Disruption of the SP-A/SP-R210L (MYO18Aα) pathway prolongs gestation and reduces fetal survival during lipopolysaccharide-induced parturition in late gestation.

Prolonged labor can lead to infection, fetal distress, asphyxia, and life-threatening harm to both the mother and the baby. Surfactant protein A (SP-A) was shown to contribute to the maintenance of pregnancy and timing of term labor. SP-A modulates the stoichiometric expression of the SP-R210L and SP-R210S isoforms of the SP-R210 receptor on alveolar macrophages (AMs). Lack of SP-R210L dysregulates macrophage inflammatory responses. We asked whether SP-A alters normal and inflammation-induced parturition through SP-R210 using SP-A- and SP-R210L-deficient mice. Labor and delivery of time-pregnant mice were monitored in real time using a time-lapse infrared camera. Intrauterine injection with either vehicle or Escherichia coli lipopolysaccharide (LPS) on embryonic (E) day 18.5 post coitus was used to assess the effect of gene disruption in chorioamnionitis-induced labor. We report that either lack of SP-A or disruption of SP-R210L delays parturition by 0.40 and 0.55 days compared with controls, respectively. LPS induced labor at 0.60, 1.01, 0.40, 1.00, and 1.31 days earlier than PBS controls in wild type (WT), SP-A-deficient, littermate controls, heterozygous, and homozygous SP-R210L-deficient mice, respectively. Lack of SP-A reduced litter size in PBS-treated mice, whereas the total number of pups delivered was similar in all LPS-treated mice. The number of live pups, however, was significantly reduced by 50%-70% in SP-A and SP-R210L-deficient mice compared with controls. Differences in gestational length were not associated with intrauterine growth restriction. The present findings support the novel concept that the SP-A/SP-R210 pathway modulates timely labor and delivery and supports fetal lung barrier integrity during fetal-to-neonatal transition in term pregnancy.NEW & NOTEWORTHY To our knowledge, this study is the first to report that SP-A prevents delay of labor and inflammation-induced stillbirth through the receptor SP-R210L.

That head lag is impressive! Infantile botulism in the NICU: a case report.

BACKGROUND: Infantile botulism (IB) is a devastating and potentially life-threatening neuromuscular disorder resulting from intestinal colonization by Clostridium botulinum and the resultant toxin production. It can present with constipation, descending paralysis, and, potentially, respiratory failure. Botulism is a diagnosis that is more commonly seen in the pediatric intensive care unit (PICU) or on the general pediatric wards and would not typically be managed in the neonatal intensive care unit (NICU), and therefore requires high clinical suspicion to ensure prompt diagnosis and treatment. CASE PRESENTATION: We discuss a case where an infant from central Pennsylvania presented to a Level IV NICU rather than to the PICU for an evaluation for sepsis and was uniquely diagnosed with IB. The infant presented with poor oral feeding and reduced oral intake, hypothermia, and lethargy. His symptoms progressed into hypoxia and acute respiratory failure. Interestingly, this infant had no known exposure to honey or any other identifiable sources of botulism contact. The infant's twin brother and the other infants who attended the mother's in-home daycare remained asymptomatic. This infant was initially evaluated and managed for a potential infectious etiology. However, a diagnosis of IB was suspected, and was later confirmed through the detection of botulinum toxin in the infant's stools. A high level of suspicion allowed for timely treatment with Botulism Immune Globulin neutralizing antibodies (BabyBIG), even prior to confirmatory testing. We describe the process of obtaining BabyBIG, as well as the natural course of illness after treatment in our patient who ultimately made a complete recovery. CONCLUSIONS: This case highlights the importance of considering infantile botulism as a diagnostic possibility even in the absence of risk factors, and the need for vigilance in diagnosing and treating this rare but potentially life-threatening condition. With timely recognition, subsequent treatment with BabyBIG, and supportive care, infants with infantile botulism can be expected to recover completely. This information is particularly important for neonatologists providing care for infants outside the neonatal period, especially during times of high patient census and resulting overflow of pediatric admissions in the NICU.

Implementation of Nasal CPAP Weaning Guidelines in Preterm Infants.

BACKGROUND: Continuous positive airway pressure (CPAP) benefits preterm infants with respiratory distress, including reduced bronchopulmonary dysplasia (BPD) incidence, surfactant use, and extubation failure. Successful CPAP weaning also promotes oral feeding. However, there is no consensus on the optimal weaning of CPAP in neonates. This study aims to determine the effects of CPAP (CPAP) weaning guideline implementation on neonatal outcomes. METHODS: CPAP gradual pressure weaning guidelines were implemented in the Penn State Children's Hospital NICU in 2020. We included baseline data from infants (Epoch1) before bubble CPAP implementation in 2018-19. We included infants (Epoch2) after implementing the guidelines during 2020-21. The inclusion criteria were infants <32 weeks gestation with CPAP support. Compliance with the CPAP weaning guidelines was the primary process measure. Primary outcome measures included successful CPAP wean on the first attempt. Balancing measures used were total days on respiratory support and length of hospital stay. RESULTS: 195 infants were included in this study, 95 infants in Epoch 1 before bubble CPAP implementation and 100 infants in Epoch 2 after implementing guidelines. Infants in the two Epochs were similar in median gestational age at 29 vs 30 weeks (p=0.47) and were similar in median birth weight at 1190 vs 1130 grams (p=0.73). After implementing weaning guidelines, the successful weaning off CPAP improved from 9.5% to 54% (p<0.001). The total days needed to achieve full oral feeds decreased by 7 days (29 vs 22 median days, p<0.001). The BPD incidence was not significantly different between the two Epochs at 17% vs 16%, p= 0.87. There was no difference in total days of respiratory support, total length of stay, the number of infants discharged on home nasogastric feeding, and demographic variables. CONCLUSION: The implementation of the bubble CPAP weaning guideline improves the successful weaning of CPAP and promotes oral feeding in preterm infants.

Proposed Screening for Congenital Hyperinsulinism in Newborns: Perspective from a Neonatal-Perinatal Medicine Group.

This perspective work by academic neonatal providers is written specifically for the audience of newborn care providers and neonatologists involved in neonatal hypoglycemia screening. Herein, we propose adding a screen for congenital hyperinsulinism (CHI) by measuring glucose and ketone (i.e., ß-hydroxybutyrate (BOHB)) concentrations just prior to newborn hospital discharge and as close to 48 h after birth as possible, at the same time that the mandated state Newborn Dried Blood Spot Screen is obtained. In the proposed protocol, we do not recommend specific metabolite cutoffs, as our primary objective is to simply highlight the concept of screening for CHI in newborns to newborn caregivers. The premise for our proposed screen is based on the known effect of hyperinsulinism in suppressing ketogenesis, thereby limiting ketone production. We will briefly discuss genetic CHI, other forms of neonatal hypoglycemia, and their shared mechanisms; the mechanism of insulin regulation by functional pancreatic islet cell membrane KATP channels; adverse neurodevelopmental sequelae and brain injury due to missing or delaying the CHI diagnosis; the principles of a good screening test; how current neonatal hypoglycemia screening programs do not fulfill the criteria for being effective screening tests; and our proposed algorithm for screening for CHI in newborns.

Corrigendum: Single nucleotide polymorphisms interactions of the surfactant protein genes associated with respiratory distress syndrome susceptibility in preterm infants.

[This corrects the article DOI: 10.3389/fped.2021.682160.].

Early Salivary miRNA Expression in Extreme Low Gestational Age Newborns.

Background: MicroRNAs (miRNA) are small non-coding RNAs that regulate gene expression playing a key role in organogenesis. MiRNAs are studied in tracheal aspirates (TA) of preterm infants. However; this is difficult to obtain in infants who are not intubated. This study examines early salivary miRNA expression as non-invasive early biomarkers in extremely low gestational age newborns (ELGANs). Methods: Saliva was collected using DNA-genotek swabs, miRNAs were analyzed using RNA seq and RT PCR arrays. Salivary miRNA expression was compared to TA using RNA seq at 3 days of age, and longitudinal changes at 28 days of age were analyzed using RT PCR arrays in ELGANs. Results: Approximately 822 ng of RNA was extracted from saliva of 7 ELGANs; Of the 757 miRNAs isolated, 161 miRNAs had significant correlation in saliva and TA at 3 days of age (r = 0.97). Longitudinal miRNA analysis showed 29 miRNAs downregulated and 394 miRNAs upregulated at 28 days compared to 3 days of age (adjusted p < 0.1). Bioinformatic analysis (Ingenuity Pathway Analysis) of differentially expressed miRNAs identified organismal injury and abnormalities and cellular development as the top physiological system development and cellular function. Conclusion: Salivary miRNA expression are source for early biomarkers of underlying pathophysiology in ELGANs.

Imaging NAD(H) Redox Alterations in Cryopreserved Alveolar Macrophages from Ozone-Exposed Mice and the Impact of Nutrient Starvation during Long Lag Times.

Employing the optical redox imaging technique, we previously identified a significant redox shift of nicotinamide adenine dinucleotide (NAD and the reduced form NADH) in freshly isolated alveolar macrophages (AM) from ozone-exposed mice. The goal here was twofold: (a) to determine the NAD(H) redox shift in cryopreserved AM isolated from ozone-exposed mice and (b) to investigate whether there is a difference in the redox status between cryopreserved and freshly isolated AM. We found: (i) AM from ozone-exposed mice were in a more oxidized redox state compared to that from filtered air (FA)-exposed mice, consistent with the results obtained from freshly isolated mouse AM; (ii) under FA exposure, there was no significant NAD(H) redox difference between fresh AM that had been placed on ice for 2.5 h and cryopreserved AM; however, under ozone exposure, fresh AM were more oxidized than cryopreserved AM; (iii) via the use of nutrient starvation and replenishment and H2O2-induced oxidative stress of an AM cell line, we showed that this redox difference between cryopreserved and freshly isolated AM is likely the result of the double "hit", i.e., the ozone-induced oxidative stress plus nutrient starvation that prevented freshly isolated AM from a full recovery after being on ice for a prolonged time period. The cryopreservation technique we developed eliminates/minimizes the effects of oxidative stress and nutrient starvation on cells. This method can be adopted to preserve lung macrophages from animal models or clinical patients for further investigations.

Single Nucleotide Polymorphisms Interactions of the Surfactant Protein Genes Associated With Respiratory Distress Syndrome Susceptibility in Preterm Infants.

Background: Neonatal respiratory distress syndrome (RDS), due to surfactant deficiency in preterm infants, is the most common cause of respiratory morbidity. The surfactant proteins (SFTP) genetic variants have been well-studied in association with RDS; however, the impact of SNP-SNP (single nucleotide polymorphism) interactions on RDS has not been addressed. Therefore, this study utilizes a newer statistical model to determine the association of SFTP single SNP model and SNP-SNP interactions in a two and a three SNP interaction model with RDS susceptibility. Methods: This study used available genotype and clinical data in the Floros biobank at Penn State University. The patients consisted of 848 preterm infants, born <36 weeks of gestation, with 477 infants with RDS and 458 infants without RDS. Seventeen well-studied SFTPA1, SFTPA2, SFTPB, SFTPC, and SFTPD SNPs were investigated. Wang's statistical model was employed to test and identify significant associations in a case-control study. Results: Only the rs17886395 (C allele) of the SFTPA2 was associated with protection for RDS in a single-SNP model (Odd's Ratio 0.16, 95% CI 0.06-0.43, adjusted p = 0.03). The highest number of interactions (n = 27) in the three SNP interactions were among SFTPA1 and SFTPA2. The three SNP models showed intergenic and intragenic interactions among all SFTP SNPs except SFTPC. Conclusion: The single SNP model and SNP interactions using the two and three SNP interactions models identified SFTP-SNP associations with RDS. However, the large number of significant associations containing SFTPA1 and/or SFTPA2 SNPs point to the importance of SFTPA1 and SFTPA2 in RDS susceptibility.

Hedgehog signaling pathway gene variant influences bronchopulmonary dysplasia in extremely low birth weight infants.

BACKGROUND: Genome wide association study identified hedgehog interacting protein gene (HHIP) variants with chronic obstructive pulmonary disease and asthma. Loss of HHIP, a key regulator of the hedgehog signaling pathway, leads to impaired lung morphogenesis and lethality in animal models, through unimpeded sonic hedgehog expression blocking mesenchymal-expressed fibroblast growth factor 10 (FGF10). Since bronchopulmonary dysplasia (BPD) is also associated with altered lung development and worsens with stimuli including mechanical ventilation, reactive oxygen species, and inflammation, HHIP and FGF10 may be candidate genes. METHODS: This was an observational, cohort study including extremely low birth weight infants that who developed BPD and those who did not. DNA was isolated from buccal swabs and subjected to allelic discrimination, using specific HHIP and FGF10 probes. Protein levels were measured in tracheal aspirates. Student's t test, Chi-square, Z test and logistic regression were used. RESULTS: Demographic characteristics did not differ except that birth weight (715 ± 153 vs. 835 ± 132 g) and gestational age (25 vs. 26 weeks) were less in babies with BPD. HHIP variant rs13147758 (GG genotype) was found to be independently protective for BPD (odds ratio 0.35, 95% confidence interval 0.15-0.82, P = - 0.02). Early airway HHIP protein levels were increased in infants with BPD compared to those without [median (interquartile range) 130.6 (55.6-297.0) and 41.2 (22.1-145.6) pg/mL, respectively; P = 0.05]. The FGF10 single nucleotide polymorphisms were not associated with BPD. CONCLUSION: HHIP, as a regulator of lung bud formation, affects BPD susceptibility, and may be valuable in understanding the specific mechanisms for this disease as well as for identifying therapeutic targets in the era of personalized medicine.

Sex and SP-A2 Dependent NAD(H) Redox Alterations in Mouse Alveolar Macrophages in Response to Ozone Exposure: Potential Implications for COVID-19.

Co-enzyme nicotinamide adenine dinucleotide (NAD(H)) redox plays a key role in macrophage function. Surfactant protein (SP-) A modulates the functions of alveolar macrophages (AM) and ozone (O3) exposure in the presence or absence of SP-A and reduces mouse survival in a sex-dependent manner. It is unclear whether and how NAD(H) redox status plays a role in the innate immune response in a sex-dependent manner. We investigated the NAD(H) redox status of AM from SP-A2 and SP-A knockout (KO) mice in response to O3 or filtered air (control) exposure using optical redox imaging technique. We found: (i) In SP-A2 mice, the redox alteration of AM in response to O3 showed sex-dependence with AM from males being significantly more oxidized and having a higher level of mitochondrial reactive oxygen species than females; (ii) AM from KO mice were more oxidized after O3 exposure and showed no sex differences; (iii) AM from female KO mice were more oxidized than female SP-A2 mice; and (iv) Two distinct subpopulations characterized by size and redox status were observed in a mouse AM sample. In conclusions, the NAD(H) redox balance in AM responds to O3 in a sex-dependent manner and the innate immune molecule, SP-A2, contributes to this observed sex-specific redox response.

SNP and Haplotype Interaction Models Reveal Association of Surfactant Protein Gene Polymorphisms With Hypersensitivity Pneumonitis of Mexican Population.

Background: Hypersensitivity pneumonitis (HP) is an interstitial lung disease caused by inhalation of common environmental organic particles. Surfactant proteins (SPs) play a role in innate immunity and surfactant function. We hypothesized that single nucleotide polymorphisms (SNPs) or haplotypes of the SP genes associate with HP. Methods: Seventy-five HP patients caused by avian antigen and 258 controls, asymptomatic antigen exposed and non-exposed were enrolled. SNP association was performed using logistic regression analysis and SNP-SNP interaction models. Results: Based on odds ratio, regression analyses showed association of (a) rs7316_G, 1A3 (protective) compared to antigen exposed; (b) male sex, smoking, rs721917_T and rs1130866_T (protective) compared to non-exposed controls with HP; (c) compared to antigen exposed, 25 interactions associated with HP in a three-SNP model; (d) compared to non-exposed, (i) rs1136451 associated with increased, whereas rs1136450 and rs1130866 associated with lower HP risk, (ii) 97 interactions associated with HP in a three-SNP model. The majority of SNP-SNP interactions associated with increased HP risk involved SNPs of the hydrophilic SPs, whereas, the majority of interactions associated with lower HP risk involved SNPs of both hydrophilic and hydrophobic SPs; (e) haplotypes of SP genes associated with HP risk. Conclusions: The complexity of SNPs interactions of the SFTP genes observed indicate that the lung inflammatory response to avian antigens is modulated by a complex gene interplay rather than by single SNPs.

Management of newborns exposed to mothers with confirmed or suspected COVID-19.

There is limited information about newborns with confirmed or suspected COVID-19. Particularly in the hospital after delivery, clinicians have refined practices in order to prevent secondary infection. While guidance from international associations is continuously being updated, all facets of care of neonates born to women with confirmed or suspected COVID-19 are center-specific, given local customs, building infrastructure constraints, and availability of protective equipment. Based on anecdotal reports from institutions in the epicenter of the COVID-19 pandemic close to our hospital, together with our limited experience, in anticipation of increasing numbers of exposed newborns, we have developed a triage algorithm at the Penn State Hospital at Milton S. Hershey Medical Center that may be useful for other centers anticipating a similar surge. We discuss several care practices that have changed in the COVID-19 era including the use of antenatal steroids, delayed cord clamping (DCC), mother-newborn separation, and breastfeeding. Moreover, this paper provides comprehensive guidance on the most suitable respiratory support for newborns during the COVID-19 pandemic. We also present detailed recommendations about the discharge process and beyond, including providing scales and home phototherapy to families, parental teaching via telehealth and in-person education at the doors of the hospital, and telehealth newborn follow-up.

Weaning of nasal CPAP in preterm infants: who, when and how? a systematic review of the literature.

BACKGROUND: There is increased use of early nasal continuous positive airway pressure (NCPAP) to manage respiratory distress in preterm infants but optimal methods and factors associated with successful wean are not well defined. A systematic review was performed to define the corrected gestational age (CGA), weight to wean NCPAP and the methods associated with successful weaning of the NCPAP among preterm infants, along with factors affecting it. METHODS: Searches were made of PubMed using the keywords-NCPAP, CPAP, weaning, withdrawal, preterm, and infants from its inception to January 1st, 2014, for studies in all languages but limited to humans. Previous reviews (including cross references) were also searched. We included all randomized and quasi-randomized controlled trials where preterm neonates were randomized to different NCPAP weaning strategies. Details of CGA, weight and methods used for weaning NCPAP were extracted along with factors which affect its withdrawal. RESULTS: Seven studies met the search criteria. The successful wean was at 32 to 33 weeks CGA and at 1600 g. Three different methods were used for weaning were sudden, gradual pressure wean and gradual graded time off wean. Criteria for readiness, success and failure to wean were defined. Factors affecting successful weaning were intubation, anemia, infection and gastro-esophageal reflux. CONCLUSIONS: The successful wean was at 32 to 33 weeks CGA and 1600 g. Criteria for readiness, success and failure to wean are well defined. Sudden weaning may be associated with a shorter weaning time. Future trials are needed comparing weaning methods using defined criteria for readiness and success of NCPAP wean and stratify the results by gestational age and birth weight.