Development Of Bronchopulmonary Dysplasia Research Articles

Hydrogen gas inhalation ameliorates LPS-induced BPD by inhibiting inflammation via regulating the TLR4–NFκB–IL6/NLRP3 signaling pathway in the placenta

IntroductionHydrogen (H2) is regarded as a novel therapeutic agent against several diseases owing to its inherent biosafety. Bronchopulmonary dysplasia (BPD) has been widely considered among adverse pregnancy outcomes, without effective treatment. Placenta plays a role in defense, synthesis, and immunity, which provides a new perspective for the treatment of BPD. This study aimed to investigate if H2 reduced the placental inflammation to protect the neonatal rat against BPD damage and potential mechanisms.MethodsWe induced neonatal BPD model by injecting lipopolysaccharide (LPS, 1 µg) into the amniotic fluid at embryonic day 16.5 as LPS group. LPS + H2 group inhaled 42% H2 gas (4 h/day) until the samples were collected. We primarily analyzed the neonatal outcomes and then compared inflammatory levels from the control group (CON), LPS group and LPS + H2 group. HE staining was performed to evaluate inflammatory levels. RNA sequencing revealed dominant differentially expressed genes. Bioinformatics analysis (GO and KEGG) of RNA-seq was applied to mine the signaling pathways involved in protective effect of H2 on the development of LPS-induced BPD. We further used qRT-PCR, Western blot and ELISA methods to verify differential expression of mRNA and proteins. Moreover, we verified the correlation between the upstream signaling pathways and the downstream targets in LPS-induced BPD model.ResultsUpon administration of H2, the inflammatory infiltration degree of the LPS-induced placenta was reduced, and infiltration significantly narrowed. Hydrogen normalized LPS-induced perturbed lung development and reduced the death ratio of the fetus and neonate. RNA-seq results revealed the importance of inflammatory response biological processes and Toll-like receptor signaling pathway in protective effect of hydrogen on BPD. The over-activated upstream signals [Toll-like receptor 4 (TLR4), nuclear factor kappa-B p65 (NF-κB p65), Caspase1 (Casp1) and NLR family pyrin domain containing 3 (NLRP3) inflammasome] in LPS placenta were attenuated by H2 inhalation. The downstream targets, inflammatory cytokines/chemokines [interleukin (IL)-6, IL-18, IL-1β, C–C motif chemokine ligand 2 (CCL2) and C-X-C motif chemokine ligand 1 (CXCL1)], were decreased both in mRNA and protein levels by H2 inhalation in LPS-induced placentas to rescue them from BPD. Correlation analysis displayed a positive association of TLR4-mediated signaling pathway both proinflammatory cytokines and chemokines in placenta.ConclusionH2 inhalation ameliorates LPS-induced BPD by inhibiting excessive inflammatory cytokines and chemokines via the TLR4–NFκB–IL6/NLRP3 signaling pathway in placenta and may be a potential therapeutic strategy for BPD.

Current Applications of Artificial Intelligence in the Neonatal Intensive Care Unit

Artificial intelligence (AI) refers to computer algorithms that replicate the cognitive function of humans. Machine learning is widely applicable using structured and unstructured data, while deep learning is derived from the neural networks of the human brain that process and interpret information. During the last decades, AI has been introduced in several aspects of healthcare. In this review, we aim to present the current application of AI in the neonatal intensive care unit. AI-based models have been applied to neurocritical care, including automated seizure detection algorithms and electroencephalogram-based hypoxic-ischemic encephalopathy severity grading systems. Moreover, AI models evaluating magnetic resonance imaging contributed to the progress of the evaluation of the neonatal developing brain and the understanding of how prenatal events affect both structural and functional network topologies. Furthermore, AI algorithms have been applied to predict the development of bronchopulmonary dysplasia and assess the extubation readiness of preterm neonates. Automated models have been also used for the detection of retinopathy of prematurity and the need for treatment. Among others, AI algorithms have been utilized for the detection of sepsis, the need for patent ductus arteriosus treatment, the evaluation of jaundice, and the detection of gastrointestinal morbidities. Finally, AI prediction models have been constructed for the evaluation of the neurodevelopmental outcome and the overall mortality of neonates. Although the application of AI in neonatology is encouraging, further research in AI models is warranted in the future including retraining clinical trials, validating the outcomes, and addressing serious ethics issues.

Protective Effects of Resveratrol Against Airway Hyperreactivity, Oxidative Stress, and Lung Inflammation in a Rat Pup Model of Bronchopulmonary Dysplasia

Oxygen therapy provides an important treatment for preterm and low-birth-weight neonates, however, it has been shown that prolonged exposure to high levels of oxygen (hyperoxia) is one of the factors contributing to the development of bronchopulmonary dysplasia (BPD) by inducing lung injury and airway hyperreactivity. There is no effective therapy against the adverse effects of hyperoxia. Therefore, this study was undertaken to test the hypothesis that natural phytoalexin resveratrol will overcome hyperoxia-induced airway hyperreactivity, oxidative stress, and lung inflammation. Newborn rats were exposed to hyperoxia (fraction of inspired oxygen - FiO2>95 % O2) or ambient air (AA) for seven days. Resveratrol was supplemented either in vivo (30 mg·kg-1·day-1) by intraperitoneal administration or in vitro to the tracheal preparations in an organ bath (100 μM). Contractile and relaxant responses were studied in tracheal smooth muscle (TSM) using the in vitro organ bath system. To explain the involvement of nitric oxide in the mechanisms of the protective effect of resveratrol against hyperoxia, a nitric oxide synthase inhibitor – Nω-nitro-L-arginine methyl ester (L-NAME), was administered in some sets of experiments. The superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities and the tumor necrosis factor-alpha (TNF-α) and interleukin-1β (IL-1β) levels in the lungs were determined. Resveratrol significantly reduced contraction and restored the impaired relaxation of hyperoxia-exposed TSM (p<0.001). L-NAME reduced the inhibitory effect of resveratrol on TSM contractility, as well as its promotion relaxant effect (p<0.01). Resveratrol preserved the SOD and GPx activities and decreased the expression of TNF-α and IL-1β in hyperoxic animals. The findings of this study demonstrate the protective effect of resveratrol against hyperoxia-induced airway hyperreactivity and lung damage and suggest that resveratrol might serve as a therapy to prevent the adverse effects of neonatal hyperoxia. Keywords: Bronchopulmonary dysplasia • Hyperoxia • Airway hyperreactivity • Resveratrol • Pro-inflammatory cytokines

Assessment of genetic markers associated with the development of bronchopulmonary dysplasia in premature infants in the structure of a prognostic model of its development

Introduction. Bronchopulmonary dysplasia (BPD) is a complex disease with a significant genetic predisposition. The aim of the study was to determine genetic markers associated with the development of bronchopulmonary dysplasia in premature infants. 
 Materials and methods. At Stage 1, whole exome sequencing followed by the bioinformatic analysis of one hundred samples was provided to evaluate the genetic variants. Sequencing data were compared with the data of the children without any congenital pulmonary diseases. At Stage 2, the obtained results were validated using real-time PCR. Further the genotyping of the control group (n = 70) was performed. The obtained frequencies of nucleotide variants were compared between the groups, as well as with general population data using the RUSeq database. 
 Results. The prevalence of genetic variant rs12489516 in gene CPA3 was significantly higher in the control group of premature infants (p = 0.03; OR = 0.2; 95% CI: 0.02–0.94). Its presence in the genotype reduces the likelihood of developing BPD by 4.76 times. Moreover, statistically significant differences were also identified in the prevalence of rs45488997 in gene CCN2 (p = 0.023). This genetic variant was specific only for children with bronchopulmonary dysplasia. It was also identified that the prevalence of the nucleotide variant rs45488997 in the CCN2 gene was statistically more common among patients with bronchopulmonary dysplasia compared with the general population (p = 0.005). In addition, genetic variants rs5744174 in gene TLR5 and rs2476601 in gene PTPN22 were less frequently observed in the investigated group compared to the general population (p = 0.03 and p = 0.003, respectively). 
 Conclusion. Identification of genetic markers together with clinical and laboratory data will contribute to the development of an effective predictive model for the calculation of the probability of BPD.

Incidence and Predictors of Bronchopulmonary Dysplasia Development and Severity Among Preterm Infants Born at 32 Weeks of Gestation or Less.

Background As the most common chronic lung disease (CLD) related to premature birth, bronchopulmonary dysplasia (BPD) is associated with long-term lung disease along with cardiovascular and neurodevelopmental disorders. However, data on the incidence and predictors of BPD in Qatar are lacking. Objectives In this study, we aimed to determine the incidence of BPD among infants born at ≤ 32 weeks gestational age (GA) at our neonatal unit, and identify risk factors for the development of BPD and moderate-severe BPD. Methods This was a retrospective observational cohort study conducted at a single site: a level-III neonatal intensive care unit (NICU) in Qatar. We included 1539 neonates born at ≤ 32 weeks of gestation with birth weights of ≤ 1500 grams who were admitted to the NICU between 2017 and 2020. Univariate and multivariate logistic regression analyses were performed to identify potential factors and predictors and their possible associations with the development of BPD and moderate-severe BPD. We also applied BPD classifications to determine the variability in the incidence of BPD in our cohort according to various definitions (2001 National Institute of Child Health and Human Development (NICHD) Diagnostic Criteria, 2016 Revisions of NICHD Criteria, and 2019 Neonatal Research Network Jensen Grading). Results A total of 451 infants (29.3%) had BPD (BPD group) while 1088 (70.7%) did not (non-BPD group), and the overall incidence of BPD was 29.3%. The most relevant risk factors associated with a higher risk of developing BPD identified in the multivariate logistic regression analysis were appropriate weight for gestational age (adjusted OR (aOR) 3.67, 95%CI 2.02-6.67, P < 0.001), presence of patent ductus arteriosus (PDA) (aOR 2.61, 95%CI 1.86-3.66, P < 0.001), late-onset sepsis (aOR 2.16; 95%CI 1.29-3.62; P = 0.003), and use of invasive ventilation (aOR 1.90; 95%CI 1.35-2.69; P < 0.001). The most relevant independent risk factors associated with a higher risk for developing moderate-severe BDP were postnatal steroids (aOR 7.12, 95%CI 3.77-13.44, P < 0.001), use of inhaled nitric oxide (aOR 3.65, 95%CI 1.48-9.01, P = 0.005), use of invasive ventilation (aOR 2.13, 95%CI 1.13-4.00, P = 0.019), late-onset sepsis (aOR 2.07, 95%CI 1.10-3.91, P = 0.025), and male sex (aOR 2.04, 95%CI 1.24-3.36, P = 0.005). The difference in the distribution of BPD severity across the three different definitions of NICHD was significant (P < 0.001). Conclusion The results of this study showed that the incidence of BPD remained high in infants born at ≤ 32 weeks of gestational age and birth weight <1500 g with appropriate weight for gestational age. The presence of PDA at birth or first echocardiography, late-onset sepsis, and use of invasive ventilation were significant risk factors for the incidence of BPD. The identification of risk factors will contribute to the implementation of lung-protective strategies for at-risk infants who may benefit from potential preventive therapy.

Quercetin alleviates hyperoxia-induced bronchopulmonary dysplasia by inhibiting ferroptosis through the MAPK/PTGS2 pathway: Insights from network pharmacology, molecular docking, and experimental evaluations.

Quercetin, a bioactive natural compound renowned for its potent anti-inflammatory, antioxidant, and antiviral properties, has exhibited therapeutic potential in various diseases. Given that bronchopulmonary dysplasia (BPD) development is closely linked to inflammation and oxidative stress, and quercetin, a robust antioxidant known to activate NRF2 and influence the ferroptosis pathway, offers promise for a wide range of age groups. Nonetheless, the specific role of quercetin in BPD remains largely unexplored. This study aims to uncover the target role of quercetin in BPD through a combination of network pharmacology, molecular docking, computer analyses, and experimental evaluations.

Immediate postnatal prediction of death or bronchopulmonary dysplasia among very preterm and very low birth weight infants based on gradient boosting decision trees algorithm: A nationwide database study in Japan.

Bronchopulmonary dysplasia (BPD) poses a substantial global health burden. Individualized treatment strategies based on early prediction of the development of BPD can mitigate preterm birth complications; however, previously suggested predictive models lack early postnatal applicability. We aimed to develop predictive models for BPD and mortality based on immediate postnatal clinical data. Clinical information on very preterm and very low birth weight infants born between 2008 and 2018 was extracted from a nationwide Japanese database. The gradient boosting decision trees (GBDT) algorithm was adopted to predict BPD and mortality, using predictors within the first 6 h postpartum. We assessed the temporal validity and evaluated model adequacy using Shapley additive explanations (SHAP) values. We developed three predictive models using data from 39,488, 39,096, and 40,291 infants to predict "death or BPD," "death or severe BPD," and "death before discharge," respectively. These well-calibrated models achieved areas under the receiver operating characteristic curve of 0.828 (95% CI: 0.828-0.828), 0.873 (0.873-0.873), and 0.887 (0.887-0.888), respectively, outperforming the multivariable logistic regression models. SHAP value analysis identified predictors of BPD, including gestational age, size at birth, male sex, and persistent pulmonary hypertension. In SHAP value-based case clustering, the "death or BPD" prediction model stratified infants by gestational age and persistent pulmonary hypertension, whereas the other models for "death or severe BPD" and "death before discharge" commonly formed clusters of low mortality, extreme prematurity, low Apgar scores, and persistent pulmonary hypertension of the newborn. GBDT models for predicting BPD and mortality, designed for use within 6 h postpartum, demonstrated superior prognostic performance. SHAP value-based clustering, a data-driven approach, formed clusters of clinical relevance. These findings suggest the efficacy of a GBDT algorithm for the early postnatal prediction of BPD.

Selenium Deficiency Exacerbates Hyperoxia-Induced Lung Injury in Newborn C3H/HeN Mice.

Extremely preterm infants are often treated with supraphysiological oxygen, which contributes to the development of bronchopulmonary dysplasia (BPD). These same infants exhibit compromised antioxidant capacities due in part to selenium (Se) deficiency. Se is essential for basal and inducible antioxidant responses. The present study utilized a perinatal Se deficiency (SeD) mouse model to identify the combined effects of newborn hyperoxia exposure and SeD on alveolarization and antioxidant responses, including the identification of affected developmental pathways. Se-sufficient (SeS) and SeD C3H/HeN breeding pairs were generated, and pups were exposed to room air or 85% O2 from birth to 14 d. Survival, antioxidant protein expression, and RNA seq analyses were performed. Greater than 40% mortality was observed in hyperoxia-exposed SeD pups. Surviving SeD pups had greater lung growth deficits than hyperoxia-exposed SeS pups. Gpx2 and 4 protein and Gpx activity were significantly decreased in SeD pups. Nrf2-regulated proteins, Nqo1 and Gclc were increased in SeD pups exposed to hyperoxia. RNA seq revealed significant decreases in the Wnt/β-catenin and Notch pathways. Se is a biologically relevant modulator of perinatal lung development and antioxidant responses, especially in the context of hyperoxia exposure. The RNA seq analyses suggest pathways essential for normal lung development are dysregulated by Se deficiency.

Itaconic acid regulation of TFEB-mediated autophagy flux alleviates hyperoxia-induced bronchopulmonary dysplasia

BackgroundPremature infants often require oxygen supplementation, which can elicit bronchopulmonary dysplasia (BPD) and lead to mitochondrial dysfunction. Mitochondria play important roles in lung development, in both normal metabolism and apoptosis. Enhancing our comprehension of the underlying mechanisms in BPD development can facilitate the effective treatments. MethodsPlasma samples from BPD and non-BPD infants were collected at 36 weeks post-menstrual age and used for metabolomic analysis. Based on hyperoxia-induced animal and cell models, changes in mitophagy and apoptosis were evaluated following treatment with itaconic acid (ITA). Finally, the mechanism of action of ITA in lung development was comprehensively demonstrated through rescue strategies and administration of corresponding inhibitors. ResultsAn imbalance in the tricarboxylic acid (TCA) cycle significantly affected lung development, with ITA serving as a significant metabolic marker for the outcomes of lung development. ITA improved the morphological changes in BPD rats, promoted SP-C expression, and inhibited the degree of alveolar type II epithelial cells (AEC II) apoptosis. Mechanistically, ITA mainly promotes the nuclear translocation of transcription factor EB (TFEB) to facilitate dysfunctional mitochondrial clearance and reduces apoptosis in AEC II cells by regulating autophagic flux. ConclusionThe metabolic imbalance in the TCA cycle is closely related to lung development. ITA can improve lung development by regulating autophagic flux and promote the nuclear translocation of TFEB, implying its potential therapeutic utility in the treatment of BPD.

The relationship between severe hypertensive diseases of pregnancy and moderate-severe bronchopulmonary dysplasia.

Determine the association between severe hypertensive disease of pregnancy (HDP) with moderate-severe bronchopulmonary dysplasia (BPD) in preterm infants (< 31 weeks' gestation). Preterm birth cohort study of 693 mother-infant dyads. Severe HDP was defined as severe preeclampsia, HELLP syndrome or eclampsia. The outcome was moderate-severe BPD classified at 36 weeks corrected gestational age, per the NICHD Consensus statement. 225 (32%) mothers developed severe HDP and 234 (34%) infants had moderate-severe BPD. There was an interaction between severe HDP and gestational age (p = 0.03). Infants born at < 25 weeks gestation to mothers with HDP had increased odds for moderate-severe BPD compared to infants of normotensive mothers delivering at the same gestational age. Infants born > 28 weeks to mothers with severe HDP had decreased odds for the outcome, though not statistically significant. Severe HDP has a differential effect on the development of moderate-severe BPD based on gestational age.

Investigation of the miRNA-mRNA Regulatory Circuits and Immune Signatures Associated with Bronchopulmonary Dysplasia.

Bronchopulmonary dysplasia (BPD) has become a major cause of morbidity and mortality in preterm infants worldwide, yet its pathogenesis and underlying mechanisms remain poorly understood. The present study sought to explore microRNA-mRNA regulatory networks and immune cells involvement in BPD through a combination of bioinformatic analysis and experimental validation. MicroRNA and mRNA microarray datasets were obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed microRNAs (DEMs) were identified in BPD patients compared to control subjects, and their target genes were predicted using miRWalk, miRNet, miRDB, and TargetScan databases. Subsequently, protein-protein interaction (PPI) and functional enrichment analyses were conducted on the target genes. 30 hub genes were screened using the Cytohubba plugin of the Cytoscape software. Additionally, mRNA microarray data was utilized to validate the expression of hub genes and to perform immune infiltration analysis. Finally, real-time PCR (RT-PCR), immunohistochemistry (IHC), and flow cytometry were conducted using a mouse model of BPD to confirm the bioinformatics findings. Two DEMs (miR-15b-5p and miR-20a-5p) targeting genes primarily involved in the regulation of cell cycle phase transition, ubiquitin ligase complex, protein serine/threonine kinase activity, and MAPK signaling pathway were identified. APP and four autophagy-related genes (DLC1, PARP1, NLRC4, and NRG1) were differentially expressed in the mRNA microarray dataset. Analysis of immune infiltration revealed significant differences in levels of neutrophils and naive B cells between BPD patients and control subjects. RT-PCR and IHC confirmed reduced expression of APP in a mouse model of BPD. Although the proportion of total neutrophils did not change appreciably, the activation of neutrophils, marked by loss of CD62L, was significantly increased in BPD mice. Downregulation of APP mediated by miR-15b-5p and miR-20a-5p may be associated with the development of BPD. Additionally, increased CD62L- neutrophil subset might be important for the immune-mediated injury in BPD.

Prediction of bronchopulmonary dysplasia by the chest radiographic thoracic area on day one in infants with exomphalos.

To determine if infants with exomphalos had abnormal antenatal lung growth as indicated by lower chest radiographic thoracic areas (CRTA) on day one compared to controls and whether the CRTA could predict the development of bronchopulmonary dysplasia (BPD). Infants with exomphalos cared for between January 2004 and January 2023 were included. The controls were term, newborn infants ventilated for absent respiratory drive at birth, without lung disease and had no supplemental oxygen requirement by 6 h of age. The radiographs were imported as digital image files by Sectra PACS software (Sectra AB, Linköping, Sweden). Free-hand tracing of the perimeter of the thoracic area was undertaken and the CRTA calculated by the software. Sixty-four infants with exomphalos and 130 controls were included. Infants with exomphalos had a lower median (IQR) CRTA (1,983 [1,657-2,471] mm2) compared to controls (2,547 [2,153-2,932] mm2, p<0.001). Following multivariable regression analysis, infants with exomphalos had lower CRTAs compared to controls (p=0.001) after adjusting for differences in gestational age and male sex. In the exomphalos group, the CRTAs were lower in those who developed BPD (n=14, 1,530 [1,307-1,941] mm2) compared to those who did not (2,168 [1,865-2,672], p<0.001). Following multivariable regression analysis, the CRTA was associated with BPD development (p=0.021) after adjusting for male sex and gestational age. Lower CRTAs on day one in the exomphalos infants compared to the controls predicted BPD development.

Implication of m6A Methylation Regulators in the Immune Microenvironment of Bronchopulmonary Dysplasia.

N6-methyladenosine (m6A) regulates gene expression and governs many important biological processes. However, the function of m6A in the development of bronchopulmonary dysplasia (BPD) remains poorly characterized. Thus, the purpose of this investigation was to evaluate the effects of m6A RNA methylation regulators on the development of BPD. BPD-related transcriptome data were downloaded from the GEO database. Differentially expressed m6A methylation regulators between BPD and control group were identified. Consensus clustering was conducted for the classification of BPD and association between clusters and BPD phenotypes were explored. Analysis of differentially expressed genes (DEGs) and immune-related DEGs was performed. The GSEA, GO and KEGG analyses were used to interpret the functional enrichments. The composition of immune cell subtypes in BPD subsets was predicted by CIBERSORT analysis. Compared with the control group, expression of most m6A regulators showed significant alteration, especially for IGF2BP1/2/3. BPD was classified into 2 subsets, and cluster 1 was correlated with severe BPD. Furthermore, the results of functional enrichment analyses showed a disturbed immune-related signaling pathway. Based on CIBERSORT analysis, we found that the proportion of immune cell subsets changed between cluster 1 and cluster 2. Our study revealed the implication of m6A methylation regulators in the development of BPD, which might provide a novel insight for the diagnosis and treatment of BPD.

The serum thioredoxin-1 levels are not associated with bronchopulmonary dysplasia and retinopathy of prematurity.

We hypothesized that the serum TRX-1 in extremely preterm infants (EPIs) after birth was associated with the development of severe bronchopulmonary dysplasia (BPD) and retinopathy of prematurity (ROP). This single-centered retrospective study enrolled EPIs treated at our institution. Serum TRX-1 concentrations of the residual samples taken on admission, day 10-20 of life, and 36-40 weeks of postmenstrual age (PMA) were measured with an enzyme-linked immunosorbent assay. The serum TRX-1 levels on admission were not different between the severe BPD (n = 46) and non-severe BPD groups (n = 67): [median (interquartile range) 147 (73.0-231) vs. 164 (80.5-248) ng/mL] (P = 0.57). These had no significant difference between the severe ROP (n = 47) and non-severe ROP groups (n = 66): [164 (71.3-237) vs. 150 (80.9-250) ng/mL] (P = 0.93). The TRX-1 levels at 10-20 days of life and 36-40 weeks of PMA also had no association with the development of severe BPD and ROP. The serum TRX-1 levels after birth are not predictive of severe BPD and ROP. Serum thioredoxin-1 levels in extremely preterm infants on the day of birth are lower than those in term or near-term infants hospitalized for transient tachypnea of the newborn. In extremely preterm infants, the serum thioredoxin-1 levels on the day of birth, at 10-20 days of life, and at postmenstrual age of 36-40 weeks were not associated with severe bronchopulmonary dysplasia and retinopathy of prematurity. The thioredoxin system is under development in extremely preterm infants; however, the serum thioredoxin-1 level is not predictive for severe bronchopulmonary dysplasia and retinopathy of prematurity.

Correlation between early postnatal body weight changes and lung ultrasound scores as predictors of bronchopulmonary dysplasia in preterm infants: A secondary analysis of a prospective study.

In a cohort of extreme preterm infants, our study revealed a positive yet weak correlation between LUS and EWC, suggesting that EWC was not the major contributing to the evolving chronic lung disease. • Recent evidence links Early Weight-Changes with bronchopulmonary dysplasia in preterm neonates. • Lung ultrasound score has shown promise in early prediction of the subsequent development of bronchopulmonary dysplasia in preterm infants.No studies have examined the correlation between Early Weight-Changes and Lung ultrasound score in preterm infants during first 2 weeks after birth. • Our study demonstrated a positive and statistically significant correlation between early LUS and EWC, indicating their potential role as early predictors for the subsequent development of BPD in extreme preterm infants. • The weak correlation between the two parameters may stem from the possible restricted influence of EWC, given that it may not be the primary factor contributing to the evolving chronic lung disease.

Combined gestational age and serum fucose for early prediction of risk for bronchopulmonary dysplasia in premature infants

ObjectiveAs the predominant complication in preterm infants, Bronchopulmonary Dysplasia (BPD) necessitates accurate identification of infants at risk and expedited therapeutic interventions for an improved prognosis. This study evaluates the potential of Monosaccharide Composite (MC) enriched with environmental information from circulating glycans as a diagnostic biomarker for early-onset BPD, and, concurrently, appraises BPD risk in premature neonates.Materials and methodsThe study incorporated 234 neonates of ≤32 weeks gestational age. Clinical data and serum samples, collected one week post-birth, were meticulously assessed. The quantification of serum-free monosaccharides and their degraded counterparts was accomplished via High-performance Liquid Chromatography (HPLC). Logistic regression analysis facilitated the construction of models for early BPD diagnosis. The diagnostic potential of various monosaccharides for BPD was determined using Receiver Operating Characteristic (ROC) curves, integrating clinical data for enhanced diagnostic precision, and evaluated by the Area Under the Curve (AUC).ResultsAmong the 234 neonates deemed eligible, BPD development was noted in 68 (29.06%), with 70.59% mild (48/68) and 29.41% moderate-severe (20/68) cases. Multivariate analysis delineated several significant risk factors for BPD, including gestational age, birth weight, duration of both invasive mechanical and non-invasive ventilation, Patent Ductus Arteriosus (PDA), pregnancy-induced hypertension, and concentrations of two free monosaccharides (Glc-F and Man-F) and five degraded monosaccharides (Fuc-D, GalN-D, Glc-D, and Man-D). Notably, the concentrations of Glc-D and Fuc-D in the moderate-to-severe BPD group were significantly diminished relative to the mild BPD group. A potent predictive capability for BPD development was exhibited by the conjunction of gestational age and Fuc-D, with an AUC of 0.96.ConclusionA predictive model harnessing the power of gestational age and Fuc-D demonstrates promising efficacy in foretelling BPD development with high sensitivity (95.0%) and specificity (94.81%), potentially enabling timely intervention and improved neonatal outcomes.

A clinical informatics approach to bronchopulmonary dysplasia: current barriers and future possibilities.

Bronchopulmonary dysplasia (BPD) is a complex, multifactorial lung disease affecting preterm neonates that can result in long-term pulmonary and non-pulmonary complications. Current therapies mainly focus on symptom management after the development of BPD, indicating a need for innovative approaches to predict and identify neonates who would benefit most from targeted or earlier interventions. Clinical informatics, a subfield of biomedical informatics, is transforming healthcare by integrating computational methods with patient data to improve patient outcomes. The application of clinical informatics to develop and enhance clinical therapies for BPD presents opportunities by leveraging electronic health record data, applying machine learning algorithms, and implementing clinical decision support systems. This review highlights the current barriers and the future potential of clinical informatics in identifying clinically relevant BPD phenotypes and developing clinical decision support tools to improve the management of extremely preterm neonates developing or with established BPD. However, the full potential of clinical informatics in advancing our understanding of BPD with the goal of improving patient outcomes cannot be achieved unless we address current challenges such as data collection, storage, privacy, and inherent data bias.

Factors Associated With Failure of Non-invasive Ventilation in Preterm Neonates Requiring Initial Respiratory Support.

Non-invasive ventilation (NIV) modalities minimize the requirement for invasive mechanical ventilation (IMV) in preterm neonates, therefore improving neonatal outcomes, as IMV is linked to increased complications. However, NIV has demonstrated an elevated likelihood of failure, for which various studies have been done, but very little research is available addressing the factors that are responsible for NIV failure in resource-limited areas of developing nations. Understanding the underlying factors and their association with NIV failure in very and moderately preterm neonates at a tertiary care hospital would be important in devising targeted strategies to increase NIV success and newborn outcomes. To compare the following factors in neonates of 28-34 weeks gestational age with or without failure of NIV: fraction of inspired oxygen (FiO2) at the time of initiating NIV, time at surfactant administration, respiratory distress syndrome presence, antenatal steroid use, time taken for post-surfactant administration stabilization, gestational age, development of bronchopulmonary dysplasia, and average weight gained or lost. This was a longitudinal observational study. One hundred two preterm neonates with a gestational age of 28-34 weeks in the neonatal intensive care unit (NICU) requiring NIV support within 24 hours of admission. Eligible newborns were re-evaluated at 72 hours after commencing NIV. Outcome was evaluated as success (no NIV or NIV with positive end-expiratory pressure (PEEP)<8 cm H2O and FiO2<0.7) or failure (NIV with PEEP≥8 cm H2O or FiO2≥0.7,intubation, or death). It was compared with regard to many parameters. About 40 (39%) study participants reported NIV failure within 72 hours of initiating NIV. In the NIV failure group, male babies constituted 75% (P = 0.027), the median gestational age (IQR) was 29 (29-31) weeks (P = 0.015), the median birth weight (IQR) was 1088 (960-1293.5) grams (P = 0.003), and the median weight gain or loss (IQR) was a loss of 21 (-70.5 to 11.75) grams (P<0.001). Vaginal birth comprised 67.5% of the NIV failure group, showing greater failure rates than births out of lower segment cesarean section (LSCS) (P = 0.003) Conclusion: NIV failure showed a significant association with lesser gestational age, male sex, lowerbirth weight, vaginal method of delivery, and lesserweight gain during hospital stay.

Plasma KL-6 as a Potential Biomarker for Bronchopulmonary Dysplasia in Preterm Infants.

KL-6 is a biomarker of interstitial lung injury and increases during repair. Our aim was to determine the predictive value of plasma KL-6 for the development of bronchopulmonary dysplasia (BPD) in preterm infants. Ninety-five extremely preterm infants (EPIs), born at <28 gestational age (GA), were divided into two main BPD groups as follows: the moderate/severe and the no/mild group. KL-6 was analyzed on days 7 and 14. Binary logistic regression analyses and ROC curve analyses were performed. Infants <26 + 0 weeks' GA have higher mean KL-6 than infants >25 + 6 weeks' GA on 7 and 14 days (335 vs. 286 U/ml and 378 vs. 260 U/ml; p = 0.005 and 0.018, respectively). In the binary regression model at KL-6 day 7, three of the prognostic factors remained significant-mechanical ventilation OR: 10.38 (95% CI: 3.57-30.14), PDA OR: 6.39 (95% CI: 0.87-46.74), and KL-6 OR: 4.98 (95% CI: 1.54-16.08). The AUC was 0.86 with a sensitivity and specificity of 79% at a cutoff value ≥0.34. In the binary regression model at KL-6 day 14, six of the prognostic factors were significant-PDA OR: 23.34 (95% CI: 2.14-254.24), KL-6 OR: 13.59 (95% CI: 3.19-57.96), GA OR: 4.58 (95% CI: 1.16-18.06), mechanical ventilation OR: 4.45 (95% CI: 1.23-16.16), antenatal steroids OR: 0.19 (95% CI: 0.04-0.95), and gender (female OR: 0.30 (95% CI 0.08-1.12)). The AUC was 0.91, and the sensitivity and accuracy for a cutoff ≥0.37 were 89% and 85%, respectively. KL-6 could be a useful screening biomarker for early detection of infants at increased risk for developing BPD.

Energizing the Lung Vasculature in the Premature Infant to Promote Alveolar Formation

Background/Objective: Chronic lung disease of prematurity, bronchopulmonary dysplasia (BPD) occurs when infants born with underdeveloped immature lungs are forced to navigate the expansion of future air spaces, with irregular vascular formation proceeding development of BPD. Lung development has distinct and dynamic metabolic requirements. We recently identified by mass spectrometry that nicotinamide adenine dinucleotide (NAD+), generated from vitamin B3 ‘Nicotinamide’ (NAM), was significantly reduced in a hyperoxia murine model of BPD. As NAM/NAD+ are dynamic regulators of tissue regenerating neovascularization in otherdisease processes, we hypothesized that NAM/NAD+ metabolic deficiencies contribute to compromised angiogenesis formation and alveolar formation.&#x0D; Methods: Impact of NAM supplementation on circulating human neonatal endothelial colonyforming cells (ECFCs) were assessed for differential capillary formation properties of angiogenesis (Matrigel), migration (wound healing), proliferation (WST1 and crystal violetstaining), and mitochondrial function in normoxia and hyperoxia (85% oxygen) conditions.&#x0D; Results: Hyperoxia suppresses ECFC angiogenesis, while NAM supplementation in hyperoxia significantly rescued vascular networks, branched nodes, and branch points (p&lt;0.001). Wound healing assays suggest that NAM promotes cell migration in normoxia and hyperoxia (p&lt;0.0001). Although NAM increased WST1 activity in hyperoxia, crystal violet analysis determined that NAM had no impact on ECFC proliferation. Lastly, NAM significantly reduced hyperoxia induced mitochondrial oxidative stress in a dose dependent manner (p&lt;0.05).&#x0D; Conclusion and Clinical Implications: Lung development has specific metabolic needs during different stages of development that are disrupted by premature birth. Replenishment of NAM promotes angiogenesis and migration in hyperoxia while reducing mitochondrial activity. Future studies are necessary to explore the role of NAM/NAD+ axis in the developing lung.