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The aim of this study is to explore the protective mechanism of human umbilical cord mesenchymal stem cell exosomes (hUCMSC-Exo) on acute lung injury (ALI) in neonatal rats, and to provide a new method for the treatment of neonatal respiratory distress syndrome (NARDS), This study constructed an animal model of ALI based on neonatal rats. After treatment with hUCMSC-Exo, it was found that the mortality rate of neonatal rats was significantly improved, and the trend of weight loss in neonatal rats was also alleviated. Lung tissue samples were collected from each group of neonatal rats to extract total protein, RNA, and homogenate. Western blot was used to detect the protein expression levels of p-NF-ķB, IL-6, Occludin, Cludin 5, β-Catenin, and Cyclin D1; the mRNA expression levels of TNF-α, IL-1β, IL-6, IL-4, IL-10 and IL-13 were detected by RT-qPCR; enzyme-linked immunosorbent assay (ELISA) was used to detect the concentrations of TNF-α, IL-6, and IL-10 in lung tissue. The results of pathological sections of lung tissue showed that the infiltration of inflammatory cells, thickening of alveolar septa, pulmonary hemorrhage, and edema were all reduced after treatment with exosomes. The research results indicate that LPS can effectively induce pulmonary inflammation in neonatal rats, leading to acute lung injury, the treatment with exosomes alleviated the degree of ALI. The results of this study can provide new strategies for the treatment of NARDS. [ABSTRACT FROM AUTHOR]

Jingli Yang,1– 4 Yu He,1– 5 Qing Ai,1– 4 Chan Liu,1– 4 Qiqi Ruan,1– 4 Yuan Shi1– 4 1Department of Neonatology, Children’s Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 2National Clinical Research Center for Child Health and Disorders, Chongqing, People’s Republic of China; 3Ministry of Education Key Laboratory of Child Development and Disorders, Children’s Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 4Chongqing Key Laboratory of Child Infection and Immunity, Children’s Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 5Department of Neonatology, Jiangxi Hospital Affiliated to Children’s Hospital of Chongqing Medical University, Jiangxi, People’s Republic of ChinaCorrespondence: Yuan Shi, Department of Neonatology, Children’s Hospital of Chongqing Medical University, Chongqing, 400014, People’s Republic of China, Email shiyuan@hospital.cqmu.edu.cnPurpose: Neonatal Acute Respiratory Distress Syndrome (NARDS) is a severe respiratory crisis threatening neonatal life. We aim to identify changes in the lung-gut microbiota and lung-plasma tryptophan metabolites in NARDS neonates to provide a differentiated tool and aid in finding potential therapeutic targets.Patients and Methods: Lower respiratory secretions, faeces and plasma were collected from 50 neonates including 25 NARDS patients (10 patients with mild NARDS in the NARDS_M group and 15 patients with moderate-to-severe NARDS in the NARDS_S group) and 25 control patients screened based on gestational age, postnatal age and birth weight. Lower airway secretions and feces underwent 16S rRNA gene sequencing to understand the microbial communities in the lung and gut, while lower airway secretions and plasma underwent LC-MS analysis to understand tryptophan metabolites in the lung and blood. Correlation analyses were performed by comparing differences in microbiota and tryptophan metabolites between NARDS and control, NARDS_S and NARDS_M groups.Results: Significant changes in lung and gut microbiota as well as lung and plasma tryptophan metabolites were observed in NARDS neonates compared to controls. Proteobacteria and Bacteroidota were increased in the lungs of NARDS neonates, whereas Firmicutes, Streptococcus, and Rothia were reduced. Lactobacillus in the lungs decreased in NARDS_S neonates. Indole-3-carboxaldehyde decreased in the lungs of NARDS neonates, whereas levels of 3-hydroxykynurenine, indoleacetic acid, indolelactic acid, 3-indole propionic acid, indoxyl sulfate, kynurenine, and tryptophan decreased in the lungs of the NARDS_S neonates. Altered microbiota was significantly related to tryptophan metabolites, with changes in lung microbiota and tryptophan metabolites having better differentiated ability for NARDS diagnosis and grading compared to gut and plasma.Conclusion: Significant changes occurred in the lung-gut microbiota and lung-plasma tryptophan metabolites of NARDS neonates. Alterations in lung microbiota and tryptophan metabolites were better discriminatory for the diagnosis and grading of NARDS.Keywords: Neonatal acute respiratory distress syndrome, NARDS, lung microbiota, gut microbiota, tryptophan metabolites, correlation analysis, predictive diagnosis

Objective To investigate the relationship between blood eosinophil (EOS), neutrophil (NEU), procalcitonin (PCT) and hypersensitive C-reactive protein (hs-CRP) levels and severity and outcome in neonatal acute respiratory distress syndrome (ARDS). Methods From January 2018 to June 2022, a total of 55 patients who were transferred to Department of Neonatal in our hospital within 24 hours after birth and met the inclusion criteria of the study were selected. According to oxygenation index, they were divided into the mild ARDS group (26 cases), the moderate ARDS group(13 cases) and the severe ARDS group(16 cases). According to the outcome, they were divided into the good outcome group (34 cases) and the comprehensive adverse outcome group(21 cases). The clinical data, EOS, NEU, PCT and hs-CRP levels of patients with different degrees and outcomes were compared separately; ROC curves were used to analyze the value of EOS, NEU and PCT in the assessment of comprehensive adverse outcomes in neonates with ARDS. Results The levels of NEU, and PCT in the severe group were higher than in the mild and moderate groups (P<0.05). The levels of hs-CRP in the severe group was higher than in the mild group (P<0.05), but the difference in hs-CRP was not significant in the moderate and severe groups (P>0.05); the levels of NEU, NLR, and PCT were higher in the comprehensive adverse outcome group than those in the good outcome group, and the levels of EOS were lower than those in the good outcome group (P<0.05); EOS, NEU, and PCT were independent risk factors for poor outcome in neonatal ARDS (P<0.05); the area under the curves for NEU, PCT levels and combined diagnosis to predict poor neonatal ARDS outcome were 0.877.0. 835 and 0.912. respectively. Conclusion The levels of serum EOS, NEU and PCT in neonatal ARDS are closely related to the severity of disease and outcome, and can be used as indicators for the assessment the outcome of neonatal ARDS. [ABSTRACT FROM AUTHOR]

Objective To investigate the expression changes of serum microRNA-877-5p (miR-877-5p) and its clini⁃ cal significance in neonates with neonatal acute respiratory distress syndrome (NARDS) . Methods Ninety-five children with NARDS (observation group) were selected, and the severity of the disease was mild (38 cases), moderate (35 cases) and severe (22 cases) . The clinical outcome within 28 days was: 21 cases died and 74 cases survived； meanwhile, 40 healthy newborns were selected as the control group. Peripheral venous blood of all subjects was collected, serum was col⁃ lected by centrifugation, and serum miR-877-5p expression was detected by real-time fluorescence quantitative polymerase chain reaction, and serum IL-1β, IL-6 and TNF-α levels were detected by enzyme-linked immunosorbent assay. Spearman correlation analysis was used to analyze the relationships between serum miR-877-5p expression and oxygen index and serum levels of IL-1β, IL-6 and TNF-α in children with NARDS. The predictive value of serum miR-877-5p expression in the diagnosis of NARDS and death of neonates was analyzed by receiver operating characteristic (ROC) curve. Results The expression of miR-877-5p in serum of the observation group was significantly lower than that in the control group, and the levels of IL-1β, IL-6, and TNF-α in serum were significantly higher than those in the control group (all P<0. 01) . With the increase of the severity of NARDS, the expression of miR-877-5p in serum of NARDS neonates decreased gradually, and the levels of IL-1β, IL-6 and TNF-α increased gradually (all P<0. 01) . Spearman correlation analysis showed that serum miR-877-5p expression was negatively correlated with oxygen index and serum levels of IL-1β, IL-6, and TNF-α in children with NARDS (rs = -0. 785, -0. 779, -0. 778, and -0. 788, respectively； all P<0. 01) . The expression of miR-877-5p in dead children with NARDS was significantly lower than that in survivors (P<0. 01) . ROC curve analysis showed that the area under the curve of serum miR-877-5p expression in the diagnosis of NARDS was 0. 857 (95% CI: 0. 77-0. 911), its optimal cut-off value was 1. 23, and the sensitivity and specificity in diagnosis of NARDS were 73. 68% and 95. 00%, respectively. The area under the curve of miR-877-5p expression in predicting the death of children with NARDS was 0. 805 (95% CI: 0. 711-0. 879), and the best cut-off value was 0. 97. At this time, the sensitivity and specificity of miR-877-5p expression in predicting the death of children with NARDS were 80. 95% and 75. 68%, respectively. Conclusion The expression of miR-877-5p in children with NARDS decreases, and its change is closely related to the severity and prognosis of NARDS； miR-877-5p may be a serum biomarker for the diagnosis and prognosis evaluation of NARDS. [ABSTRACT FROM AUTHOR]

Summary: Background: Neonatal acute respiratory distress syndrome (ARDS) is a critical clinical disease with high disability and mortality rates. Early identification and treatment of neonatal ARDS is critical. This study aimed to build a perinatal prediction nomogram for early prediction of neonatal ARDS. Methods: A prediction model was built including 243 late-preterm and full-term infants from Daping Hospital in Chongqing, China, hospitalised between Jan 1, 2018 and Dec 31, 2019. 80 patients from the Children's Hospital in Chongqing, China, hospitalised between Jan 1, 2018 and June 30, 2018 were considered for external validation. Multivariate logistic regression was performed to identify independent predictors and establish a nomogram to predict the occurrence of neonatal ARDS. Both discrimination and calibration were assessed by bootstrapping with 1000 resamples. Findings: Multivariate logistic regression demonstrated that mother's education level (odds ratio [OR] 0·478, 95% confidence interval [CI] 0·324–0·704), premature rupture of membrane (OR 0·296, 95% CI 0·133–0·655), infectious disease within 7 days before delivery (OR 0·275, 95% CI 0·083–0·909), hospital level (OR 2·479, 95% CI 1·260–4·877), and Apgar 5-min score (OR 0·717, 95% CI 0·563–0·913) were independent predictors for neonatal ARDS in late-preterm and full-term infants, who experienced dyspnoea within 24 h after birth and required mechanical ventilation. The area under the curve and concordance index of the nomogram constructed from the above five factors were 0·760 and 0·757, respectively. The Hosmer–Lemeshow test showed that the model was a good fit (P = 0.320). The calibration curve of the nomogram was close to the ideal diagonal line. Furthermore, the decision curve analysis demonstrated significantly better net benefit in the model. The external validation proved the reliability of the prediction nomogram. Interpretation: A nomogram based on perinatal factors was developed to predict the occurrence of neonatal ARDS in late-preterm and full-term infants who experienced dyspnoea within 24 h after birth and required mechanical ventilation. It provided clinicians with an accurate and effective tool for the early prediction and timely management of neonatal ARDS. Funding: No funding was associated with this study.

Previous studies pointed out that a variety of microRNAs (miRNAs) are involved in the pathogenesis of neonatal acute respiratory distress syndrome (NARDS) and play different roles in the pathological process. However, there have been few studies reporting the connection between circular RNA (circRNA) and NARDS, so the expression profile of circRNAs in newborns with acute respiratory distress syndrome remains largely unknown. In the present study, 10 samples obtained from remaining clinical blood samples of newborns hospitalized in a neonatal ward of the First Affiliated Hospital of Nanjing Medical University from January 2020 to October 2020 were divided into the “NARDS” group and “non-NARDS” group according to the Montelux standard and then were analyzed in microarray, and 10 other samples collected from the same place and from January 1, 2021 to August 31, 2021, were used to do RT-qPCR experiment. circRNA expression profiles, in which 741 circRNAs were downregulated and 588 were upregulated, were screened with circRNA high-throughput sequencing. Subsequently, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis of parent genes of the differentially expressed circRNAs revealed that these circRNAs may be related to the process of protein synthesis and metabolism in NARDS. Moreover, five circRNAs—hsa_circ_0058495, hsa_circ_0000367, hsa_circ_0005389, hsa_circ_0059571, and hsa_circ_0006608—were selected randomly among the top 10 circRNAs of the downregulated or upregulated expression profiles. Then, bioinformatics tools were used to predict correlative miRNA and its target genes, which were also subjected to the same bioinformatics analysis for further study. The top 30 enriched KEGG pathway analyses of the 125 target genes suggested that these target genes are widely involved in the synthesis and secretion of endocrine hormones, and the top 30 enriched GO terms based on the 125 target genes are also focused on the protein and DNA processing. Thus, the present results show that circRNAs could promote the inflammation of NARDS which may provide a new therapeutic direction and it can be used as molecular markers for early diagnosis of NARDS, but further molecular biology verification is needed to define the specific role of differentially expressed circRNAs in NARDS.

Objective: Extracorporeal membrane oxygenation (ECMO) has supported oxygen delivery and carbon dioxide removal in neonatal severe respiratory failure for more than 4 decades. The definition and diagnosis of neonatal acute respiratory distress syndrome (ARDS) was made according to the criteria first established by a Montreux Conference in 2017. By far, there has been no ECMO efficiency studies in neonatal ARDS. We aimed to compare the outcomes of neonates with severe ARDS supported with and without ECMO.Design: Retrospective pair-matched study.Setting: In the present retrospective pair-matched study, the outcomes of severe ARDS with ECMO support and without ECMO support were analyzed and compared. Propensity score matching was conducted. The study subjects were selected from a China Neonatal ECMO (CNECMO) study. In total, five hospitals were included in the CNECMO study. The patients were matched with demographic and clinical data. The primary endpoint was in-hospital mortality. Secondary outcomes included ventilator-time, ICU stay, hospitalization costs and cranial MRI results.Patients: 145 neonates with severe ARDS (Oxygenation Index, OI ≥16) from 5 hospitals.Interventions: No interventions.Measurements and Main Results: We collected the data of 145 neonates with severe ARDS (Oxygenation Index, OI≥16) from 5 hospitals. Among them, 42 neonates received venoarterial (VA) ECMO support, and the remaining 103 neonates were treated with conventional mechanical ventilation. The mortality of ECMO-supported neonates was not significantly different compared with the ESLO neonatal respiratory-supported from 2012 to 2018 (23.8 vs. 32.5%, p = 0.230). After matching with the propensity score we got 31 pairs. The ECMO-supported neonates had a lower in-hospital mortality (6 of 31, 19.4%) vs. non ECMO-supported patients (18 of 31, 58.1%) (p = 0.002). Hospitalization costs of survivors in ECMO-supported neonates were significantly higher than that of non-ECMO-supported neonates (p < 0.001). There was no difference of ventilator-times (p = 0.206), ICU stay (p = 0.879) and cranial MRI (p = 0.899) between the survivors of ECMO-supported and non–ECMO-supported neonates with ARDS.Conclusions: By far, there has been no ECMO efficiency studies in neonatal ARDS. This study found that ECMO-support have superior outcomes compared with non–ECMO-support in neonates with severe ARDS.

No in vivo data are available regarding the effect of meconium on human surfactant in the early stages of severe meconium aspiration syndrome (MAS). In the present study, we sought to characterize the changes in surfactant composition, function, and structure during the early phase of meconium injury. We designed a translational prospective cohort study of nonbronchoscopic BAL of neonates with severe MAS (n = 14) or no lung disease (n = 18). Surfactant lipids were analyzed by liquid chromatography-high-resolution mass spectrometry. Secretory phospholipase A2 subtypes IB, V, and X and SP-A (surfactant protein A) were assayed by ELISA. SP-B and SP-C were analyzed by Western blotting under both nonreducing and reducing conditions. Surfactant function was assessed by adsorption test and captive bubble surfactometry, and lung aerationwas evaluated by semiquantitative lung ultrasound. Surfactant nanostructure was studied using cryo-EM and atomic force microscopy. Several changes in phospholipid subclasses were detected during MAS. Lysophosphatidylcholine species released by phospholipase A2 hydrolysis were increased. SP-B and SP-C were significantly increased together with some shorter immature forms of SP-B. Surfactant function was impaired and correlated with poor lung aeration. Surfactant nanostructure was significantly damaged in terms of vesicle size, tridimensional complexity, and compactness. Various alterations of surfactant phospholipids and proteins were detected in the early phase of severe meconium aspiration and were due to hydrolysis and inflammation and a defensive response. This impairs both surfactant structure andfunction, finally resulting in reduced lung aeration. These findings support the development of new surfactant protection and antiinflammatory strategies for severeMAS. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To probe into the clinical efficacy of pulmonary surfactant injections combined with adjuvant ventilation in treatment of full-term neonatal acute respiratory distress syndrome. METHODS: 80 patients with full-term neonatal acute respiratory distress syndrome admitted into Hubei Gueheng County People’s Hospital from Jan. 2016 to Jan. 2017 were extracted to be divided into observation group and control group via the random envelope method, with 40 cases in each. The control group was given conventional adjuvant ventilation, while the observation group received pulmonary surfactant injections combined with adjuvant ventilation. The highest MAP level, mechanical ventilation time, high oxygen duration, physical recovery time, length of stay, clinical efficacy and incidence of complication of two groups were observed. RESULTS: After treatment, the highest mean arterial pressure(MAP) level of observation group was significantly lower than that of control group, yet the mechanical ventilation time, high oxygen duration, physical recovery time, length of stay of observation group were significantly shorter than those of control group, with statistically significant difference(P <0. 05). The death rate of observation group was 12. 50% (5/40), significantly lower than that of control group [40. 00% (16/40)], with statistically significant difference(P <0. 05). The incidence of complication of observation group was 12. 50% (5/40), significantly lower than that of control group [50. 00% (20/40)], with statistically significant difference(P < 0. 05). CONCLUSIONS: The efficacy of pulmonary surfactant injections combined with adjuvant ventilation in treatment of full-term neonatal acute respiratory distress syndrome is remarkable. [ABSTRACT FROM AUTHOR]

Background: Neonatal acute respiratory distress syndrome (ARDS) is a critical clinical disease with high disability and mortality rates. Early identification and treatment of neonatal ARDS is critical. This study aimed to build a perinatal prediction nomogram for early prediction of neonatal ARDS., Methods: A prediction model was built including 243 late-preterm and full-term infants from Daping Hospital in Chongqing, China, hospitalised between Jan 1, 2018 and Dec 31, 2019. 80 patients from the Children's Hospital in Chongqing, China, hospitalised between Jan 1, 2018 and June 30, 2018 were considered for external validation. Multivariate logistic regression was performed to identify independent predictors and establish a nomogram to predict the occurrence of neonatal ARDS. Both discrimination and calibration were assessed by bootstrapping with 1000 resamples., Findings: Multivariate logistic regression demonstrated that mother's education level (odds ratio [OR] 0·478, 95% confidence interval [CI] 0·324-0·704), premature rupture of membrane (OR 0·296, 95% CI 0·133-0·655), infectious disease within 7 days before delivery (OR 0·275, 95% CI 0·083-0·909), hospital level (OR 2·479, 95% CI 1·260-4·877), and Apgar 5-min score (OR 0·717, 95% CI 0·563-0·913) were independent predictors for neonatal ARDS in late-preterm and full-term infants, who experienced dyspnoea within 24 h after birth and required mechanical ventilation. The area under the curve and concordance index of the nomogram constructed from the above five factors were 0·760 and 0·757, respectively. The Hosmer-Lemeshow test showed that the model was a good fit ( P  = 0.320). The calibration curve of the nomogram was close to the ideal diagonal line. Furthermore, the decision curve analysis demonstrated significantly better net benefit in the model. The external validation proved the reliability of the prediction nomogram., Interpretation: A nomogram based on perinatal factors was developed to predict the occurrence of neonatal ARDS in late-preterm and full-term infants who experienced dyspnoea within 24 h after birth and required mechanical ventilation. It provided clinicians with an accurate and effective tool for the early prediction and timely management of neonatal ARDS., Funding: No funding was associated with this study., Competing Interests: None of the authors have conflicts of interest to disclose. None of the authors have financial relationships relevant to this article to disclose., (© 2022 The Authors.)

Previous studies pointed out that a variety of microRNAs (miRNAs) are involved in the pathogenesis of neonatal acute respiratory distress syndrome (NARDS) and play different roles in the pathological process. However, there have been few studies reporting the connection between circular RNA (circRNA) and NARDS, so the expression profile of circRNAs in newborns with acute respiratory distress syndrome remains largely unknown. In the present study, 10 samples obtained from remaining clinical blood samples of newborns hospitalized in a neonatal ward of the First Affiliated Hospital of Nanjing Medical University from January 2020 to October 2020 were divided into the "NARDS" group and "non-NARDS" group according to the Montelux standard and then were analyzed in microarray, and 10 other samples collected from the same place and from January 1, 2021 to August 31, 2021, were used to do RT-qPCR experiment. circRNA expression profiles, in which 741 circRNAs were downregulated and 588 were upregulated, were screened with circRNA high-throughput sequencing. Subsequently, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis of parent genes of the differentially expressed circRNAs revealed that these circRNAs may be related to the process of protein synthesis and metabolism in NARDS. Moreover, five circRNAs-hsa&#95;circ&#95;0058495, hsa&#95;circ&#95;0000367, hsa&#95;circ&#95;0005389, hsa&#95;circ&#95;0059571, and hsa&#95;circ&#95;0006608-were selected randomly among the top 10 circRNAs of the downregulated or upregulated expression profiles. Then, bioinformatics tools were used to predict correlative miRNA and its target genes, which were also subjected to the same bioinformatics analysis for further study. The top 30 enriched KEGG pathway analyses of the 125 target genes suggested that these target genes are widely involved in the synthesis and secretion of endocrine hormones, and the top 30 enriched GO terms based on the 125 target genes are also focused on the protein and DNA processing. Thus, the present results show that circRNAs could promote the inflammation of NARDS which may provide a new therapeutic direction and it can be used as molecular markers for early diagnosis of NARDS, but further molecular biology verification is needed to define the specific role of differentially expressed circRNAs in NARDS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhou, Chanda, Chen, Wang, You, Zhang, Cheng, Yang and Chen.)

Objective: Extracorporeal membrane oxygenation (ECMO) has supported oxygen delivery and carbon dioxide removal in neonatal severe respiratory failure for more than 4 decades. The definition and diagnosis of neonatal acute respiratory distress syndrome (ARDS) was made according to the criteria first established by a Montreux Conference in 2017. By far, there has been no ECMO efficiency studies in neonatal ARDS. We aimed to compare the outcomes of neonates with severe ARDS supported with and without ECMO. Design: Retrospective pair-matched study. Setting: In the present retrospective pair-matched study, the outcomes of severe ARDS with ECMO support and without ECMO support were analyzed and compared. Propensity score matching was conducted. The study subjects were selected from a China Neonatal ECMO (CNECMO) study. In total, five hospitals were included in the CNECMO study. The patients were matched with demographic and clinical data. The primary endpoint was in-hospital mortality. Secondary outcomes included ventilator-time, ICU stay, hospitalization costs and cranial MRI results. Patients: 145 neonates with severe ARDS (Oxygenation Index, OI ≥16) from 5 hospitals. Interventions: No interventions. Measurements and Main Results: We collected the data of 145 neonates with severe ARDS (Oxygenation Index, OI≥16) from 5 hospitals. Among them, 42 neonates received venoarterial (VA) ECMO support, and the remaining 103 neonates were treated with conventional mechanical ventilation. The mortality of ECMO-supported neonates was not significantly different compared with the ESLO neonatal respiratory-supported from 2012 to 2018 (23.8 vs. 32.5%, p = 0.230). After matching with the propensity score we got 31 pairs. The ECMO-supported neonates had a lower in-hospital mortality (6 of 31, 19.4%) vs. non ECMO-supported patients (18 of 31, 58.1%) ( p = 0.002). Hospitalization costs of survivors in ECMO-supported neonates were significantly higher than that of non-ECMO-supported neonates ( p < 0.001). There was no difference of ventilator-times ( p = 0.206), ICU stay ( p = 0.879) and cranial MRI ( p = 0.899) between the survivors of ECMO-supported and non-ECMO-supported neonates with ARDS. Conclusions: By far, there has been no ECMO efficiency studies in neonatal ARDS. This study found that ECMO-support have superior outcomes compared with non-ECMO-support in neonates with severe ARDS., (Copyright © 2020 Hong, Zhao, Liu, Liu, Wang, Quan, Wu, Ji, Sun, Cheng, Feng and Shi.)