Decreasing Percentage of Infants With Very Low 5-Minute Apgar Scores at a Safety-Net Level III NICU.

OBJECTIVES: Low 5-minute Apgar scores predict mortality and may be associated with poor neurologic outcomes. Our percentage of infants with low 5-minute Apgar scores was higher than the national average (2.4%). Therefore, we aimed to decrease the percentage of infants with Apgar scores <4 at 5 minutes from a mean of 5.12% to <2.4% and decrease the percentage of infants receiving chest compressions (CCs) before intubation from 21% to <5%. METHODS: We completed 4 plan-do-study-act (PDSA) cycles from April 2015 through November 2018, including providing 24-hour advanced practice provider coverage (PDSA 1), initiating advanced practice provider-led delivery room scenarios for residents and education to secure the airway before CCs (PDSA 2), developing "Go Bags" with supplies (PDSA 3), and performing multidisciplinary mock codes (PDSA 4). We used a statistical process control p-chart to evaluate our primary outcome measure of the percentage of infants with 5-minute Apgar scores <4 from January 2012 through September 2021. RESULTS: The percent of infants with Apgar scores <4 at 5 minutes decreased from 5.12% in the baseline and intervention period to 2.16% in the sustainment period. We detected special cause with 8 points below the centerline. Infants born in the baseline period were 7.9 times more likely to receive CCs before intubation than in the intervention and sustainment periods (P = .002). CONCLUSIONS: We decreased the percentage of infants with 5-minute Apgar scores <4 and the percentage of infants receiving chest compressions before intubation. Ultimately, rigorous education and team collaboration through frequent multidisciplinary team mock codes were critical to our success.

BLOSSoM: Improving Human Milk Provision in Preterm Infants Through Texting Support.

Mother's own milk (MOM) reduces complications of preterm birth. Despite high initiation rates of expression, half of preterm infants do not receive MOM at discharge. Frequent outreach and a short message service (SMS) have improved MOM provision in term dyads. We aimed to improve MOM provision rate from 61% to >80% by implementing standardized lactation education and Breastfeeding & Lactation Outreach via SMS Supporting Mothers (BLOSSoM). Methods: The baseline period was June 2019 to April 2020. A multidisciplinary team implemented PDSA cycles: education/documentation (standardized lactation education and education documentation, May 2020-April 2021), and BLOSSoM (SMS program providing educational texts/videos, reminders, 2-way communication with neonatal intensive care unit (NICU) lactation, May 2021-December 2021). The primary outcome was MOM provision at NICU discharge/transfer for infants younger than 34 weeks, as analyzed on the SPC chart. BLOSSoM participants evaluated the program using a 5-point Likert scale. Results: Demographic and clinical characteristics were unchanged among the three periods. However, the monthly MOM provision rate improved from 61% to 81%. Eighty-seven percent of BLOSSoM participants completed the evaluation with 83% rating the program most supportive, 78% rating the videos as the most helpful, followed by team check-ins (54%) and 2-way texting (24%). Conclusions: Using a multidisciplinary approach, we improved the monthly MOM provision rate at discharge/transfer for preterm infants. SMS providing educational texts/media and 2-way communication supporting lactating NICU mothers was critical to our success. Providing another method of communication through SMS was well accepted and valued by the majority.

Improving timeliness of hepatitis B vaccine administration in an urban safety net level III NICU.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Novel myostatin-specific antibody enhances muscle strength in muscle disease models.

Myostatin, a member of the transforming growth factor-ß 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.

Prolonged Tracheal Intubation and the Association Between Patent Ductus Arteriosus and Bronchopulmonary Dysplasia: A Secondary Analysis of the PDA-TOLERATE trial.

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.

Comparative effectiveness of drugs used to constrict the patent ductus arteriosus: a secondary analysis of the PDA-TOLERATE trial (NCT01958320).

OBJECTIVE: To evaluate the effectiveness of drugs used to constrict patent ductus arteriosus (PDA) in newborns < 28 weeks. METHODS: 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). RESULTS: 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%)). CONCLUSION: Indomethacin was more effective than acetaminophen in producing ductus constriction.

PDA-TOLERATE Trial: An Exploratory Randomized Controlled Trial of Treatment of Moderate-to-Large Patent Ductus Arteriosus at 1 Week of Age.

OBJECTIVE: 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. STUDY DESIGN: 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. RESULTS: 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%). CONCLUSIONS: 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. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01958320.

Coupling of bone resorption and formation by RANKL reverse signalling.

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.

Mucous fistula refeeding decreases parenteral nutrition exposure in postsurgical premature neonates.

BACKGROUND/PURPOSE: Premature neonates can develop intraabdominal conditions requiring emergent bowel resection and enterostomy. Parenteral nutrition (PN) is often required, but results in cholestasis. Mucous fistula refeeding allows for functional restoration of continuity. We sought to determine the effect of refeeding on nutrition intake, PN dependence, and PN associated hepatotoxicity while evaluating the safety of this practice. METHODS: A retrospective review of neonates who underwent bowel resection and small bowel enterostomy with or without mucous fistula over 2years was undertaken. Patients who underwent mucous fistula refeeding (RF) were compared to those who did not (OST). Primary outcomes included days from surgery to discontinuation of PN and goal enteral feeds, and total days on PN. Secondary outcomes were related to PN hepatotoxicity. RESULTS: Thirteen RF and eleven OST were identified. There were no significant differences among markers of critical illness (p>0.20). In the interoperative period, RF patients reached goal enteral feeds earlier than OST patients (median 28 versus 43days; p=0.03) and were able to have PN discontinued earlier (median 25 versus 41days; p=0.04). Following anastomosis, the magnitude of effect was more pronounced, with RF patients reaching goal enteral feeds earlier than OST patients (median 7.5 versus 20days; p≤0.001) and having PN discontinued sooner (30.5 versus 48days; p=0.001). CONCLUSIONS: RF neonates reached goal feeds and were able to be weaned from PN sooner than OST patients. A prospective multicenter trial of refeeding is needed to define the benefits and potential side effects of refeeding in a larger patient population in varied care environments.

Prenatal cerebellar hemorrhage: fetal and postnatal neuroimaging findings and postnatal outcome.

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.

The effects of electronic cigarette emissions on systemic cotinine levels, weight and postnatal lung growth in neonatal mice.

BACKGROUND/OBJECTIVE: 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. METHODS/MAIN RESULTS: 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.

Late-onset bloodstream infections in hospitalized term infants.

BACKGROUND: The epidemiology and incidence of late-onset blood stream infections (BSIs) in premature infants have been described, but studies describing late-onset BSI in term infants are sparse. We sought to describe the pathogens, incidence, risk factors and mortality of late-onset BSI in hospitalized term infants. METHODS: A cohort study was conducted of infants ≥37 weeks gestational age and ≤120 days of age discharged from Pediatrix Medical Group neonatal intensive care units from 1997 to 2010. We examined all cultures obtained from day of life 4-120 and used multivariable regression to assess risk factors for late-onset BSI. RESULTS: We found a total of 206,019 infants cared for between day of life 4 and 120, and the incidence of late-onset BSI was 2.7/1000 admissions. We identified Gram-positive organisms in 64% of the cultures and Gram-negative organisms in 26%. We found a decreased risk of late-onset BSI in infants with the following characteristics: small for gestational age, delivery by Cesarean, antenatal antibiotic use and discharged in the later years of the study. Late-onset BSI increased the risk of death after controlling for confounders [odds ratio 8.43 (95% confidence interval 4.42-16.07)]. CONCLUSION: Our data highlight the importance of late-onset BSI in hospitalized term infants. We identified Gram-positive organisms as the most common pathogen, and late-onset BSI was an independent risk factor for death.

Respiratory outcomes of children with BPD and gastrostomy tubes during the first 2 years of life.

OBJECTIVES: Infants with bronchopulmonary dysplasia (BPD) often undergo gastrostomy tube (GT) placement and/or Nissen fundoplication (Nissen) to improve weight gain and to attenuate chronic respiratory symptoms related to feeding difficulties. After initial hospitalization little is known how these children do with regard to respiratory symptoms when compared to children with BPD who did not receive GTs. This study was done to determine if differences in respiratory outcomes were associated with the presence of a GT or Nissen/GT in children with BPD during the first 2 years of life. METHODS: Children (n = 398) were recruited from the Johns Hopkins BPD Outpatient Clinic. Medical charts were reviewed and acute care usage and respiratory symptoms were assessed by caregiver questionnaires. RESULTS: Ninety-two children with BPD had GTs, with the majority placed by 6 months of age. Of children with GTs, 64.7% also had Nissen fundoplication. Children with Nissen/GTs were more likely to have birth weights <10th percentile and to be discharged on supplemental oxygen. After initial hospitalization, children with GTs and Nissen/GTs weaned off supplemental oxygen at significantly older ages than children without GTs. Children with Nissen/GTs also had more hospitalizations than children without GTs. Caregivers of children with GTs and Nissen/GTs reported similar respiratory symptoms as caregivers of children without GTs. CONCLUSION: Weaning off supplemental oxygen occurred later in children with GTs and Nissen/GTs compared to children without GTs. Although children with Nissen/GTs had more re-hospitalizations, there were no differences in reported respiratory symptoms between any of the groups by caregiver questionnaire.

RANKL subcellular trafficking and regulatory mechanisms in osteocytes.

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.