Opportunistic dried blood spot sampling validates and optimizes a pediatric population pharmacokinetic model of metronidazole.

Pharmacokinetic models rarely undergo external validation in vulnerable populations such as critically ill infants, thereby limiting the accuracy, efficacy, and safety of model-informed dosing in real-world settings. Here, we describe an opportunistic approach using dried blood spots (DBS) to evaluate a population pharmacokinetic model of metronidazole in critically ill preterm infants of gestational age (GA) ≤31 weeks from the Metronidazole Pharmacokinetics in Premature Infants (PTN_METRO, NCT01222585) study. First, we used linear correlation to compare 42 paired DBS and plasma metronidazole concentrations from 21 preterm infants [mean (SD): post natal age 28.0 (21.7) days, GA 26.3 (2.4) weeks]. Using the resulting predictive equation, we estimated plasma metronidazole concentrations (ePlasma) from 399 DBS collected from 122 preterm and term infants [mean (SD): post natal age 16.7 (15.8) days, GA 31.4 (5.1) weeks] from the Antibiotic Safety in Infants with Complicated Intra-Abdominal Infections (SCAMP, NCT01994993) trial. When evaluating the PTN_METRO model using ePlasma from the SCAMP trial, we found that the model generally predicted ePlasma well in preterm infants with GA ≤31 weeks. When including ePlasma from term and preterm infants with GA >31 weeks, the model was optimized using a sigmoidal Emax maturation function of postmenstrual age on clearance and estimated the exponent of weight on volume of distribution. The optimized model supports existing dosing guidelines and adds new data to support a 6-hour dosing interval for infants with postmenstrual age >40 weeks. Using an opportunistic DBS to externally validate and optimize a metronidazole population pharmacokinetic model was feasible and useful in this vulnerable population.

Scholarly Activity during Neonatal-Perinatal Medicine Fellowship.

OBJECTIVE: This study aimed to describe scholarly activity training during neonatal-perinatal medicine (NPM) fellowship and factors associated with scholarship productivity. STUDY DESIGN: NPM fellowship program directors (FPDs) were surveyed between March and October 2019, as part of a larger study of all pediatric subspecialty programs, to define barriers, resources, and productivity for fellow scholarly activity. High productivity was defined as >75% of fellows in a program in the last 5 years having a manuscript accepted for publication based on fellowship scholarly work. RESULTS: Fifty-four percent (54/100) of NPM FPDs completed the survey. Nineteen fellowship programs (35%, 19/54) met the definition for high productivity. High productivity in scholarly activity was associated with a greater likelihood of having funds to conduct scholarship (p = 0.011), more protected months dedicated to scholarly activity (p = 0.03), and fellow extramural grant applications (submitted or accepted, p = 0.047). FPDs of productive programs were less likely to report lack of an adequate core research curriculum (p = 0.018), lack of adequate expertise on the fellowship scholarly oversight committee (p = 0.048), and lack of sufficient divisional mentorship (p = 0.048) as barriers to completion of scholarly activity during fellowship. CONCLUSION: Research funding, protected research time, established research mentors, and a research curriculum are associated with higher scholarly activity productivity among NPM fellowship programs. Further investment in these resources may improve scholarly activity productivity during fellowship training. KEY POINTS: · Fellow productivity depends on protected time.. · Inadequate funding impacts fellow productivity.. · Mentorship is important for fellow scholarship.. · A research curriculum impacts research outcomes..

Relationship between epa level of supervision with their associated subcompetency milestone levels in pediatric fellow assessment.

BACKGROUND: Entrustable Professional Activities (EPA) and competencies represent components of a competency-based education framework. EPAs are assessed based on the level of supervision (LOS) necessary to perform the activity safely and effectively. The broad competencies, broken down into narrower subcompetencies, are assessed using milestones, observable behaviors of one's abilities along a developmental spectrum. Integration of the two methods, accomplished by mapping the most relevant subcompetencies to each EPA, may provide a cross check between the two forms of assessment and uncover those subcompetencies that have the greatest influence on the EPA assessment. OBJECTIVES: We hypothesized that 1) there would be a strong correlation between EPA LOS ratings with the milestone levels for the subcompetencies mapped to the EPA; 2) some subcompetencies would be more critical in determining entrustment decisions than others, and 3) the correlation would be weaker if the analysis included only milestones reported to the Accreditation Council for Graduate Medical Education (ACGME). METHODS: In fall 2014 and spring 2015, the Subspecialty Pediatrics Investigator Network asked Clinical Competency Committees to assign milestone levels to each trainee enrolled in a pediatric fellowship for all subcompetencies mapped to 6 Common Pediatric Subspecialty EPAs as well as provide a rating for each EPA based upon a 5-point LOS scale. RESULTS: One-thousand forty fellows were assessed in fall and 1048 in spring, representing about 27% of all fellows. For each EPA and in both periods, the average milestone level was highly correlated with LOS (rho range 0.59-0.74; p < 0.001). Correlations were similar when using a weighted versus unweighted milestone score or using only the ACGME reported milestones (p > 0.05). CONCLUSIONS: We found a strong relationship between milestone level and EPA LOS rating but no difference if the subcompetencies were weighted, or if only milestones reported to the ACGME were used. Our results suggest that representative behaviors needed to effectively perform the EPA, such as key subcompetencies and milestones, allow for future language adaptations while still supporting the current model of assessment. In addition, these data provide additional validity evidence for using these complementary tools in building a program of assessment.

Effect of Coronavirus Disease-2019 on the Workload of Neonatologists.

OBJECTIVE: To describe the impact of coronavirus disease-2019 (COVID-19) on the neonatology workforce, focusing on professional and domestic workloads. STUDY DESIGN: We surveyed US neonatologists in December 2020 regarding the impact of COVID-19 on professional and domestic work during the pandemic. We estimated associations between changes in time spent on types of professional and domestic work and demographic variables with multivariable logistic regression analyses. RESULTS: Two-thirds (67.6%) of the 758 participants were women. Higher proportions of women than men were in the younger age group (63.3% vs 29.3%), held no leadership position (61.4% vs 46.3%), had dependents at home (68.8% vs 56.3%), did not have a partner or other adult at home (10.6% vs 3.2%), and had an employed partner (88.1% vs 64.6%) (P < .01 for all). A higher proportion of women than men reported a decrease in time spent on scholarly work (35.0% vs 29.0%; P = .02) and career development (44.2% vs 34.9%; P < .01). A higher proportion of women than men reported spending more time caring for children (74.2% vs 55.8%; P < .01). Reduced time spent on career development was associated with younger age (aOR, 2.21; 95% CI, 1.20-4.08) and number of dependents (aOR, 1.21; 95% CI, 1.01-1.45). Women were more likely to report an increase in time spent time doing domestic work (aOR, 1.53; 95% CI, 1.07-2.19) and a reduction in time on self-care (aOR, 0.49; 95% CI, 0.29-0.81). CONCLUSIONS: COVID-19 significantly impacts the neonatology workforce, disproportionately affecting younger, parent, and women physicians. Targeted interventions are needed to support postpandemic career recovery and advance physician contributions to the field.

ErbB4 alternative splicing mediates fetal mouse alveolar type II cell differentiation in vitro.

BACKGROUND: Alternative splicing (AS) creates different protein isoforms, an important mechanism regulating cell-specific function. Little is known about AS in lung development, particularly in alveolar type II (ATII) cells. ErbB4 receptor isoforms Jma and Jmb have significant and opposing functions in the brain, heart, and lung development and/or disease. However, the regulators of ErbB4 AS are unknown. ErbB4 AS regulators in fetal mouse ATII cells control its function in ATII cell maturation. METHODS: Candidate ErbB4 AS regulators were found using in silico analysis. Their developmental expression was studied in fetal mouse ATII cells. The effects of splice factor downregulation and upregulation on ATII cell maturation were analyzed. RESULTS: ErbB4-Jma increased significantly in ATII cells after gestation E16.5. In silico analysis found four candidate splice factors: FOX2, CUG/CELF1, TIAR, and HUB. Fetal ATII cells expressed these factors in distinct developmental profiles. HUB downregulation in E17.5 ATII cells increased Jma isoform levels and Sftpb gene expression and decreased Jmb. HUB overexpression decreased Jma and Sftpb. CONCLUSIONS: ErbB4 AS is developmentally controlled by HUB in fetal ATII cells, promoting ATII differentiation. Regulated AS expression during ATII cell differentiation suggests novel therapeutic strategies to approach human disease. IMPACT: Alternative splicing (AS) of the ErbB4 receptor, involving mutually exclusive exon inclusion, creates Jma and Jmb isoforms with distinct differences in receptor processing and function. The Jma isoform of ErbB4 promotes differentiation of fetal lung alveolar type II cells. The AS is mediated in part by the RNA-binding protein HUB. The molecular mechanism of AS for ErbB4 has not been previously described. The regulation of ErbB4 AS has important implications in the development of organs, such as the lung, brain, and heart, and for disease, including cancer.

Bone marrow stem cells accelerate lung maturation and prevent the LPS-induced delay of morphological and functional fetal lung development in the presence of ErbB4.

ErbB4 is a regulator in lung development and disease. Prenatal infection is an important risk factor for the delay of morphologic lung development, while promoting the maturation of the surfactant system. Bone marrow-derived mesenchymal stem cells (BMSCs) have the potential to prevent lung injury. We hypothesized that BMSCs in comparison with hematopoietic control stem cells (HPSCs) minimize the lipopolysaccharide (LPS)-induced lung injury only when functional ErbB4 receptor is present. We injected LPS and/or murine green fluorescent protein-labeled BMSCs or HPSCs into the amniotic cavity of transgenic ErbB4heart mothers at gestational day 17. Fetal lungs were analyzed 24 h later. BMSCs minimized significantly LPS-induced delay in morphological lung maturation consisting of a stereologically measured increase in mesenchyme and septal thickness and a decrease of future airspace and septal surface. This effect was more prominent and significant in the ErbB4heart+/- lungs, suggesting that the presence of functioning ErbB4 signaling is required. BMSC also diminished the LPS induced increase in surfactant protein (Sftp)a mRNA and decrease in Sftpc mRNA is only seen if ErbB4 is present. The reduction of morphological delay of lung development and of levels of immune-modulating Sftp was more pronounced in the presence of the ErbB4 receptor. Thus, ErbB4 may be required for the protective signaling of BMSCs.

Synthetic Surfactant CHF5633 Compared with Poractant Alfa in the Treatment of Neonatal Respiratory Distress Syndrome: A Multicenter, Double-Blind, Randomized, Controlled Clinical Trial.

OBJECTIVE: To compare efficacy and safety of a new synthetic surfactant, CHF5633, enriched with surfactant proteins, SP-B and SP-C peptide analogues, with porcine surfactant, poractant alfa, for the treatment of respiratory distress syndrome in infants born preterm. STUDY DESIGN: Neonates born preterm on respiratory support requiring fraction of inspired oxygen (FiO2) ≥0.30 from 240/7 to 266/7 weeks and FiO2 ≥0.35 from 270/7 to 296/7 weeks of gestation to maintain 88%-95% oxygen saturation were randomized to receive 200 mg/kg of CHF5633 or poractant alfa. If necessary, redosing was given at 100 mg/kg. Efficacy end points were oxygen requirement (FiO2, respiratory severity score [FiO2 × mean airway pressure]) in the first 24 hours, 7 and 28 days, discharge home, and/or 36 weeks of postmenstrual age; mortality and bronchopulmonary dysplasia at 28 days and 36 weeks of PMA. Adverse events and immunogenicity were monitored for safety. RESULTS: Of the 123 randomized neonates, 113 were treated (56 and 57 in CHF5633 and poractant alfa groups, respectively). In both arms, FiO2 and respiratory severity score decreased from baseline at all time points (P < .001) with no statistically significant differences between groups. Rescue surfactant use (19 [33.9%] vs 17 [29.8%]), bronchopulmonary dysplasia (31 [55.4%] and 32 [56.1%]), and mortality at day 28 (4 [7.1%] and 3 [5.3%]) were similar in the CHF5633 and poractant alfa groups, respectively. In 2 (3.4%) and 1 (1.7%) neonates, adverse drug reactions were reported in CHF5633 and poractant alfa groups, respectively. No immunogenicity was detected. CONCLUSIONS: Treatment with CHF5633 showed similar efficacy and safety as poractant alfa in neonates born preterm with moderate-to-severe respiratory distress syndrome. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02452476.

Simulation in Neonatal-Perinatal Medicine Fellowship Programs.

OBJECTIVE: This study aimed to investigate the use of simulation in neonatal-perinatal medicine (NPM) fellowship programs. STUDY DESIGN: This was a cross-sectional survey of program directors (PDs) and simulation educators in Accreditation Council for Graduate Medical Education (ACGME) accredited NPM fellowship programs. RESULTS: Responses were received from 59 PDs and 52 simulation educators, representing 60% of accredited programs. Of responding programs, 97% used simulation, which most commonly included neonatal resuscitation (94%) and procedural skills (94%) training. The time and scope of simulation use varied significantly. The majority of fellows (51%) received ≤20 hours of simulation during training. The majority of PDs (63%) wanted fellows to receive >20 hours of simulation. Barriers to simulation included lack of faculty time, experience, funding, and curriculum. CONCLUSION: While the majority of fellowship programs use simulation, the time and scope of fellow exposure to simulation experiences are limited. The creation of a standardized simulation curriculum may address identified barriers to simulation.

Dissociated presenilin-1 and TACE processing of ErbB4 in lung alveolar type II cell differentiation.

Neuregulin (NRG) stimulation of ErbB4 signaling is important for type II cell surfactant synthesis. ErbB4 may mediate gene expression via a non-canonical pathway involving enzymatic cleavage releasing its intracellular domain (4ICD) for nuclear trafficking and gene regulation. The accepted model for release of 4ICD is consecutive cleavage by Tumor necrosis factor alpha Converting Enzyme (TACE) and γ-secretase enzymes. Here, we show that 4ICD mediates surfactant synthesis and its release by γ-secretase is not dependent on previous TACE cleavage. We used siRNA to silence Presenilin-1 (PSEN-1) expression in a mouse lung type II epithelial cell line (MLE12 cells), and both siRNA knockdown and chemical inhibition of TACE. Knockdown of PSEN-1 significantly decreased baseline and NRG-stimulated surfactant phospholipid synthesis, expression of the surfactant proteins SP-B and SP-C, as well as 4ICD levels, with no change in ErbB4 ectodomain shedding. Neither siRNA knockdown nor chemical inhibition of TACE inhibited 4ICD release or surfactant synthesis. PSEN-1 cleavage of ErbB4 for non-canonical signaling through 4ICD release does not require prior cleavage by TACE.

ErbB4 is an upstream regulator of TTF-1 fetal mouse lung type II cell development in vitro.

TTF-1 is an important transcription factor in lung development and lung disease and is essential for lung cell differentiation, specifically surfactant protein (Sftp) expression. The molecular mechanisms that drive the expression and transcriptional control of TTF-1 are not fully understood. In the fetal lung, ErbB4 functions as a transcriptional co-factor and regulates the timely onset of fetal Sftp expression. We speculate that ErbB4 is an upstream regulator of TTF-1 and regulates Sftpb expression via this pathway in alveolar type II cells. Neuregulin-induced ErbB4 and TTF-1 signaling interactions were studied by co-immunoprecipitation and confocal microscopy. Overexpression of ErbB4 and TTF-1 was analyzed in its effect on cell viability, Sftpb expression, TTF-1 expression, and Sftpb and TTF-1 promoter activity. The effect of ErbB4 deletion and ErbB4 nuclear translocation on TTF-1 expression was studied in primary fetal type II epithelial cells, isolated from transgenic HER4(heart(-/-)) mice. ErbB4 ligand neuregulin induces ErbB4 and TTF-1 co-precipitation and nuclear colocalization. Combined ErbB4 and TTF-1 overexpression inhibits cell viability, while promoting Sftpb expression more than single overexpression of each protein. NRG stimulates TTF-1 expression in ErbB4-overexpressing epithelial cells, while this effect is absent in ErbB4-depleted cells. In primary fetal type II cells, ErbB4 nuclear translocation is critical for its regulation of TTF-1-induced Sftpb upregulation. TTF-1 overexpression did not overcome this important requirement. We conclude that ErbB4 is a critical upstream regulator of TTF-1 in type II epithelial cells and that this interaction is important for Sftpb regulation.

Implementing Entrustable Professional Activities in Pediatric Fellowships: Facilitating the Process.

BACKGROUND AND OBJECTIVES: Entrustable professional activities (EPAs) will be used for initial certification by the American Board of Pediatrics by 2028. Less than half of pediatric fellowships currently use EPAs for assessment, yet all will need to adopt them. Our objectives were to identify facilitators and barriers to the implementation of EPAs to assess pediatric fellows and to determine fellowship program directors' (FPD) perceptions of EPAs and Milestones. METHODS: We conducted a survey of FPDs from 15 pediatric subspecialties. EPA users were asked about their implementation of EPAs, barriers encountered, and perceptions of EPAs. Nonusers were queried about deterrents to using EPAs. Both groups were asked about potential facilitators of implementation and their perceptions of Milestones. RESULTS: The response rate was 65% (575/883). Of these, 344 (59.8%) were EPA users and 231 (40.2%) were nonusers. Both groups indicated work burden as a barrier to implementation. Nonusers reported more barriers than users (mean [SD]: 7 [3.8] vs 5.8 [3.4], P < .001). Both groups identified training materials and premade assessment forms as facilitators to implementation. Users felt that EPAs were easier to understand than Milestones (89%) and better reflected what it meant to be a practicing subspecialty physician (90%). In contrast, nonusers felt that Milestones were easy to understand (57%) and reflected what it meant to be a practicing subspecialist (58%). CONCLUSIONS: Implementing EPA-based assessment will require a substantial investment by FPDs, facilitated by guidance and easily accessible resources provided by multiple organizations. Perceived barriers to be addressed include FPD time constraints, a need for additional assessment tools, and outcomes data.

Stretch-induced fetal type II cell differentiation is mediated via ErbB1-ErbB4 interactions.

Stretch-induced differentiation of lung fetal type II epithelial cells is mediated through EGFR (ErbB1) via release of HB-EGF and TGF-α ligands. Employing an EGFR knock-out mice model, we further investigated the role of the ErbB family of receptors in mechanotranduction during lung development. Deletion of EGFR prevented endogenous and mechanical stretch-induced type II cell differentiation via the ERK pathway, which was rescued by overexpression of a constitutively active MEK. Interestingly, the expression of ErbB4, the only ErbB receptor that EGFR co-precipitates in wild-type cells, was decreased in EGFR-deficient type II cells. Similar to EGFR, ErbB4 was activated by stretch and participated in ERK phosphorylation and type II cell differentiation. However, neuregulin (NRG) or stretch-induced ErbB4 activation were blunted in EGFR-deficient cells and not rescued after ErbB4 overexpression, suggesting that induction of ErbB4 phosphorylation is EGFR-dependent. Finally, we addressed how shedding of ligands is regulated by EGFR. In knock-out cells, TGF-α, a ligand for EGFR, was not released by stretch, while HB-EGF, a ligand for EGFR and ErbB4, was shed by stretch although to a lower magnitude than in normal cells. Release of these ligands was inhibited by blocking EGFR and ERK pathway. In conclusion, our studies show that EGFR and ErbB4 regulate stretch-induced type II cell differentiation via ERK pathway. Interactions between these two receptors are important for mechanical signals in lung fetal type II cells. These studies provide novel insights into the cell signaling mechanisms regulating ErbB family receptors in lung cell differentiation.

The neonatal perspective of paid family medical leave (PFML).

Paid family medical leave (PFML) offers infants, parents, and society at large numerous health and economic benefits. It has been shown to improve neonatal and maternal outcomes, breastfeeding rates, familial relationships, and decrease gender inequalities in the workplace. Though the economic feasibility of PFML has been well established in many countries, the USA lacks a cohesive and comprehensive federal PFML policy. Neonatal healthcare providers play a critical role in impacting neonatal health and should actively advocate for the development and promotion of a federal PFML policy, particularly one that is inclusive of both mothers and fathers and is at least 12 weeks in duration.

Gender analysis of Journal of Perinatology authorship during COVID-19.

OBJECTIVE: To examine authorship gender distributions before and during COVID-19 in the Journal of Perinatology. STUDY DESIGN: We collected data from the Journal of Perinatology website. The author gender was determined using Genderize.io or a systematic internet search. Our primary outcome was the difference between the number of published articles authored by women during the pandemic period (March 2020-May 2021, period two), compared with the preceding 15-month period (period one). We analyzed the data using chi-square tests. RESULTS: Publications increased from period one to two by 8.9%. There were slightly more female than male first (62%) and overall (53%) authors, but fewer last authors (43%) for the combined time periods. Female authorship distribution was not different between periods. CONCLUSIONS: Though publications increased overall, authorship gender distribution did not change significantly during the COVID-19 pandemic. Women authors remain underrepresented overall and specifically as last author, considering the majority of neonatologists are women.