Receptor-interacting protein kinase-3 (RIPK3): a new biomarker for necrotising enterocolitis in preterm infants.

OBJECTIVE: This study aimed to evaluate the role of receptor-interacting protein kinase-3 (RIPK3) in the diagnosis, estimation of disease severity, and prognosis of premature infants with necrotising enterocolitis (NEC). METHODS: RIPK3, lactic acid (LA), and C-reactive protein (CRP) levels were measured in the peripheral blood of 108 premature infants between 2019 and 2023, including 24 with stage II NEC, 18 with stage III NEC and 66 controls. Diagnostic values of the indicators for NEC were evaluated via receiver operating characteristic (ROC) curve analysis. RESULTS: Plasma RIPK3 and LA levels upon NEC suspicion in neonates with stage III NEC were 32.37 ± 16.20 ng/mL. The ROC curve for the combination of RIPK3, LA, CRP for NEC diagnosis were 0.925. The time to full enteral feeding (FEFt) after recovery from NEC was different between two expression groups of plasma RIPK3 (RIPK3 < 20.06 ng/mL and RIPK3 ≥ 20.06 ng/mL). CONCLUSION: Plasma RIPK3 can be used as a promising marker for the diagnosis and estimation of disease severity of premature infants with NEC and for the guidance on proper feeding strategies after recovery from NEC.

Establishment and validation of a risk prediction model incorporating concentrations of linezolid and its metabolite PNU142300 for linezolid-induced thrombocytopenia.

BACKGROUND: Linezolid-induced thrombocytopenia is the main factor restricting the clinical application of linezolid. OBJECTIVES: To investigate the relationship between PNU-14230 concentration and linezolid-induced thrombocytopenia and further develop and validate a risk model for predicting linezolid-induced thrombocytopenia. METHODS: A regression model was constructed to predict the occurrence of linezolid-induced thrombocytopenia, and further externally validated. The predictive performance was evaluated by receiver operating characteristic curve and Hosmer-Lemeshow test. Linezolid Cmin and PNU-142300 concentrations were compared for different kidney function groups. The Kaplan-Meier method was used to estimate the difference in cumulative incidence of linezolid-induced thrombocytopenia among different kidney function patients. RESULTS: In the derivation (n = 221) and validation (n = 158) cohorts, 28.5% and 24.1% of critically ill patients developed linezolid-induced thrombocytopenia. Logistic regression analysis indicated that the independent risk factors were linezolid Cmin, PNU-142300 concentration, baseline platelet count, renal insufficiency (RI) and continuous venovenous haemofiltration (CVVH). The AUC for the risk model was 0.901, and the model was good (P = 0.633). The model also showed good discrimination (AUC 0.870) and calibration (P = 0.282) in the external validation cohort. Compared with normal kidney function patients, patients with RI and CVVH had higher linezolid Cmin and PNU-142300 concentrations (P < 0.001) and higher cumulative incidence of linezolid-induced thrombocytopenia (P < 0.001). CONCLUSIONS: PNU142300 concentration, as well as linezolid Cmin, might identify patients at risk of linezolid-induced thrombocytopenia. The risk prediction model had good predictive performance for linezolid-induced thrombocytopenia development. Concentrations of linezolid and PNU-142300 accumulated in patients with RI and CVVH.

Dose optimisation of linezolid in critically ill patients based on a population pharmacokinetic model: A two-centre prospective interventional study.

OBJECTIVES: This study evaluated the intervention effect of clinical pharmacist-mediated optimisation of a linezolid regimen using a population pharmacokinetic (PPK) model. METHODS: Patients treated with linezolid in two medical centres from January 2020 to June 2021 were retrospectively included in the control group; those treated from July 2021 to June 2022 were prospectively enrolled in the intervention group. Clinical pharmacists optimised the dosage regimen according to a published linezolid PPK model in the intervention group. An interrupted times series approach was used to analyse the data. The incidence of linezolid-induced thrombocytopenia (LIT), target attainment of pharmacokinetic/pharmacodynamic parameters and other adverse drug reactions (ADRs) were compared between the two groups. RESULTS: In total, 77 and 103 patients were enrolled in the control and intervention groups, respectively. The intervention group had a lower incidence of LIT and other ADRs than the control group (10.7% vs. 23.4%, P = 0.002; 1.0% vs. 7.8%, P = 0.027). The intervention group exhibited a considerably lower trough concentration (Cmin) and area under the concentration-time curve/MIC ratio (AUC24/MIC) (P = 0.001 and P < 0.001). Cmin and AUC24/MIC rates within the target range were substantially higher in the intervention group (49.6% vs. 20.0%, adjusted P < 0.05; 48.1% vs. 25.6%, adjusted P < 0.05). CONCLUSION: Interventions by clinical pharmacists reduced the incidence of LIT and other ADRs. Implementation of model-informed precision dosing (MIPD) for linezolid markedly increased the Cmin and AUC24/MIC rates within the target range. We recommend MIPD-guided linezolid dose reduction for patients with renal impairment.

Use of antenatal corticosteroids among infants with gestational age at 24 to 31 weeks in 57 neonatal intensive care units of China: a cross-sectional study.

BACKGROUND: Antenatal corticosteroids (ACS) can significantly improve the outcomes of preterm infants. This study aimed to describe the ACS use rates among preterm infants admitted to Chinese neonatal intensive care units (NICU) and to explore perinatal factors associated with ACS use, using the largest contemporary cohort of very preterm infants in China. METHODS: This cross-sectional study enrolled all infants born at 24 +0 to 31 +6 weeks and admitted to 57 NICUs of the Chinese Neonatal Network from January 1st, 2019 to December 30th, 2019. The ACS administration was defined as at least one dose of dexamethasone and betamethasone given before delivery. Multiple logistic regressions were applied to determine the association between perinatal factors and ACS usage. RESULTS: A total of 7828 infants were enrolled, among which 6103 (78.0%) infants received ACS. ACS use rates increased with increasing gestational age (GA), from 177/259 (68.3%) at 24 to 25 weeks' gestation to 3120/3960 (78.8%) at 30 to 31 weeks' gestation. Among infants exposed to ACS, 2999 of 6103 (49.1%) infants received a single complete course, and 33.4% (2039/6103) infants received a partial course. ACS use rates varied from 30.2% to 100% among different hospitals. Multivariate regression showed that increasing GA, born in hospital (inborn), increasing maternal age, maternal hypertension and premature rupture of membranes were associated with higher likelihood to receive ACS. CONCLUSIONS: The use rate of ACS remained low for infants at 24 to 31 weeks' gestation admitted to Chinese NICUs, with fewer infants receiving a complete course. The use rates varied significantly among different hospitals. Efforts are urgently needed to propose improvement measures and thus improve the usage of ACS.

A Regression Model to Predict Linezolid Induced Thrombocytopenia in Neonatal Sepsis Patients: A Ten-Year Retrospective Cohort Study.

Background: Linezolid-induced thrombocytopenia (LIT) is the main factor limiting the clinical application of linezolid (LZD). The incidence and risk factors of LIT in neonatal patients were possibly different from other populations based on pathophysiological characteristics. The purpose of this study was to establish a regression model for predicting LIT in neonatal sepsis patients. Methods: We retrospectively included 518 patients and divided them into the LIT group and the non-LIT group. A logistic regression analysis was used to analyze the factors related to LIT, and a regression model was established. A receiver operating characteristic (ROC) curve was drawn to evaluate the model's predictive value. We prospectively collected 39 patients' data to validate the model and evaluate the effect of LZD pharmacokinetics on LIT. Results: Among the 518 patients, 103 patients (19.9%) developed LIT. The Kaplan-Meier plot revealed that the overall median time from the initiation of LZD treatment to the onset of LIT in preterm infants was much shorter when compared with term infants [10 (6, 12) vs. 13 (9.75, 16.5), p = 0.004]. Multiple logistic regression analysis indicated that the independent risk factors of LIT were lower weight at medication, younger gestational ages, late-onset sepsis, necrotizing enterocolitis, mechanical ventilation, longer durations of LZD treatment, and lower baseline of platelet level. We established the above seven-variable prediction regression model and calculated the predictive probability. The ROC curve showed that the predicted probability of combined body weight, gestational age, duration of LZD treatment, and baseline of platelet had better sensitivity (84.4%), specificity (74.2%), and maximum AUC (AUC = 0.873). LIT occurred in 9 out of 39 patients (23.1%), and the accuracies of positive and negative predictions of LIT were 88.9 and 76.7%, respectively. Compared with the non-LIT patients, the LIT patients had higher trough concentration [11.49 (6.86, 15.13) vs. 5.51 (2.80, 11.61) mg/L; p = 0.028] but lower apparent volume of distribution (Vd) [0.778 (0.687, 1.421) vs. 1.322 (1.099, 1.610) L; p = 0.010]. Conclusion: The incidence of LIT was high in neonatal sepsis patients, especially in preterm infants. LIT occurred earlier in preterm infants than in term infants. The regression model of seven variables had a high predictive value for predicting LIT. LIT was correlated with higher trough concentration and lower Vd.

Incidence of extrauterine growth retardation and its risk factors in very preterm infants during hospitalization: a multicenter prospective study. / ä½é™¢æžæ—©äº§å„¿å®«å¤–ç”Ÿé•¿è¿Ÿç¼“åŠç›¸å ³å› ç´ çš„å¤šä¸­å¿ƒå‰çž»æ€§ç ”ç©¶.

OBJECTIVES: To investigate the incidence of extrauterine growth retardation (EUGR) and its risk factors in very preterm infants (VPIs) during hospitalization in China. METHODS: A prospective multicenter study was performed on the medical data of 2 514 VPIs who were hospitalized in the department of neonatology in 28 hospitals from 7 areas of China between September 2019 and December 2020. According to the presence or absence of EUGR based on the evaluation of body weight at the corrected gestational age of 36 weeks or at discharge, the VPIs were classified to two groups: EUGR group (n=1 189) and non-EUGR (n=1 325). The clinical features were compared between the two groups, and the incidence of EUGR and risk factors for EUGR were examined. RESULTS: The incidence of EUGR was 47.30% (1 189/2 514) evaluated by weight. The multivariate logistic regression analysis showed that higher weight growth velocity after regaining birth weight and higher cumulative calorie intake during the first week of hospitalization were protective factors against EUGR (P<0.05), while small-for-gestational-age birth, prolonged time to the initiation of total enteral feeding, prolonged cumulative fasting time, lower breast milk intake before starting human milk fortifiers, prolonged time to the initiation of full fortified feeding, and moderate-to-severe bronchopulmonary dysplasia were risk factors for EUGR (P<0.05). CONCLUSIONS: It is crucial to reduce the incidence of EUGR by achieving total enteral feeding as early as possible, strengthening breastfeeding, increasing calorie intake in the first week after birth, improving the velocity of weight gain, and preventing moderate-severe bronchopulmonary dysplasia in VPIs.

Vancomycin in neonatal sepsis: predictive performance of a Chinese neonatal population pharmacokinetic model and clinical efficacy evaluation.

BACKGROUND: In the neonatal population, individual calculation and adjustment of vancomycin (VCM) doses has been recommended based on population pharmacokinetics (PPK) methods. OBJECTIVE: Our previous study established a Chinese neonatal VCM PPK model. The main goal of this study was to evaluate the predictive performance of this PPK model for VCM trough concentration. METHODS: The data on neonatal severe infection patients treated with VCM were retrospectively collected. The predictive performance of this PPK model was expressed using mean prediction error (MPE), mean absolute prediction error (MAPE), sensitivity and specificity. Linear regression analysis was used to compare predicted and measured VCM concentrations. We drew the receiver operating characteristic (ROC) curve to evaluate the predictive efficacy of the ratio of area under the concentration-time curve over 24 hours to minimum inhibitory concentration (AUC0-24/MIC) and trough concentration for clinical efficacy. RESULTS: A total of 40 neonates with Gram-positive bacterial sepsis were included. After VCM treatment, 32 (80%) neonates were clinically cured. Eight cases were a clinical failure: the trough concentrations and AUC0-24 were lower than that of the clinical cure patients (8.70±4.30 vs 14.30±4.50 mg/L, p=0.003; 404.30±122.80 vs 515.40±131.70, p=0.037). The measured and predicted trough concentration were 11.16 (5.96, 16.53) mg/L and 10.13 (6.61, 15.73) mg/L, respectively. The MPE and MAPE were 4.62% and 13.26% (5.30%, 25.88%), respectively. The proportion of MAPE <30% in the adjusted regimen was higher than the initial regimen (89.66% vs 65.00%, p=0.039). Predictions of sensitivity and specificity by this PPK model were 88.24% and 94.29%, respectively. The coefficients of determination of linear regression analysis were 0.9171 and 0.9009 for the initial and adjusted regimen, respectively. The AUC0-24 was correlated with the trough concentration (r=0.587, p<0.001). The ROC curve indicated that the optimal cut-off points for predicting clinical efficacy were AUC0-24/MIC >425.47 and trough concentration >9.45 mg/L. CONCLUSION: This PPK model has good predictive performance in Chinese neonatal patients. Both AUC0-24/MIC and trough concentration can predict the clinical efficacy of antibacterial treatment.

The potential value of plasma receptor interacting protein 3 in neonates with culture-positive late-onset sepsis.

BACKGROUND: Late-onset sepsis (LOS) is a systemic inflammatory response syndrome in neonates, and the molecular mechanism of LOS is incompletely characterized. The purpose of this study was to explore the potential value of receptor interacting protein 3 (RIP3) in LOS. METHODS: 63 neonates with LOS supported by positive culture and 79 neonates without sepsis were enrolled in this study from September 2019 to March 2021. Plasma RIP3 was detected by enzyme-linked immunosorbent assay (ELISA) and assessed along with the whole blood hypersensitive C-reactive protein (hs-CRP) level and platelet count (PLT). Differences in RIP3, hs-CRP and PLT between the two groups were compared. Changes in the three indicators in sepsis were also observed after treatment. The diagnostic value of indicators for LOS was evaluated by receiver operating characteristic (ROC) curve analysis. RESULTS: In the sepsis group, RIP3 and hs-CRP levels were significantly higher than those in the control group (RIP3, p < 0.0001; hs-CRP, p < 0.0001), and PLT was significantly lower than that in the control group (p < 0.0001). After treatment, RIP3 and hs-CRP levels among septic survivors were significantly decreased (p < 0.0001) and PLT significantly improved (p = 0.0216). With RIP3 > 15,845.19 pg/mL, hs-CRP > 5.00 mg/L, and PLT < 204.00 × 109/L as the positive criteria, the sensitivity values of the three indicators in the diagnosis of LOS were 69.8%, 60.3%, 60.3%, respectively, and the specificity values were 92.4%, 96.2%, 79.8%, respectively. The combination of RIP3, hs-CRP and PLT had a sensitivity of 77.8% and specificity of 97.5%. CONCLUSIONS: RIP3 may contribute to the early diagnosis of LOS and monitoring of treatment effect. The combined detection of RIP3, hs-CRP and PLT may be more effective than individual detection in the diagnosis of LOS.

Dynamic changes and clinical significance of LXA4 in the perioperative period of cardiopulmonary bypass.

Dynamic changes in lipoxin A4 (LXA4) in child patients with congenital heart disease (CHD), in the perioperative period of cardiopulmonary bypass (CPB) were studied. Peripheral blood was collected from 16 child patients (CPB group) before operation (Tc), after operation (T0), at 1 day after operation (T1), at 3 days after operation (T3), and at 7 days after operation (T7); and from 17 children with no CHD (control group). The level of LXA4 in peripheral blood was detected via enzyme-linked immunosorbent assay (ELISA). Clinical data of the child patients were collected. The white blood cell (WBC) count, the proportion of neutrophils (N%) and high-sensitivity C-reactive protein (hs-CRP) levels were also detected, followed by statistical analysis. The plasma LXA4 levels in CPB group at Tc were significantly lower compared to that in the control group (P<0.01). In CPB group, the level of LXA4 showed an increasing trend at T0, WBC and hs-CRP were transiently increased at T0 and increased most significantly at T1. N% was obviously increased at T0 compared to that at Tc and was still significantly higher at T7 compared to that at Tc. The CPB time and aortic clamping time were positively correlated with the time in the Pediatric Intensive Care Unit (PICU), the application time of ventilator, and the hs-CRP level at T0. The LXA4 level at each time-point had no correlation with other indexes. In conclusion, the inflammatory response after CPB increases the synthesis of LXA4 with an anti-inflammatory effect, but LXA4 cannot be used as a sensitive index for monitoring inflammation.

FTY720 attenuates intestinal injury and suppresses inflammation in experimental necrotizing enterocolitis via modulating CXCL5/CXCR2 axis.

Necrotizing enterocolitis (NEC) remains one of the leading causes of death in neonatal infants and new therapeutic strategies for NEC are urgently required. The immunomodulatory agent FTY720 has been shown to have protective effects in various inflammatory diseases. In this study, we hypothesized that treatment with FTY720 confers protection against experimental NEC. Experimental NEC was induced in five-day-old C57BL/6 neonatal mice by hyperosmolar formula feeding plus hypoxia and lipopolysaccharide (LPS) challenges. Induction of NEC resulted in substantial weight loss and high mortality compared to the control group, whereas FTY720 treatment significantly attenuated weight loss and improved survival in NEC-challenged neonatal mice. FTY720 treatment strongly ameliorated NEC-induced intestinal injury with reduced apoptosis and up-regulation of intestinal barrier proteins in the ileal tissues. Furthermore, FTY720 treatment abrogated NEC-initiated intestinal and systemic inflammation with markedly diminished inflammatory cytokines and chemokines. Moreover, FTY720 treatment suppressed NEC-activated CXCL5/CXCR2 axis with down-regulated expression of CXCL5 and CXCR2 at both mRNA and protein levels. Thus, we demonstrate that FTY720 protects neonatal mice against NEC-associated lethality by ameliorating intestinal injury and attenuating inflammation, possibly via its down-regulation of NEC-induced activation of intestinal CXCL5/CXCR2 axis.

KPT-330, a potent and selective CRM1 inhibitor, exhibits anti-inflammation effects and protection against sepsis.

Sepsis, a systemic inflammatory response caused by infection or injury, is still one of the most important causes of death in clinical patients. The ongoing search for the pathogenesis of sepsis and novel therapeutic methods are highly urgent. In this study, we hypothesized that KPT330, a potent and specific small molecule inhibitor of CRM1, could reduce inflammation and attenuate the severity of sepsis. In LPS-induced sepsis model in vivo, administration of KPT330 increased survival rate and ameliorated LPS-induced lung injury, with suppressed levels of TNF-α, IL-6 and HMGB1 in the circulation and decreased macrophage and PMN subpopulations in peritoneal cavity. In vitro investigations showed that KPT330 dose-dependently inhibited LPS-triggered proinflammatory cytokines production including TNF-α, IL-6 and HMGB1 in macrophages. Furthermore, KPT330 treatment significantly suppressed TNF-α and IL-6 mRNA expression and inhibited HMGB1 necleocytoplasmic translocation by inhibiting CRM1 distribution. Moreover, the mechanism analysis demonstrated that KPT330 exerted anti-inflammation effects by inhibiting the production of pro-inflammatory cytokines through suppressing activation of NF-κB and p38 signaling. Thus, pharmacologic stimulation of KPT330 may present a promising therapeutic strategy for sepsis.

[Clinical efficacy of heated humidified high-flow nasal cannula in preventing extubation failure in neonates: a Meta analysis].

OBJECTIVE: To evaluate the efficacy and safety of heated humidified high-flow nasal cannula (HHHFNC) in preventing extubation failure in neonates. METHODS: A literature search was performed using PubMed, Cochrane Library, FMRS, and CNKI to collect the randomized controlled trials (RCTs) and quasi-RCTs which compared the clinical efficacy of HHHFNC and nasal continuous positive airway pressure (NCPAP) in preventing extubation failure in neonates. The identified studies were finally selected after full-text search and quality assessment and then subjected to a Meta analysis using RevMan 5.3. RESULTS: Five eligible trials involving 1040 neonates were included in the Meta analysis. The Meta analysis showed that there was no significant difference in treatment failure rate between the HHHFNC and the NCPAP groups. The HHHFNC group had significantly lower incidence rates of nasal trauma (OR=0.49, 95% CI: 0.34-0.71, P=0.0001) and pneumothorax (OR=0.27, 95% CI: 0.07-0.97, P=0.04) than the NCPAP group, but there were no significant differences in the duration to reach full oral feedings and the incidence rates of serious adverse events or other complications between the two groups, such as in-hospital mortality, bronchopulmonary dysplasia, intraventricular hemorrhage, necrotizing enterocolitis, and retinopathy of prematurity. CONCLUSIONS: HHHFNC is safe and effective in preventing extubation failure in neonates.

Low level of galacto-oligosaccharide in infant formula stimulates growth of intestinal Bifidobacteria and Lactobacilli.

AIM: To investigate the effect of a new infant formula supplemented with a low level (0.24 g/100 mL) of galacto-oligosaccharide (GOS) on intestinal micro-flora (Bifidobacteria, Lactobacilli and E. coli) and fermentation characteristics in term infants, compared with human milk and a standard infant formula without GOS. METHODS: Term infants (n = 371) were approached in this study in three hospitals of China. All infants started breast-feeding. Those who changed to formula-feeding within 4 wk after birth were randomly assigned to one of the two formula groups. Growth and stool characteristics, and side effects that occurred in recruited infants were recorded in a 3-mo follow-up period. Fecal samples were collected from a subpopulation of recruited infants for analysis of intestinal bacteria (culture technique), acetic acid (gas chromatography) and pH (indicator strip). RESULTS: After 3 mo, the intestinal Bifidobacteria, Lactobacilli, acetic acid and stool frequency were significantly increased, and fecal pH was decreased in infants fed with the GOS-formula or human milk, compared with those fed with the formula without GOS. No significant differences were observed between the GOS formula and human milk groups. Supplementation with GOS did not influence the incidence of crying, regurgitation and vomiting. CONCLUSION: A low level of GOS (0.24 g/100 mL) in infant formula can improve stool frequency, decrease fecal pH, and stimulate intestinal Bifidobacteria and Lactobacilli as in those fed with human milk.