Prenatal prediction of neonatal respiratory morbidity: a radiomics method based on imbalanced few-shot fetal lung ultrasound images

Background To develop a non-invasive method for the prenatal prediction of neonatal respiratory morbidity (NRM) by a novel radiomics method based on imbalanced few-shot fetal lung ultrasound images. Methods A total of 210 fetal lung ultrasound images were enrolled in this study, including 159 normal newborns and 51 NRM newborns. Fetal lungs were delineated as the region of interest (ROI), where radiomics features were designed and extracted. Integrating radiomics features selected and two clinical features, including gestational age and gestational diabetes mellitus, the prediction model was developed and evaluated. The modelling methods used were data augmentation, cost-sensitive learning, and ensemble learning. Furthermore, two methods, which embed data balancing into ensemble learning, were employed to address the problems of imbalance and few-shot simultaneously. Results Our model achieved sensitivity values of 0.82, specificity values of 0.84, balanced accuracy values of 0.83 and area under the curve values of 0.87 in the test set. The radiomics features extracted from the ROIs at different locations within the lung region achieved similar classification performance outcomes. Conclusion The feature set we designed can efficiently and robustly describe fetal lungs for NRM prediction. RUSBoost shows excellent performance compared to state-of-the-art classifiers on the imbalanced few-shot dataset. The diagnostic efficacy of the model we developed is similar to that of several previous reports of amniocentesis and can serve as a non-invasive, precise evaluation tool for NRM prediction.

Histogenetic morphotypes of rats respiratory system at the stages of early and late fetogenesis

Aim. Morphological analysis of the deployment of histogenetic information of pulmonary parenchyma at the stages of late embryogenesis and fetogenesis in laboratory rats within the limits of the norm of reaction with verification according to morphometric criteria of individual morphotypes.Materials and methods. Comparative morphological study of histogenesis of endodermal derivatives of the lungs of rats at critical periods of intrauterine development – late embryogenesis (day 14 of gestation), and late fetogenesis (day 20 of gestation) was performed using morphometric identification of plane parameters and a complex of plane form factors of epithelial structures of the lung. Morphometric studies were carried out in the Morphometer program on semi-thin sections of the rat lung.Results. Two critical stages of histogenesis of entodermal beginnings of fetal lungs are described – pseudoglandular and canalicular. The options of discordance of individual development within the response norm are justified. The lungs of the fetus at the pseudoglandular stage and the canalicular stage show significant fluctuations in the plane values of the pulmonary parenchyma, the presence in different individuals of variants of the plane values of entodermal derivatives, which indicated individual morphotypes of the development of the rat lung. At the pseudoglandular stage, in fetus with type I, called “compact”, the total area of the tubular system and the total perimeter are significantly inferior (p<0.001) to the same indicators of the lung II morphotype, designated as “air”. The values of one tubule (the outer perimeter, its area, the dimensions of the X-projection and Y-projection, the length of the epithelial tubes) in type I, on the contrary, are significantly larger than in type II (p<0.01). Among form factors, reliable differences have elongation (FE), squareness (FQ) and equivalent radius (FR) (p<0.01), less significant compactness (FF) and roundness (FC) (p<0.05). The discordance of development is established by a number of reliable values at the stage of late fetogenesis: the area of the tubule (p<0.01), the area of the epithelium of the preacinar department (p<0.001), the value of the outer perimeter of the tubule, the length and, to a lesser extent, the width of the tubule (p<0.05) significantly exceed such type II indicators. In this regard, the dimensions of X- and Y-projections for type I are also increased (p<0.05).Conclusion. As a result of morphological studies, the development of entodermal derivatives of pulmonary parenchyma at the pseudoglandular stage (day 14 of gestation) and the canalicular stage (day 20 of gestation) in rat fetus was verified; morphometric criteria for assessing the histogenesis of entodermal parenchyma units at critical stages of development have been introduced; comparative analysis of morphometric indices of different individuals in gestation dynamics; individual variants of two morphotypes are objectified – “compact-I” and “air-II” in the process of histogenesis of the fetal lungs.

Prenatal Prediction of Neonatal Respiratory Morbidity: A Radiomics Method Based on Imbalanced Few-Shot Fetal Lung Ultrasound Images

Background: To develop a non-invasive method for the prenatal prediction of neonatal respiratory morbidity (NRM) by a novel radiomics method based on imbalanced few-shot fetal lung ultrasound images.Methods: A total of 210 fetal lung ultrasound images were enrolled in this study, including 159 normal newborns and 51 NRM newborns. Fetal lungs were delineated as the region of interest (ROI), where radiomics features were designed and extracted. Integrating radiomics features selected and two clinical features, including gestational age (GA) and gestational diabetes mellitus (GDM), the prediction model was developed and evaluated. The modelling methods used were data augmentation, cost-sensitive learning, and ensemble learning. Furthermore, two methods, which embed data balancing into ensemble learning, were employed to address the problems of imbalance and few-shot simultaneously.Results: Our model achieved sensitivity values of 0.82, specificity values of 0.84, accuracy values of 0.84 and area under the curve values of 0.87 in the test set. The radiomics features extracted from the ROIs at different locations within the lung region achieved similar classification performance outcomes.Conclusion: The feature set we designed can efficiently and robustly describe fetal lungs for NRM prediction. RUSBoost shows excellent performance compared to state-of-the-art classifiers on the imbalanced few-shot dataset. The diagnostic efficacy of the model we developed is similar to that of several previous reports of amniocentesis and can serve as a non-invasive, precise evaluation tool for NRM prediction.

Calcium-Sensing Receptor Contributes to Hyperoxia Effects on Human Fetal Airway Smooth Muscle

Supplemental O2 (hyperoxia), necessary for maintenance of oxygenation in premature infants, contributes to neonatal and pediatric airway diseases including asthma. Airway smooth muscle (ASM) is a key resident cell type, responding to hyperoxia with increased contractility and remodeling [proliferation, extracellular matrix (ECM) production], making the mechanisms underlying hyperoxia effects on ASM significant. Recognizing that fetal lungs experience a higher extracellular Ca2+ ([Ca2+]o) environment, we previously reported that the calcium sensing receptor (CaSR) is expressed and functional in human fetal ASM (fASM). In this study, using fASM cells from 18 to 22 week human fetal lungs, we tested the hypothesis that CaSR contributes to hyperoxia effects on developing ASM. Moderate hyperoxia (50% O2) increased fASM CaSR expression. Fluorescence [Ca2+]i imaging showed hyperoxia increased [Ca2+]i responses to histamine that was more sensitive to altered [Ca2+]o, and promoted IP3 induced intracellular Ca2+ release and store-operated Ca2+ entry: effects blunted by the calcilytic NPS2143. Hyperoxia did not significantly increase mitochondrial calcium which was regulated by CaSR irrespective of oxygen levels. Separately, fASM cell proliferation and ECM deposition (collagens but not fibronectin) showed sensitivity to [Ca2+]o that was enhanced by hyperoxia, but blunted by NPS2143. Effects of hyperoxia involved p42/44 ERK via CaSR and HIF1α. These results demonstrate functional CaSR in developing ASM that contributes to hyperoxia-induced contractility and remodeling that may be relevant to perinatal airway disease.

Paracrine stimulation of perinatal lung functional and structural maturation by mesenchymal stem cells

Background Mesenchymal stem cells (MSCs) were shown to harbor therapeutic potential in models of respiratory diseases, such as bronchopulmonary dysplasia (BPD), the most common sequel of preterm birth. In these studies, cells or animals were challenged with hyperoxia or other injury-inducing agents. However, little is known about the effect of MSCs on immature fetal lungs and whether MSCs are able to improve lung maturity, which may alleviate lung developmental arrest in BPD. Methods We aimed to determine if the conditioned medium (CM) of MSCs stimulates functional and structural lung maturation. As a measure of functional maturation, Na+ transport in primary fetal distal lung epithelial cells (FDLE) was studied in Ussing chambers. Na+ transporter and surfactant protein mRNA expression was determined by qRT-PCR. Structural maturation was assessed by microscopy in fetal rat lung explants. Results MSC-CM strongly increased the activity of the epithelial Na+ channel (ENaC) and the Na,K-ATPase as well as their mRNA expression. Branching and growth of fetal lung explants and surfactant protein mRNA expression were enhanced by MSC-CM. Epithelial integrity and metabolic activity of FDLE cells were not influenced by MSC-CM. Since MSC’s actions are mainly attributed to paracrine signaling, prominent lung growth factors were blocked. None of the tested growth factors (VEGF, BMP, PDGF, EGF, TGF-β, FGF, HGF) contributed to the MSC-induced increase of Na+ transport. In contrast, inhibition of PI3-K/AKT and Rac1 signaling reduced MSC-CM efficacy, suggesting an involvement of these pathways in the MSC-CM-induced Na+ transport. Conclusion The results demonstrate that MSC-CM strongly stimulated functional and structural maturation of the fetal lungs. These effects were at least partially mediated by the PI3-K/AKT and Rac1 signaling pathway. Thus, MSCs not only repair a deleterious tissue environment, but also target lung cellular immaturity itself.

Paracrine stimulation of perinatal lung functional and structural maturation by mesenchymal stem cells.

Background: Mesenchymal stem cells (MSCs) were shown to harbor therapeutic potential in models of respiratory diseases, such as Bronchopulmonary Dysplasia (BPD), the most common sequel of preterm birth. In these studies cells or animals were challenged with hyperoxia or other injury-inducing agents. However, little is known about the effect of MSCs on immature fetal lungs and whether MSCs are able to improve lung maturity, which may alleviate lung developmental arrest in BPD. Methods: We aimed to determine if conditioned medium (CM) of MSCs stimulates functional and structural lung maturation. As a measure of functional maturation, Na + transport in primary fetal distal lung epithelial cells (FDLE) was studied in Ussing chambers. Na + transporter and surfactant protein mRNA expression was determined by qRT-PCR. Structural maturation was assessed by microscopy in fetal rat lung explants. Results: MSC-CM strongly increased the activity of the epithelial Na + channel (ENaC) and the Na,K-ATPase as well as their mRNA expression. Branching and growth of fetal lung explants, and surfactant protein mRNA expression were enhanced by MSC-CM. Epithelial integrity and metabolic activity of FDLE cells were not influenced by MSC-CM. Since MSC’ actions are mainly attributed to paracrine signaling, prominent lung growth factors were blocked. None of the tested growth factors (VEGF, BMP, PDGF, EGF, TGF-β, FGF, HGF) contributed to the MSC-induced increase of Na + transport. In contrast, inhibition of PI3-K/AKT and Rac1 signaling reduced MSC-CM efficacy, suggesting an involvement of these pathways in the MSC-CM-induced Na + transport. Conclusion: The results demonstrate that MSC-CM strongly stimulated functional and structural maturation of fetal lungs. These effects were at least partially mediated by the PI3-K/AKT and Rac1 signaling pathway. Thus MSCs not only repair a deleterious tissue environment, but also target lung cellular immaturity itself.

Paracrine Stimulation of Perinatal Lung Functional and Structural Maturation by Mesenchymal Stem Cells.

Background: Mesenchymal stem cells (MSCs) were shown to harbor therapeutic potential in models of respiratory diseases, such as Bronchopulmonary Dysplasia (BPD), the most common sequel of preterm birth. In these studies cells or animals were challenged with hyperoxia or other injury-inducing agents. However, little is known about the effect of MSCs on immature fetal lungs and whether MSCs are able to improve lung maturity, which may alleviate lung developmental arrest in BPD.Methods: We aimed to determine if conditioned medium (CM) of MSCs stimulates functional and structural lung maturation. As a measure of functional maturation, Na+ transport in primary fetal distal lung epithelial cells (FDLE) was studied in Ussing chambers. Na+ transporter and surfactant protein mRNA expression was determined by qRT-PCR. Structural maturation was assessed by microscopy in fetal rat lung explants.Results: MSC-CM strongly increased the activity of the epithelial Na+ channel (ENaC) and the Na,K-ATPase as well as their mRNA expression. Branching and growth of fetal lung explants, and surfactant protein mRNA expression were enhanced by MSC-CM. Epithelial integrity and metabolic activity of FDLE cells were not influenced by MSC-CM. Since MSC’ actions are mainly attributed to paracrine signaling, prominent lung growth factors were blocked. None of the tested growth factors (VEGF, BMP, PDGF, EGF, TGF-β, FGF, HGF) contributed to the MSC-induced increase of Na+ transport. In contrast, inhibition of PI3-K/AKT and Rac1 signaling reduced MSC-CM efficacy, suggesting an involvement of these pathways in the MSC-CM-induced Na+ transport.Conclusion: The results demonstrate that MSC-CM strongly stimulated functional and structural maturation of fetal lungs. These effects were at least partially mediated by the PI3‑K/AKT and Rac1 signaling pathway. Thus MSCs not only repair a deleterious tissue environment, but also target lung cellular immaturity itself.