quantifies a large number of metabolites. From adolescence, specific metabolites are influenced by age, sex and body mass index; data on early-life metabolic profiles are limited. We investigated associations between sex, birth weight, weight and adiposity with NMR metabolic profile at age 12 months. METHODS The plasma NMR metabolic profile was quantified in infants (n = 485) from the Barwon Infant Study. Associations between 74 metabolites and sex, birth weight z-score and 12-month measures (weight z-score, skinfold thickness, weight-for-length z-score) were examined using linear regression models. RESULTS Several cholesterol and fatty acid measures were higher (0.2–0.3 SD) in girls than in boys; we observed modest sex-specific associations of birth weight z-scores and 12-month sum of skinfold thicknesses with metabolites. The pattern of associations between weight z-score and weight-for-length z-score with metabolites at 12 months was more pronounced in girls, particularly for fatty acid ratios. CONCLUSIONS We identified sex differences in the infant metabolic profile. Sex-specific patterns observed differ from those reported in older children and adults. We also identified modest cross-sectional associations between anthropometric and adiposity measures and metabolites, some of which were sex specific.

    更新日期:2020-01-17
  • Dysregulation of Notch signaling in cardiac mesenchymal cells of patients with tetralogy of Fallot
    Pediatr. Res. (IF 2.880) Pub Date : 2020-01-17
    Ivan Kozyrev; Pavel Dokshin; Aleksandra Kostina; Artem Kiselev; Elena Ignatieva; Alexey Golovkin; Tatiana Pervunina; Evgeny Grekhov; Mikhail Gordeev; Anna Kostareva; Anna Malashicheva

    BACKGROUND Tetralogy of Fallot (TF) is a severe congenital defect of heart development. Fine-tuned sequential activation of Notch signaling genes is responsible for proper heart chamber development. Mutations in Notch genes have been associated with TF. The aim of this study was to analyze the activity of the Notch pathway in cardiac mesenchymal cells derived from ventricular tissue of TF patients. METHODS Cardiac mesenchymal cells were isolated from 42 TF patients and from 14 patients with ventricular septal defects (VSDs), used as a comparison group. The Notch pathway was analyzed by estimating the expression of Notch-related genes by qPCR. Differentiation and proliferation capacity of the cells was estimated. RESULTS The TF-derived cells demonstrated a dysregulated pattern of Notch-related gene expression comparing to VSD-derived cells. Correlation of Notch signaling activation level by HEY1/HES1 expression level with proliferation and cardiogenic-like differentiation of cardiac mesenchymal cells was observed but not with clinical parameters nor with the age of the patients. CONCLUSIONS The data suggest a contribution of dysregulated Notch signaling to the pathogenesis of tetralogy of Fallot and importance of Notch signaling level for the functional state of cardiac mesenchymal cells, which could be critical considering these cells for potential cell therapy approaches.

    更新日期:2020-01-17
  • An experience with a bubble CPAP bundle: is chronic lung disease preventable?
    Pediatr. Res. (IF 2.880) Pub Date : 2020-01-17
    Hany Aly; Mohamed A. Mohamed

    Background Continuous positive airway pressure (CPAP) is associated with marginal decrease in chronic lung disease (CLD). This study aims to report outcomes, with focus on CLD, of preterm infants managed with a bubble CPAP (b-CPAP) bundle of care. Methods Infants <1500 g were stratified into four groups depending on intubation status through first 3 days of life. The incidence of mortality, CLD and other morbidities were compared over four chronological epochs. Outcomes of the most recent epoch were compared to contemporaneous benchmarks from Vermont Oxford Network (VON). Results Of 773 infants (median GA = 28 weeks, average BW = 995 g), 24.5% were intubated in DR and 11.7% in the first day of life. Mechanical ventilation, bCPAP and oxygen days in survivors were 1.5, 29 and 14, respectively. Overall incidence of CLD was 6.4% that remained consistent in the four epochs (7.6%, 7.5%, 5.8% and 5%), respectively. In comparison to VON, CLD was significantly less (p < 0.001). Initial DR intubation was not associated with increased CLD compared to initial management with CPAP that required subsequent intubation. Conclusion It is feasible and sustainable to administer a b-CPAP bundle of care to decrease CLD. Cluster randomized trials are needed to validate the reproducibility of this approach.

    更新日期:2020-01-17
  • Indole-3-lactic acid, a metabolite of tryptophan, secreted by Bifidobacterium longum subspecies infantis is anti-inflammatory in the immature intestine
    Pediatr. Res. (IF 2.880) Pub Date : 2020-01-16
    Di Meng; Eduardo Sommella; Emanuela Salviati; Pietro Campiglia; Kriston Ganguli; Karim Djebali; Weishu Zhu; W. Allan Walker

    Background Necrotizing enterocolitis (NEC), a necrotic inflammation of the intestine, represents a major health problem in the very premature infant. Although prevention is difficult, the combination of ingestion of maternal-expressed breastmilk in conjunction with a probiotic provides the best protection. In this study, we establish a mechanism for breastmilk/probiotic protection. Methods Ultra-high-performance liquid chromatography-tandem mass spectrometry of Bifidobacterium longum subsp. infantis (B. infantis) secretions was used to identify an anti-inflammatory molecule. Indole-3-lactic acid (ILA) was then tested in an established human immature small intestinal cell line, necrotizing colitis enterocytes, and other immature human enteroids for anti-inflammatory effects and to establish developmental function. ILA was also examined in immature and mature enterocytes. Results We have identified ILA, a metabolite of breastmilk tryptophan, as the anti-inflammatory molecule. This molecule is developmentally functional in immature but not mature intestinal enterocytes; ILA reduces the interleukin-8 (IL-8) response after IL-1β stimulus. It interacts with the transcription factor aryl hydrocarbon receptor (AHR) and prevents transcription of the inflammatory cytokine IL-8. Conclusions This molecule produced by B. infantis (ATCC No. 15697) interaction with ingested breastmilk functions in a complementary manner and could become useful in the treatment of all at-risk premature infants for NEC if safety and clinical studies are performed.

    更新日期:2020-01-16
  • Editor's Focus
    Pediatr. Res. (IF 2.880) Pub Date : 2020-01-14
    更新日期:2020-01-15
  • Non-invasive forced oscillometry to quantify respiratory mechanics in term neonates
    Pediatr. Res. (IF 2.880) Pub Date : 2020-01-14
    Andrew P. Klinger; Colm P. Travers; Abigail Martin; Hui-Chien Kuo; Ammar Saadoon Alishlash; William T. Harris; Waldemar A. Carlo; Namasivayam Ambalavanan

    Background To determine normative data by forced oscillation technique (FOT) in non-sedated normal term neonates and test the hypothesis that infants with transient tachypnea of the newborn (TTN) have higher resistance (R) and lower reactance (X) on day 1. Methods Healthy term infants (n = 138) and infants with TTN (n = 17) were evaluated on postnatal days 1 through 3 (NCT03346343). FOT was measured with a mask using a TremoFlo C-100 Airwave System™. R, X, and area under the reactance curve (AX) were measured at prime frequencies 7–41 Hz for 8 s. Results In all, 86% of control infants had adequate measurements (coherence >0.8, CV < 0.25) on day 1. Infants with TTN had higher resistance at 13 Hz (TTN 32.5 cm H2O·s/L [95% CI 25.5–39.4]; controls 23.8 cm H2O·s/L [95% CI 22.2 to 25.3], P = 0.007) and lower reactance from 17 to 37 Hz (TTN −35.1 to −10.5; controls −26.3 to −6.1, P < 0.05). In healthy controls, lung mechanics were unchanged from days 1 to 3. In TTN, lung mechanics normalized on days 2 and 3. Conclusions FOT is feasible in neonates and distinguishes normal control infants from those with TTN on postnatal day 1. Oscillometry offers a non-invasive, longitudinal technique to assess lung mechanics in newborns.

    更新日期:2020-01-14
  • N -acetylcysteine mitigates acute opioid withdrawal behaviors and CNS oxidative stress in neonatal rats
    Pediatr. Res. (IF 2.880) Pub Date : 2020-01-14
    Price Ward; Hunter G. Moss; Truman R. Brown; Peter Kalivas; Dorothea D. Jenkins

    Background Neonatal abstinence syndrome (NAS) is a significant problem. Opioid withdrawal induces oxidative stress and disrupts glutamate and glutathione homeostasis. We hypothesized that N-acetylcysteine (NAC) administered during acute opioid withdrawal in neonatal rats would decrease withdrawal behaviors and normalize CNS glutathione and glutamate. Methods Osmotic minipumps with methadone (opioid dependent, OD) and saline (Sham) were implanted into Sprague Dawley dams 7 days prior to delivery. Pups were randomized to receive either naloxone plus saline or NAC (50–100 mg/kg), administered on postnatal day (PND) 7. We performed MR spectroscopy on PND6–7 before, 30 min, and 120 min after withdrawal. On PND7, we assessed withdrawal behaviors for 90 min after naloxone administration and summed scores during peak withdrawal period. Results Mean summed behavioral scores were significantly different between groups (χ2 (2) = 10.49, p = 0.005) but not different between NAC/NAL/OD and Sham (p = 0.14): SAL/NAL/OD = 17.2 ± 4.2 (n = 10); NAC/NAL/OD = 11.3 ± 5.6 (n = 9); Sham = 6.5 ± 0.6 (n = 4). SAL/NAL/OD pups had decreased glutathione at 120 min (p = 0.01), while NAC/NAL/OD pups maintained pre-withdrawal glutathione (p = 0.26). Conclusion In antenatal OD, NAC maintains CNS glutathione and mitigates acute opioid withdrawal in neonatal rats. This is the first study to demonstrate acute opioid withdrawal neurochemical changes in vivo in neonatal OD. NAC is a potential novel treatment for NAS.

    更新日期:2020-01-14
  • Enhanced formation of neutrophil extracellular traps in Kawasaki disease
    Pediatr. Res. (IF 2.880) Pub Date : 2020-01-14
    Yusuke Yoshida; Seiichiro Takeshita; Yoichi Kawamura; Takashi Kanai; Yuki Tsujita; Shigeaki Nonoyama

    BACKGROUND Neutrophils contribute to the clearance of pathogens through the formation of neutrophil extracellular traps (NETs) in a process known as NETosis, but the excessive release of NETs has been reported to be involved in the pathogenesis of various diseases, including vasculitis, by inducing tissue injury. The aim of the present study was to investigate whether or not NETosis is enhanced in the acute phase of Kawasaki disease (KD). METHODS After neutrophils isolated from the peripheral blood of patients with KD and healthy children (HC) were cultured in vitro, the degree of spontaneous NETosis was evaluated by measuring the number of NETs formed and the titers of cell-free DNA (cfDNA) and neutrophil elastase (NE)-DNA complex. RESULTS Spontaneous NET formation in vitro was observed in neutrophils isolated from KD patients, and the number of NET formations was significantly higher in acute KD than in convalescent KD and HC. The increased levels of cfDNA and NE-DNA complexes in the acute phase of KD tended to decrease in the convalescent phase. CONCLUSIONs Spontaneous NET formation was enhanced in neutrophils from patients with acute KD, suggesting that circulating neutrophils may be primed to undergo NETosis in KD vasculitis.

    更新日期:2020-01-14
  • Comparison of INVOS 5100C and Nonin SenSmart X-100 oximeter performance in preterm infants with spontaneous apnea
    Pediatr. Res. (IF 2.880) Pub Date : 2020-01-14
    Bjørn Andresen; Gorm Greisen; Simon Hyttel-Sorensen

    Background Tissue oximeters are not interchangeable. Two instruments with sensors dedicated to preterm infants—INVOS 5100C and Nonin SenSmart X-100—have not yet been compared. Methods By measuring cerebral oxygenation in ten preterm infants with spontaneous apneic episodes defined by pulse oximeter readings (SpO2) below 80%, as well as tissue oxygenation during vascular occlusion on the forearm of ten adults, simultaneously we compared performance in the hypoxic range. Results We found the mean conversion equations to be StO2,SenSmart X-100 = 0.34 × StO2,INVOS 5100C + 44.8% during apnea in infants and StO2,SenSmart X-100 = 0.59 × StO2,INVOS 5100C + 34.4% during vascular occlusion. The individual regressions displayed large and statistically significant variations in both infants and adults. In three infants the INVOS sensor showed very little reaction to decreases in SpO2. Conclusion These findings confirm that different NIRS devices give very different estimates when the oxygenation is low. The large variation when compared to SpO2 suggest that the sensor placement is very important in preterm infants.

    更新日期:2020-01-14
  • Assessing childhood health outcome inequalities with area-based socioeconomic measures: a retrospective cross-sectional study using Manitoba population data
    Pediatr. Res. (IF 2.880) Pub Date : 2020-01-14
    Atul K. Sharma; Kristine Kroeker; Dan Chateau; Marni Brownell; Celia J. Rodd

    Background Socioeconomic gradients in health exist in Canada. Although multiple Canadian area-based socioeconomic measures (ABSM) have been developed, none have been specifically validated against pediatric outcomes. Our objective was to compare the strength of association between key pediatric health outcomes and a number of ABSM, including income quintile. Methods This was a retrospective cross-sectional assessment of the association between socioeconomic status (SES) measured by ABSM and 20 specific pediatric health outcomes. Data from the Manitoba Population Research Data Repository were used for residents aged 0–19 years from 2010 to 2015. Outcomes included birth-related events (e.g. mortality), vaccination uptake, hospitalizations, and teen pregnancy. Regression goodness of fit was used to assess the strength of individual associations. Inequality was measured by slope index of inequality (SII) and relative index of inequality (RII). Results Overall, 19 of 20 outcomes had socioeconomic gradients identified by SII and RII. The multidimensional CAN-Marg indices had the best explanatory power in standard regression models. The simplest ABSM—income quintile—detected 16 of 19 confirmed inequalities, more than any other single measure. Conclusions At all ages, many pediatric health outcomes in Manitoba were associated with significant socioeconomic inequalities; while income quintile detected most, CAN-Marg composite indices had the best explanatory power.

    更新日期:2020-01-14
  • Confounding biases in studies on early- versus late-caffeine in preterm infants: a systematic review
    Pediatr. Res. (IF 2.880) Pub Date : 2020-01-13
    Sandra Nylander Vujovic; Chiara Nava; Minna Johansson; Matteo Bruschettini

    Background Caffeine is indicated for the management of apnoea of prematurity and extubation in preterm infants. Early initiation of caffeine administration has increased in the past decades with the purpose of reducing respiratory morbidity. However, there might be harms associated with this approach. This systematic review aims to assess whether early administration of caffeine reduces morbidity and mortality in preterm infants. Methods The methods were published in a preregistered protocol. The literature search was performed in February 2019 with no restrictions for language or publication date. Randomised controlled trials (RCTs) and cohort studies comparing early versus late caffeine administration to infants born before week 34 were included. Results Two RCTs and 14 cohort studies were included. All studies but one had a serious/critical overall risk of bias. Few studies reported on long-term or patient-relevant outcomes. No meta-analysis could be performed. Conclusion Based on the available evidence, no conclusions about the optimal timing of caffeine administration can be drawn. There are inherent methodological problems in the cohort studies. RCTs are needed to answer the question of optimal timing for caffeine administration in neonatal care. Future trials should focus on outcomes relevant to patients and their families and include long-term outcomes.

    更新日期:2020-01-13
  • How to introduce MSC-based therapy for the developing lung safely into clinical care?
    Pediatr. Res. (IF 2.880) Pub Date : 2020-01-13
    Mario Rüdiger; Haresh Kirpalani; Robin Steinhorn; Jonathan M. Davis; Bernard Thebaud

    Extreme prematurity is associated with an increased risk to develop bronchopulmonary dysplasia (BPD). Severe BPD is associated with a significant long-term burden for the affected infant, families and society. Currently there are limited prevention and treatment options. Regenerative approaches using mesenchymal stromal cells (MSC) are associated with promising benefits in animal experiments. First clinical studies, using MSC in humans, suggest safety. To accelerate the process of bench to bed-side development of MSC-based therapies, a global and collaborative approach is needed that includes all key stakeholders. Results of a workshop that was held during the Pediatric Academic Societies meeting in 2019 are summarized. A roadmap is provided discussing next steps of bringing MSC-based interventions into clinical practice.

    更新日期:2020-01-13
  • Modification of the effects of prenatal manganese exposure on child neurodevelopment by maternal anemia and iron deficiency
    Pediatr. Res. (IF 2.880) Pub Date : 2020-01-11
    Allison Kupsco; Guadalupe Estrada-Gutierrez; Alejandra Cantoral; Lourdes Schnaas; Ivan Pantic; Chitra Amarasiriwardena; Katherine Svensson; David C. Bellinger; Martha María Téllez-Rojo; Andrea A. Baccarelli; Robert O. Wright

    Background We evaluated: (1) associations of prenatal manganese (Mn) levels with child neurodevelopment at 4–6 years; (2) effect modification by maternal anemia and iron deficiency; and (3) sex-specific effects. Methods We measured blood Mn, hemoglobin, and serum ferritin in mothers at the second trimester, third trimester, and at birth, and in cord blood from a prospective birth cohort in Mexico City (n = 571). McCarthy Scales of Children’s Abilities were measured at 4–6 years. Using linear regression, we estimated associations between prenatal Mn and neurodevelopment, examined anemia and iron deficiency as effect modifiers, and analyzed associations by child sex. Results No direct associations were observed between Mn, anemia, or iron deficiency and McCarthy Scales. Second trimester iron deficiency and third trimester anemia modified the effect of Mn on child neurodevelopment. For instance, second trimester Mn was positively associated child memory scores in mother’s with normal ferritin (1.85 (0.02, 3.45)), but negatively associated in mother’s with low ferritin (−2.41 (−5.28, 0.47), interaction P value = 0.01), a pattern observed across scales. No effect modification at birth or in cord blood was observed. Conclusions Anemia/iron deficiency during pregnancy may modify Mn impacts on child neurodevelopment, particularly in boys.

    更新日期:2020-01-13
  • Surfactant replacement therapy: from biological basis to current clinical practice
    Pediatr. Res. (IF 2.880) Pub Date : 2020-01-11
    Roland Hentschel; Kajsa Bohlin; Anton van Kaam; Hans Fuchs; Olivier Danhaive

    This review summarizes the current knowledge on the physiological action of endogenous and exogenous pulmonary surfactant, the role of different types of animal-derived and synthetic surfactants for RDS therapy, different modes of administration, potential risks and strategies of ventilation, and highlights the most promising aims for future development. Scientists have clarified the physicochemical properties and functions of the different components of surfactant, and part of this successful research is derived from the characterization of genetic diseases affecting surfactant composition or function. Knowledge from functional tests of surfactant action, its immunochemistry, kinetics and homeostasis are important also for improving therapy with animal-derived surfactant preparations and for the development of modified surfactants. In the past decade newly designed artificial surfactants and additives have gained much attention and have proven different advantages, but their particular role still has to be defined. For clinical practice, alternative administration techniques as well as postsurfactant ventilation modes, taking into account alterations in lung mechanics after surfactant placement, may be important in optimizing the potential of this most important drug in neonatology.

    更新日期:2020-01-13
  • Body composition and neuromotor development in the year after NICU discharge in premature infants
    Pediatr. Res. (IF 2.880) Pub Date : 2020-01-11
    Dan M. Cooper; Gay L. Girolami; Brenda Kepes; Annamarie Stehli; Candice Taylor Lucas; Fadia Haddad; Frank Zalidvar; Nitzan Dror; Irfan Ahmad; Antoine Soliman; Shlomit Radom-Aizik

    Background Hypothesis: neuromotor development correlates to body composition over the first year of life in prematurely born infants and can be influenced by enhancing motor activity. Methods Forty-six female and 53 male infants [27 ± 1.8 (sd) weeks] randomized to comparison or exercise group (caregiver provided 15–20 min daily of developmentally appropriate motor activities) completed the year-long study. Body composition [lean body and fat mass (LBM, FM)], growth/inflammation predictive biomarkers, and Alberta Infant Motor Scale (AIMS) were assessed. Results AIMS at 1 year correlated with LBM (r = 0.32, p < 0.001) in the whole cohort. However, there was no effect of the intervention. LBM increased by ~3685 g (p < 0.001)); insulin-like growth factor-1 (IGF-1) was correlated with LBM (r = 0.36, p = 0.002). IL-1RA (an inflammatory biomarker) decreased (−75%, p < 0.0125). LBM and bone mineral density were significantly lower and IGF-1 higher in the females at 1 year. Conclusions We found an association between neuromotor development and LBM suggesting that motor activity may influence LBM. Our particular intervention was ineffective. Whether activities provided largely by caregivers to enhance motor activity in prematurely born infants can affect the interrelated (1) balance of growth and inflammation mediators, (2) neuromotor development, (3) sexual dimorphism, and/or (4) body composition early in life remains unknown.

    更新日期:2020-01-13
  • Right ventricular end-systolic remodeling index in the assessment of pediatric pulmonary arterial hypertension. The European Pediatric Pulmonary Vascular Disease Network (EPPVDN)
    Pediatr. Res. (IF 2.880) Pub Date : 2020-01-10
    Martin Koestenberger; Alexander Avian; Phillippe Chouvarine; Andreas Gamillscheg; Gerhard Cvirn; Sabrina Schweintzger; Stefan Kurath-Koller; Massimiliano Cantinotti; Dagmar Hohmann; Georg Hansmann

    Background Echocardiographic determination of the right ventricular end-systolic remodeling index (RVES RI) has clinical value for the assessment of pulmonary hypertension (PH) in adults. We aim to determine RVES RI values in pediatric PH and to correlate RVES RI data with echocardiographic variables and NYHA functional class (FC). Methods Prospective echocardiography study in 49 children with PH. The 49 matched control subjects were chosen from 123 healthy children used to construct pediatric normal reference values. The associations with invasive hemodynamic variables were also investigated in a validation cohort of 12 PH children and matched controls. Results RVES RI was increased in children with PH vs. healthy controls (1.45 ± 0.16 vs. 1.16 ± 0.06; p < 0.01; confirmed in the validation cohort). RVES RI was associated with invasive hemodynamic variables, i.e. the mean pulmonary artery pressure. RVES RI values increased with worsening NYHA-FC. The highest RVES RI values were observed in PH children with NYHA FC 3 (1.60 ± 0.12). Conclusions RVES RI is a useful indicator of RV remodeling and dilation in the setting of increased RV pressure load, especially when the degree of regurgitation of the tricuspid and pulmonary valves is insufficient to numerically estimate RV systolic pressure and mPAP, due to incomplete Doppler envelopes.

    更新日期:2020-01-11
  • Transmembrane 6 superfamily member 2 167K allele improves renal function in children with obesity
    Pediatr. Res. (IF 2.880) Pub Date : 2020-01-10
    Pierluigi Marzuillo; Anna Di Sessa; Grazia Cirillo; Giuseppina Rosaria Umano; Marcella Pedullà; Angela La Manna; Stefano Guarino; Emanuele Miraglia del Giudice

    Background The transmembrane 6 superfamily member 2 (TM6SF2) E167K polymorphism influences estimated glomerular filtration rate (eGFR) in adults without diabetes and without obesity. We aimed exploring the impact of this polymorphism on eGFR in children with obesity with and without non-alcoholic fatty liver disease (NAFLD). Methods We genotyped 531 children with obesity for TM6SF2 E167K polymorphism. NAFLD was defined by ultrasound detected liver steatosis and/or ALT > 40 IU/L. Results Patients carrying the TM6SF2 167K allele showed higher eGFR levels compared with E167 homozygous patients both among subjects with and without NAFLD. A general linear model confirmed a direct and significant association of eGFR values with TM6SF2 genotype both in patients with and without NAFLD. This association, however, was stronger in patients with NAFLD. Conclusions Children with obesity carrying the TM6SF2 167K allele show higher eGFR levels compared with E167 allele homozygous subjects, independently of NAFLD. A major effect of this polymorphism in the presence of NAFLD was captured.

    更新日期:2020-01-11
  • Bidirectional association between GERD and asthma in children: two longitudinal follow-up studies using a national sample cohort
    Pediatr. Res. (IF 2.880) Pub Date : 2020-01-10
    So Young Kim; Hye-Rim Kim; Chanyang Min; Dong Jun Oh; Bumjung Park; Hyo Geun Choi

    Background The causal relationship between asthma and gastroesophageal reflux disease (GERD) is unknown in children. Methods The Korean Health Insurance Review and Assessment Service-National Sample Cohort 2002–2013 was used. The population age <15 years was selected. In study I, 86,096 asthmatic children were 1:1 matched with 86,096 control I participants. In study II, 532 GERD children were 1:2 matched with 1064 control II participants. The stratified Cox proportional hazard ratios for GERD in patients with asthma (study I) and asthma in patients with GERD (study II) were analyzed. Results In total, 0.7% (583/86,096) of the asthma group and 0.5% (430/86,096) of the control I group had GERD (P < 0.001). The asthma group demonstrated a 1.36 times higher HR for GERD than the control I group (95% CI = 1.20–1.54, P < 0.001). Subgroup analyses according to age and sex showed consistent results. In total, 15.0% (80/532) of the GERD group and 10.0% (106/1,064) of the control II group had asthma (P < 0.001). The GERD group showed a 1.62-fold higher HR for asthma than the control II group (95% CI = 1.21–2.18, P < 0.001). Conclusion GERD and asthma demonstrated a bidirectional relationship in children.

    更新日期:2020-01-11
  • Correction: Editor’s focus
    Pediatr. Res. (IF 2.880) Pub Date : 2020-01-08

    A correction to this paper has been published and can be accessed via a link at the top of the paper.

    更新日期:2020-01-08
  • Correction: Nitric oxide and preterm resuscitation: some words of caution
    Pediatr. Res. (IF 2.880) Pub Date : 2020-01-06
    Maximo Vento; Ángel Sánchez-Illana

    A correction to this paper has been published and can be accessed via a link at the top of the paper.

    更新日期:2020-01-06
  • Prevalence of alcohol use in late pregnancy
    Pediatr. Res. (IF 2.880) Pub Date : 2020-01-03
    Amna Umer; Christa Lilly; Candice Hamilton; Aileen Baldwin; Janine Breyel; Amy Tolliver; Christina Mullins; Collin John; Stefan Maxwell

    Background Prenatal alcohol exposure (PAE) can result in detrimental developmental complications. The objective of this study was to estimate the most recent PAE prevalence data for the state of West Virginia (WV) and associated factors. Method In all, 1830 newborn residual dried blood spots (DBS) in the WV Newborn Screening Repository were analyzed for phosphatidylethanol (PETH). Data were matched with Project WATCH data (94% match, N = 1729). Results The prevalence of late pregnancy PAE was 8.10% (95%CI: 6.81, 9.38) for all births, 7.61% (95%CI: 6.26, 8.97) for WV residents only, and ranged from 2.27 to 17.11% by region. The significant factors associated with PAE included smoking (OR: 2.03, 95% CI: 1.40, 2.94), preterm births (OR: 1.88; 95% CI: 1.23, 2.89), birth weight of ≤2000 g vs. >3000 g (OR: 2.62, 95%CI: 1.19, 5.79), no exclusive breastfeeding intention (OR: 1.45, 95% CI: 1.02, 2.04), and not exclusively breastfeeding before discharge (OR: 1.61; 95% CI: 1.09, 2.38). Conclusion The prevalence of PAE is higher than previously shown for the state. Accurate and timely estimates are vital to inform public health workers, policymakers, researchers, and clinicians to develop and promote effective prevention strategies to lower PAE prevalence and provide targeted interventions and treatment services for infants affected by PAE.

    更新日期:2020-01-04
  • Association of UCP1 , UCP2 and UCP3 gene polymorphisms with cardiovascular disease risk factors in European adolescents: the HELENA study
    Pediatr. Res. (IF 2.880) Pub Date : 2020-01-03
    Jose M. Pascual-Gamarra; Diego Salazar-Tortosa; Idoia Labayen; Azahara I. Rupérez; Catherine Leclercq; Ascension Marcos; Sonia Gómez; Luis A. Moreno; Aline Meirhaeghe; Manuel J. Castillo; Jonatan R. Ruiz

    Background Cardiovascular diseases (CVDs) are responsible for 31% of all deaths worldwide. Genetic predisposition to CVDs in adolescents remains largely unknown. The aim of this study was to examine the association of UCP1, UCP2 and UCP3 gene polymorphisms with CVD risk factors in European adolescents. Method A cross-sectional study that involves 1.057 European adolescents (12–18 years old) from the HELENA study. A total of 18 polymorphisms of UCP1, UCP2 and UCP3 genes were genotyped. We measured serum total cholesterol, high-density lipoprotein, ApoA1, ApoB, leptin, triglycerides, glucose, insulin and blood pressure, and calculated HOMA (homeostatic model assessment) and a CVD risk score. Results The G allele of UCP2 rs2735572 and T allele of UCP2 rs17132534 were associated with higher diastolic blood pressure (P = 0.001; false discovery rate [FDR] = 0.009 and P = 8e − 04; FDR = 0.009, respectively). We observed that the AATAG haplotype of UCP1 was associated with higher serum ApoB/ApoA1 (P = 0.008; FDR = 0.031) and ApoB levels (P = 0.008; FDR = 0.031). Moreover, the ACC haplotype of UCP3 was associated with a higher CVD risk score (P = 0.0036; FDR = 0.01). Conclusions Two UCP2 polymorphisms and haplotypes of UCP1 and UCP3 were associated with CVD risk factors. These findings suggest that UCPs may have a role in the development of CVD already in adolescents.

    更新日期:2020-01-04
  • The influence of pain, agitation, and their management on the immature brain
    Pediatr. Res. (IF 2.880) Pub Date : 2020-01-02
    Christopher McPherson; Steven P. Miller; Mohamed El-Dib; An N. Massaro; Terrie E. Inder

    Preterm infants are exposed to frequent painful procedures and agitating stimuli over the many weeks of their hospitalization in the neonatal intensive care unit (NICU). The adverse neurobiological impact of pain and stress in the preterm infant has been well documented, including neuroimaging and neurobehavioral outcomes. Although many tools have been validated to assess acute pain, few methods are available to assess chronic pain or agitation (a clinical manifestation of neonatal stress). Both nonpharmacologic and pharmacologic approaches are used to reduce the negative impact of pain and agitation in the preterm infant, with concerns emerging over the adverse effects of analgesia and sedatives. Considering benefits and risks of available treatments, units must develop a stepwise algorithm to prevent, assess, and treat pain. Nonpharmacologic interventions should be consistently utilized prior to mild to moderately painful procedures. Sucrose may be utilized judiciously as an adjunctive therapy for minor painful procedures. Rapidly acting opioids (fentanyl or remifentanil) form the backbone of analgesia for moderately painful procedures. Chronic sedation during invasive mechanical ventilation represents an ongoing challenge; appropriate containment and an optimal environment should be standard; when indicated, low-dose morphine infusion may be utilized cautiously and dexmedetomidine infusion may be considered as an emerging adjunct.

    更新日期:2020-01-02
  • What drives change in neonatal intensive care units? A qualitative study with physicians and nurses in six European countries
    Pediatr. Res. (IF 2.880) Pub Date : 2020-01-02
    Marina Cuttini; Emanuela Forcella; Carina Rodrigues; Elizabeth S. Draper; Ana F. Martins; Agnés Lainé; Janet Willars; Asbjørn Hasselager; Rolf F. Maier; Ileana Croci; Mercedes Bonet; Jennifer Zeitlin

    Background Innovation is important to improve patient care, but few studies have explored the factors that initiate change in healthcare organizations. Methods As part of the European project EPICE on evidence-based perinatal care, we carried out semi-structured interviews (N = 44) with medical and nursing staff from 11 randomly selected neonatal intensive care units in 6 countries. The interviews focused on the most recent clinical or organizational change in the unit relevant to the care of very preterm infants. Thematic analysis was performed using verbatim transcripts of recorded interviews. Results Reported changes concerned ventilation, feeding and nutrition, neonatal sepsis, infant care, pain management and care of parents. Six categories of drivers to change were identified: availability of new knowledge or technology; guidelines or regulations from outside the unit; need to standardize practices; participation in research; occurrence of adverse events; and wish to improve care. Innovations originating within the unit, linked to the availability of new technology and seen to provide clear benefit for patients, were more likely to achieve consensus and rapid implementation. Conclusions Innovation can be initiated by several drivers that can impact on the success and sustainability of change.

    更新日期:2020-01-02
  • Human ucMSCs seeded in a decellularized kidney scaffold attenuate renal fibrosis by reducing epithelial–mesenchymal transition via the TGF-β/Smad signaling pathway
    Pediatr. Res. (IF 2.880) Pub Date : 2020-01-02
    Dong Hu; Deying Zhang; Bo Liu; Yang Liu; Yu Zhou; Yihang Yu; Lianju Shen; Chunlan Long; Dan Zhang; Xing Liu; Tao Lin; Dawei He; Tao Xu; Peter Timashev; Denis Butnaru; Yuanyuan Zhang; Guanghui Wei

    BACKGROUND Renal fibrosis occurs largely through epithelial–mesenchymal transition (EMT). This study explored the beneficial effects of a human umbilical cord mesenchymal stem cell-loaded decellularized kidney scaffold (ucMSC-DKS) on renal fibrosis in a rodent model of post-transplantation renal failure, and the underlying mechanism. METHODS Rat-derived DKSs were examined after preparation, and then recellularized with human ucMSCs to prepare cell-loaded patches. A rat model of renal failure was established after subtotal nephrectomy (STN). The cell patches were transplanted to remnant kidneys. Changes in renal function, histology, EMT, and proteins related to the transforming growth factor-β (TGF-β)/Smad signaling pathway in the remnant kidneys were examined 8 weeks after surgery, compared with non-cell patch controls. RESULTS The DKSs were acellular and porous, with rich cytokine and major extracellular matrix components. The ucMSCs were distributed uniformly in the DKSs. Renal function was improved, renal fibrosis and EMT were reduced, and the TGF-β/Smad signaling pathway was inhibited compared with controls at 8 weeks after ucMSC-DKS patch transplantation. CONCLUSIONS The ucMSC-DKS restores renal function and reduces fibrosis by reducing EMT via the TGF-β/Smad signaling pathway in rats that have undergone STN. It provides an alternative for renal fibrosis treatment.

    更新日期:2020-01-02
  • Brain temperature of infants with neonatal encephalopathy following perinatal asphyxia calculated using magnetic resonance spectroscopy
    Pediatr. Res. (IF 2.880) Pub Date : 2020-01-02
    Kim V. Annink; Floris Groenendaal; Daan Cohen; Niek E. van der Aa; Thomas Alderliesten; Jeroen Dudink; Manon J.N.L. Benders; Jannie P. Wijnen

    Background Little is known about brain temperature of neonates during MRI. Brain temperature can be estimated non-invasively with proton Magnetic Resonance Spectroscopy (1H-MRS), but the most accurate 1H-MRS method has not yet been determined. The primary aim was to estimate brain temperature using 1H-MRS in infants with neonatal encephalopathy following perinatal asphyxia (NE). The secondary aim was to compare brain temperature during MRI with rectal temperatures before and after MRI. Methods In this retrospective study, brain temperature in 36 (near-)term infants with NE was estimated using short (36 ms) and long (288 ms) echo time (TE) 1H-MRS. Brain temperature was calculated using two different formulas: formula of Wu et al. and a formula based on phantom calibration. The methods were compared. Rectal temperatures were collected <3 h before and after MRI. Results Brain temperatures calculated with the formula of Wu et al. and the calibrated formula were similar as well as brain temperatures derived from short and long TE 1H-MRS. Rectal temperature did not differ before and after MRI. Conclusions Brain temperature can be measured using 1H-MRS in daily clinical practice using the formula of Wu et al. with both short and long TE 1H-MRS. Brain temperature remained within physiological range during MRI.

    更新日期:2020-01-02
  • Plasma ammonia concentrations in extremely low birthweight infants in the first week after birth: secondary analysis from the ProVIDe randomized clinical trial
    Pediatr. Res. (IF 2.880) Pub Date : 2020-01-02
    Barbara E. Cormack; Yannan Jiang; Jane E. Harding; Caroline A. Crowther; Adrienne Lynn; Arun Nair; Michael Hewson; Mike Meyer; Roland Broadbent; Dianne Webster; Emma Glamuzina; Bryony Ryder; Frank H. Bloomfield

    Background Little is known about normative ammonia concentrations in extremely low birthweight (ELBW) babies and whether these vary with birth characteristics. We aimed to determine ammonia concentrations in ELBW babies in the first week after birth and relationships with neonatal characteristics and protein intake. Methods Arterial blood samples for the measurement of plasma ammonia concentration were collected within 7 days of birth from ProVIDe trial participants in six New Zealand neonatal intensive care units. Results Three hundred and twenty-two babies were included. Median (range) gestational age was 25.7 (22.7–31.6) weeks. Median (interquartile range (IQR)) ammonia concentration was 102 (80–131) µg/dL. There were no statistically significant associations between ammonia concentrations and birthweight or sex. Ammonia concentrations were weakly correlated with mean total (Spearman’s rs = 0.11, P = 0.047) and intravenous (rs = 0.13, P = 0.02) protein intake from birth, gestational age at birth (rs = −0.13, P = 0.02) and postnatal age (rs = −0.13, P = 0.02). Conclusions Plasma ammonia concentrations in ELBW babies are similar to those of larger and more mature babies and only weakly correlated with protein intake. Currently, recommended thresholds for investigation of hyperammonaemia are appropriate for ELBW babies. Protein intake should not be limited by concerns about potential hyperammonaemia.

    更新日期:2020-01-02
  • Effects of a potassium channel opener on brain injury and neurologic outcomes in an animal model of neonatal hypoxic–ischemic injury
    Pediatr. Res. (IF 2.880) Pub Date : 2020-01-02
    Dayalan Sampath; Philip M. Lam; Maddy Laoprasert; Michael J. Diaz; Nicolas Busquet; Andrew M. White; Marco I. Gonzalez; Yogendra H. Raol

    Background Hypoxia–ischemia (HI) is the most common cause of brain injury in newborns and the survivors often develop cognitive and sensorimotor disabilities that undermine the quality of life. In the current study, we examined the effectiveness of flupirtine, a potassium channel opener, shown previously in an animal model to have strong anti-neonatal-seizure efficacy, to provide neuroprotection and alleviate later-life disabilities caused by neonatal hypoxic–ischemic injury. Methods The rats were treated with a single dose of flupirtine for 4 days following HI induction in 7-day-old rats. The first dose of flupirtine was given after the induction of HI and during the reperfusion period. The effect of treatment was examined on acute and chronic brain injury, motor functions, and cognitive abilities. Results Flupirtine treatment significantly reduced HI-induced hippocampal and cortical tissue loss at acute time point. Furthermore, at chronic time point, flupirtine reduced contralateral hippocampal volume loss and partially reversed learning and memory impairments but failed to improve motor deficits. Conclusion The flupirtine treatment regimen used in the current study significantly reduced brain injury at acute time point in an animal model of neonatal hypoxic–ischemic encephalopathy. However, these neuroprotective effects were not persistent and only modest improvement in functional outcomes were observed at chronic time points.

    更新日期:2020-01-02
  • Kidney and blood pressure abnormalities 6 years after acute kidney injury in critically ill children: a prospective cohort study
    Pediatr. Res. (IF 2.880) Pub Date : 2020-01-02
    Kelly Benisty; Catherine Morgan; Erin Hessey; Louis Huynh; Ari R. Joffe; Daniel Garros; Adrian Dancea; Reginald Sauve; Ana Palijan; Michael Pizzi; Sudeshna Bhattacharya; Julie Ann Doucet; Vedran Cockovski; Ronald G. Gottesman; Stuart L. Goldstein; Michael Zappitelli

    Background Acute kidney injury (AKI) in pediatric intensive care unit (PICU) children may be associated with long-term chronic kidney disease or hypertension. Objectives: To estimate (1) prevalence of kidney abnormalities (low estimated glomerular filtration rate (eGFR) or albuminuria) and blood pressure (BP) consistent with pre-hypertension or hypertension, 6 years after PICU admission; (2) if AKI is associated with these outcomes. Methods Longitudinal study of children admitted to two Canadian PICUs (January 2005–December 2011). Exposures (retrospective): AKI or stage 2/3 AKI (KDIGO creatinine-based definition) during PICU. Primary outcome (single visit 6 years after admission): presence of (a) low eGFR (<90 ml/min/1.73 m2) or albuminuria (albumin to creatinine ratio >30 mg/g) (termed “CKD signs”) or (b) BP consistent with ≥pre-hypertension (≥90th percentile) or hypertension (≥95th percentile). Results Of 277 children, 25% had AKI. AKI and stage 2/3 AKI were associated with 2.2- and 6.6-fold higher adjusted odds, respectively, for the 6-year outcomes. Applying new hypertension guidelines attenuated associations; stage 2/3 AKI was associated with 4.5-fold higher adjusted odds for 6-year CKD signs or ≥elevated BP. Conclusions Kidney and BP abnormalities are common 6 years after PICU admission and associated with AKI. Other risk factors must be elucidated to develop follow-up recommendations and reduce cardiovascular risk.

    更新日期:2020-01-02
  • Association between maternal acetaminophen use and adverse birth outcomes in a pregnancy and birth cohort
    Pediatr. Res. (IF 2.880) Pub Date : 2019-12-18
    Jasleen Arneja; Rayjean J. Hung; Ryan A. Seeto; Julia A. Knight; Sheryl L. Hewko; Alan Bocking; Stephen J. Lye; Jennifer D. Brooks

    Introduction Acetaminophen is the only analgesic recommended for use during pregnancy. This use has recently been linked to childhood developmental disorders, a finding that requires further investigation. Adverse birth outcomes—preterm birth, low birthweight, and small for gestational age—are associated with increased risk of developmental disorders and can serve as intermediate outcomes when examining the impact of maternal acetaminophen use. Methods Clinical and lifestyle-factor data were gathered from 1200 women within the Ontario Birth Study who delivered between January 2013 and June 2017. Poisson regression with robust error variance was used to estimate the relationship between acetaminophen use before and during pregnancy and low birthweight, preterm birth, and small for gestational age. Results Offspring of mothers who used acetaminophen before pregnancy had a higher risk of low birthweight and small for gestational age. Acetaminophen use

    更新日期:2019-12-19
  • The development of neonatal neurointensive care
    Pediatr. Res. (IF 2.880) Pub Date : 2019-12-18
    Topun Austin

    Brain injury remains one of the major unsolved problems in neonatal care, with survivors at high risk of lifelong neurodisability. It is unlikely that a single intervention can ameliorate neonatal brain injury, given the complex interaction between pathological processes, developmental trajectory, genetic susceptibility, and environmental influences. However, a coordinated, interdisciplinary approach to understand the root cause enables early detection, and diagnosis with enhanced clinical care offers the best chance of improving outcomes and facilitate new lines of neuroprotective treatments. Adult neurointensive care has existed as a speciality in its own right for over 20 years; however, it is only recently that large prospective studies have demonstrated the benefit of this model of care. The ‘Neuro-intensive Care Nursery’ model originated at the University of California San Francisco in 2008, and since then a growing number of units worldwide have adopted this approach. As well as providing consistent coordinated care for infants from a multidisciplinary team, it provides opportunities for specialist education and training in neonatal neurology, neuromonitoring, neuroimaging and nursing. This review outlines the origins of brain-oriented care of the neonate and the development of the Neuro-NICU (neonatal intensive care unit) and discusses some of the challenges and opportunities in expanding this model of care.

    更新日期:2019-12-19
  • Clinical features, genetic background, and outcome in infants with urinary tract infection and type IV renal tubular acidosis
    Pediatr. Res. (IF 2.880) Pub Date : 2019-12-18
    Min-Hua Tseng; Jing-Long Huang; Shih-Ming Huang; Jeng-Daw Tsai; Tai-Wei Wu; Wen-Lang Fan; Jhao-Jhuang Ding; Shih-Hua Lin

    Background Type IV renal tubular acidosis (RTA) is a severe complication of urinary tract infection (UTI) in infants. A detailed clinical and molecular analysis is still lacking. Methods Infants with UTI who exhibited features of type IV RTA were prospectively enrolled. Clinical, laboratory, and image characteristics and sequencing of genes responsible for phenotype were determined with follow-up. Results The study cohort included 12 infants (9 males, age 1–8 months). All exhibited typical type IV RTA such as hyperkalemia with low transtubular potassium gradient, hyperchloremic metabolic acidosis with positive urine anion gap, hypovolemic hyponatremia with renal salt wasting, and high plasma renin and aldosterone levels. Seven had hyperkalemia-related arrhythmia and two of them developed life-threatening ventricular tachycardia. With prompt therapy, all clinical and biochemical abnormalities resolved within 1 week. Five had normal urinary tract anatomy, and three of them carried genetic variants on NR3C2. Three variants, c.1645T>G (S549A), c.538G>A (V180I), and c.1-2C>G, on NR3C2 were identified in four patients. During follow-up, none of them had recurrent type IV RTA, but four developed renal scaring. Conclusions Genetic mutation on NR3C2 may contribute to the development of type IV RTA as a complication of UTI in infants without identifiable risk factors, such as urinary tract anomalies.

    更新日期:2019-12-19
  • Clinical validation of the Neonatal Infant Stressor Scale with preterm infant salivary cortisol
    Pediatr. Res. (IF 2.880) Pub Date : 2019-12-17
    Shaliz Pourkaviani; Xueying Zhang; Emily A. Spear; Madeline D’ Agostino; Rebecca E. Satty; Shelley H. Liu; Annemarie Stroustrup

    Background Preterm infants face unique stress states in early life. Early-life stress has been associated with changes in cortisol reactivity and behavioral abnormalities later in childhood in non-preterm populations. The Neonatal Infant Stressor Scale (NISS) has been used to estimate infant stress in the neonatal intensive care unit (NICU) but has not been biomarker validated. The relationship between NISS scores and salivary cortisol is unknown. Objective To test the association between NISS scores and salivary cortisol in the NICU Hospital Exposures and Long-Term Health (NICU-HEALTH) preterm birth cohort. Methods Three hundred and eighty-six salivary cortisol specimens were collected from 125 NICU-HEALTH participants during the NICU hospitalization. NISS scores were calculated to represent the infant’s experience in the 6 h prior to specimen collection. Adjusted mixed-effect regression models were used to assess the association between each NISS score and salivary cortisol. Results Acute and total NISS scores were significantly associated with salivary cortisol level (P = 0.002 and 0.05, respectively). The chronic NISS score was not associated with salivary cortisol levels. Caffeine treatment and postmenstrual age of the infant at the time of exam were important covariates in all models. Conclusion Acute and total NISS score are associated with salivary cortisol level in hospitalized moderately preterm infants.

    更新日期:2019-12-18
  • Maternal serum levels of perfluoroalkyl substances in early pregnancy and offspring birth weight
    Pediatr. Res. (IF 2.880) Pub Date : 2019-12-13
    Sverre Wikström; Ping-I Lin; Christian H. Lindh; Huan Shu; Carl-Gustaf Bornehag

    Background Perfluoroalkyl substances (PFASs) are widespread, bioaccumulating, and persistent and show placental transfer. Emerging research indicates associations between prenatal exposure and low birth weight. The aim of this study was to assess the associations between first trimester exposure to PFASs and birth weight (BW) in the Swedish Environmental, Longitudinal, Mother and child, Asthma and allergy (SELMA) study and examine whether associations differ between girls and boys. Methods Eight PFASs were analyzed in maternal serum (median: 10 weeks of pregnancy). Associations between prenatal PFAS exposure and birth outcomes with BW, BW for gestational age, and birth small for gestational age (SGA) were assessed in 1533 infants, adjusted for potential confounders and stratified by sex. Results Increased maternal perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), and perfluoroundecanoic acid (PFUnDA) were associated with lower BW, lower BW for gestational age, and SGA birth. Associations were significant only in girls, where prenatal exposure in the upper quartile was associated with a 93–42-g lower BW when compared with that of the lowest quartile exposure. The associations were not mediated by effects on gestational age. Conclusions We found associations between prenatal exposure for five different PFASs and birth weight, with more pronounced associations in girls than in boys.

    更新日期:2019-12-13
  • Pulmonary mechanics and structural lung development after neonatal hyperoxia in mice
    Pediatr. Res. (IF 2.880) Pub Date : 2019-12-13
    Andrew M. Dylag; Jeannie Haak; Min Yee; Michael A. O’Reilly

    Background Supplemental oxygen exposure administered to premature infants is associated with chronic lung disease and abnormal pulmonary function. This study used mild (40%), moderate (60%), and severe (80%) oxygen to determine how hyperoxia-induced changes in lung structure impact pulmonary mechanics in mice. Methods C57BL/6J mice were exposed to room air or hyperoxia from birth through postnatal day 8. Baseline pulmonary function and methacholine challenge was assessed at 4 and 8 weeks of age, accompanied by immunohistochemical assessments of both airway (smooth muscle, tethering) and alveolar (simplification, elastin deposition) structure. Results Mild/moderate hyperoxia increased baseline airway resistance (40% only) and airway hyperreactivity (40 and 60%) at 4 weeks accompanied by increased airway smooth muscle deposition, which resolved at 8 weeks. Severe hyperoxia increased baseline compliance, baseline resistance, and total elastin/surface area ratio without increasing airway hyperreactivity, and was accompanied by increased alveolar simplification, decreased airway tethering, and changes in elastin distribution at both time points. Conclusions Mild to moderate hyperoxia causes changes in airway function and airway hyperreactivity with minimal parenchymal response. Severe hyperoxia drives its functional changes through alveolar simplification, airway tethering, and elastin redistribution. These differential responses can be leveraged to further develop hyperoxia mouse models.

    更新日期:2019-12-13
  • Precise neonatal arterial ischemic stroke classification with a three-dimensional map of the arterial territories of the neonatal brain
    Pediatr. Res. (IF 2.880) Pub Date : 2019-12-13
    Christian Núñez; Gemma Arca; Thais Agut; Christian Stephan-Otto; Alfredo García-Alix

    Background Data regarding neonatal arterial ischemic stroke (NAIS) topography are still sparse and inaccurate. Despite the importance of locating NAIS to predict the long-term outcome of neonates, a map of arterial territories is not yet available. Our aim was therefore to generate the first three-dimensional map of arterial territories of the neonatal brain (ATNB) and test its usefulness. Methods Three-dimensional time-of-flight magnetic resonance angiography images were acquired from four neonates without NAIS. Arteries were semi-automatically segmented to build a symmetric arterial template. This allowed us to delineate the volumetric extension of each arterial territory, giving rise to the ATNB map, which is publicly available. Its applicability was tested on a sample of 34 neonates with NAIS. Results After applying the ATNB map to the neonatal sample, the posterior trunk of the middle cerebral artery, followed by its anterior trunk, were identified as the most affected arterial territories. When comparing the results obtained employing the map with the original diagnoses made during the standard clinical evaluation of NAIS, major diagnostic errors were found in 18% of cases. Conclusion The ATNB map has been proven useful to precisely identify the arterial territories affected by an NAIS, as well as to increase the accuracy of clinical diagnoses.

    更新日期:2019-12-13
  • Neurodevelopmental outcome of preterm twins at 5 years of age
    Pediatr. Res. (IF 2.880) Pub Date : 2019-12-12
    Milla Ylijoki; Leena Haataja; Annika Lind; Eeva Ekholm; Liisa Lehtonen

    Background Twins are considered to be at an increased risk for perinatal mortality and morbidities, but it is unclear whether preterm twins are at an increased risk for poor developmental outcomes when compared to preterm singletons. Our aim was to compare the neurodevelopmental outcome of preterm twins vs singletons at 5 years of age. Methods Very low birth weight and very low gestational age infants (twins n = 66, singletons n = 157) were recruited as a part of the PIPARI project in the Turku University Hospital, covering a regional population. Cognitive development, neuropsychological performance, and neurodevelopmental impairments (including cerebral palsy, hearing deficit, visual impairment, and intellectual disability) were evaluated at 5 years of age. Results Twins and singletons had otherwise similar perinatal background factors, except for the higher proportion of preterm rupture of membranes in singletons. Twins had cognitive and neuropsychological outcomes that were otherwise comparable with singletons, but they had a slightly lower verbal intelligence quotient (estimate −5.81, 95% CI −11.14 to −0.48, p = 0.03). Being a twin was not a risk for neurodevelopmental impairments. Conclusions Our study shows that, contrary to a common hypothesis, the overall neurodevelopment of very preterm twins does not significantly differ from that of preterm singletons.

    更新日期:2019-12-13
  • Postnatal skeletal growth is driven by the epiphyseal stem cell niche: potential implications to pediatrics
    Pediatr. Res. (IF 2.880) Pub Date : 2019-12-12
    Andrei S. Chagin; Phillip T. Newton

    Children’s longitudinal growth is facilitated by the activity of the growth plates, cartilage discs located near the ends of the long-bones. In order to elongate these bones, growth plates must continuously generate chondrocytes. Two recent studies have demonstrated that there are stem cells and a stem cell niche in the growth plate, which govern the generation of chondrocytes during the postnatal growth period. These stem cells and their niche appear at the same time as the secondary ossification center (SOC) matures into a bone epiphysis. Thus, the mechanism of chondrocyte generation differs substantially between neonatal and postnatal age, i.e., before and after the formation of the mineralized epiphyses. Hence, at the neonatal age bone growth is based on a consumption of chondro-progenitors whereas postnatally it is based on the activity of the stem cell niche. Here we discuss potential implications of these observations in relation to longitudinal growth, including the effects of estrogens, nutrition and growth hormone.

    更新日期:2019-12-13
  • Acetaminophen increases pulmonary and systemic vasomotor tone in the newborn rat
    Pediatr. Res. (IF 2.880) Pub Date : 2019-12-12
    Liran Tamir Hostovsky; Jingyi Pan; Patrick J. McNamara; Jaques Belik

    Background Acetaminophen is widely prescribed to both neonates and young children for a variety of reasons. In adults, therapeutic usage of acetaminophen induces systemic arterial pressure changes and exposure to high doses promotes tissue toxicity. The pulmonary vascular effects of acetaminophen at any age are unknown. Hypothesizing that, early in life, it promotes vasomotor tone changes via oxidative stress, we tested the in vitro acetaminophen effects on intrapulmonary and carotid arteries from newborn and adult rats. Methodology We measured the acetaminophen dose–response in isometrically mounted arteries and pharmacologically evaluated the factors accounting for its vasomotor effects. Results Acetaminophen induced concentration- and age-dependent vasomotor tone changes. Whereas a progressive increase in vasomotor tone was observed in the newborn, the adult arteries showed mostly vasorelaxation. Inhibition of endogenous nitric oxide generation with l-NAME and the use of the peroxynitrite decomposition catalyst FeTPPS (Fe(III)5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrinato chloride) mostly abolished the drug-induced increase in newborn pulmonary vasomotor tone Conclusions In newborn rats, acetaminophen increases pulmonary vasomotor tone via peroxynitrite generation. Given its therapeutic usage, further clinical studies are warranted to assess the acetaminophen effects on the newborn pulmonary and systemic vascular resistance.

    更新日期:2019-12-13
  • Differences in areal bone mineral density between metabolically healthy and unhealthy overweight/obese children: the role of physical activity and cardiorespiratory fitness
    Pediatr. Res. (IF 2.880) Pub Date : 2019-12-10
    Esther Ubago-Guisado, Luis Gracia-Marco, María Medrano, Cristina Cadenas-Sánchez, Lide Arenaza, Jairo H. Migueles, José Mora-González, Ignacio Tobalina, Victoria Escolano-Margarit, Maddi Oses, Miguel Martín-Matillas, Idoia Labayen, Francisco B. Ortega

    Objectives To examine whether areal bone mineral density (aBMD) differs between metabolically healthy (MHO) and unhealthy (MUO) overweight/obese children and to examine the role of moderate-to-vigorous physical activity (MVPA) and cardiorespiratory fitness (CRF) in this association. Methods A cross-sectional study was developed in 188 overweight/obese children (10.4 ± 1.2 years) from the ActiveBrains and EFIGRO studies. Participants were classified as MHO or MUO based on Jolliffe and Janssen’s metabolic syndrome cut-off points for triglycerides, glucose, high-density cholesterol and blood pressure. MVPA and CRF were assessed by accelerometry and the 20-m shuttle run test, respectively. Body composition was measured by dual-energy X-ray absorptiometry. Results In model 1 (adjusted for sex, years from peak high velocity, stature and lean mass), MHO children had significantly higher aBMD in total body less head (Cohen’s d effect size, ES = 0.34), trunk (ES = 0.43) and pelvis (ES = 0.33) than MUO children. These differences were attenuated once MVPA was added to model 1 (model 2), and most of them disappeared once CRF was added to the model 1 (model 3). Conclusions This novel research shows that MHO children have greater aBMD than their MUO peers. Furthermore, both MVPA and more importantly CRF seem to partially explain these findings.

    更新日期:2019-12-11
  • Assessment of neonatal EEG background and neurodevelopment in full-term small for their gestational age infants
    Pediatr. Res. (IF 2.880) Pub Date : 2019-12-10
    José R. Castro Conde, Candelaria González Campo, Nieves L. González González, Beatriz Reyes Millán, Desiré González Barrios, Alejandro Jiménez Sosa, Itziar Quintero Fuentes

    Background Delayed brain function development in small-gestational-age (SGA) infants has been reported. We aimed to quantify rates of immature neonatal EEG patterns and their association with neurodevelopment in SGA full-term neonates. Methods Using a cohort design, 50 SGA (birthweight <10th percentile) and 44 appropriate-gestational-age (AGA) term neonates underwent continuous video-EEG recordings lasting >3 h. Seventy-three of them were assessed at 2-years-old using Bayley-III-Scales. For EEG analysis, several segments of discontinuous/alternating EEG tracings were selected. Main outcomes measured: (1) Visual analysis (patterns of EEG maturity); (2) Power spectrum in δ, θ, α and β frequency bands; and (3) scores in motor, cognitive and language development. Results (1) SGA infants, compared to AGA, showed: (a) higher percentages of discontinuous EEG, both asynchrony and interhemispheric asymmetry, and bursts with delta-brushes, longer interburst-interval duration and more transients/hour; (b) lower relative power spectrum in δ and higher in α; and (c) lower scores on motor, language and cognitive neurodevelopment. (2) Asymmetry >5%, interburst-interval >5 s, discontinuity >11%, and bursts with delta-brushes >11% were associated with lower scores on Bayley-III. Conclusions In this prospective study, SGA full-term neonates showed high rates of immature EEG patterns. Low-birthweight and immaturity EEG were both correlated with low development scores.

    更新日期:2019-12-11
  • Long-term neuropathological and/or neurobehavioral effects of antenatal corticosteroid therapy in animal models: a systematic review
    Pediatr. Res. (IF 2.880) Pub Date : 2019-12-10
    Johannes L. van der Merwe, Adalina Sacco, Jaan Toelen, Jan Deprest

    Background Antenatal corticosteroids (ACSs) are recommended to all women at risk for preterm delivery; currently, there is controversy about the subsequent long-term neurocognitive sequelae. This systematic review summarizes the long-term neurodevelopmental outcomes after ACS therapy in animal models. Methods An electronic search strategy incorporating MeSH and keywords was performed using all known literature databases and in accordance with PRISMA guidance (PROSPERO CRD42019119663). Results Of the 669 studies identified, eventually 64 were included. The majority of studies utilized dexamethasone at relative high dosages and primarily involved rodents. There was a high risk of bias, mostly due to lack of randomization, allocation concealment, and blinding. The main outcomes reported on was neuropathological, particularly glucocorticoid receptor expression and neuron densities, and neurobehavior. Overall there was an upregulation of glucocorticoid receptors with lower neuron densities and a dysregulation of the dopaminergic and serotonergic systems. This coincided with various adverse neurobehavioral outcomes. Conclusions In animal models, ACSs consistently lead to deleterious long-term neurocognitive effects. This may be due to the specific agents, i.e., dexamethasone, or the repetitive/higher total dosing used. ACS administration varied significantly between studies and there was a high risk of bias. Future research should be standardized in well-characterized models.

    更新日期:2019-12-11
  • Simvastatin attenuates lung functional and vascular effects of hyperoxia in preterm rabbits
    Pediatr. Res. (IF 2.880) Pub Date : 2019-12-09
    Thomas Salaets, Bieke Tack, Julio Jimenez, Andre Gie, Flore Lesage, Derek de Winter, Nathalie Berghen, Karel Allegaert, Jan Deprest, Jaan Toelen

    Background Bronchopulmonary dysplasia (BPD) remains a frequent complication following preterm birth, affecting respiratory health throughout life. Transcriptome analysis in a preterm rabbit model for BPD revealed dysregulation of key genes for inflammation, vascular growth and lung development in animals exposed to hyperoxia, which could be prevented by simvastatin. Methods Preterm rabbits were randomized to either normoxia (21% O2) or hyperoxia (95% O2) and within each condition to treatment with 5 mg/kg simvastatin daily or control. Lung function, structure and mRNA-expression was assessed on day 7. Results Simvastatin partially prevented the effect of hyperoxia on lung function, without altering alveolar structure or inflammation. A trend towards a less fibrotic phenotype was noted in simvastatin-treated pups, and airways were less muscularized. Most importantly, simvastatin completely prevented hyperoxia-induced arterial remodeling, in association with partial restoration of VEGFA and VEGF receptor 2 (VEGFR2) expression. Simvastatin however decreased survival in pups exposed to normoxia, but not to hyperoxia. Conclusion Repurposing of simvastatin could be an advantageous therapeutic strategy for bronchopulmonary dysplasia and other developmental lung diseases with pulmonary vascular disease. The increased mortality in the treated normoxia group however limits the translational value at this dose and administration route.

    更新日期:2019-12-11
  • Role of dopamine and selective dopamine receptor agonists on mouse ductus arteriosus tone and responsiveness
    Pediatr. Res. (IF 2.880) Pub Date : 2019-12-09
    Stacey L. Crockett, Micah Harris, Naoko Boatwright, Rachel L. Su, Michael T. Yarboro, Courtney D. Berger, Elaine L. Shelton, Jeff Reese, Jeffrey L. Segar

    Background Indomethacin treatment for patent ductus arteriosus (PDA) is associated with acute kidney injury (AKI). Fenoldopam, a dopamine (DA) DA1-like receptor agonist dilates the renal vasculature and may preserve renal function during indomethacin treatment. However, limited information exists on DA receptor-mediated signaling in the ductus and fenoldopam may prevent ductus closure given its vasodilatory nature. Methods DA receptor expression in CD-1 mouse vessels was analyzed by qPCR and immunohistochemistry. Concentration−response curves were established using pressure myography. Pretreatment with SCH23390 (DA1-like receptor antagonist), phentolamine (α -adrenergic receptor antagonist) or indomethacin addressed mechanisms for DA-induced changes. Fenoldopam’s effects on postnatal ductus closure were evaluated in vivo. Results DA1 receptors were expressed equally in ductus and aorta. High-dose DA induced modest vasoconstriction under newborn O2 conditions. Phentolamine inhibited DA-induced constriction, while SCH23390 augmented constriction, consistent with a vasodilatory role for DA1 receptors. Despite this, fenoldopam had little effect on ductus tone nor indomethacin- or O2-induced constriction and did not impair postnatal closure in vivo. Conclusion(s) DA receptors are present in the ductus but have limited physiologic effects. DA-induced ductus vasoconstriction is mediated via α-adrenergic pathways. The absence of DA1-mediated impairment of ductus closure supports the study of potential role for fenoldopam during PDA treatment.

    更新日期:2019-12-11
  • Fungal cutaneous microbiome and host determinants in preterm and term neonates
    Pediatr. Res. (IF 2.880) Pub Date : 2019-12-09
    Anshu A. Paul, Kristi L. Hoffman, Joseph L. Hagan, Venkatesh Sampath, Joseph F. Petrosino, Mohan Pammi

    Background The neonatal cutaneous mycobiome has not been characterized in preterm infants. Invasive fungal infections in preterm neonates are associated with high mortality. The immaturity of the preterm skin predisposes neonates to invasive infection by skin colonizers. We report the clinical and host determinants that influence the skin mycobiome. Methods Skin swabs from the antecubital fossa, forehead, and gluteal region of 15 preterm and 15 term neonates were obtained during the first 5 weeks of life. The mycobiome was sequenced using the conserved pan-fungal ITS2 region. Blood samples were used to genotype immune modulating genes. Clinical metadata was collected to determine the clinical predictors of the abundance and diversity of the skin mycobiome. Results The neonatal mycobiome is characterized by few taxa. Alpha diversity of the mycobiome is influenced by antibiotic exposure, the forehead body site, and the neonatal intensive care unit (NICU) environment. Beta diversity varies with mode of delivery, diet, and body site. The host determinants of the cutaneous microbiome include single-nucleotide polymorphisms in TLR4, NLRP3, CARD8, and NOD2. Conclusion The neonatal cutaneous mycobiome is composed of few genera and is influenced by clinical factors and host genetics, the understanding of which will inform preventive strategies against invasive fungal infections.

    更新日期:2019-12-09
  • Identification of increased expression of activating Fc receptors and novel findings regarding distinct IgE and IgM receptors in Kawasaki disease
    Pediatr. Res. (IF 2.880) Pub Date : 2019-12-09
    Ling-Sai Chang, Mindy Ming-Huey Guo, Mao-Hung Lo, Ho-Chang Kuo

    Background Kawasaki disease (KD) is associated with expression and methylation of Fc gamma receptor genes. We characterized immunoglobulin A (IgA), IgE, IgG, and IgM receptor expression levels in KD. Methods Fc receptor expression levels were characterized using GeneChip Human Transcriptome Array 2.0 (HTA 2.0) with 18 KD patients, 18 non-febrile controls, and 18 febrile controls. Another 48 control individuals and 46 patients with KD were measured using pyrosequencing for the methylation levels. Results The mRNA expression levels of FCER1A and FCER2 were significantly lower in KD patients than in non-febrile controls and then rose following treatments with intravenous immunoglobulin (IVIG). Expression levels of FCER1G increased compared to the non-febrile subjects and then subsided after IVIG. FCER1A methylation was significantly lower among KD patients and even lower in KD patients with IVIG resistance. HTA analysis revealed higher mRNA levels of FCAR, FCGR1C, and FCGR2A in KD patients. FCMR mRNA expression levels were significantly lower in KD patients. FCMR expression levels rose after IVIG treatment. After IVIG, FCGR1A, B, and C decreased even lower than the febrile controls. Conclusion This is the first study indicating that IgA, IgE, IgG, and IgM receptors are associated with KD. We highlighted potential biomarkers related to Fc receptors and their regulation.

    更新日期:2019-12-09
  • Clinical and molecular evidence of accelerated ageing following very preterm birth
    Pediatr. Res. (IF 2.880) Pub Date : 2019-12-07
    James R. C. Parkinson, Robby Emsley, Jane L. Tarry Adkins, Nick Longford, Susan E. Ozanne, Elaine Holmes, Neena Modi

    Background The mechanisms responsible for the associations between very preterm birth and a higher risk of poor cardiovascular and metabolic health in adult life are unknown. Methods Here, we compare the clinical and molecular phenotypes of healthy, normal-weight young adults (18–27 years), born very preterm (<33 weeks gestational age (GA)) and at full-term (37–42 weeks GA). Outcomes included whole-body MRI, hepatic and muscle 1H MRS, blood pressure measurements and telomere length. Results We recruited 156 volunteers, 69 preterm (45 women; 24 men) and 87 born at full-term (45 women; 42 men). Preterm individuals had a significantly altered blood pressure profile, including higher systolic blood pressure (SBP mmHg: preterm men 133.4 ± 10.1, term men 23.0 ± 6.9; preterm women 124.3 ± 7.1, term women 118.4 ± 8.0, p < 0.01 for all). Furthermore, preterm men had fewer long telomeres (145–48.5 kb: preterm men 14.1 ± 0.9%, term men 17.8 ± 1.1%, p < 0.05; 48.5–8.6 kb: preterm men 28.2 ± 2.6, term men 37.0 ± 2.4%, p < 0.001) and a higher proportion of shorter telomeres (4.2–1.3 kb: preterm men 40.4 ± 3.5%, term men 29.9 ± 3.2%, p < 0.01). Conclusion Our data indicate that healthy young adults born very preterm manifest clinical and molecular evidence of accelerated ageing.

    更新日期:2019-12-07
  • Impact of multiple placental pathologies on neonatal death, bronchopulmonary dysplasia, and neurodevelopmental impairment in preterm infants
    Pediatr. Res. (IF 2.880) Pub Date : 2019-12-07
    Imran N. Mir, Lina F. Chalak, L. Steven Brown, Sarah Johnson-Welch, Roy Heyne, Charles R. Rosenfeld, Vishal S. Kapadia

    Objectives To determine the association of placental pathology, including multiple placental lesions, with the occurrence and severity of bronchopulmonary dysplasia (BPD), death, and neurodevelopmental impairment (NDI) in preterm infants. Study design A retrospective cohort study of neonates <29 weeks gestational age (GA) born at Parkland Hospital from 08/2009 to 08/2012. Infants were stratified as follows: Group 1: no significant placental pathology; Group 2: single significant placental lesion; and Group 3: ≥2 placental lesions (multiple lesions). Primary outcome was death and/or BPD. Two-year neurodevelopmental follow-up was compared. Results In all, 42% (100/241) of infants had one placental lesion, and 34% (82/241) ≥2 lesions. As the number of the pathologic lesions increased (no lesions vs. 1 vs. ≥2), the occurrence of death or BPD increased (25%, 37%, and 52%, respectively; P = 0.004). Moreover, infants with multiple pathologic lesions were more likely to have NDI (29%, 29%, and 46%, respectively; P = 0.03). After logistic regression, infants with multiple pathologic lesions were more likely to develop moderate-to-severe BPD [P < 0.01; OR 3.9 (1.5–10.1)] but not NDI. Conclusion(s) Neonates <29 weeks GA with multiple placental pathologic lesions have an increased risk for developing BPD, suggesting an interaction between placental inflammation and vascular pathology and the pathogenesis of BPD; however, the risk of NDI is not increased.

    更新日期:2019-12-07
  • Foetal lung volumes in pregnant women who deliver very preterm: a pilot study
    Pediatr. Res. (IF 2.880) Pub Date : 2019-12-07
    Lisa Story, Tong Zhang, Johannes K. Steinweg, Jana Hutter, Jacqueline Matthew, Theodore Dassios, Paul T. Seed, Dharmintra Pasupathy, Joanna Allsop, Joseph V. Hajnal, Anne Greenough, Andrew H. Shennan, Mary Rutherford

    Background Infants born preterm are at increased risk of pulmonary morbidity. The contribution of antenatal factors to impairments in lung structure/function has not been fully elucidated. This study aimed to compare standardized lung volumes from foetuses that were delivered <32 weeks’ gestation with foetuses that were delivered >37 weeks. Methods Fourteen women who delivered <32 weeks gestation and 56 women who delivered >37 underwent a foetal MRI. Slice-volume reconstruction was then used and the foetal lungs were then segmented using multi-atlas approaches. Body volumes were calculated by manual segmentation and lung:body volume ratios generated. Results Mean gestation at MRI of the preterm group was 27+2 weeks (SD 2.9, range 20+6–31+3) and control group 25+3 weeks (SD 4.7 range 20+5–31+6). Mean gestation at delivery of the preterm group was 29+2 weeks (SD 2.6, range 22+0–32+0). Lung:body volume ratios and foetal lung volumes were smaller in foetuses that were delivered preterm both with and without preterm premature rupture of membranes compared to those born at term (p < 0.001 in all cases). Conclusions Foetuses that were delivered very preterm had reduced lung volumes when standardized for foetal size, irrespective of ruptured membranes. These are novel findings and suggest an antenatal aetiology of insult and possible focus for future preventative therapies.

    更新日期:2019-12-07
  • Long-term neurological effects of neonatal caffeine treatment in a rabbit model of preterm birth
    Pediatr. Res. (IF 2.880) Pub Date : 2019-12-07
    Lennart Van der Veeken, Susanne Grönlund, Erik Gerdtsson, Bo Holmqvist, Jan Deprest, David Ley, Matteo Bruschettini

    Objective Neonatal caffeine treatment might affect brain development. Long-term studies show conflicting results on brain-related outcomes. Herein we aimed to investigate the long-term effects of neonatal caffeine administration in a rabbit model of preterm birth. Methods Preterm (born day 29) and term (day 32) pups were raised by wet nurses and allocated to treatment with saline or caffeine for 7 or 17 days. At pre-puberty, neurobehavioral tests were performed and brains were harvested for immunostaining of neurons, synapses, myelin, and astrocytes. Results Survival was lower in preterm saline pups than in controls, whereas caffeine-treated preterm pups did not differ from term control pups. Preterm saline pups covered less distance compared to controls and were more likely to stay in the peripheral zone of the open field. Corresponding differences were not seen in preterm caffeine pups. Preterm animals had lower neuron density compared to controls, which was not influenced by caffeine treatment. Synaptic density, astrocytes, and myelin were not different between groups. Conclusion Caffeine appeared to be safe. All preterm rabbits had lower neuron density but anxious behavior seen in preterm saline rabbits was not seen in caffeine-treated preterm pups.

    更新日期:2019-12-07
  • Nephron loss detected by MRI following neonatal acute kidney injury in rabbits
    Pediatr. Res. (IF 2.880) Pub Date : 2019-12-05
    Jennifer R. Charlton, Edwin J. Baldelomar, Kimberly deRonde, Helen P. Cathro, Nathan P. Charlton, Stacey Criswell, Dylan Hyatt, Sejin Nam, Valeria Pearl, Kevin M. Bennett

    Background Acute kidney injury affects nearly 30% of preterm neonates in the intensive care unit. We aimed to determine whether nephrotoxin-induced AKI disrupted renal development assessed by imaging (CFE-MRI). Methods Neonatal New Zealand rabbits received indomethacin and gentamicin (AKI) or saline (control) for 4 days followed by cationic ferritin (CF) at 6 weeks. Ex vivo images were acquired using a gradient echo pulse sequence on 7 T MRI. Glomerular number (Nglom) and apparent glomerular volume (aVglom) were determined. CF toxicity was assessed at 2 and 28 days in healthy rabbits. Results Nglom was lower in the AKI group as compared to controls (74,034 vs 198,722, p < 0.01). aVglom was not different (AKI:7.3 × 10−4 vs control: 6.2 × 10−4 mm3, p = 0.69). AKI kidneys had a band of glomeruli distributed radially in the cortex that were undetectable by MRI. Following CF injection, there was no difference in body or organ weights except for the liver, and transient changes in serum iron, platelets and white blood cell count. Conclusions Brief nephrotoxin exposure during nephrogenesis results in fewer glomeruli and glomerular maldevelopment in a unique pattern detectable by MRI. Whole kidney evaluation by CFE-MRI may provide an important tool to understand the development of CKD following AKI.

    更新日期:2019-12-06
  • Meningitis, urinary tract, and bloodstream infections in very low birth weight infants enrolled in a heart rate characteristic monitoring trial
    Pediatr. Res. (IF 2.880) Pub Date : 2019-12-04
    Joern-Hendrik Weitkamp, Judy L. Aschner, Wallly A. Carlo, Eduardo Bancalari, Jose A. Perez, Cristina T. Navarrete, Robert L. Schelonka, M. Whit Walker, Peter Porcelli, Thomas M. O’Shea, Charles Palmer, Sarah Grossarth, Douglas E. Lake, Karen D. Fairchild

    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). Objective To test whether HRC indices rise before diagnosis of urinary tract infection (UTI) or meningitis, with and without concomitant BSI. Design/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.

    更新日期:2019-12-04
  • Comorbidities in adolescents with inflammatory bowel disease: findings from a population-based cohort study
    Pediatr. Res. (IF 2.880) Pub Date : 2019-12-04
    Itai Ghersin, Neron Khateeb, Lior H. Katz, Saleh Daher, Raanan Shamir, Amit Assa

    Background Inflammatory bowel diseases are associated with various immune- and non-immune-mediated conditions. We aimed to assess the association of inflammatory bowel diseases with comorbidities at late adolescence. Methods Jewish Israeli adolescents who underwent a general health evaluation prior to enlistment to the Israeli Defense Forces from 2002 to 2016 were included. Results Overall, 891 subjects (595 Crohn’s disease, 296 ulcerative colitis, median age 17.1 years) and 1,141,841 controls were analyzed. Crohn’s disease was associated with arthritis (odds ratio (OR) 4.7, 95% confidence interval (CI) 2.4–9.1), thyroid disease (OR 2.6, 95% CI 1.2–5.5), atopic dermatitis (OR 2, 95% CI 1.1–3.6), autoimmune hepatitis (OR 4.4, 95% CI 2.3–8.6), nephrolithiasis (OR 3.6, 95% CI 1.2–11.4), and pancreatitis (OR 41.8, 95% CI 17.2–101.9). Ulcerative colitis was associated with arthritis (OR 3.6, 95% CI 1.0–9.8), thyroid disease (OR 4.8, 95% CI 1.2–19.4), autoimmune hepatitis (OR 8, 95% CI 4–16.2), and pancreatitis (OR 51, 95% CI 16.1–158.9). Primary sclerosing cholangitis was associated with both diseases. Asthma, celiac, type 1 diabetes, psoriasis, and bone fractures were not more common in both diseases. Male predominance was noted for most associations. Conclusions At adolescence, both Crohn’s disease and ulcerative colitis are associated with multiple comorbidities, not limited to autoimmune disorders.

    更新日期:2019-12-04
  • Chronic pain in children: structural and resting-state functional brain imaging within a developmental perspective
    Pediatr. Res. (IF 2.880) Pub Date : 2019-12-02
    Ravi R. Bhatt, Arpana Gupta, Emeran A. Mayer, Lonnie K. Zeltzer

    Chronic pain is a major public health problem in the United States costing $635 billion annually. Hospitalizations for chronic pain in childhood have increased almost tenfold in the past decade, without breakthroughs in novel treatment strategies. Findings from brain imaging studies using structural and resting-state fMRI could potentially help personalize treatment to address this costly and prevalent health problem by identifying the underlying brain pathways that contribute, facilitate, and maintain chronic pain. The aim of this review is to synthesize structural and resting-state network pathology identified by recent brain imaging studies in pediatric chronic pain populations and discuss the potential impact of chronic pain on cortical development. Sex differences as well as treatment effects on these cortical alterations associated with symptom changes are also summarized. This area of research is still in its infancy with currently limited evidence available from a small number of studies, some of which suffer from limitations such as small sample size and suboptimal methodology. The identification of brain signatures of chronic pain in children may help to develop new pathways for future research as well as treatment strategies.

    更新日期:2019-12-02
  • Body mass index growth trajectories, early pubertal maturation, and short stature
    Pediatr. Res. (IF 2.880) Pub Date : 2019-12-02
    Hsien-Yu Fan, Yungling L. Lee, Rong-Hong Hsieh, Chen Yang, Yang-Ching Chen

    Background Childhood body mass index (BMI) trajectory classes are rarely linked to early puberty risk, particularly among Chinese children. We estimated early puberty risk across BMI trajectory classes, investigated factors contributing to pubertal development, and examined differences in final adult height between children exhibiting early and nonearly pubertal maturation across the classes. Methods The Taiwan Children Health Study recruited 10-year-old children in 2010 from 14 Taiwanese communities and resurveyed them at age 11, 12, and 18 years. The study comprised 3109 children (50.4% boys) with available data for BMI (age 6–11 years) and pubertal stages (age 11, 12, and 18 years). Results Classes 1–4 were persistently healthy weight, rapid BMI growth, chronically overweight/obese, and early transient overweight/obese. Children in class 3 exhibited the highest risk of early pubertal maturation. Puberty genetic score, low sleep quality, and high fat-free mass collectively explained 15% of the variance in Tanner stages among class 3 children. Early pubertal maturation was considered to cause short and tall stature in boys and girls, respectively. Conclusions Modifying sleep quality and fat-free mass may reduce early puberty risk in children with chronic overweight/obesity. Vigorous physical activity may reduce adiposity and increase the final adult height in the children.

    更新日期:2019-12-02
  • Editor's Focus
    Pediatr. Res. (IF 2.880) Pub Date : 2019-12-02
    更新日期:2019-12-02
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