To compare early routine pharmacologic treatment of moderate-to-large patent ductus arteriosus (PDA) at the end of week 1 with a conservative approach that requires prespecified respiratory and ...hemodynamic criteria before treatment can be given.
A total of 202 neonates of <28 weeks of gestation age (mean, 25.8 ± 1.1 weeks) with moderate-to-large PDA shunts were enrolled between age 6 and 14 days (mean, 8.1 ± 2.2 days) into an exploratory randomized controlled trial.
At enrollment, 49% of the patients were intubated and 48% required nasal ventilation or continuous positive airway pressure. There were no differences between the groups in either our primary outcome of ligation or presence of a PDA at discharge (early routine treatment ERT, 32%; conservative treatment CT, 39%) or any of our prespecified secondary outcomes of necrotizing enterocolitis (ERT, 16%; CT, 19%), bronchopulmonary dysplasia (BPD) (ERT, 49%; CT, 53%), BPD/death (ERT, 58%; CT, 57%), death (ERT,19%; CT, 10%), and weekly need for respiratory support. Fewer infants in the ERT group met the rescue criteria (ERT, 31%; CT, 62%). In secondary exploratory analyses, infants receiving ERT had significantly less need for inotropic support (ERT, 13%; CT, 25%). However, among infants who were ≥26 weeks gestational age, those receiving ERT took significantly longer to achieve enteral feeding of 120 mL/kg/day (median: ERT, 14 days range, 4.5-19 days; CT, 6 days range, 3-14 days), and had significantly higher incidences of late-onset non-coagulase-negative Staphylococcus bacteremia (ERT, 24%; CT,6%) and death (ERT, 16%; CT, 2%).
In preterm infants age <28 weeks with moderate-to-large PDAs who were receiving respiratory support after the first week, ERT did not reduce PDA ligations or the presence of a PDA at discharge and did not improve any of the prespecified secondary outcomes, but delayed full feeding and was associated with higher rates of late-onset sepsis and death in infants born at ≥26 weeks of gestation.
ClinicalTrials.gov: NCT01958320.
Myostatin, a member of the transforming growth factor-β superfamily, is an attractive target for muscle disease therapy because of its role as a negative regulator of muscle growth and strength. ...Here, we describe a novel antibody therapeutic approach that maximizes the potential of myostatin-targeted therapy. We generated an antibody, GYM329, that specifically binds the latent form of myostatin and inhibits its activation. Additionally, via "sweeping antibody technology", GYM329 reduces or "sweeps" myostatin in the muscle and plasma. Compared with conventional anti-myostatin agents, GYM329 and its surrogate antibody exhibit superior muscle strength-improvement effects in three different mouse disease models. We also demonstrate that the superior efficacy of GYM329 is due to its myostatin specificity and sweeping capability. Furthermore, we show that a GYM329 surrogate increases muscle mass in normal cynomolgus monkeys without any obvious toxicity. Our findings indicate the potential of GYM329 to improve muscle strength in patients with muscular disorders.
Electronic cigarette (E-cigarettes) emissions present a potentially new hazard to neonates through inhalation, dermal and oral contact. Exposure to nicotine containing E-cigarettes may cause ...significant systemic absorption in neonates due to the potential for multi-route exposure. Systemic absorption of nicotine and constituents of E-cigarette emissions may adversely impact weight and lung development in the neonate. To address these questions we exposed neonatal mice to E-cigarette emissions and measured systemic cotinine levels and alveolar lung growth.
Neonatal mice were exposed to E-cigarettes for the first 10 days of life. E-cigarette cartridges contained either 1.8% nicotine in propylene glycol (PG) or PG vehicle alone. Daily weights, plasma and urine cotinine levels and lung growth using the alveolar mean linear intercept (MLI) method were measured at 10 days of life and compared to room air controls. Mice exposed to 1.8% nicotine/PG had a 13.3% decrease in total body weight compared to room air controls. Plasma cotinine levels were found to be elevated in neonatal mice exposed to 1.8% nicotine/PG E-cigarettes (mean 62.34± 3.3 ng/ml). After adjusting for sex and weight, the nicotine exposed mice were found to have modestly impaired lung growth by MLI compared to room air control mice (p<.054 trial 1; p<.006 trial 2). These studies indicate that exposure to E-cigarette emissions during the neonatal period can adversely impact weight gain. In addition exposure to nicotine containing E-cigarettes can cause detectable levels of systemic cotinine, diminished alveolar cell proliferation and a modest impairment in postnatal lung growth.
ABSTRACT
The receptor activator of the NF‐κB ligand (RANKL) is the central player in the regulation of osteoclastogenesis, and the quantity of RANKL presented to osteoclast precursors is an important ...factor determining the magnitude of osteoclast formation. Because osteoblastic cells are thought to be a major source of RANKL, the regulatory mechanisms of RANKL subcellular trafficking have been studied in osteoblastic cells. However, recent reports showed that osteocytes are a major source of RANKL presentation to osteoclast precursors, prompting a need to reinvestigate RANKL subcellular trafficking in osteocytes. Investigation of molecular mechanisms in detail needs well‐designed in vitro experimental systems. Thus, we developed a novel co‐culture system of osteoclast precursors and osteocytes embedded in collagen gel. Experiments using this model revealed that osteocytic RANKL is provided as a membrane‐bound form to osteoclast precursors through osteocyte dendritic processes and that the contribution of soluble RANKL to the osteoclastogenesis supported by osteocytes is minor. Moreover, the regulation of RANKL subcellular trafficking, such as OPG‐mediated transport of newly synthesized RANKL molecules to lysosomal storage compartments, and the release of RANKL to the cell surface upon stimulation with RANK are confirmed to be functional in osteocytes. These results provide a novel understanding of the regulation of osteoclastogenesis.
To evaluate the effectiveness of drugs used to constrict patent ductus arteriosus (PDA) in newborns < 28 weeks.
We performed a secondary analysis of the multi-center PDA-TOLERATE trial (NCT01958320). ...Infants with moderate-to-large PDAs were randomized 1:1 at 8.1 ± 2.1 days to either Drug treatment (n = 104) or Conservative management (n = 98). Drug treatments were assigned by center rather than within center (acetaminophen: 5 centers, 27 infants; ibuprofen: 7 centers, 38 infants; indomethacin: 7 centers, 39 infants).
Indomethacin produced the greatest constriction (compared with spontaneous constriction during Conservative management): RR (95% CI) = 3.21 (2.05-5.01)), followed by ibuprofen = 2.03 (1.05-3.91), and acetaminophen = 1.33 (0.55-3.24). The initial rate of acetaminophen-induced constriction was 27%. Infants with persistent moderate-to-large PDA after acetaminophen were treated with indomethacin. The final rate of constriction after acetaminophen ± indomethacin was 60% (similar to the rate in infants receiving indomethacin-alone (62%)).
Indomethacin was more effective than acetaminophen in producing ductus constriction.
Abstract Background Despite significant progress in fetal neuroimaging techniques, only a few well-documented examples of prenatal cerebellar hemorrhages are available in the literature. In the ...majority of these individuals, the diagnosis of prenatal cerebellar hemorrhages led to termination of pregnancy or death occurred in utero ; data about postnatal outcome of children with prenatal diagnosis of cerebellar hemorrhages are scant. We describe fetal and postnatal neuroimaging findings and the neurodevelopmental outcome of a child with a large cerebellar hemorrhage that occurred at approximately 27 weeks' gestation. Method Data about neurological features and neurodevelopmental outcome were collected from the clinical history and follow-up examination. All pre- and postnatal MRI data were qualitatively evaluated for infra- and supratentorial abnormalities. Results Fetal MRI at 27 weeks' gestation showed a T1-hyperintense and T2-hypointense lesion within the cerebellum suggestive of bilateral cerebellar hemorrhages with extension into the adjacent subarachnoid, subdural, and intraventricular spaces. The prenatal cerebellar hemorrhage was possibly related to maternal sepsis. Postnatal MRI showed encephalomalacic changes involving the vermis and both cerebellar hemispheres. Neurodevelopmental follow-up at 15 months of age was concerning for global developmental delay and significant right esotropia. Conclusion This child illustrates (1) the role of prenatal neuroimaging in the diagnosis of fetal cerebellar hemorrhages, (2) the significance of cerebellar involvement for neurodevelopment, and (3) the importance of the collection of postnatal outcome data in children with prenatal diagnosis of cerebellar hemorrhage.
Receptor activator of nuclear factor-kappa B (RANK) ligand (RANKL) binds RANK on the surface of osteoclast precursors to trigger osteoclastogenesis. Recent studies have indicated that osteocytic ...RANKL has an important role in osteoclastogenesis during bone remodelling; however, the role of osteoblastic RANKL remains unclear. Here we show that vesicular RANK, which is secreted from the maturing osteoclasts, binds osteoblastic RANKL and promotes bone formation by triggering RANKL reverse signalling, which activates Runt-related transcription factor 2 (Runx2). The proline-rich motif in the RANKL cytoplasmic tail is required for reverse signalling, and a RANKL(Pro29Ala) point mutation reduces activation of the reverse signalling pathway. The coupling of bone resorption and formation is disrupted in RANKL(Pro29Ala) mutant mice, indicating that osteoblastic RANKL functions as a coupling signal acceptor that recognizes vesicular RANK. RANKL reverse signalling is therefore a potential pharmacological target for avoiding the reduced bone formation associated with inhibition of osteoclastogenesis.
To avoid preventable consequences of perinatal hepatitis B infection, all infants should be given hepatitis B vaccine (HBV) within 24 hours of birth if birth weight is ≥2 kg and at 30 days of life or ...at discharge if <2 kg, to provide highest seroprotection rates while ensuring universal vaccination prior to discharge. We aimed to achieve timely HBV administration in >80% of eligible infants in both birthweight groups and decrease infants discharged home without receiving HBV to <1% over an 18-month period and sustain results for an additional 15 months.
Data were collected from June 2016 to May 2020 in a level III neonatal intensive care unit. A multidisciplinary team identified barriers and interventions through Plan-Do-Study-Act cycles from September 2017 to February 2019: using pharmacists as champions, overcoming legal barriers, staff education and best practice alerts (BPAs) embedded in electronic health records. Statistical process control (SPC) p charts were used to evaluate the primary outcome measure, monthly percentage of infants receiving timely HBV administration stratified by birthweight categories (≥2 and <2 kg). For infants receiving HBV outside the time frame, absolute difference of timeliness was calculated.
Mean timely HBV administration improved from 45% to 95% (≥2 kg) and from 45% to 85% (<2 kg) with special cause variation in SPC charts. Infants discharged without receiving HBV decreased from 4.6% to 0.22%. Of those given HBV outside the recommended time frame, median absolute time between recommended and actual administration time decreased significantly: from 3.5 days (IQR 1.6, 8.6) to 0.3 day (IQR 0.1, 0.8) (p<0.001) in ≥2 kg group and from 6 days (IQR 1, 15) to 1 day (IQR 1, 6.5) (p=0.009) in <2 kg group.
Using a multidisciplinary approach, we significantly improved and sustained timely HBV administration and nearly eliminated infants discharged home without receiving HBV. Pharmacists as champions and BPAs were critical to our success.
Neonate with Hypoglycemia and Persistent Jaundice Rosenbaum, Adam René P; Patterson, Kelsey C; Hayashi, Madoka
Neoreviews (Elk Grove Village, Ill.),
05/2023, Letnik:
24, Številka:
5
Journal Article
In the PDA-TOLERATE trial, persistent (even for several weeks) moderate to large patent ductus arteriosus (PDA) was not associated with an increased risk of BPD when the infant required <10 days of ...intubation. However, in infants requiring intubation for ≥10 days, prolonged PDA exposure (≥11 days) was associated with an increased risk of moderate/severe BPD.
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