UNASSIGNED: To explore risk factors for Stage-III necrotizing enterocolitis (NEC-III) in preterm neonates.
UNASSIGNED: This was a retrospective case-control study of neonates born <33 weeks gestational age (GA) who were admitted to a tertiary neonatal intensive care unit, between 2015 and 2018. NEC-III cases were compared with Stage-II NEC (NEC-II) and non-NEC controls. Two to four non-NEC controls were matched by GA ± 1 week and date of birth ± 3 months, to one NEC-III case. Univariate and multivariate analyses were used to examine risk factors for NEC-III.
UNASSIGNED: Of 1360 neonates born <33 weeks, 71 (5.2%) had NEC-II and above, with 46% being NEC-III. Mean age of onset of NEC-III was 13.7 days versus 23.9 days for NEC-II (p = 0.01). Neonates with NEC-III were of lower GA (NEC-III 25.4 weeks, NEC-II 27.3 weeks, and non-NEC 26 weeks; p = 0.0008) and had higher Score for Neonatal Acute Physiology Perinatal Extension-II scores (NEC-III 47.5, NEC-II 28.4 and non-NEC 37, p = 0.003). Multivariate analysis showed duration of umbilical arterial catheter (UAC) >5 days was significantly associated with the development of NEC-III with adjusted odds ratio (AOR) 3.8; 95% confidence interval (CI) (1.05-13.66) for NEC-III versus non-NEC and AOR 5.57; 95% CI (1.65-18.73), p = 0.006 for NEC-III versus NEC-II. Rupture of membranes (ROM) >1 week was associated with NEC-III (AOR 6.93; 95% CI [1.56-30.69] vs. non-NEC and AOR 11.74; 95% CI [1.14-120.34] vs. NEC-II).
UNASSIGNED: The increased association of NEC-III with duration of UAC and ROM could be further examined in prospective studies, and an upper limit for UAC duration could be considered in NEC prevention bundles.

The aim of this study was to compare sequelae and acute kidney injury (AKI) occurrence among patients with necrotizing enterocolitis (NEC) after changing institutional guidelines replacing vancomycin with ampicillin for gram-positive coverage. This was a retrospective, single-center cohort analysis of patients from 2016-2020 (n = 73) with NEC at a surgical neonatal intensive care unit with a high community prevalence of methicillin-resistant Staphylococcus aureus (MRSA). Multivariate logistic regression was utilized to assess associations. Twenty-five (34%) patients had at least 1 sequela related to NEC. Ampicillin containing regimens were not associated with any sequelae type or AKI. Postmenstrual age < 29 weeks at diagnosis ([OR] 5.8 [1.2-28.8], P = .03; and receipt of vasopressors [OR] 3.3 [1.1-10.2], P = .04) were independently associated with sequalae. Stage III NEC was independently associated with AKI, OR 10.6 (2-55.6), P = .005. In conclusion, ampicillin-containing regimens are effective for NEC management at our institution despite a high prevalence of MRSA.

BACKGROUND: The notable decline in the number of Tregs within Necrotizing enterocolitis (NEC) intestinal tissues，contribute to excessive inflammation and necrosis, yet the precise underlying factors remain enigmatic. Ferroptosis, a novel cell death stemming from a disrupted lipid redox metabolism, is the focus of this investigation. Specifically, this study delves into the ferroptosis of Treg cells in the context of NEC and observes the protective effects exerted by vitamin E intervention, which aims to mitigate ferroptosis of Treg cells.
METHODS: To investigate the reduction of Treg cells in NEC intestine, we analyzed its association with ferroptosis from multiple angles. We constructed a mouse with a specific knockout of Gpx4 in Treg cells, aiming to examine the impact of Treg cell ferroptosis on NEC intestinal injury and localized inflammation. Ultimately, we employed vitamin E treatment to mitigate ferroptosis in NEC intestine\'s Treg cells, monitoring the subsequent amelioration in intestinal inflammatory damage.
RESULTS: The diminution of Treg cells in NEC is attributed to ferroptosis stemming from diminished GPX4 expression. Gpx4-deficient Treg cells exhibit impaired immunosuppressive function and are susceptible to ferroptosis. This ferroptosis of Treg cells exacerbates intestinal damage and inflammatory response in NEC. Notably, Vitamin E can inhibit the ferroptosis of Treg cells, subsequently alleviating intestinal damage and inflammation in NEC. Additionally, Vitamin E bolsters the anti-lipid peroxidation capability of Treg cells by upregulating the expression of GPX4.
CONCLUSIONS: In the context of NEC, the ferroptosis of Treg cells represents a significant factor contributing to intestinal tissue damage and an exaggerated inflammatory response. GPX4 is pivotal for the viability and functionality of Treg cells. Vitamin E exhibits the capability to mitigate the ferroptosis of Treg cells, thereby enhancing their number and function, which plays a crucial role in mitigating intestinal tissue damage and inflammatory response in NEC.

Preterm newborns represent a population at risk of developing intestinal dysbiosis as well as being predisposed to sepsis and Necrotizing Enterocolitis. Necrotizing Enterocolitis is a condition burdened by many complications and mortality due to an alteration of the intestinal barrier, an immaturity of the immune system, and intestinal dysbiosis. Low gestational age at birth, low birth weight, and early use of antibiotics are other predisposing factors. Instead, breast milk and probiotics are protective factors in providing intestinal homeostasis and microbiome regulation. In this mini-review, we analysed the protective role of probiotics in the onset of Necrotizing Enterocolitis in preterm populations.

Reduction-oxidation (redox) chemistry plays a vital role in human homeostasis. These reactions play critical roles in energy generation, as part of innate immunity, and in the generation of secondary messengers with various functions such as cell cycle progression or the release of neurotransmitters. Despite this cornerstone role, if left unchecked, the body can overproduce reactive oxygen species (ROS) or reactive nitrogen species (RNS). When these overwhelm endogenous antioxidant systems, oxidative stress (OS) occurs. In neonates, OS has been associated with retinopathy of prematurity (ROP), leukomalacia, and bronchopulmonary dysplasia (BPD). Given its broad spectrum of effects, research has started to examine whether OS plays a role in necrotizing enterocolitis (NEC). In this paper, we will discuss the basics of redox chemistry and how the human body keeps these in check. We will then discuss what happens when these go awry, focusing mostly on NEC in neonates.

BACKGROUND: Necrotizing enterocolitis (NEC) is a complex disease characterized by gastrointestinal inflammation and is one of the most common gastrointestinal emergencies in neonates. Mild to moderate cases of NEC require medical treatment, whereas severe cases necessitate surgical intervention. However, evidence for surgical indications is limited and largely dependent on the surgeon\'s experience, leading to variability in outcomes. The primary aim of this study is to identify the risk factors for surgical intervention in neonatal NEC, which will aid in predicting the optimal timing for surgical intervention.
METHODS: A literature search was conducted in PubMed, Embase, and Web of Science databases for case-control studies exploring risk factors for NEC requiring surgical intervention. The search was completed on June 16, 2024, and data analysis was performed using R Studio 4.3.2.
RESULTS: 18 studies were included, comprising 1,104 cases in the surgery group and 1,686 in the medical treatment group. The meta-analysis indicated that high C-reactive protein (CRP) levels [OR = 1.42, 95% CI (1.01, 1.99)], lower gestational age [OR = 0.52, 95% CI (0.3, 0.91)], sepsis [OR = 2.94, 95% CI (1.87, 4.60)], coagulation disorder [OR = 3.45, 95% CI (1.81, 6.58)], lack of enteral feeding [OR = 3.18, 95% CI (1.37, 7.35)], and hyponatremia [OR = 1.22, 95% CI (1.07, 1.39)] are significant risk factors for surgical treatment in neonatal NEC.
CONCLUSIONS: High CRP levels, coagulation disorders, sepsis, lower gestational age, lack of enteral feeding, and hyponatremia are significant risk factors for surgical intervention in neonatal NEC. These findings have potential clinical significance for predicting surgical risk.

Necrotizing enterocolitis (NEC) is one of the most devasting diseases affecting preterm neonates. However, despite a lot of research, NEC\'s pathogenesis remains unclear. It is known that the pathogenesis is a multifactorial process, including (1) a pathological microbiome with abnormal bacterial colonization, (2) an immature immune system, (3) enteral feeding, (3) an impairment of microcirculation, and (4) possibly ischemia-reperfusion damage to the intestine. Overall, the immaturity of the mucosal barrier and the increased expression of Toll-like receptor 4 (TLR4) within the intestinal epithelium result in an intestinal hyperinflammation reaction. Concurrently, a deficiency in counter-regulatory mediators can be seen. The sum of these processes can ultimately result in intestinal necrosis leading to very high mortality rates of the affected neonates. In the last decade no substantial advances in the treatment of NEC have been made. Thus, NEC animal models as well as in vitro models have been employed to better understand NEC\'s pathogenesis on a cellular and molecular level. This review will highlight the different models currently in use to study immunological aspects of NEC.

BACKGROUND: Optimal oxygen saturation targets remain unknown for extremely preterm infants.
METHODS: Cohort analysis of eligible preterm infants born <29 weeks\' gestation admitted between 2011 and 2018 to centers submitting data to the Canadian Neonatal Network (CNN) database. Site questionnaires to determine saturation targets, alarm settings, and date of change, allowed assignation of centers to intermediate (88-93%) or high (90-95%) saturation targets. A 6-month washout period was applied to sites which switched targets during the study period. Our primary outcome was survival free of major morbidity. Secondary outcomes were death, necrotizing enterocolitis (NEC), bronchopulmonary dysplasia (BPD), treated retinopathy of prematurity, and evidence of brain injury during admission. Generalized estimating equations were applied to compensate for demographic differences and site practices.
RESULTS: There were 2,739 infants in the high (mean gestational age [GA] 26 ± 1.6 weeks) and 6,813 infants in the intermediate (mean GA 26.2 ± 1.6 weeks) saturation target group. Survival without morbidity was higher in the intermediate target group (adjusted odds ratio [aOR] 1.59; 95% CI: 1.04, 2.45). There was no difference in mortality between groups (aOR 0.81; 95% CI: 0.59, 1.11), in NEC, treated retinopathy, or brain injury. On subgroup analysis, restricting data to sites which switched targets during the study, intermediate saturation targets were associated with lower rates of BPD (aOR 0.45; 95% CI: 0.28, 0.72).
CONCLUSIONS: For neonates <29 weeks\' gestation, intermediate saturation target was associated with higher odds of survival without major morbidity compared to higher oxygen saturation target.

BACKGROUND: Necrotizing enterocolitis is the most severe life-threatening acquired gastrointestinal disorder among preterm neonates. We describe here an outbreak of Clostridium butyricum-related necrotizing enterocolitis in preterm neonates that occurred in three different neonatal centres, in southeast France.
METHODS: We defined a confirmed case of C. butyricum-related necrotizing enterocolitis in preterm neonates by the presence of clinical signs according to modified Bell criteria and C. butyricum identified from stools sample using real-time polymerase chain reaction or culture. A phylogenetic analysis of the isolated strains by whole genome sequencing was also performed.
RESULTS: Between 5 and 27 January 2022, we identified ten confirmed cases of C. butyricum-related necrotizing enterocolitis, including five from neonatal centre 1, four from neonatal centre 2, and one from neonatal centre 3. The attack rate of necrotizing enterocolitis in neonatal centre 1 was 7.1% (5/70). The positivity rate of C. butyricum detected from stool samples was higher during the outbreak period (37/276; 13.4%) than outside this period (7/369; 1.9%), while systematic screening was maintained (P<0.001). Phylogenetic analysis showed a clonality between strains inside four clusters. Two clusters included neonates hospitalised in different neonatal centres, suggesting the transmission of C. butyricum strains during the transfer of neonates between neonatal centres.
CONCLUSIONS: This outbreak of C. butyricum-related necrotizing enterocolitis confirms a cross-transmission between preterm neonates, including twin or triplet siblings, and involving necrotizing enterocolitis cases together with asymptomatic carriers. After three months of follow-up, no further cases were identified following the implementation of contact precautions with sporicidal agents.

Necrotizing enterocolitis (NEC) is a severe gastrointestinal disease in preterm infants and the most common cause of neonatal death, whereas the molecular mechanism of intestinal injury remains unclear accompanied by deficiency of effective therapeutic approaches. GIT2 (G-protein-coupled receptor kinase interacting proteins 2) can affect innate and adaptive immunity and has been involved in multiple inflammatory disorders. In this study, we investigated whether GIT2 participates in the pathogenesis of NEC. Here we found that intestinal Git2 gene expression was significantly increased in NEC patients and NEC mice, which positively correlated with the tissue damage severity, and Git2 deficiency could potently protect against NEC development in mice. Mechanistically, Git2 gene knockout dramatically increased the recruitment of MDSCs in the intestine, and in vivo depletion of MDSCs almost completely abrogated the protective effect of Git2 deficiency on NEC. Moreover, Git2 deficiency induced MDSCs intestinal accumulation mainly relied on CXCL1/CXCL12 signaling, as evidenced by the significant increment of CXCL1 and CXCL12 levels in intestinal epithelium of Git2-/- mice and dramatically decrease of MDSCs accumulation in intestine as well as increase of NEC severity upon treatment of CXCL1/CXCL12 pathway inhibitors. In addition, Git2 deficiency induced up-regulation of CXCL1 and CXCL12 is at least partially mediated through activating NF-κB signaling. Thus, our findings suggest that GIT2 is involved in the pathogenesis of NEC, and targeting GIT2 may be a potential preventive and therapeutic approach for NEC.