The efficacy and ocular safety following aflibercept, conbercept, ranibizumab, bevacizumab, and laser for retinopathy of prematurity: a systematic review and meta-analysis.

BACKGROUND: Retinopathy of prematurity (ROP) is typically treated with laser photocoagulation and/or intravitreal anti-vascular endothelial growth factor (anti-VEGF). To the best of our knowledge, most systematic reviews have focused on comparing anti-VEGF against laser treatment while comparisons between different anti-VEGF agents are lacking. Thus, we conducted this meta-analysis to compare the efficacy and safety of different anti-VEGF agents or laser after primary ROP therapy. METHODS: We conducted a comprehensive search across multiple databases up to November 2022. We included studies that used anti-VEGF or laser for ROP with comparable cohorts. RESULTS: Overall, 44 studies were included in this meta-analysis. When comparing anti-VGEF with laser, we found that the anti-VEGF group had a significantly higher retreatment rate (RR = 1.56, 95%CI = [1.06, 2.31], p = 0.03), a longer time from treatment to retreatment (WMD = 5.99 weeks, 95%CI = [4.03, 7.95], p < 0.001), a lower retinal detachment rate (RR = 0.55, 95%CI = [0.30, 0.91], p = 0.02), higher spherical equivalent (WMD = 1.69D, 95%CI = [0.61, 2.77], p = 0.002), lower myopia rate (RR = 0.69, 95%CI = [0.50, 0.97], p = 0.03) and lower anisometropia rate (RR = 0.44, 95%CI = [0.29, 0.67], p = 0.0001). In comparisons between ranibizumab and bevacizumab, the intravitreal ranibizumab (IVR) group was associated with higher recurrence rate (RR = 2.02, 95%CI = [1.49, 2.73], p < 0.0001), higher retreatment rate (RR = 1.70, 95%CI = [1.17, 2.47], p = 0.0006), and lower high myopia rate (RR = 0.31, 95%CI = [0.12, 0.77], p = 0.01). Similarly, when compared to aflibercept and conbercept, the IVR cohort also demonstrated higher recurrence and retreatment rates. While no significant differences were observed in any of the variables included in the statistical analysis in the comparison between bevacizumab and aflibercept. CONCLUSIONS: Anti-VEGF was associated with higher retreatment and lesser incidence of myopia as compared to laser. Laser therapy was linked to more complications like retinal detachment and myopia. Ranibizumab exhibited higher recurrence and retreatment rates compared to bevacizumab, aflibercept, and conbercept.

[Establishment of a nomogram model for predicting the risk of early-onset sepsis in very preterm infants]. / 预测极早产儿早发型败血症发生风险的列线图模型的构建.

OBJECTIVES: To identify risk factors associated with early-onset sepsis (EOS) in very preterm infants and develop a nomogram model for predicting the risk of EOS. METHODS: A retrospective analysis was conducted on 344 very preterm infants delivered at the First Affiliated Hospital of Zhengzhou University and admitted to the Department of Neonatology between January 2020 and December 2022. These infants were randomly divided into a training set (241 infants) and a validating set (103 infants) in a 7:3 ratio. The training set was further divided into two groups based on the presence or absence of EOS: EOS (n=64) and non-EOS (n=177). Multivariate logistic regression analysis was performed to identify risk factors for EOS in the very preterm infants. The nomogram model was developed using R language and validated using the validating set. The discriminative ability, calibration, and clinical utility of the model were assessed using receiver operating characteristic (ROC) curve analysis, calibration curve analysis, and decision curve analysis, respectively. RESULTS: The multivariate logistic regression analysis revealed that gestational age, need for tracheal intubation in the delivery room, meconium-stained amniotic fluid, serum albumin level on the first day of life, and chorioamnionitis were risk factors for EOS in very preterm infants (P<0.05). The area under the ROC curve for the training set was 0.925 (95%CI: 0.888-0.963), and that for the validating set was 0.796 (95%CI: 0.694-0.898), confirming the model's good discrimination. The Hosmer-Lemeshow goodness-of-fit test suggested that the model was well-fitting (P=0.621). The calibration curve analysis and decision curve analysis demonstrated that the model had high predictive efficacy and clinical applicability. CONCLUSIONS: Gestational age, need for tracheal intubation in the delivery room, meconium-stained amniotic fluid, serum albumin level on the first day of life, and chorioamnionitis are significantly associated with the development of EOS in very preterm infants.The nomogram model for predicting the risk of EOS in very preterm infants, constructed based on these factors, has high predictive efficacy and clinical applicability.

The effect of time interval between antenatal corticosteroid administration and delivery on outcomes in late preterm neonates born to mothers with diabetes: a retrospective cohort study.

Objectives: The study aims to investigate whether the time interval between administering antenatal corticosteroids (ACS) and delivery influences the neonatal outcomes in late preterm (LPT) neonates (34 + 0 to 36 + 6 weeks) born to mothers with diabetes. Study design: This retrospective cohort study included women with any type of diabetes who gave birth between 34 + 0 weeks and 36 + 6 weeks of gestation. Based on the time interval between the first dose of corticosteroid and delivery, the cases were stratified into the following groups: <2, 2-7, and >7 days. Women unexposed to ACS served as the control group. The primary outcomes included the incidence of neonatal hypoglycemia and respiratory distress syndrome/transient tachypnea of the newborn. Multivariate logistic regression was used to assess the relationship between the time interval and neonatal outcomes and adjust for potential confounders. Results: The study enrolled a total of 636 parturients. Among them, 247 (38.8%) delivered within 2 days after ACS administration, 169 (26.6%) within 2-7 days, and 126 (19.8%) at >7 days. Baseline characteristics such as type of diabetes, methods of glycemic control, preterm premature rupture of membrane, placenta previa, cesarean delivery, indication for delivery, percentage of large for gestational age, birth weight, and HbA1c in the second or third trimester were significantly different among the four groups. The multivariate analysis showed no statistically significant difference in the incidence of primary or secondary neonatal outcomes between the case and control groups. Conclusions: ACS treatment was not associated with neonatal hypoglycemia and respiratory outcomes in LPT neonates born to diabetic mothers, regardless of the time interval to delivery.

The Impact of Time Interval Between First Extubation and Reintubation on Bronchopulmonary Dysplasia or Death in Very Low Birth Weight Infants.

Objective: To explore the association between time from first extubation to reintubation and moderate-to-severe bronchopulmonary dysplasia (BPD) or death in very low birth weight infants. Study Design: Infants weighing <1,500 g at birth, requiring mechanical ventilation, and undergoing their initial extubation were retrospectively included from January 2014 to December 2021. They were divided into the moderate-to-severe BPD/death group and the comparison group according to the incidence of moderate-to-severe BPD or death. We defined time to reintubation as the time interval between first extubation and reintubation. In a stepwise multivariate logistic regression analysis, we examined the association between time to reintubation and moderate-to-severe BPD/death using different observation windows after initial extubation (24-h intervals). Results: A total of 244 infants were recruited, including 57 cases in the moderate-severe BPD/death group and 187 cases in the comparison group, and 93 (38.1%) cases were reintubated at least one time after their first extubation. Univariate analysis showed that reintubation rates within different observation windows in the moderate-to-severe BPD/death group were statistically significantly (p < 0.05) higher than those in the comparison group. Multivariate regression analysis showed that reintubation within observation windows 48 h or 72 h post-extubation was an independent risk factor in moderate-to-severe BPD/death and death, but not moderate-to-severe BPD. When the time window was 48 h, the probability of moderate-to-severe BPD/death [odds ratio (OR): 3.778, 95% confidence interval (CI): 1.293-11.039] or death (OR: 4.734, 95% CI: 1.158-19.354) was highest. While after extending the observation window to include reintubations after 72 h from initial extubation, reintubation was not associated with increased risk of moderate-to-severe BPD and/or death. Conclusions: Not all reintubations conferred increased risks of BPD/death. Only reintubation within 72 h from initial extubation was independently associated with increased likelihood of moderate-to-severe BPD/death and death in very low birth weight infants, and reintubation within the first 48 h post-extubation posed the greatest risk.

Time Interval From Early-Term Antenatal Corticosteroids Administration to Delivery and the Impact on Neonatal Outcomes.

Objectives: To determine the association between the time interval from antenatal corticosteroids administration to delivery and neonatal complications in diabetic mothers undergoing early term (37+0 to 38+6 weeks) scheduled cesarean section (ETSCS). Study Design: A retrospective cohort study of women with any form of diabetes in pregnancy undergoing ETSCS was included. Cases were stratified into the following groups based on the time interval from the first dose of corticosteroids administration to delivery: <2, 2-7, and >7 days. Women undergoing ETSCS, who did not receive corticosteroids were included as controls. We assessed the association between the time interval and neonatal outcomes in a multivariate regression model that controlled for potential confounders. Primary outcomes were the incidence of respiratory distress syndrome (RDS)/transient tachypnea of the newborn (TTN) and neonatal hypoglycemia. Results: The study cohort comprised 1,165 neonates. Of those, 159 (13.6%) were delivered within 2 days of maternal corticosteroids administration, 131 (11.2%) were delivered within 2-7 days after maternal corticosteroids administration, and 137 (11.8%) delivered more than 7 days after maternal corticosteroids administration. The remaining 738 (63.3%) were not exposed to corticosteroids. Multivariate analysis demonstrated that delivery within any time of antenatal corticosteroids administration was not associated with decreased risks of RDS/TTN. The risk of neonatal hypoglycemia was highest in the delivery of <2 days group (adjusted odds ratio [aOR]: 2.684, 95% confidence interval [CI]: 1.647-4.374 for control group; aOR: 2.827, 95% CI: 1.250-6.392 for delivery 2-7 days group; aOR:2.975, 95% CI: 1.265-6.996 for delivery >7 days group). Conclusions: Corticosteroids treatment for diabetic mothers undergoing ETSCS was not associated with beneficial neonatal respiratory outcomes. In addition, delivery, <2 days after antenatal corticosteroids administration was associated with an increased risk of neonatal hypoglycemia.

Sildenafil protects against pulmonary hypertension induced by hypoxia in neonatal rats via activation of PPARγ­mediated downregulation of TRPC.

Persistent pulmonary hypertension of the newborn (PPHN) is a common pulmonary vascular disease during the neonatal period, and it is associated with a high clinical mortality rate and a poor prognosis. At present, the treatment of PPHN is based mainly on inhaled nitric oxide (iNO), high­frequency ventilation, and pulmonary vasodilators. Sildenafil has gradually begun to be used in recent years for the treatment of PPHN and has exhibited some success; however, its detailed mechanism of action requires further elucidation. An animal model of neonatal pulmonary hypertension (neonatal rats, 48 h after birth, 10% O2, 14 days) as well as a cell model [human pulmonary artery smooth muscle cells (PASMCs), 4% O2, 60 h] were established. The effects of sildenafil on pulmonary hypertension in neonatal rats were evaluated by hematoxylin and eosin staining, immunofluorescence analysis, western blotting and PCR, and the changes in peroxisome proliferator­activated receptor Î³ (PPARγ), transient receptor potential canonical (TRPC)1, TRPC6 and Ki67 expression levels were detected under hypoxic conditions. The results revealed that sildenafil reversed the increases in the right ventricular mean pressure and right ventricular hypertrophy index induced by hypoxia, and attenuated pulmonary arterial remodeling as well as PASMC proliferation. The inhibitory effects of sildenafil on TRPC expression and PASMC proliferation were attenuated by GW9662 and PPARγ small interfering RNA. In conclusion, sildenafil protects against hypoxia­induced pulmonary hypertension and right ventricular hypertrophy in neonatal rats by upregulating PPARγ expression and downregulating TRPC1 and TRPC6 expression.

Short-term effects of intravitreal anti-vascular endothelial growth factor agents on body weight and multiple systems after treatment for retinopathy of prematurity.

Objectives: This study's goal was to assess the short-term effect on body weight and multiple systems following intravitreal injections of ranibizumab and aflibercept for retinopathy of prematurity (ROP). Methods: We retrospectively assessed infants with ROP who received intravitreal anti-vascular endothelial growth factor agents (VEGF) treatment at our hospital. They were classified into 2 groups based on the drugs administered: the intravitreal ranibizumab (IVR) group and the intravitreal aflibercept (IVA) group. The body weight (BW) gains for the pre-treatment week, the 1st week after treatment, and the 2nd week after treatment were compared for each group. Additionally, other parameters such as blood pressure, heart rate, oxygen concentration, volume of milk and output of urine at four time points were also measured. We used repeated measurement analysis of variance analyzed these data. Results: In total, 95 preterm infants were recruited, including 51 cases in the IVR group and 44 cases in the IVA group. The BW gain for the 1st week after treatment was significantly lower than the pre-treatment week in each group (P < 0.05), while there was no decrease in weekly BW gain in the 2nd week after treatment compared with that pre-treatment week. Based on the comparison between groups, the BW gain in the IVR group was significantly higher than in the IVA group in the second post-treatment week. Repeated measurement analysis of variance showed that there were no significant differences in blood pressure, heart rate, oxygen concentration, volume of milk and output of urine in both groups over time. Conclusions: IVR and IVA could have a short-term inhibitive effect on body weight gain in infants after treatment for ROP, whereas there is no significant impact on other systems.

Autophagy inducers restore impaired autophagy, reduce apoptosis, and attenuate blunted alveolarization in hyperoxia-exposed newborn rats.

AIM: Autophagy is a common process during development. Abnormal autophagy can impact cell apoptosis. Previous studies have shown that apoptosis is present during bronchopulmonary dysplasia (BPD). However, there is no consensus on the level of coexisting autophagy. This study was designed to investigate the role of autophagy and the effects of autophagy inducers in a BPD model. METHOD: A total of 100 newborn Sprague-Dawley rats were randomly assigned to model and control groups. BPD models were established by hyperoxic induction(FiO2 0.80). Some of them were treated with autophagy-inducing agents. RESULT: As compared to the control group, more autophagic bodies were found within Type II alveolar epithelial cells (AT-II cells) under transmission electron microscopy (TEM) in the model group at 3 d . These autophagic bodies were also accompanied by apoptotic bodies and expression of both bodies peaked at 7 d. As shown by TdT-mediated dUTP nick end labeling (TUNEL), there were more apoptotic cells in the model group than in the control group. Protein expression levels of LC3B-II, p62, Lamp1, and cleaved Caspase-3 increased with increased hyperoxic exposure time. No significant differences were observed in the mRNA expression levels of LC3B, p62, and Lamp1. After introducing an autophagy inducer, either rapamycin or lithium chloride, the radial alveolar count (RAC) value of BPD model group increased as compared with placebo group, the thickness of alveolar septum decreased, while apoptosis decreased. CONCLUSION: Reduced autophagy resulting from blocked autophagy flow may be a key link in the pathogenesis of BPD. By enhancing repressed autophagy, apoptosis could be reduced and alveolar development improved.

Neuronalinjury and roles of apoptosis and autophagy in a neonatal rat model of hypoxia-ischemia-induced periventricular leukomalacia.

As research into periventricular leukomalacia (PVL) gradually increases, concerns are emerging about long­term neuron injury. The present study aimed to investigate neuronal injury and the relevant alterations in apoptosis and autophagy in a PVL model established previously. A rat model of hypoxia­ischemia­induced PVL was established. In the model group, Sprague­Dawley (SD) rats [postnatal day 3 (P3)] were subjected to right common carotid artery ligation followed by suturing and exposed to 6­8% oxygen for 2 h; in the control group, SD rats (P3) were subjected to right common carotid artery dissection followed by suturing, without ligation and hypoxic exposure. At 1, 3, 7 and 14 days following modeling, brain tissue samples were collected and stained with hematoxylin and eosin. Cellular apoptosis was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and the protein and mRNA expression alterations of neuronal nuclei (NeuN), caspase­3 and Beclin 1 in the model group were detected by western blot analysis and reverse transcription­quantitative polymerase chain reaction (RT­qPCR) analyses. Compared with the control group, the protein and mRNA expression levels of NeuN (a marker of mature neurons) were markedly reduced, the number of positive cells was increased as detected by TUNEL, and the protein and mRNA expression levels of caspase­3 and Beclin 1 were elevated in the model group. In the rat model of hypoxia­ischemia­induced PVL, oligodendrocyte injury and myelinization disorders were observed, in addition to neuron injury, a decrease in mature neurons and the co­presence of apoptosis and autophagy. However, apoptosis and autophagy exist in different phases: Apoptosis is involved in neuron injury, while autophagy is likely to have a protective role.

Effects of FHL1 and P21 on hypoxia-induced pulmonary vascular remodeling in neonatal rats.

Numerous studies have demonstrated that altered expression levels of four and a half LIM domains 1 (FHL1) and P21 are necessary for hypoxia-induced pulmonary vascular remodeling in both adult rats and human patients with idiopathic pulmonary arterial hypertension. However, whether FHL1 and P21 are present in the pulmonary artery and whether these proteins affect pulmonary vascular remodeling in hypoxia-induced pulmonary hypertension (HPH) in neonatal rats remain unknown. The present study investigated the effects of altered FHL1 and P21 expression on pulmonary vascular remodeling in neonatal rats with HPH. A total of 32 newborn Sprague-Dawley rats were exposed to hypoxia or room air for 7 or 14 days (n=8/subgroup). Parameters including the percentage of medial wall thickness (WT%), the percentage of medial wall area (WA%), right ventricular (RV) mean pressure, RV hypertrophy index (RVHI) and RV systolic pressure (RVSP) were measured to evaluate the development of HPH. Additionally, the expressions of FHL1 and P21 in the pulmonary artery smooth muscle cells (PASMCs) were measured by reverse transcription-quantitative polymerase chain reaction, western blot analysis and immunohistochemical staining. WA%, WT%, RV mean pressure, RVHI and RVSP were significantly increased in the HPH model group when compared with the control group (P<0.01). The protein expression levels of FHL1 were significantly increased in the HPH group (P<0.05), while the mRNA and protein expression levels of P21 were significantly reduced (P<0.05). Pearson correlation analysis indicated that the protein expressions of FHL1 and P21 were correlated with WA% and WT% (all P<0.001), and that the protein expression of P21 was negatively correlated with that of FHL1 (P<0.01). The results indicated that the expressions of FHL1 and P21 were altered in the PASMCs of newborn rats with HPH. Furthermore, FHL1 and P21 may serve important roles in pulmonary vascular remodeling.

Altered expression of PPAR­Î³ and TRPC in neonatal rats with persistent pulmonary hypertension.

Persistent pulmonary hypertension of the newborn (PPHN) is a life­threatening disease that is commonly observed in the neonatal intensive care unit. PPHN is pathologically characterized by pulmonary vascular remodeling and, in particular, pulmonary artery smooth muscle cell (PASMC) proliferation. Decreased expression levels of peroxisome proliferator­activated receptor γ (PPAR­Î³), which is a member of the nuclear receptor hormone superfamily, in combination with elevated expressions of transient receptor potential cation channel, subfamily C, member 1 (TRPC1) and TRPC6 contributes to the PASMC proliferation and excessive pulmonary vascular remodeling in adult pulmonary hypertension (PH). Whether PPAR­Î³, TRPC1 and TRPC6 affect the development of vascular remodeling in PPHN model rats remains unknown. The aim of the present study was to investigate the roles of PPAR­Î³, TRPC1 and TRP6 on the pathogenesis of PPHN in rats. The rat model of PPHN was established by exposure to hypoxic conditions and indomethacin treatment. Lung tissues, hearts and blood from PPHN model and Control rats were collected and examined. Parameters, including the percentage of medial wall thickness (WT %), the percentage of medial wall area (WA %), right ventricular hypertrophy (RVH) and the plasma concentration of B­type natriuretic peptide (BNP) were used to estimate the development of PPHN. The expression levels of PPAR­Î³, TRPC1 and TRPC6 in lung tissues were detected by immunohistochemistry, western blotting and reverse transcription­quantitative polymerase chain reaction. Significant increases were observed in the WT %, WA %, RVH and plasma BNP in the PPHN group compare with the Control group (P<0.01). In addition, the mRNA and protein expression levels of PPAR­Î³ were markedly downregulated (P<0.05 vs. Control). In the PPHN group, the protein expression levels of TRPC1 and TRPC6 were higher compared to the control group; however, there was no difference in the mRNA expression levels (P>0.05). In conclusion, the present study successfully established a PPHN rat model, and the altered expressions of PPAR­Î³, TRPC1 and TRPC6 in the pulmonary artery located in the lungs of newborn rats with PPHN suggested that these proteins may be important mediators of PPHN.

MicroRNA expression profiles and target prediction in neonatal Wistar rat lungs during the development of bronchopulmonary dysplasia.

In this study, we investigated the mechanisms through which microRNAs (miRNAs or miRs) regulate lung development after birth, as well as the role of miRNAs in the development of bronchopulmonary dysplasia (BPD). For this purpose, a total of 90 neonatal Wistar rats were randomly and equally assigned to either a model group or a control group. On postnatal days 3, 7 and 14, the lung tissues were collected for histological analysis to determine morphological changes. The expression levels of proliferating cell nuclear antigen (PCNA) and platelet endothelial cell adhesion molecule-1 (PECAM-1, also known as CD31) were measured by RT-qPCR and western blot analysis. A miRCURY™ LNA array was employed to screen for differentially expressed miRNAs, and the possible target genes of those miRNAs were predicted. Our results revealed that, compared with the control group, the following changes induced by hyperoxia were observed in the model group over time: a decrease in the number, but an increase in the size of the alveoli, and a decrease in the number of secondary septa formed. In the model group, from postnatal days 3-14, the mRNA and protein expression levels of PCNA and CD31 were significantly lower than those in the control group. The differentially expressed miRNAs between the 2 groups were identified on days 3, 7 and 14 after birth. Possible target genes were identified for 32 differentially expressed miRNAs. Taken together, these findings suggest that during the development of BPD, an alveolarization disorder with microvascular dysplasia co-exists with the differential expression of certain miRNAs during the different stages of alveolar development in a neonatal rat model of hyperoxia­induced BPD. This indicates that miRNAs may participate in the occurrence and development of BPD.