Faculty Bibliography

OBJECTIVE: Human milk (HM) has antibacterial properties due to the presence of immune-modulators, including lactoferrin (LF). This study will determine effect(s) of HM maturation, fortification, and storage conditions on LF levels and its antibacterial properties. STUDY DESIGN/METHODS:. RESULTS: The highest level of LF in preterm HM was observed in the first week of lactation. However, storage of preterm HM at 4°C decreased LF levels significantly. Both LF levels and antibacterial activity in preterm HM was lower compared with term HM, but significantly higher than donor HM even after HM-based fortification. LF supplementation of donor HM improved its antibacterial activity. CONCLUSION/CONCLUSIONS: Preterm infants fed donor HM, formula, or stored HM at 4°C may benefits from LF supplementation to improve HM antibacterial properties. KEY POINTS/CONCLUSIONS:· Milk LF levels vary with storage and maturity.. · Donor milk is deficient in LF even after adding HM-based fortification.. · Donor HM and formula fed infants may benefit from LF..

Purpose of Study Early use of non-invasive ventilation (NIV) in neonates decreases the risk of lung injury and is the preferred mode of ventilation even in extremely premature neonates. Preterm infants are at an increased risk of nasal injuries due to the continuous pressure from the interface on their fragile skin. With the increasing use of NIV, the incidence of nasal pressure injuries (PI) in the neonatal intensive care unit (NICU) is estimated to be as high as 60%. These injuries can cause pain, infection, and rarely damage to underlying nasal cartilage leading to severe nasal deformities. After observing an increased incidence of NIV-related PI in our NICU, we launched a quality improvement project to tackle this problem. The objective of this study is to decrease the rate of nasal PI by 30% from a baseline of 0.36 injuries/100 NIV days to a goal of 0.25 injuries/100 NIV days by December 2020. The secondary aim is to eliminate any serious harm nasal PI (stage 3 and beyond as per the national pressure injury advisory panel staging). Methods Used An interdisciplinary team was formulated in late 2017 and the collection of data on NIV-related PI and NIV days was started. We conducted a series of plan-dostudy- act (PDSA) cycles focused around early detection of injury, change of NIV interface and alternating mask and prongs at the first sign of injury, use of nasal cannulaide as a protective barrier, engagement of both frontline nursing and respiratory therapy staff to do daily skin checks, and increased involvement of wound care nursing. NIV-related PI rates/100 NIV days were analyzed monthly using run charts (figure 1). Summary of Results Through this series of PDSA cycles, we were able to significantly decrease our rate of nasal PI from a baseline of 0.34 from January 2018 to Q2 2019 to 0.24 injuries/ 100 NIV days by December 2020, with a continued improvement noted in 2021 with a rate of 0.11 injuries/100 NIV days. There was no serious harm nasal PI after 2019. A spike of events was noted in the second quarter of 2020 during the COVID-19 surge in New York. This increase is likely secondary to the strain on healthcare resources during that time. Conclusions Using quality improvement methodology, we identified opportunities for improvement and instituted measures to decrease nasal PI in neonates. Multidisciplinary collaboration, accessibility to alternative interface(s) if needed, and the use of a barrier between interface and skin are effective strategies to decrease nasal PI in the NICU. (Figure Presented)

Diagnostic tests for sepsis aim to either detect the infectious agent (such as microbiological cultures) or detect host markers that commonly change in response to an infection (such as C-reactive protein). The latter category of tests has advantages compared to culture-based methods, including a quick turnaround time and in some cases lower requirements for blood samples. They also provide information on the immune response of the host, a critical determinant of clinical outcome. However, they do not always differentiate nonspecific host inflammation from true infection and can inadvertently lead to antibiotic overuse. Multiple noninfectious conditions unique to neonates in the first days after birth can lead to inflammatory marker profiles that mimic those seen among infected infants. Our goal was to review noninfectious conditions and patient characteristics that alter host inflammatory markers commonly used for the diagnosis of early-onset sepsis. Recognizing these conditions can focus the use of biomarkers on patients most likely to benefit while avoiding scenarios that promote false positives. We highlight approaches that may improve biomarker performance and emphasize the need to use patient outcomes, in addition to conventional diagnostic performance analysis, to establish clinical utility.

Introduction/UNASSIGNED:Parenteral Nutrition (PN) can lead to intestinal failure associated liver disease (IFALD). There are no human studies to date studying specifically the benefits of light-protection on neonatal IFALD. Recently, the European Medicines Agency and the American Society for Parenteral and Enteral Nutrition (ASPEN) both recommended full light protection of PN to reduce the risk of adverse clinical outcomes. Objective/UNASSIGNED:The primary objective of this study was to evaluate the impact of light-protecting PN on the incidence of cholestasis and peak direct bilirubin levels in premature infants. Study design/UNASSIGNED:Retrospective chart review of preterm infants requiring PN for a minimum of 2 weeks with or without light-protection. After light protection of the PN solution, primary outcomes (including cholestasis and direct bilirubin levels) of both groups were compared. Secondary outcomes include evaluation of bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), retinopathy of prematurity (ROP), sepsis and mortality. Results/UNASSIGNED:= 0.0223). There was no difference in NEC, ROP, sepsis or mortality. Conclusion/UNASSIGNED:Our study supports that the practice of light-protecting PN may reduce the incidence of IFALD in premature infants. Moreover, there was a trend toward decreased incidence of severe BPD in the light-protection group. Further light protection studies are needed to confirm these findings.

BACKGROUND:Pregnancy represents a unique challenge for the maternal-fetal immune interface, requiring a balance between immunosuppression, which is essential for the maintenance of a semi-allogeneic fetus, and pro-inflammatory host defense to protect the maternal-fetal interface from invading organisms. Adaptation to repeated inflammatory stimuli (endotoxin tolerance) may be critical in preventing inflammation-induced preterm birth resulting from exaggerated maternal inflammatory responses to mild/moderate infections that are common during pregnancy. However, the exact mechanisms contributing to the maintenance of tolerance to repeated infections are not completely understood. miRNAs play important roles in pregnancy, with several miRNAs implicated in gestational tissue function, as well as in pathologic pregnancy conditions. miRNA-519c, a member of the C19MC cluster, is a human-specific miRNA mainly expressed in the placenta. However, its role in pregnancy is largely unknown. OBJECTIVES/OBJECTIVE:To explore the role of "endotoxin tolerance" failure in the pathogenesis of an exaggerated inflammatory response often seen in inflammation-mediated preterm birth. In this study, we investigated the role of miRNA-519c, a placenta-specific miRNA, as a key regulator of endotoxin tolerance at the maternal-fetal interface. STUDY DESIGN/METHODS:-trimester placentas were treated with LPS. After 24 hours, the conditioned media was collected for analysis, and the placental explants were re-exposed to repeated doses of LPS for 3 days. The supernatant was analyzed for inflammatory markers, presence of extracellular vesicles (EVs) and microRNAs. To study the possible mechanism of action of the microRNAs, we evaluated the phosphodiesterase 3 B (PDE3B) pathway involved in TNF-α production using a miRNAs mimic and PDE3B siRNA transfection. Finally, we analyzed human placental samples from different gestational ages and from women affected by inflammation-associated pregnancies. RESULTS:Our data showed that repeated exposure of the human placenta to endotoxin challenges induced a tolerant phenotype characterized by decreased TNF-α and upregulated IL-10 levels. This reaction was mediated by the placenta-specific miRNA-519c packaged within placental EVs. LPS treatment increased the EVs that were positive for the exosome tetraspanin markers, namely CD9, CD63, and CD81, and secreted primarily by trophoblasts. Primary human trophoblast cells transfected with miR-519c mimic decreased PDE3B. While lack of PDE3B, achieved by siRNA transfection, resulted in a decreased TNF-α production. These data supported the hypothesis that the anti-inflammatory action of miRNA-519c was mediated by a downregulation of the phosphodiesterase 3 B pathway, leading to inhibition of TNF-α production. Furthermore, human placentas from normal and inflammation-associated pregnancies demonstrated that decreased placental miRNA-519c level was linked to infection-induced inflammatory pathologies during pregnancy. CONCLUSION/CONCLUSIONS:We identified miRNA-519c, a human placenta-specific miRNA, as a novel regulator of immune adaptation associated with infection-induced preterm birth at the maternal-fetal interface. Our study can serve as a basis for future experiments to explore the potential use of miRNA-519c as a biomarker for infection-induced preterm birth.

OBJECTIVE:The primary objective was to evaluate hydrocortisone's efficacy for decreasing respiratory support in premature infants with developing bronchopulmonary dysplasia (BPD). Secondary objectives included assessment of the impact of intrauterine growth restriction (IUGR), maternal history of chorioamnionitis, side effects and route of administration associated with hydrocortisone's efficacy. Dexamethasone as second-line treatment to decrease respiratory support was reviewed. METHODS:Retrospective chart review of preterm infants requiring respiratory support receiving hydrocortisone. RESULTS:A total of 48 patients were included. Successful extubation was achieved in 50% of intubated patients after hydrocortisone treatment with no major complications. In our small study, history of maternal chorioamnionitis, IUGR or route of administration did not affect the response. Rescue dexamethasone after hydrocortisone therapy was ineffective in the ten patients who failed extubation following hydrocortisone. CONCLUSION/CONCLUSIONS:Hydrocortisone is effective in decreasing respiratory support in patients with developing BPD without major complications. Randomized studies are warranted to confirm our findings.

Ewingella americana is a Gram-negative, catalase positive and anaerobic enterobacterium first described in 1983. Infections caused by this pathogen, such as bacteremia and pneumonia, are extremely rare and primarily occur in patients with underlying pathologies or immunosuppression. There is still a debate as to whether Ewingella americana is a real pathogen or if it can be considered an opportunistic infectious agent. We report the first documented case of Ewingella americana meningitis in literature and the first case of this pathogen causing infection in a newborn. Case presentation: A term newborn male was born via spontaneous vaginal delivery to a Gravida 2 Para 0, 28 year old woman with negative prenatal screening tests with a birth weight of 4.70 kilograms and Apgar scores of 9 and 9 at 1 and 5 minutes respectively. Rupture of membranes was 27 hours prior to delivery. Infant was noted to be febrile to 101°F at birth, so infant was admitted in the neonatal intensive care unit and started empirically on ampicillin and gentamycin. Cerebrospinal fluid (CSF) drawn due to irritability on day of life 1 presented normal cell and protein count but grew Gram negative rods after 2 days, identified subsequently as Ewingella americana; repeat CSF analysis done at 6 days of life showed pleocytosis. Brain MRI performed at 2 weeks of life showed leptomeningitis. The infant was treated with ceftazidime for 21 days from the first negative CSF culture. He has since followed up with the neurologist and infectious disease specialist. He had a normal electroencephalogram (EEG) and is meeting all developmental milestones at the 24 months of age follow up visit. Conclusion: Our case highlights that Ewingella americana can cause serious invasive infections such as meningitis in the neonatal period with minimal symptomatology. Antibiotic treatment in the neonatal period can present challenges due to the Ewingella americana's variable sensitivity. The role of these emerging low virulence organisms in causing infections has to be further elucidated, especially in vulnerable patients such as newborns.

Inflammation-induced FGF10 protein deficiency is associated with bronchopulmonary dysplasia (BPD), a chronic lung disease of prematurely born infants characterized by arrested alveolar development. So far, experimental evidence for a direct role of FGF10 in lung disease is lacking. Using the hyperoxia-induced neonatal lung injury as a mouse model of BPD, the impact of Fgf10 deficiency in Fgf10^+/- versus Fgf10^+/+ pups was investigated. In normoxia, no lethality of Fgf10^+/+ or Fgf10^+/- pups was observed. By contrast, all Fgf10^+/- pups died within 8 days of hyperoxic injury, with lethality starting at day 5, whereas Fgf10^+/+ pups were all alive. Lungs of pups from the two genotypes were collected on postnatal day 3 following normoxia or hyperoxia exposure for further analysis. In hyperoxia, Fgf10^+/- lungs exhibited increased hypoalveolarization. Analysis by FACS of the Fgf10^+/- versus control lungs in normoxia revealed a decreased ratio of alveolar epithelial type II (AECII) cells over total Epcam-positive cells. In addition, gene array analysis indicated reduced AECII and increased AECI transcriptome signatures in isolated AECII cells from Fgf10^+/- lungs. Such an imbalance in differentiation is also seen in hyperoxia and is associated with reduced mature surfactant protein B and C expression. Attenuation of the activity of Fgfr2b ligands postnatally in the context of hyperoxia also led to increased lethality with decreased surfactant expression. In summary, decreased Fgf10 mRNA levels lead to congenital lung defects, which are compatible with postnatal survival, but which compromise the ability of the lungs to cope with sub-lethal hyperoxic injury. Fgf10 deficiency affects quantitatively and qualitatively the formation of AECII cells. In addition, Fgfr2b ligands are also important for repair after hyperoxia exposure in neonates. Deficient AECII cells could be an additional complication for patients with BPD.

Lipid-containing alveolar interstitial fibroblasts (lipofibroblasts) are increasingly recognized as an important component of the epithelial stem cell niche in the rodent lung. Although lipofibroblasts were initially believed merely to assist type 2 alveolar epithelial cells in surfactant production during neonatal life, recent evidence suggests that these cells are indispensable for survival and growth of epithelial stem cells during adulthood. Despite increasing interest in lipofibroblast biology, little is known about their cellular origin or the molecular pathways controlling their formation during embryonic development. Here, we show that a population of lipid-droplet-containing stromal cells emerges in the developing mouse lung between E15.5 and E16.5. This is accompanied by significant upregulation, in the lung mesenchyme, of peroxisome proliferator-activated receptor gamma (master switch of lipogenesis), adipose differentiation-related protein (marker of mature lipofibroblasts) and fibroblast growth factor 10 (previously shown to identify a subpopulation of lipofibroblast progenitors). We also demonstrate that although only a subpopulation of total embryonic lipofibroblasts derives from Fgf10(+) progenitor cells, in vivo knockdown of Fgfr2b ligand activity and reduction in Fgf10 expression lead to global reduction in the expression levels of lipofibroblast markers at E18.5. Constitutive Fgfr1b knockouts and mutants with conditional partial inactivation of Fgfr2b in the lung mesenchyme reveal the involvement of both receptors in lipofibroblast formation and suggest a possible compensation between the two receptors. We also provide data from human fetal lungs to demonstrate the relevance of our discoveries to humans. Our results reveal an essential role for Fgf10 signaling in the formation of lipofibroblasts during late lung development.