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Necrotizing enterocolitis (NEC) is a severe gastrointestinal disease primarily affecting premature neonates, marked by poorly understood pro-inflammatory signaling cascades. Recent advancements have shed light on a subset of endogenous molecular patterns, termed chromatin-associated molecular patterns (CAMPs), which belong to the broader category of damageassociated molecular patterns (DAMPs). CAMPs play a crucial role in recognizing pattern recognition receptors and orchestrating inflammatory responses. This review focuses into the realm of CAMPs, highlighting key players such as extracellular cold-inducible RNA-binding protein (eCIRP), high mobility group box 1 (HMGB1), cell-free DNA, neutrophil extracellular traps (NETs), histones, and extracellular RNA. These intrinsic molecules, often perceived as foreign, have the potential to trigger immune signaling pathways, thus contributing to NEC pathogenesis. In this review, we unravel the current understanding of the involvement of CAMPs in both preclinical and clinical NEC scenarios. We also focus on elucidating the downstream signaling pathways activated by these molecular patterns, providing insights into the mechanisms that drive inflammation in NEC. Moreover, we scrutinize the landscape of targeted therapeutic approaches, aiming to mitigate the impact of tissue damage in NEC. This in-depth exploration offers a comprehensive overview of the role of CAMPs in NEC, bridging the gap between preclinical and clinical insights. [ABSTRACT FROM AUTHOR]

Background: Necrotizing enterocolitis (NEC) and intracranial hemorrhage are severe emergencies in the neonatal period. The two do not appear to be correlated. However, our report suggests that parenchymal brain hemorrhage in full-term newborns may put patients at risk for NEC by altering intestinal function through the brain-gut axis. Case presentation: We present a case of spontaneous parenchymal cerebral hemorrhage in a full-term newborn who developed early-stage NEC on Day 15. Conclusions: It is possible to consider brain parenchymal hemorrhage as a risk factor for the appearance of NEC. Clinicians should be highly cautious about NEC in infants who have experienced parenchymal hemorrhage. This article is the first to discuss the relationship between parenchymal hemorrhage and NEC in full-term newborns. [ABSTRACT FROM AUTHOR]

The nutrition of preterm infants remains contaminated by wrong beliefs that reflect inexactitudes and perpetuate old practices. In this narrative review, we report current evidence in preterm neonates and in preterm neonates undergoing surgery. Convictions that necrotizing enterocolitis is reduced by the delay in introducing enteral feeding, a slow advancement in enteral feeds, and the systematic control of residual gastric volumes, should be abandoned. On the contrary, these practices prolong the time to reach full enteral feeding. The length of parenteral nutrition should be as short as possible to reduce the infectious risk. Intrauterine growth restriction, hemodynamic and respiratory instability, and patent ductus arteriosus should be considered in advancing enteral feeds, but they must not translate into prolonged fasting, which can be equally dangerous. Clinicians should also keep in mind the risk of refeeding syndrome in case of high amino acid intake and inadequate electrolyte supply, closely monitoring them. Conversely, when preterm infants undergo surgery, nutritional strategies are still based on retrospective studies and opinions rather than on randomized controlled trials. Finally, this review also highlights how the use of adequately fortified human milk is strongly recommended, as it offers unique benefits for immune and gastrointestinal health and neurodevelopmental outcomes. [ABSTRACT FROM AUTHOR]

A severe condition of sepsis can be a complication of necrotizing enterocolitis (NEC), which can occur in premature infants and becomes a medical challenge in the neonatal intensive care unit (NICU). It is a multifactorial intestinal disease (can affect both the small and large intestine) that can lead to ischemia of the intestinal tissues that evolves into acute organ necrosis. One of these factors is that different types of nutrition can influence the onset or the progression of the disease. Cow-milk-based infant formulas have been shown to cause it in premature infants more frequently than human milk. Recently, nutrition has been shown to be beneficial after surgery. Several issues still under study, such as the pathogenesis and the insufficient and often difficult therapeutic approach, as well as the lack of a common and effective prevention strategy, make this disease an enigma in daily clinical practice. Recent studies outlined the emerging role of the host immune system and resident gut microbiota, showing their close connection in NEC pathophysiology. In its initial stages, broad-spectrum antibiotics, bowel rest, and breastfeeding are currently used, as well as probiotics to help the development of the intestinal microbiota and its eubiosis. This paper aims to present the current knowledge and potential fields of research in NEC pathophysiology and therapeutic assessment. [ABSTRACT FROM AUTHOR]

Background: Investigating the trend of changes in the occurrence of necrotizing enterocolitis (NEC) in preterm infants during 9 years and analyzing the risk factors of NEC with the purpose of providing reference for clinical diagnosis and treatment of NEC. Methods: Clinical data of NEC in preterm infants with Bell's stage ≥ II from January 2013 to December 2021 in the Neonatology Department of the Third Affiliated Hospital of Zunyi Medical University was retrospectively analyzed. Trends in the occurrence of NEC in preterm infants were analyzed by the trend chi-square test. Subsequently, the general data (sex, gestational age, singleton or multiple births, birth weight, serum albumin, alkaline phosphatase, sepsis, blood transfusion, mechanical ventilation, RDS, arterial catheterization) and perinatal data (intrauterine distress, turbid amniotic fluid, premature rupture of membranes, mode of delivery, fetal heart abnormalities, diabetes mellitus) were collected; then, the risk factors for NEC were analyzed by univariate and multivariate logistic-regression analysis. Results: In the past 9 years, 77 cases of NEC occurred, with the incidence rate of 1.95%, and the incidence of NEC in preterm infants has been increasing year by year (P < 0.05). The results of univariate analysis showed that the morbidity of NEC in preterm infants was associated with premature rupture of membranes, blood transfusion, sepsis, and the of serum albumin (P < 0.05). Multivariate logistic regression analysis revealed that blood transfusion (OR = 2.232, 95% CI: 1.012–4.923) and sepsis (OR = 0.899, 95% CI: 0.809–3.915) were independent risk factors of NEC in preterm infants, while high serum albumin (OR = 0.899, 95% CI: 0.809–3.915) was an independent protective factor of NEC in preterm infants. Conclusion: The morbidity of NEC is gradually increasing. Inhibition of infection and limitation of blood transfusion are effective measures to reduce the occurrence of NEC. Meanwhile, high serum albumin is a protective factor for NEC. [ABSTRACT FROM AUTHOR]

Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency of prematurity. Postulated mechanisms leading to inflammatory necrosis of the ileum and colon include activation of the pathogen recognition receptor Toll-like receptor 4 (TLR4) and decreased levels of transforming growth factor beta (TGFβ). Extracellular nicotinamide phosphoribosyltransferase (eNAMPT), a novel damage-associated molecular pattern (DAMP), is a TLR4 ligand and plays a role in a number of inflammatory disease processes. To test the hypothesis that eNAMPT is involved in NEC, an eNAMPT-neutralizing monoclonal antibody, ALT-100, was used in a well-established animal model of NEC. Preterm Sprague–Dawley pups delivered prematurely from timed-pregnant dams were exposed to hypoxia/hypothermia and randomized to control—foster mother dam-fed rats, injected IP with saline (vehicle) 48 h after delivery; control + mAB—foster dam-fed rats, injected IP with 10 µg of ALT-100 at 48 h post-delivery; NEC—orally gavaged, formula-fed rats injected with saline; and NEC + mAb—formula-fed rats, injected IP with 10 µg of ALT-100 at 48 h. The distal ileum was processed 96 h after C-section delivery for histological, biochemical, molecular, and RNA sequencing studies. Saline-treated NEC pups exhibited markedly increased fecal blood and histologic ileal damage compared to controls (q < 0.0001), and findings significantly reduced in ALT-100 mAb-treated NEC pups (q < 0.01). Real-time PCR in ileal tissues revealed increased NAMPT in NEC pups compared to pups that received the ALT-100 mAb (p < 0.01). Elevated serum levels of tumor necrosis factor alpha (TNFα), interleukin 6 (IL-6), interleukin-8 (IL-8), and NAMPT were observed in NEC pups compared to NEC + mAb pups (p < 0.01). Finally, RNA-Seq confirmed dysregulated TGFβ and TLR4 signaling pathways in NEC pups that were attenuated by ALT-100 mAb treatment. These data strongly support the involvement of eNAMPT in NEC pathobiology and eNAMPT neutralization as a strategy to address the unmet need for NEC therapeutics. [ABSTRACT FROM AUTHOR]

Data from the Neonatal Oxygenation Prospective Meta-analysis (NeOProM) indicate that targeting a higher (91–95%) versus lower (85–89%) pulse oximeter saturation (SpO2) range may reduce mortality and necrotizing enterocolitis (NEC) and increase retinopathy of prematurity (ROP). Aiming to re-evaluate the strength of this evidence, we conducted a Bayesian reanalysis of the NeOProM data. We used Bayes factors (BFs) to evaluate the likelihood of the data under the combination of models assuming the presence vs. absence of effect, heterogeneity, and moderation by sex. The Bayesian reanalysis showed moderate evidence in favor of no differences between SpO2 targets (BF10 = 0.30) in death or major disability, but moderate evidence (BF10 = 3.60) in favor of a lower mortality in the higher SpO2 group. Evidence in favor of differences was observed for bronchopulmonary dysplasia (BPD) (BF10 = 14.44, lower rate with lower SpO2), severe NEC (BF10 = 9.94), and treated ROP (BF10 = 3.36). The only outcome with moderate evidence in favor of sex differences was BPD. This reanalysis of the NeOProM trials confirmed that exposure to a lower versus higher SpO2 range is associated with a higher mortality and risk of NEC, but a lower risk of ROP and BPD. The Bayesian approach can help in assessing the strength of evidence supporting clinical decisions. [ABSTRACT FROM AUTHOR]

Yunhan Zhang,1,&ast; Yuyun Chen,2,&ast; Jilin Lv,1 Xiao Xiang,1 Peiyao Wang,1 Wei Feng,1 Zhenhua Guo1 1Department of Neonatal Surgery, Children’s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development, Chongqing Key Laboratory of Structural Birth Defect and Reconstruction, Chongqing, People’s Republic of China; 2Fujian Children’s Hospital, Fujian Branch of Shanghai Children’s Medical Center, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, People’s Republic of China&ast;These authors have contributed equally to this workCorrespondence: Zhenhua Guo, Department of neonatal surgery, Children’s Hospital of Chongqing Medical University, 20 Jinyu Road, Yubei District, Chongqing, 400025, People’s Republic of China, Tel +86-23-68370286, Email zhguo@cqmu.edu.cnBackground: This study aims to investigate the potential significance of mean platelet volume (MPV) and platelet distribution width (PDW) in predicting surgical neonatal necrotizing enterocolitis (NEC) and establish the correlation between MPV/PDW levels and the severity/prognosis of NEC.Methods: A retrospective study was conducted on a cohort of 372 patients diagnosed with NEC. The patients were categorized into two groups based on whether they underwent surgical therapy. Univariate /multivariate analysis were employed to compare the MPV and PDW between the two groups. Moreover, patients in surgical group were categorized into multiple subgroups based on intraoperative findings and postoperative prognosis, and the levels of MPV and PDW were compared among these subgroups.Results: Of the 372 patients, the operative group exhibited significantly higher levels of MPV and PDW than the nonoperative group (P < 0.05). Logistic regression analysis revealed that MPV (OR = 4.895, P < 0.001) and PDW (OR = 1.476, P < 0.001) independently associated with surgical NEC. The analysis of the receiver operating characteristic (ROC) curve revealed that the area under the curve (AUC) was 0.706 for MPV alone, with a cut-off value of 11.8 fL. Similarly, the AUC was 0.728 for PDW alone, with a cut-off value of 16%. However, when MPV and PDW were combined, the AUC increased to 0.906 for predicting surgical NEC. In accordance with the intraoperative findings, the levels of MPV and PDW were found to be higher in the large area necrosis group than in the partial or mild necrosis group (P < 0.01). Furthermore, the MPV and PDW values in the death group were significantly greater than those in the survival group (P =0.040, P =0.008).Conclusion: MPV and PDW may serve as potentially valuable indicators for determining the need for surgical intervention and predicting the prognosis of patients with NEC.Keywords: mean platelet volume, platelet distribution width, necrotizing enterocolitis, neonatal

Objective To investigate the mechanism of autoinducer-2(AI-2) in relieving intestinal injury in neonatal mouse model of necrotizing enterocolitis (NEC). Methods Thirty-six 7-day-old C57BL/6J mice were randomly divided into Control group (fed by mother mice), NEC group (NEC model induced by formula+lipopolysaccharide administration, hypoxia and cold stress), and NEC+AI-2 group (AI-2 solution added to the modeled formula milk), with 12 mice in each group.The body weight and survival rate of each group were recorded during the modeling period.In 3 d after modeling, the mice were euthanized, and the histopathological changes in the terminal ileum were observed using HE staining.The mRNA expression levels of aryl hydrocarbon receptor (AHR), cytochrome P450 1A1(CYP1A1), TNF-α, IL-6 and IL-22 in intestinal tissue were detected with RT-qPCR.The protein levels of AHR and CYP1A1 in intestinal tissues were measured with Western blotting.The contents of TNF-α, IL-6 and IL-22 in intestinal tissues were detected using enzyme-linked immunosorbent assay (ELISA). Results The survival rate of neonatal rats was significantly higher in the NEC+AI-2 group than the NEC group (91.7%vs 66.7%, P < 0.05).The NEC+AI-2 group had obviously lower intestinal pathological injury score (1.33±0.21 vs 2.67±0.33, P < 0.05), increased mRNA and protein levels of AHR and CYP1A1 in intestinal tissues (P < 0.05), decreased expression levels of pro-inflammatory factors TNF-α and IL-6 in intestinal tissues (P < 0.05), while increased expression level of anti-inflammatory factor IL-22(P < 0.05) when compared with the NEC group.Furthermore, the expression and activation of intestinal AHR were negatively correlated with the intestinal pathological injury score (P < 0.001). Conclusion AI-2 alleviates intestinal injury in neonatal mice with NEC by activating AHR to regulate inflammatory response.

Abstract Background Necrotizing enterocolitis (NEC) and intracranial hemorrhage are severe emergencies in the neonatal period. The two do not appear to be correlated. However, our report suggests that parenchymal brain hemorrhage in full-term newborns may put patients at risk for NEC by altering intestinal function through the brain-gut axis. Case presentation We present a case of spontaneous parenchymal cerebral hemorrhage in a full-term newborn who developed early-stage NEC on Day 15. Conclusions It is possible to consider brain parenchymal hemorrhage as a risk factor for the appearance of NEC. Clinicians should be highly cautious about NEC in infants who have experienced parenchymal hemorrhage. This article is the first to discuss the relationship between parenchymal hemorrhage and NEC in full-term newborns.

A severe condition of sepsis can be a complication of necrotizing enterocolitis (NEC), which can occur in premature infants and becomes a medical challenge in the neonatal intensive care unit (NICU). It is a multifactorial intestinal disease (can affect both the small and large intestine) that can lead to ischemia of the intestinal tissues that evolves into acute organ necrosis. One of these factors is that different types of nutrition can influence the onset or the progression of the disease. Cow-milk-based infant formulas have been shown to cause it in premature infants more frequently than human milk. Recently, nutrition has been shown to be beneficial after surgery. Several issues still under study, such as the pathogenesis and the insufficient and often difficult therapeutic approach, as well as the lack of a common and effective prevention strategy, make this disease an enigma in daily clinical practice. Recent studies outlined the emerging role of the host immune system and resident gut microbiota, showing their close connection in NEC pathophysiology. In its initial stages, broad-spectrum antibiotics, bowel rest, and breastfeeding are currently used, as well as probiotics to help the development of the intestinal microbiota and its eubiosis. This paper aims to present the current knowledge and potential fields of research in NEC pathophysiology and therapeutic assessment.

Abstract Background Investigating the trend of changes in the occurrence of necrotizing enterocolitis (NEC) in preterm infants during 9 years and analyzing the risk factors of NEC with the purpose of providing reference for clinical diagnosis and treatment of NEC. Methods Clinical data of NEC in preterm infants with Bell’s stage ≥ II from January 2013 to December 2021 in the Neonatology Department of the Third Affiliated Hospital of Zunyi Medical University was retrospectively analyzed. Trends in the occurrence of NEC in preterm infants were analyzed by the trend chi-square test. Subsequently, the general data (sex, gestational age, singleton or multiple births, birth weight, serum albumin, alkaline phosphatase, sepsis, blood transfusion, mechanical ventilation, RDS, arterial catheterization) and perinatal data (intrauterine distress, turbid amniotic fluid, premature rupture of membranes, mode of delivery, fetal heart abnormalities, diabetes mellitus) were collected; then, the risk factors for NEC were analyzed by univariate and multivariate logistic-regression analysis. Results In the past 9 years, 77 cases of NEC occurred, with the incidence rate of 1.95%, and the incidence of NEC in preterm infants has been increasing year by year (P

Abstract The practice of routine gastric residual aspiration in preterm infants remains controversial, with conflicting evidence regarding its impact on necrotizing enterocolitis (NEC). As front-line caregivers, nurses play a vital role in gastric aspiration procedures and must be informed by evidence. This quasi-experimental nursing study aimed to assess whether gastric aspiration is clinically relevant in reducing the risk of NEC in preterm infants. A total of 250 preterm infants from two NICUs in Egypt were allocated to the gastric aspiration (n = 125) and non-aspiration (n = 125) groups. Feeding practices, gastric residuals, and incidence/severity of NEC were compared between groups according to modified Bell’s criteria. Risk factors were analyzed using multivariate regression. There were no significant baseline differences between the groups. The gastric residual attributes and feeding outcomes did not differ substantially from aspiration. The overall incidence of NEC was 14–15%, with no significant differences in the odds of onset or progression of NEC by stage between the groups. Lower gestational age and birth weight emerged as stronger predictors of NEC. Routine gastric aspiration does not appear to directly prevent or reduce the severity of NEC in this population. Although gastric residuals retain clinical importance, study findings question assumptions that aspiration protects against NEC and informs nursing practice. Evidence-based feeding protocols must continually evolve through ongoing research on modifiable risk factors for this devastating intestinal disease in preterm infants.

Abstract Background Extremely preterm infants, defined as those born before 28 weeks’ gestational age, are a very vulnerable patient group at high risk for adverse outcomes, such as necrotizing enterocolitis and death. Necrotizing enterocolitis is an inflammatory gastrointestinal disease with high incidence in this cohort and has severe implications on morbidity and mortality. Previous randomized controlled trials have shown reduced incidence of necrotizing enterocolitis among older preterm infants following probiotic supplementation. However, these trials were underpowered for extremely preterm infants, rendering evidence for probiotic supplementation in this population insufficient to date. Methods The Probiotics in Extreme Prematurity in Scandinavia (PEPS) trial is a multicenter, double-blinded, placebo-controlled and registry-based randomized controlled trial conducted among extremely preterm infants (n = 1620) born at six tertiary neonatal units in Sweden and four units in Denmark. Enrolled infants will be allocated to receive either probiotic supplementation with ProPrems® (Bifidobacterium infantis, Bifidobacterium lactis, and Streptococcus thermophilus) diluted in 3 mL breastmilk or placebo (0.5 g maltodextrin powder) diluted in 3 mL breastmilk per day until gestational week 34. The primary composite outcome is incidence of necrotizing enterocolitis and/or mortality. Secondary outcomes include incidence of late-onset sepsis, length of hospitalization, use of antibiotics, feeding tolerance, growth, and body composition at age of full-term and 3 months corrected age after hospital discharge. Discussion Current recommendations for probiotic supplementation in Sweden and Denmark do not include extremely preterm infants due to lack of evidence in this population. However, this young subgroup is notably the most at risk for experiencing adverse outcomes. This trial aims to investigate the effects of probiotic supplementation on necrotizing enterocolitis, death, and other relevant outcomes to provide sufficiently powered, high-quality evidence to inform probiotic supplementation guidelines in this population. The results could have implications for clinical practice both in Sweden and Denmark and worldwide. Trial registration ( Clinicaltrials.gov ): NCT05604846

Abstract The integrity of the intestinal mucus barrier is crucial for human health, as it serves as the body's first line of defense against pathogens. However, postnatal development of the mucus barrier and interactions between maturity and its ability to adapt to external challenges in neonatal infants remain unclear. In this study, we unveil a distinct developmental trajectory of the mucus barrier in preterm piglets, leading to enhanced mucus microstructure and reduced mucus diffusivity compared to term piglets. Notably, we found that necrotizing enterocolitis (NEC) is associated with increased mucus diffusivity of our large pathogen model compound, establishing a direct link between the NEC condition and the mucus barrier. Furthermore, we observed that addition of sodium decanoate had varying effects on mucus diffusivity depending on maturity and health state of the piglets. These findings demonstrate that regulatory mechanisms governing the neonatal mucosal barrier are highly complex and are influenced by age, maturity, and health conditions. Therefore, our results highlight the need for specific therapeutic strategies tailored to each neonatal period to ensure optimal gut health.

Abstract Purpose This study was aimed to investigate the risk factors of necrotizing enterocolitis (NEC) in twin preterm infants. Methods The clinical data of 67 pairs of twin preterm infants admitted to the neonatal department of our hospital from January 2010 to December 2021 were retrospectively collected. One of the twins had NEC (Bell II and above) and the other twin without NEC. They were divided into NEC group and control group according to whether NEC occurred or not. Results Univariate analysis showed that NEC was associated with congenital heart disease, small for gestational age, mild asphyxia at birth and feeding intolerance (P

Wei Meng,1 Qing Wang,1 Qingyu Xu,2 Hongli Gao,3 Yunjun Zhou,1 Wei Shao1 1Department of Pediatric Internal Medicine, Hongqi Hospital Affiliated to Mudanjiang Medical University, Mudanjiang, Heilongjiang, People’s Republic of China; 2Department of Pediatrics Surgery, Hongqi Hospital Affiliated to Mudanjiang Medical University, Mudanjiang, Heilongjiang, People’s Republic China; 3Department of Digestive Endoscopy Center, Hongqi Hospital Affiliated to Mudanjiang Medical University, Mudanjiang, Heilongjiang, People’s Republic of ChinaCorrespondence: Wei Shao, Department of Pediatrics, Hongqi Hospital Affiliated to Mudanjiang Medical University, No. 5 Tongxiang Road, Aimin District, Mudanjiang, Heilongjiang, 157000, People’s Republic of China, Tel +86-4536602008, Email 3649971511@qq.comBackground: The occurrence of necrotizing enterocolitis (NEC) is a common and severe disease of the digestive system in neonates. This study aims to assess the value of the intestinal tissue oxygen saturation (rintSO2) combined with the levels of procalcitonin (PCT) and mean platelet volume (MPV) in predicting the severity of NEC in preterm infants.Methods: This experiment was a retrospective cohort study conducted in the Department of Pediatrics, Hongqi Hospital Affiliated to Mudanjiang Medical University between January 2017 and July 2022. Premature neonates with NEC were enrolled and divided into mild-moderate NEC group and severe NEC group according to Bell’s stage. The general information data, rintSO2 and blood parameters such as the white blood cell (WBC) count, platelet count (PLT), PCT, MPV, red blood cell distribution width (RDW), hemoglobin (Hb), C-reactive protein (CRP) were compared between the two groups.Results: A total of 122 patients were enrolled, including 79 mild-moderate NEC and 43 severe NEC. The rintSO2 was lower in severe group than in mild-moderate group (P = 0.042), the PCT and MPV were both higher in severe group than in mild-moderate group (P = 0.048, P = 0.049). The results of logistic regression suggested that the rintSO2 (OR = 1.491, P = 0.003), PCT (OR = 3.071, P = 0.001) and MPV (OR = 4.027, P = 0.015) were independent predictive factors for severity of NEC. The area under the curve (AUC) of the rintSO2 combined with PCT and MPV showed good diagnostic ability in the severity of NEC.Conclusion: The rintSO2 combined with PCT and MPV may be considered as the early biomarkers in the severity of NEC and could help us to diagnose the case early with early treatment with better prognosis.Keywords: premature infants, necrotizing enterocolitis, intestinal tissue oxygen saturation, procalcitonin, mean platelet volume

Background Necrotizing enterocolitis (NEC) is a major cause of morbidity in premature infants. However, effective treatment options for NEC are currently lacking. Purpose This study aimed to determine the optimal dose of intraperitoneally administered bone marrow-derived mesenchymal stem cells (BM-MSCs) and investigate the therapeutic potential of orally administered BM-MSCs in NEC. Methods Neonatal mice were fed maternal breast milk for the first 2 days of life. On day 3, the neonatal mice were randomly divided into control, negative control, and BM-MSC-treated groups. Lipopolysaccharide (LPS) was administered for 3 days, and cold stress (4°C, 10 minutes) was applied 3 times a day to induce NEC. High-dose (1×106 cells) or low-dose (1×105 cells) BM-MSCs were administered intraperitoneally 1 or 3 times between days 6 and 8 to treat the NEC. The orally administered group received a low dose of BM-MSCs on day 6. Furthermore, except for the control group, intraepithelial cells (IECs) of the small intestine of neonatal mice were treated with LPS and exposed to 5% O2/95% N2 hypoxic stress for 2 hours. Thereafter, each was treated with BM-MSCs. Results Tissue injury, apoptosis, and inflammatory marker levels were significantly reduced after BM-MSC administration. Oral administration was as effective as intraperitoneal administration, even at a low dose (1×105 cells) of BM-MSCs. The efficacy of high (1×106 cells) or multiple divided doses of BM-MSCs did not differ from that of low-dose treatment. Significantly improved wound healing was observed after BM-MSC administration to injured IECs. Conclusion The oral administration of BM-MSCs is a promising treatment option for NEC in infants. Further human studies of BM-MSCs are necessary to determine the optimal dose required to achieve safe and effective outcomes.

Abstract Objective To investigate the clinical characteristics of neonatal necrotizing enterocolitis (NEC) complicated by intestinal perforation and predict the incidence of intestinal perforation in NEC. Methods Neonates diagnosed with NEC at the Affiliated Hospital of Zunyi Medical University from January 2012 to May 2022 were enrolled, and the clinical data were collected and analyzed retrospectively. The patients were divided into two groups based on intestinal perforation occurrence or not. Mann-Whitney U tests, t-tests, chi-square tests, and fisher’s exact tests were performed between-group comparisons. Logistic and lasso regressions were applied to screen independent risk factors for concomitant bowel perforation, and R software (RMS package) was used to formulate the nomogram prediction model. In addition, the receiver operating curve (ROC) and the calibration curve were drawn to verify the predictive power, while decision curve analysis (DCA) was constructed to evaluate the clinical applicability of the nomogram model. Results One hundred eighty neonates with NEC were included, of which 48 had intestinal perforations, and 132 did not; the overall incidence of intestinal perforation was 26.67% (48/180). Bloody stool (OR = 5.60), APTT ≥ 50 s (OR = 3.22), thrombocytopenia (OR = 4.74), and hypoalbuminemia (OR = 5.56) were identified as independent risk variables for NEC intestinal perforation (P

Abstract Background Necrotizing enterocolitis (NEC) is a multifactorial gastrointestinal disease with high morbidity and mortality among premature infants. However, studies with large samples on the factors of NEC in China have not been reported. This meta-analysis aims to systematically review the literature to explore the influencing factors of necrotizing enterocolitis in premature infants in China and provide a reference for the prevention of NEC. Methods PubMed, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure (CNKI), China Biomedical Literature Database (CBM), Wanfang and VIP databases were systematically searched from inception to February 2023. We used Stata14.0 software to perform the systematic review and meta-analysis. We used fixed or random effects models with combined odds ratios (ORs) and 95% confidence intervals (CIs), and quality was evaluated using the Newcastle‒Ottawa Scale (NOS). Results The total sample was 8616 cases, including 2456 cases in the intervention group and 6160 cases in the control group. It was found that 16 risk factors and 3 protective factors were related to necrotizing enterocolitis in premature infants. Septicemia (OR = 3.91), blood transfusion (OR = 2.41), neonatal asphyxia (OR = 2.46), pneumonia (OR = 6.17), infection (OR = 5.99), congenital heart disease (OR = 4.80), intrahepatic cholestasis of pregnancy (ICP) (OR = 2.71), mechanical ventilation (OR = 1.44), gestational diabetes mellitus (GDM) (OR = 3.08), respiratory distress syndrome (RDS) (OR = 3.28), hypoalbuminemia (OR = 2.80), patent ductus arteriosus (PDA) (OR = 3.10), respiratory failure (OR = 7.51), severe anemia (OR = 2.86), history of antibiotic use (OR = 2.12), and meconium-stained amniotic fluid (MSAF) (OR = 3.14) were risk factors for NEC in preterm infants in China. Breastfeeding (OR = 0.31), oral probiotics (OR = 0.36), and prenatal use of glucocorticoids (OR = 0.38) were protective factors for NEC in preterm infants. Conclusions Septicemia, blood transfusion, neonatal asphyxia, pneumonia, infection, congenital heart disease, ICP, GDM, RDS, hypoproteinemia, PDA, respiratory failure, severe anemia, history of antibiotic use and MSAF will increase the risk of NEC in premature infants, whereas breastfeeding, oral probiotics and prenatal use of glucocorticoids reduce the risk. Due to the quantity and quality of the included literature, the above findings need to be further validated by more high-quality studies.

Chorioamnionitis is a risk factor for necrotizing enterocolitis (NEC). Ureaplasma parvum (UP) is clinically the most isolated microorganism in chorioamnionitis, but its pathogenicity remains debated. Chorioamnionitis is associated with ileal barrier changes, but colonic barrier alterations, including those of the mucus barrier, remain under-investigated, despite their importance in NEC pathophysiology. Therefore, in this study, the hypothesis that antenatal UP exposure disturbs colonic mucus barrier integrity, thereby potentially contributing to NEC pathogenesis, was investigated. In an established ovine chorioamnionitis model, lambs were intra-amniotically exposed to UP or saline for 7 d from 122 to 129 d gestational age. Thereafter, colonic mucus layer thickness and functional integrity, underlying mechanisms, including endoplasmic reticulum (ER) stress and redox status, and cellular morphology by transmission electron microscopy were studied. The clinical significance of the experimental findings was verified by examining colon samples from NEC patients and controls. UP-exposed lambs have a thicker but dysfunctional colonic mucus layer in which bacteria-sized beads reach the intestinal epithelium, indicating undesired bacterial contact with the epithelium. This is paralleled by disturbed goblet cell MUC2 folding, pro-apoptotic ER stress and signs of mitochondrial dysfunction in the colonic epithelium. Importantly, the colonic epithelium from human NEC patients showed comparable mitochondrial aberrations, indicating that NEC-associated intestinal barrier injury already occurs during chorioamnionitis. This study underlines the pathogenic potential of UP during pregnancy; it demonstrates that antenatal UP infection leads to severe colonic mucus barrier deficits, providing a mechanistic link between antenatal infections and postnatal NEC development. [ABSTRACT FROM AUTHOR]

Objective: To know the association of abdominal ultrasound findings in preterm newborns with necrotizing enterocolitis. Method: Transverse, analytical study, patients with necrotizing enterocolitis abdominal ultrasound was performed: free fluid, large wall more than 2.5 mm, small bowel wall less than 1.1 mm, gas in portal vein, intestinal pneumatosis, decreased and/or absence of peristalsis, increase and/or absence of intestinal blood infusion. Chi square and Mann-Whitney U tests were used to establish association ultrasound findings and necrotizing enterocolitis, alpha level < 0.05, SPSS v.23.0 program. Results: 37 patients. IA stage: small intestine wall less than 1.1 mm with a total of 15 (40%), 13 (35%) decreased peristalsis 11 (29%), absence of peristalsis 8 (21.62%). IB stage: free liquid, increased blood infusion 2 (5%). IIA stage: peristalsis decreased 7 (18%), small intestine wall less than 1.1 mm 4 (10%), free liquid 3 (8%), pneumatosis 2 (5%), absent blood infusion 1 (2%). IIIA stage: 1 (2%) free liquid, thinning of small intestine wall less than 1.1 mm, absence of peristalsis and blood infusion. Conclusion: There is an association of ultrasonographic findings in patients with necrotizing enterocolitis. Most frequent finding: small bowel wall less than 1.1 mm, free fluid, decreased peristalsis. It would be important to implement it as a diagnostic method in all cases for medical and surgical decision-making. [ABSTRACT FROM AUTHOR]

OBJECTIVE Acetaminophen (APAP) is an alternative to indomethacin and ibuprofen for treatment of patent ductus arteriosus (PDA). The side effect profile of non-steroidal anti-inflammatory drugs (NSAIDs) presents enteral feeding safety concerns; however, the safety of enteral feeding on APAP is largely unknown. Optimal feeding strategies during pharmacological PDA treatment are unknown, leading to practice variation. This study aims to assess the incidence of adverse gastrointestinal (GI) outcomes in neonates treated with APAP for PDA closure while receiving enteral feedings. METHODS Single-center retrospective cohort study of 59 extremely low birth weight (ELBW), premature neonates who received APAP for PDA treatment divided into Low Volume (LV; ≤ 20 mL/kg/day) and High Volume (HV; > 20 mL/kg/day) enteral feeding groups. The primary outcome was the incidence of any suspected or confirmed necrotizing enterocolitis (NEC). Timing of nutrition milestones, parenteral nutrition (PN) days, and adverse outcomes (feeding intolerance, liver dysfunction, death prior to discharge) were evaluated. RESULTS The incidence of suspected or confirmed NEC was 19.5% in the LV group and 13.3% in the HV group (p = 0.593). The HV group reached full feeds 6 days sooner (18 vs 24 days, p = 0.024) and had fewer PN days (17 vs 23.5 days, p = 0.044) with no difference in adverse outcomes. CONCLUSIONS Provision of > 20 mL/kg/day of enteral feeds during APAP treatment of PDA decreased time to full feeds and PN days compared to trophic feedings (≤ 20 mL/kg/day) with no difference in adverse GI outcomes. Continuing enteral feeding during APAP PDA treatment appears safe while improving achievement of nutritional milestones. [ABSTRACT FROM AUTHOR]

Human milk contains extracellular vesicles (HMEVs). Pre‐clinical models suggest that HMEVs may enhance intestinal function and limit inflammation; however, it is unknown if HMEVs or their cargo survive neonatal human digestion. This limits the ability to leverage HMEV cargo as additives to infant nutrition or as therapeutics. This study aimed to develop an EV isolation pipeline from small volumes of human milk and neonatal intestinal contents after milk feeding (digesta) to address the hypothesis that HMEVs survive in vivo neonatal digestion to be taken up intestinal epithelial cells (IECs). Digesta was collected from nasoduodenal sampling tubes or ostomies. EVs were isolated from raw and pasteurized human milk and digesta by density‐gradient ultracentrifugation following two‐step skimming, acid precipitation of caseins, and multi‐step filtration. EVs were validated by electron microscopy, western blotting, nanoparticle tracking analysis, resistive pulse sensing, and super‐resolution microscopy. EV uptake was tested in human neonatal enteroids. HMEVs and digesta EVs (dEVs) show typical EV morphology and are enriched in CD81 and CD9, but depleted of β‐casein and lactalbumin. HMEV and some dEV fractions contain mammary gland‐derived protein BTN1A1. Neonatal human enteroids rapidly take up dEVs in part via clathrin‐mediated endocytosis. Our data suggest that EVs can be isolated from digestive fluid and that these dEVs can be absorbed by IECs. [ABSTRACT FROM AUTHOR]

The integrity of the intestinal mucus barrier is crucial for human health, as it serves as the body's first line of defense against pathogens. However, postnatal development of the mucus barrier and interactions between maturity and its ability to adapt to external challenges in neonatal infants remain unclear. In this study, we unveil a distinct developmental trajectory of the mucus barrier in preterm piglets, leading to enhanced mucus microstructure and reduced mucus diffusivity compared to term piglets. Notably, we found that necrotizing enterocolitis (NEC) is associated with increased mucus diffusivity of our large pathogen model compound, establishing a direct link between the NEC condition and the mucus barrier. Furthermore, we observed that addition of sodium decanoate had varying effects on mucus diffusivity depending on maturity and health state of the piglets. These findings demonstrate that regulatory mechanisms governing the neonatal mucosal barrier are highly complex and are influenced by age, maturity, and health conditions. Therefore, our results highlight the need for specific therapeutic strategies tailored to each neonatal period to ensure optimal gut health. [ABSTRACT FROM AUTHOR]

Purpose: This study was aimed to investigate the risk factors of necrotizing enterocolitis (NEC) in twin preterm infants. Methods: The clinical data of 67 pairs of twin preterm infants admitted to the neonatal department of our hospital from January 2010 to December 2021 were retrospectively collected. One of the twins had NEC (Bell II and above) and the other twin without NEC. They were divided into NEC group and control group according to whether NEC occurred or not. Results: Univariate analysis showed that NEC was associated with congenital heart disease, small for gestational age, mild asphyxia at birth and feeding intolerance (P < 0.05). Conclusion: Occurrence of NEC was associated with congenital heart disease, small for gestational age, and asphyxia at birth. For twin preterm infants with congenital heart disease, small for gestational age, or asphyxia at birth, special attention should be paid to the occurrence of NEC to minimize and avoid the occurrence of NEC. [ABSTRACT FROM AUTHOR]

Inflammation, oxidative injury, and gut dysbiosis play an important role in the pathogenesis of necrotising enterocolitis (NEC). Plant-derived substances have historically been used as therapeutic agents due to their anti-inflammatory, antioxidant, and antimicrobial properties. We aimed to review pre-clinical evidence for plant-derived substances in the prevention and treatment of NEC. A systematic review was conducted using the following databases: PubMed, EMBASE, EMCARE, MEDLINE and Cochrane Library (PROSPERO CRD42022365477). Randomized controlled trials (RCTs) and quasi-RCTs that evaluated a plant-derived substance as an intervention for NEC in an animal model of the illness and compared pre-stated outcomes (e.g., clinical severity, severity of intestinal injury, mortality, laboratory markers of inflammation and oxidative injury) were included. Sixteen studies (n = 610) were included in the systematic review. Ten of the sixteen included RCTs (Preterm rat pups: 15, Mice: 1) reported mortality and all reported NEC-related histology. Meta-analysis showed decreased mortality [12/134 vs. 27/135; RR: 0.48 (95% CI: 0.26 to 0.87); p = 0.02, 10 RCTs] and decreased NEC in the experimental group [24/126 vs. 55/79; RR: 0.34 (95% CI: 0.22 to 0.52); p < 0.001, 6 RCTs]. Markers of inflammation (n = 11) and oxidative stress (n = 13) improved in all the studies that have reported this outcome. There was no significant publication bias for the outcome of mortality. Plant-derived substances have the potential to reduce the incidence and severity of histologically diagnosed NEC and mortality in rodent models. These findings are helpful in guiding further pre-clinical studies towards developing a food supplement for the prevention of NEC in preterm infants. [ABSTRACT FROM AUTHOR]

Introduction: Necrotizing enterocolitis (NEC) poses a significant threat to preterm infants, with nonspecific early manifestations complicating timely diagnosis. Therefore, this study aimed to develop a novel scoring system for early diagnosis of NEC, incorporating clinical and laboratory data with urinary caveolin-1 levels. Material and methods: A single-center prospective cohort study was conducted at a tertiary hospital in East Java, Indonesia. NEC diagnosis was established by Bell's criteria and proven gut dysbiosis. Urinary levels of claudin-2, caveolin-1, and epidermal growth factor (EGF) were assessed as potential indicators of tight junction disruption. The selected urine biomarker cutoff value was determined using symbolic classification analysis and combined with clinical and laboratory parameters from Bell's criteria to create an NEC scoring system, validated with the Aiken index. Sensitivity and specificity analyses were performed. Results: Thirty-four neonates, comprising NEC, preterm non-NEC, and term infants, were included. qPCR analysis highlighted elevated Klebsiella, Lactobacillus, Clostridium, and Bacteroides levels in NEC patients, indicating a gut dysbiosis trend. Among 3 biomarkers, caveolin-1 ≥ 17.81 ng/dl on day 3 demonstrated 72.86% negative predictive value and 87.50% positive predictive value. The combined scoring system which comprised abdominal cellulitis, distension, radiology, advanced resuscitation at birth, prematurity or low birthweight, platelet count, sepsis, orogastric retention, metabolic acidosis and caveolin-1 findings exhibited an AUC of 0.922 (95% CI: 0.81-1.00, p < 0.001), with ≥ 1.81 as the cutoff, offering 93% sensitivity and 94% specificity. Conclusions: Urine caveolin-1 on day 3 signifies enterocyte tight junction damage and the acute phase of NEC in premature infants. The proposed scoring system demonstrates good performance in predicting NEC incidence in preterm infants. [ABSTRACT FROM AUTHOR]

Molecular oxygen is typically delivered to patients via oxygen inhalation or extracorporeal membrane oxygenation (ECMO), potentially resulting in systemic hyperoxia from liberal oxygen inhalation or localized hyperoxia in the lower body from peripheral venoarterial (VA) ECMO. Consequently, this exposes the gastrointestinal tract to excessive oxygen levels. Hyperoxia can trigger organ damage due to the overproduction of reactive oxygen species and is associated with increased mortality. The gut and gut microbiome play pivotal roles in critical illnesses and even small variations in oxygen levels can have a dramatic influence on the physiology and ecology of gut microbes. Here, we reviewed the emerging preclinical evidence which highlights how excessive inhaled oxygen can provoke diffuse villous damage, barrier dysfunction in the gut, and gut dysbiosis. The hallmark of this dysbiosis includes the expansion of oxygen-tolerant pathogens (e.g., Enterobacteriaceae) and the depletion of beneficial oxygen-intolerant microbes (e.g., Muribaculaceae). Furthermore, we discussed potential impact of oxygen on the gut in various underlying critical illnesses involving inspiratory oxygen and peripheral VA-ECMO. Currently, the available findings in this area are somewhat controversial, and a consensus has not yet to be reached. It appears that targeting near-physiological oxygenation levels may offer a means to avoid hyperoxia-induced gut injury and hypoxia-induced mesenteric ischemia. However, the optimal oxygenation target may vary depending on special clinical conditions, including acute hypoxia in adults and neonates, as well as particular patients undergoing gastrointestinal surgery or VA-ECMO support. Last, we outlined the current challenges and the need for future studies in this area. Insights into this vital ongoing research can assist clinicians in optimizing oxygenation for critically ill patients. [ABSTRACT FROM AUTHOR]

Diagnosis of necrotizing enterocolitis (NEC) relies heavily on imaging, but uncertainty in the language used in imaging reports can result in ambiguity, miscommunication, and potential diagnostic errors. To determine the degree of uncertainty in reporting imaging findings for NEC, we conducted a secondary analysis of the data from a previously completed pilot diagnostic randomized controlled trial (2019–2020). The study population comprised sixteen preterm infants with suspected NEC randomized to abdominal radiographs (AXRs) or AXR + bowel ultrasound (BUS). The level of uncertainty was determined using a four-point Likert scale. Overall, we reviewed radiology reports of 113 AXR and 24 BUS from sixteen preterm infants with NEC concern. The BUS reports showed less uncertainty for reporting pneumatosis, portal venous gas, and free air compared to AXR reports (pneumatosis: 1 [1–1.75) vs. 3 [2–3], p < 0.0001; portal venous gas: 1 [1–1] vs. 1 [1–1], p = 0.02; free air: 1 [1–1] vs. 2 [1–3], p < 0.0001). In conclusion, we found that BUS reports have a lower degree of uncertainty in reporting imaging findings of NEC compared to AXR reports. Whether the lower degree of uncertainty of BUS reports positively impacts clinical decision making in infants with possible NEC remains unknown. [ABSTRACT FROM AUTHOR]

This comprehensive review examines the role of Neutrophil Extracellular Traps (NETs) in pediatric surgery. Focusing on NET formation, functions, and implications, this study highlights their dual impact in infection control and contribution to tissue damage after surgery. It covers the role of NET formation in a range of pediatric conditions including immunothrombosis, formation of peritoneal adhesions, appendicitis, burns, gallstones, tumors, and necrotizing enterocolitis (NEC). The results underscore the significance of NETs in fighting infections and their association with complications like sepsis and delayed wound healing. The breakdown products of NETs as a diagnostic tool of the clinical course of acute appendicitis will also be discussed. Understanding NET formation in the pathophysiology can potentially help to find new therapeutic approaches such as the application of DNase and elastase inhibitors to change the clinical course of various diseases in pediatric surgery such as improvement of wound healing, adhesion formation, NEC, and many more. [ABSTRACT FROM AUTHOR]

Objectives: To determine the difference in time to attainment of full enteral feeds between fetal growth restricted (FGR) preterm neonates with and without absent/reversed end-diastolic flow (AREDF). Secondary objectives were to compare the short-term outcomes including the incidence of necrotizing enterocolitis (NEC) and feed intolerance between the two groups and to determine the factors affecting the time to attainment of full enteral feeds (FEF) among preterm FGR neonates. Methods: A prospective cohort study was conducted among consecutive preterm FGR neonates delivered at 28–36 weeks gestation admitted in level III NICU. An umbilical artery doppler ultrasound was performed antenatally for all participants to detect AREDF. FGR neonates with AREDF were taken as the study group and those without AREDF were taken as the comparison group. Time to attain FEF was defined as time taken to establish enteral feeds of 150 ml/kg/day and tolerating it for the next 3 consecutive days. Delayed attainment of FEF was taken as ≥10 days needed to attain FEF. Result: The median (IQR) time to attainment of full feeds was longer among neonates with AREDF compared to those without AREDF [12 (8, 16.5) vs 8 (5, 10) days; P < 0.001]. Neonates with AREDF had more feed intolerance [RR, 95% CI = 1.51 (1.13–2.02); P = 0.004], higher mortality [RR, 95% CI = 2.5 (1.02–6.2); P = 0.036], prolonged time to regain birth weight [15 (11.5, 19) days, P = 0.035], longer NICU stay [10 (7, 15), P < 0.001] and longer hospital stay [33 (23, 49), P < 0.001]. Also, neonates with AREDF had more hypoglycemia [RR, 95% CI=2.15 (1.2–3.7); P = 0.004], hypoxic ischemic encephalopathy [RR, 95% CI 5.05 (1.13–22.4); P = 0.016], hypothyroidism [RR, 95% CI= 8.08 (1.02–63.4), P = 0.016], cholestasis (P = 0.007), prolonged parenteral nutrition requirement [10 (7, 15) days, P < 0.001] and oxygen requirement [4.5 (2, 8) days, P < 0.001]. Multivariable logistic regression showed, AREDF [aOR 95% CI 2.91 (1.49–5.68), P = 0.002], lower gestational age [aOR 95% CI 0.724 (0.604–0.867), P < 0.001] and thrombocytopenia at birth [aOR 95% CI 2.625 (1.342–5.136), P = 0.005] are significant predictors of delayed attainment of full feeds among preterm FGR neonates. Conclusion: Preterm FGR neonates with AREDF are slower to attain FEF, have more feed intolerance, higher mortality, need longer time to regain birth weight, prolonged NICU stay and hospital stay. AREDF, lower gestation, sepsis and thrombocytopenia at birth are significant predictors of delayed full feed attainment among preterm FGR neonates. It is essential to devise strategies to reduce morbidity and mortality among this group of preterm neonates. [ABSTRACT FROM AUTHOR]

Background: Necrotizing enterocolitis (NEC) is a multifactorial gastrointestinal disease with high morbidity and mortality among premature infants. However, studies with large samples on the factors of NEC in China have not been reported. This meta-analysis aims to systematically review the literature to explore the influencing factors of necrotizing enterocolitis in premature infants in China and provide a reference for the prevention of NEC. Methods: PubMed, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure (CNKI), China Biomedical Literature Database (CBM), Wanfang and VIP databases were systematically searched from inception to February 2023. We used Stata14.0 software to perform the systematic review and meta-analysis. We used fixed or random effects models with combined odds ratios (ORs) and 95% confidence intervals (CIs), and quality was evaluated using the Newcastle‒Ottawa Scale (NOS). Results: The total sample was 8616 cases, including 2456 cases in the intervention group and 6160 cases in the control group. It was found that 16 risk factors and 3 protective factors were related to necrotizing enterocolitis in premature infants. Septicemia (OR = 3.91), blood transfusion (OR = 2.41), neonatal asphyxia (OR = 2.46), pneumonia (OR = 6.17), infection (OR = 5.99), congenital heart disease (OR = 4.80), intrahepatic cholestasis of pregnancy (ICP) (OR = 2.71), mechanical ventilation (OR = 1.44), gestational diabetes mellitus (GDM) (OR = 3.08), respiratory distress syndrome (RDS) (OR = 3.28), hypoalbuminemia (OR = 2.80), patent ductus arteriosus (PDA) (OR = 3.10), respiratory failure (OR = 7.51), severe anemia (OR = 2.86), history of antibiotic use (OR = 2.12), and meconium-stained amniotic fluid (MSAF) (OR = 3.14) were risk factors for NEC in preterm infants in China. Breastfeeding (OR = 0.31), oral probiotics (OR = 0.36), and prenatal use of glucocorticoids (OR = 0.38) were protective factors for NEC in preterm infants. Conclusions: Septicemia, blood transfusion, neonatal asphyxia, pneumonia, infection, congenital heart disease, ICP, GDM, RDS, hypoproteinemia, PDA, respiratory failure, severe anemia, history of antibiotic use and MSAF will increase the risk of NEC in premature infants, whereas breastfeeding, oral probiotics and prenatal use of glucocorticoids reduce the risk. Due to the quantity and quality of the included literature, the above findings need to be further validated by more high-quality studies. [ABSTRACT FROM AUTHOR]

Objective: To investigate the clinical characteristics of neonatal necrotizing enterocolitis (NEC) complicated by intestinal perforation and predict the incidence of intestinal perforation in NEC. Methods: Neonates diagnosed with NEC at the Affiliated Hospital of Zunyi Medical University from January 2012 to May 2022 were enrolled, and the clinical data were collected and analyzed retrospectively. The patients were divided into two groups based on intestinal perforation occurrence or not. Mann-Whitney U tests, t-tests, chi-square tests, and fisher's exact tests were performed between-group comparisons. Logistic and lasso regressions were applied to screen independent risk factors for concomitant bowel perforation, and R software (RMS package) was used to formulate the nomogram prediction model. In addition, the receiver operating curve (ROC) and the calibration curve were drawn to verify the predictive power, while decision curve analysis (DCA) was constructed to evaluate the clinical applicability of the nomogram model. Results: One hundred eighty neonates with NEC were included, of which 48 had intestinal perforations, and 132 did not; the overall incidence of intestinal perforation was 26.67% (48/180). Bloody stool (OR = 5.60), APTT ≥ 50 s (OR = 3.22), thrombocytopenia (OR = 4.74), and hypoalbuminemia (OR = 5.56) were identified as independent risk variables for NEC intestinal perforation (P < 0.05) through multivariate logistic regression analysis. These factors were then applied to develop a nomogram prediction model (C-index = 0.838) by using the R software. The area under the curve (AUC) for the nomogram in the training and validation cohorts were 0.838 (95% Cl: 0.768, 0.908) and 0.802 (95% CI: 0.659, 0.944), respectively. The calibration curve shown that the nomogram has a good predictive ability for predicting the risk of intestinal perforation occurrence. And the decision curve and clinical impact curve analyses demonstrated good clinical utility of the nomogram model. Conclusion: We found that Bloody stool, APTT ≥ 50 s, Thrombocytopenia, and hypoalbuminemia could be used as independent risk factors for predicting intestinal perforation in neonates with NEC. The nomogram model based on these variables had high predictive values to identify NEC patients with intestinal perforation. [ABSTRACT FROM AUTHOR]

Introduction: Disruptions of the gut microbiota of preterm infants admitted to the neonatal intensive care unit (NICU) during the first 2 weeks of life are of critical importance. These infants are prone to various complications, including necrotizing enterocolitis (NEC) and sepsis. Studying the gut microbiota will improve outcomes in preterm infants. In the present study, we examined the gut microbiota of preterm infants admitted to the NICU in the first month of life. Methods: Neonates admitted to the NICU were recruited, and stool samples were collected weekly from the seventh day of the infant's life until the 30th day of life. DNA was extracted using a DNeasy Powersoil DNA isolation kit. 16S rRNA gene sequencing targeting the V3-V4 region was performed using the MiSeq platform. Sequenced reads were processed on DADA2 pipeline to obtain an amplicon sequence variant (ASV) table. All bioinformatic and statistical analyses were performed using different packages in the R statistical framework. Results: Fourteen preterm infants were recruited, and 48 samples were collected. Alpha diversity metrics, observed ASV count, and Shannon index were found to have no differences in any clinical variables. Permutational multivariate analysis of variance (PERMANOVA) showed discrimination of neonates by gestational age and administration of probiotics. Differential abundance analysis showed a decreased abundance of Bifidobacterium Breve in extremely preterm infants (gestational age <28 weeks) compared to moderate preterm infants (gestational age 29-32 weeks). Supplementation with probiotics decreased Acinetobacter and increased Bifidobacterium in the gut of preterm neonates regardless of gestational age. Conclusion: Gestational age and probiotic supplementation alter the gut microbiota of preterm infants admitted to the NICU. [ABSTRACT FROM AUTHOR]

Necrotizing enterocolitis (NEC) is a destructive gastrointestinal disease primarily affecting preterm babies. Despite advancements in neonatal care, NEC remains a significant cause of morbidity and mortality in neonatal intensive care units worldwide and the etiology of NEC is still unclear. Risk factors for NEC include prematurity, very low birth weight, feeding with formula, intestinal dysbiosis and bacterial infection. A review of the literature would suggest that supplementation of prebiotics and probiotics prevents NEC by altering the immune responses. Innate T cells, a highly conserved subpopulation of T cells that responds quickly to stimulation, develops differently from conventional T cells in neonates. This review aims to provide a succinct overview of innate T cells in neonates, encompassing their phenotypic characteristics, functional roles, likely involvement in the pathogenesis of NEC, and potential therapeutic implications. [ABSTRACT FROM AUTHOR]

In recent years, interest in probiotics in publications has been steadily increasing. This is associated with the discovery of the relationship between disruptions in the gut microbiome and dysfunction of the immune system, and consequently, the development of various diseases and allergies. The composition of the natural gut microbiota in newborns can undergo changes, and as a result, we can influence it both prenatally and postnatally. According to available research, factors influencing it include the timing and method of delivery, maternal antibiotic use during pregnancy and breastfeeding, as well as antibiotic use in newborns after birth, and the method of feeding the child. It is suspected that disturbances in the composition of gut microbiota from the earliest stages of life contribute to the development of disorders such as functional gastrointestinal disorders (diarrhea, constipation, irritable bowel syndrome), inflammatory bowel diseases, allergies, atopic dermatitis, neurodevelopmental disorders (autism spectrum disorders), and increased risk of obesity in later years of the child's life. When significant dysbiosis occurs, stimulating the growth of protective and nutritive autochthonous bacteria on the intestinal epithelium is difficult to achieve in any other way than using appropriately selected probiotic strains. However, it is important to remember to choose probiotics with a well-researched quantitative and qualitative composition, and to select them depending on the underlying disease, as well as the age and other conditions of the patient.

Necrotizing enterocolitis (NEC) is one of the most common and serious intestinal illnesses in newborns and seriously affects their long-term prognosis and survival. Butyrate is a short-chain fatty acid that can relieve intestinal inflammation, but its mechanism of action is unclear. Results from an in vivo neonatal rat model has shown that butyrate caused an improved recovery from NEC. These protective effects were associated with the metabolite of hesperetin, as determined by metabolomics and molecular biological analysis. Furthermore, transcriptomics combined with inhibitor assays were used to investigate the mechanism of action of hesperetin in an in vitro NEC model (IEC-6 cells exposed to LPS) to further investigate the mechanism by which butyrate attenuates NEC. The transcriptomics analysis showed that the PI3K-Akt signaling pathway was involved in the anti-NEC effect of hesperitin. Subsequently, the results using an inhibitor of PI3K (LY294002) indicated that the suppression could be explained by the hesperetin-induced expression of tight junction (TJ) proteins by potentially blocking the PI3K-Akt signaling pathway. In summary, the present study demonstrated that butyrate could improve recovery from NEC with a hesperetin metabolite, causing potential inhibition of the phosphorylation of the PI3K-Akt signaling pathway, resulting in the increased expression of TJ proteins. These findings reveal a potential new therapeutic pathway for the treatment of NEC.

Necrotizing enterocolitis (NEC) is a serious gastrointestinal condition that primarily affects premature infants, although it can also occur in full-term infants. It is characterized by inflammation and injury of the intestinal tissue, which can progress to necrosis and perforation of the bowel. NEC is a leading cause of morbidity and mortality in neonatal intensive care units (NICUs), particularly among very low birth weight infants. Diagnosis of NEC is based on clinical signs and symptoms, radiographic findings, and laboratory tests. Management of NEC involves a multidisciplinary approach, including supportive care, medical therapy, and surgical intervention when necessary. Supportive care includes bowel rest, intravenous fluids, and nutritional support. Medical therapy may include antibiotics, gastric decompression, and parenteral nutrition. Surgical intervention may be required for infants with intestinal perforation, severe NEC, or complications such as intestinal stricture or short bowel syndrome. This condition and its complications may carry consequences for life and especially sport performance in the child’s future. Strategies for preventing NEC include promoting breastfeeding, avoiding unnecessary antibiotic exposure, minimizing enteral feeding interruptions, practicing strict infection control measures, and implementing protocols for gradual feeding advancement in premature infants. Overall, NEC is a complex and multifactorial disease that poses significant challenges in neonatal care. Early recognition, prompt intervention, and comprehensive management are essential for optimizing outcomes for affected infants. Further research is needed to better understand the pathophysiology of NEC and to develop more effective prevention and treatment strategies.

Necrotizing enterocolitis (NEC) is a severe gastrointestinal disease primarily affecting premature neonates, marked by poorly understood pro-inflammatory signaling cascades. Recent advancements have shed light on a subset of endogenous molecular patterns, termed chromatin-associated molecular patterns (CAMPs), which belong to the broader category of damage-associated molecular patterns (DAMPs). CAMPs play a crucial role in recognizing pattern recognition receptors and orchestrating inflammatory responses. This review focuses into the realm of CAMPs, highlighting key players such as extracellular cold-inducible RNA-binding protein (eCIRP), high mobility group box 1 (HMGB1), cell-free DNA, neutrophil extracellular traps (NETs), histones, and extracellular RNA. These intrinsic molecules, often perceived as foreign, have the potential to trigger immune signaling pathways, thus contributing to NEC pathogenesis. In this review, we unravel the current understanding of the involvement of CAMPs in both preclinical and clinical NEC scenarios. We also focus on elucidating the downstream signaling pathways activated by these molecular patterns, providing insights into the mechanisms that drive inflammation in NEC. Moreover, we scrutinize the landscape of targeted therapeutic approaches, aiming to mitigate the impact of tissue damage in NEC. This in-depth exploration offers a comprehensive overview of the role of CAMPs in NEC, bridging the gap between preclinical and clinical insights.

ObjectiveThe purpose of this study is to develop a multimodal model based on artificial intelligence to assist clinical doctors in the early diagnosis of necrotizing enterocolitis in newborns.MethodsThis study is a retrospective study that collected the initial laboratory test results and abdominal x-ray image data of newborns (non-NEC, NEC) admitted to our hospital from January 2022 to January 2024.A multimodal model was developed to differentiate multimodal data, trained on the training dataset, and evaluated on the validation dataset. The interpretability was enhanced by incorporating the Gradient-weighted Class Activation Mapping (GradCAM) analysis to analyze the attention mechanism of the multimodal model, and finally compared and evaluated with clinical doctors on external datasets.ResultsThe dataset constructed in this study included 11,016 laboratory examination data from 408 children and 408 image data. When applied to the validation dataset, the area under the curve was 0.91, and the accuracy was 0.94. The GradCAM analysis shows that the model's attention is focused on the fixed dilatation of the intestinal folds, intestinal wall edema, interintestinal gas, and portal venous gas. External validation demonstrated that the multimodal model had comparable accuracy to pediatric doctors with ten years of clinical experience in identification.ConclusionThe multimodal model we developed can assist doctors in early and accurate diagnosis of NEC, providing a new approach for assisting diagnosis in underdeveloped medical areas.

Necrotizing enterocolitis (NEC) is a devastating disease of the neonatal intestine, causing widespread intestinal necrosis as well systemic illness that frequently results in death. Because the clinical onset of NEC is sudden and difficult to predict, NEC is considered an acute event. However, NEC does not occur in utero, meaning that postnatal exposures are required, and it does not typically occur right after birth, suggesting that longitudinal changes may be occurring before NEC can develop. In this perspective, the author considers whether NEC should be re-considered as a problem of disordered intestinal epithelial development, with required maladaptation over time prior to the onset of the necrotic event. This framework is similar to how bronchopulmonary dysplasia is currently conceptualized. They also advocate that NEC researchers incorporate this possibility into future studies on NEC susceptibility and pathogenesis.

Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency in neonates, particularly preterm infants. Many factors can lead to NEC, but microbial dysbiosis is one of the most important risk factors that can induce this disease. Given the major role of the gut virome in shaping bacterial homeostasis, virome research is a fledgling but rapidly evolving area in the field of microbiome that is increasingly connected to human diseases, including NEC. This review provides an overview of the development of the gut virome in newborns, discusses its emerging role in NEC, and explores promising therapeutic applications, including phage therapy and fecal virome transplantation.

Neuroendocrine carcinomas (NECs) of the gallbladder are very rare and aggressive tumors with poor prognosis. Most of them are poorly differentiated and belong to the small cell type. We report a case of a 59-year-old woman who presented with abdominal pain and distension. Contrast-enhanced computed tomography revealed a large heterogeneous mass in the liver, adjacent to the gallbladder, and omental nodules. CA 19-9 level was elevated and ascitic fluid cytology was suspicious for malignancy. Percutaneous biopsy of the liver mass confirmed the diagnosis of small cell NEC of the gallbladder. The patient was considered inoperable and planned for chemotherapy, but she died 20 days after admission. This case illustrates the diagnostic challenges and the dismal outcome of small cell NEC of the gallbladder. Early detection and multimodal treatment are essential for improving the survival of these patients. [ABSTRACT FROM AUTHOR]

IntroductionChorioamnionitis is common in preterm birth and associated with a higher risk of intestinal inflammation and necrotizing enterocolitis. The intestinal inflammation influences the enteric nervous system development. We hypothesized that inflammation and innervation in the fetal ileum may be modified by chorioamnionitis induced by repeated challenge with lipopolysaccharide and/or preexisting Ureaplasma parvum infection at very low gestational age equivalent to 60% of term.Materials and methodsTime mated ovine fetuses were exposed by intraamniotic injections to chronic Ureaplasma parvum for 24 days and/or lipopolysaccharide for 7 days, 2 days, or 7 & 2 days before delivery at 94 +/-2 days of gestational age (term at approximately 150 days). Intestinal inflammation as well as structural changes of the enteric nervous system were assessed.ResultsLipopolysaccharide exposure increased CD3 and myeloperoxidase-positive cells (p < 0.05). Repetitive exposure to lipopolysaccharide or combined Ureaplasma parvum & lipopolysaccharide exposure increased intestinal inflammation (p < 0.05). The reduction of nuclei of neurons was most significant with repetitive lipopolysaccharide exposures but could be detected in all other intervention groups compared to the control group. Astrocyte-like glial cells increased if exposure to lipopolysaccharide was only 2 days before delivery or chronic exposure to Ureaplasma parvum existed beforehand (p < 0.05).DiscussionAfter exposure to chorioamnionitis induced by Ureaplasma parvum and/or lipopolysaccharide, inflammatory responses as well as structural changes of the enteric nervous system were more pronounced the longer and the more frequent the exposure to pro-inflammatory stimuli before birth. These changes may cause functional effects of clinical importance.

Necrotizing enterocolitis (NEC) is the leading cause of death caused by gastrointestinal disease in preterm infants. Major risk factors include prematurity, formula feeding, and gut microbial colonization. Microbes have been linked to NEC, yet there is no evidence of causal species, and select probiotics have been shown to reduce NEC incidence in infants. In this study, we evaluated the effect of the probiotic Bifidobacterium longum subsp. infantis (BL. infantis), alone and in combination with a human milk oligosaccharide (HMO)-sialylactose (3'SL)-on the microbiome, and the incidence of NEC in preterm piglets fed an infant formula diet. We studied 50 preterm piglets randomized between 5 treatments: (1) Preterm infant formula, (2) Donor human milk (DHM), (3) Infant formula + 3'SL, (4) Infant formula + BL. infantis, and (5) Infant formula and BL. infantis + 3'SL. NEC incidence and severity were assessed through the evaluation of tissue from all the segments of the GI tract. The gut microbiota composition was assessed both daily and terminally through 16S and whole-genome sequencing (WGS) of rectal stool samples and intestinal contents. Dietary BL. infantis and 3'SL supplementation had no effect, yet DHM significantly reduced the incidence of NEC. The abundance of BL. infantis in the gut contents negatively correlated with disease severity. Clostridium sensu stricto 1 and Clostridium perfringens were significantly more abundant in NEC and positively correlated with disease severity. Our results suggest that pre- and probiotics are not sufficient for protection from NEC in an exclusively formula-based diet. The results highlight the differences in microbial species positively associated with both diet and NEC incidence.

Necrotizing Enterocolitis (NEC) is one of the leading causes of gastrointestinal emergency in preterm infants. Although NEC was formally described in the 1960's, there is still difficulty in diagnosis and ultimately treatment for NEC due in part to the multifactorial nature of the disease. Artificial intelligence (AI) and machine learning (ML) techniques have been applied by healthcare researchers over the past 30 years to better understand various diseases. Specifically, NEC researchers have used AI and ML to predict NEC diagnosis, NEC prognosis, discover biomarkers, and evaluate treatment strategies. In this review, we discuss AI and ML techniques, the current literature that has applied AI and ML to NEC, and some of the limitations in the field.

Katherine B Snyder,1,2 Chase L Calkins,3 Alena Golubkova,1,2 Tyler Leiva,1,2 Camille Schlegel,1 Catherine J Hunter1,2 1Division of Pediatric Surgery, Oklahoma City, OK, 73104, USA; 2Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA; 3College of Medicine, The University of Oklahoma College of Medicine, Oklahoma City, OK, 73104, USACorrespondence: Catherine J Hunter, Department of Pediatric Surgery, Oklahoma Children’s Hospital, 1200 Everett Drive, ET NP 2320, Oklahoma City, OK, 73104, USA, Email catherine-hunter@ouhsc.eduBackground: Necrotizing enterocolitis (NEC) is the leading gastrointestinal cause of death of premature neonates. NEC is associated with prematurity, a hyperinflammatory response, and dysregulation of intestinal barrier function. We hypothesize that patients with NEC will have, and continue to have after recovery, an increased hyperinflammatory intestinal response compared to those patients without NEC.Methods: Neonates with NEC, those that have recovered from NEC, and those without NEC undergoing intestinal resections had specimens collected and snap frozen or generated into enteroids. The enteroids were treated with 100ug/mL lipopolysaccharide (LPS) and subjected to 24 hr of hypoxia together, then compared with untreated controls. Expression of Tumor Necrosis Factor (TNF-α) and interleukin 8 (IL-8) were evaluated via RT-qPCR and ELISA to measure inflammatory response. ANOVA determined statistical significance (p< 0.05).Results: There was no difference in inflammatory markers in recovered NEC tissue compared to non-NEC tissue on RTqPCR (p=0.701 TNF-α and 0.861 IL-8). However, recovered NEC enteroids demonstrate elevated levels of inflammatory markers after treatment compared to non-NEC enteroids after treatment on RTqPCR (p=0.0485 TNF-α, p=0.0057 IL-8) and ELISA (p=0.0354 TNF-α, p=0.0011 IL-8). Recovered NEC enteroids that underwent treatment demonstrated increased inflammatory markers compared to recovered NEC enteroids without treatment on RTqPCR (p=0.0045 TNF-α, p=0.0002 IL-8) and ELISA (p=0.034 TNF-α, p=0.0002 IL-8) suggesting a heightened inflammatory response to a second hit.Conclusion: Intestinal tissue resected from neonates with NEC has an elevated hyperinflammatory response compared to neonates recovered from NEC and neonates without NEC. Enteroids generated from patients that have recovered from NEC have a heightened inflammatory response in response to NEC inducing stimuli compared to controls. This tendency towards an increased hyperinflammatory state may be correlated with an infant’s proclivity to develop NEC and demonstrates the significance of a second hit on this tissue creating a heightened inflammatory response. This could be correlated with the impact and trajectory of an illness post recovery from NEC.Keywords: necrotizing enterocolitis, recovery, hyperinflammatory, enteroids

Abstract Background The status of anastomotic blood perfusion is associated with the occurrence of anastomotic leakage after intestinal anastomosis. Fluorescence angiography (FA) with indocyanine green (ICG) can objectively assess intestinal blood perfusion. This study aims to investigate whether anastomotic perfusion assessment with ICG influences surgical decision-making during laparoscopic intestinal resection and primary anastomosis for colonic stricture after necrotizing enterocolitis. Methods Patients who underwent laparoscopic intestinal resection and primary anastomosis between January 2022 and December 2022 were retrospectively analyzed. Before intestinal anastomosis, the ICG fluorescence technology was used to evaluate the blood perfusion of intestinal tubes on both sides of the anastomosis. After the completion of primary anastomosis, the anastomotic blood perfusion was assessed again. Results Of the 13 cases, laparoscopy was used to determine the extent of the diseased bowel to be excised, and the normal bowel was preserved for anastomosis. The anastomosis was established under the guidance of ICG fluorescence technology, and FA was performed after anastomosis to confirm good blood flow in the proximal bowel. The anastomotic intestinal tube was changed in one case because FA showed a difference between the normal range of intestinal blood flow and the macroscopic prediction. There was no evidence of ICG allergy, anastomotic leakage, anastomotic stricture, or other complications. The median follow-up was 6 months, and all patients recovered well. Conclusions The ICG fluorescence technology is helpful in precisely and efficiently determining the anastomotic intestinal blood flow during stricture resection and in avoiding anastomotic leakage caused by poor anastomotic intestinal blood flow to some extent, with satisfactory short-term efficacy.