Fecal virus-like particles are sufficient to reduce necrotizing enterocolitis.

Fecal filtrate transfer (FFT) is emerging as a safer alternative to traditional fecal microbiota transplantation (FMT) - particularly in the context of necrotizing enterocolitis (NEC), a severe gastrointestinal condition affecting preterm infants. Using a preterm piglet model, FFT has demonstrated superiority over FMT in safety and NEC prevention. Since FFT is virtually devoid of bacteria, prokaryotic viruses (bacteriophages) are assumed to mediate the beneficial effects. However, this assumption remains unproven. To address this gap, we separated virus-like particles (30 kDa to 0.45 µm) of donor feces from the residual postbiotic fluid. We then compared clinical and gut microbiota responses to these fractions with the parent FFT solution after transferring them to NEC-susceptible preterm piglets. Virome transfer was equally effective as FFT in reducing the severity of NEC-like pathology. The bacterial compositional data corroborated clinical findings as virome transfer reduced the relative abundance of several NEC-associated pathogens e.g. Klebsiella pneumoniae and Clostridium perfringens. Virome transfer diversified gut viral communities with concomitant constraining effects on the bacterial composition. Unexpectedly, virome transfer, but not residual postbiotic fluid, led to earlier diarrhea. While diarrhea may be a minor concern in human infants, future work should identify ways of eliminating this side effect without losing treatment efficacy.

Umbilical Catheter Extravasation Mimicking Necrotizing Enterocolitis in a Preterm Neonate: A Diagnostic Challenge.

Managing acute abdomen in very low birth weight (VLBW) and premature infants presents a diagnostic challenge, often necessitating a thorough assessment to discern underlying causes. Umbilical venous catheters (UVCs), commonly used in neonatal intensive care, are essential but not without risks. A 29-week premature male infant, born to a 23-year-old mother, was referred to our clinic on the 16th day of life with a suspected diagnosis of necrotizing enterocolitis (NEC). The infant had spent the first day intubated and received non-invasive respiratory support for 15 days. A 5 French UVC was inserted at the 2nd hour of life, and by the 3rd day of life, the infant transitioned to minimal enteral feeding. Between the 12th and 16th days of life, the infant initially diagnosed with NEC due to symptoms such as decreased stool passage and abdominal distension. The patient had been on a continuous course of antibiotic treatment throughout the entirety of his life, commencing on the very first day due to suspected early neonatal sepsis, followed by nosocomial sepsis during the hospitalization, and persisting with antibiotic therapy for suspected NEC. The case took a unique turn upon further evaluation after being referred to our unit. Despite a preliminary NEC diagnosis, further evaluation revealed umbilical catheter complications, leading to total parenteral nutrition extravasation. Removal of the catheter, drainage, and antibiotic adjustment resulted in improved clinical outcomes. In neonatal care, cautious management is vital when dealing with infants exhibiting abdominal symptoms. A nuanced approach, including differential diagnosis and careful antibiotic use, is essential.

The entwined circles of quality improvement & advocacy.

Health policy and quality improvement initiatives exist symbiotically. Quality projects can be spurred by policy decisions, such as the creation of financial incentives for high-value care. Then, advocacy can streamline high-value care, offering opportunities for quality improvement scholars to create projects consistent with evidenced-based care. Thirdly, as pediatrics and neonatology reconcile with value-based payment structures, successful quality initiatives may serve as demonstration projects, illustrating to policy-makers how best to allocate and incentivize resources that optimize newborn health. And finally, quality improvement (QI) can provide an essential link between broad reaching advocacy principles and boots-on-the-ground local or regional efforts to implement good ideas in ways that work practically in particular environments. In this paper, we provide examples of how national legislation elevated the importance of QI, by penalizing hospitals for low quality care. Using Medicaid coverage of pasteurized human donor milk as an example, we discuss how advocacy improved cost-effectiveness of treatments used as tools for quality projects related to reduction of necrotizing enterocolitis and improved growth. We discuss how the future of QI work will assist in informing the agenda as neonatology transitions to value-based care. Finally, we consider how important local and regional QI work is in bringing good ideas to the bedside and the community.

Core Outcome Set for Necrotizing Enterocolitis Treatment Trials.

BACKGROUND AND OBJECTIVES: Variability in outcome reporting in necrotizing enterocolitis (NEC) treatment trials hinders conducting meta-analyses and implementing novel treatments. We aimed to develop a core outcome set (COS) for NEC treatment trials including outcome measures most relevant to patients and physicians, from NEC diagnosis to adulthood. METHODS: Clinicians and/or researchers from low-middle- and high-income countries were approached based on their scientific contributions to NEC literature, and patients and parents through local organizations. We presented participants with 45 outcomes used in NEC research, identified through a systematic review. To achieve consensus, outcomes were rated on a scale of 1 to 9 in 3 online Delphi rounds, and discussed at a final consensus meeting. RESULTS: Seventy-one participants from 25 countries completed all Delphi rounds, including 15 patients and family representatives. Thirteen outcomes reached consensus in one of the stakeholder groups and were included in the consensus meeting, 6 outcomes reached consensus in both groups. Twenty-seven participants from both high- and low-middle-income countries attended the online consensus meeting, including family representatives and NEC patients. After discussion and a final vote, 5 outcomes reached consensus to be included: mortality, NEC-related mortality, short bowel syndrome, quality of life, and neurodevelopmental impairment. CONCLUSIONS: This NEC COS includes 5 predominantly long-term outcomes agreed upon by clinicians, patients, and family representatives. Use of this international COS will help standardize outcome selection in clinical trials, ensure these are relevant to those most affected by NEC care, and, ultimately, improve the care of infants with NEC.

Neonatal Necrotizing Enterocolitis: An Update on Pathophysiology, Treatment, and Prevention.

Necrotizing enterocolitis (NEC) is a life-threatening disease predominantly affecting premature and very low birth weight infants resulting in inflammation and necrosis of the small bowel and colon and potentially leading to sepsis, peritonitis, perforation, and death. Numerous research efforts have been made to better understand, treat, and prevent NEC. This review explores a variety of factors involved in the pathogenesis of NEC (prematurity, low birth weight, lack of human breast milk exposure, alterations to the microbiota, maternal and environmental factors, and intestinal ischemia) and reports treatment modalities surrounding NEC, including pain medications and common antibiotic combinations, the rationale for these combinations, and recent antibiotic stewardship approaches surrounding NEC treatment. This review also highlights the effect of early antibiotic exposure, infections, proton pump inhibitors (PPIs), and H2 receptor antagonists on the microbiota and how these risk factors can increase the chances of NEC. Finally, modern prevention strategies including the use of human breast milk and standardized feeding regimens are discussed, as well as promising new preventative and treatment options for NEC including probiotics and stem cell therapy.

Role of innate T cells in necrotizing enterocolitis.

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.

Outcomes by disease onset, sex, and intervention in neonates with SIP and surgical NEC.

BACKGROUND: Outcomes of infants following surgical necrotizing enterocolitis (NEC) and spontaneous intestinal perforation (SIP) categorized by the age of onset, interventions, and sex are not well defined. METHODS: Retrospective comparison of infants categorized by age of onset (NEC at <10, 10-20, and >20 days) and SIP at <7 versus ≥7 days), sex, and intervention [Penrose Drain (PD) vs. laparotomy]. RESULTS: A total of 114 infants had NEC and 37 had SIP. On multinomial logistic regression, infants with NEC/SIP onset >20 days had significantly lower odds of small bowel involvement (aOR = 0.07, 95% CI: 0.01-0.33, p = 0.001), higher necrosis (aOR = 3.59, 95% CI: 1.34-9.65, p = 0.012) and higher CRP (p = 0.004) than onset <10 days. Initial laparotomy was associated with more bowel loss (24.1 cm [12.3; 40.6] vs.12.1 [8.00; 23.2]; p = 0.001), small and large intestine involvement (47.1% vs 17.2%; p = 0.01), and ileocecal valve resection (42% vs. 19.4%; p = 0.036) than initial PD therapy. Females underwent fewer small bowel resections (52.3% vs 73.6%; p = 0.025) but had higher surgical morbidity (53.7% vs. 24.7%.; p = 0.001) than males. CONCLUSION: Clinical, radiological, and histopathological presentation and outcomes in preterm infants with surgical NEC/SIP are associated with age of disease onset, sex, and initial intervention. IMPACT: Neonates with surgical NEC onset >20 days had more severe necrosis, inflammation, kidney injury, and bowel loss than those with <10 days. Initial laparotomy was associated with later age onset, more bowel loss, and ileocecal valve resection compared to initial PD treatment, but not with differences in mortality or length of stay. Female sex was associated with lower maturity, more placental malperfusion, less often small bowel involvement, lower pre-NEC hematocrit as well as higher surgical morbidity than males. Whether the management of surgical NEC and SIP should differ by the age of onset requires further investigation.

Research Models to Mimic Necrotizing Enterocolitis and Inflammatory Bowel Diseases: Focus on Extracellular Vesicles Action.

This review focuses on the crucial role of the intestinal epithelium in maintaining intestinal homeostasis and its significance in the pathogenesis of necrotizing enterocolitis (NEC) and inflammatory bowel diseases (IBD). NEC is a devastating neonatal disease, while IBD represents a global healthcare problem with increasing incidence. The breakdown of the intestinal barrier in neonates is considered pivotal in the development and progression of both disorders. This review provides an overview of the current state of in vitro, ex vivo, and animal models to study epithelial injury in NEC and IBD, addressing pertinent questions that engage clinicians and researchers alike. Despite significant advancements in early recognition and aggressive treatment, no single therapy has been conclusively proven effective in reducing the severity of these disorders. Although early interventions have improved clinical outcomes, NEC and IBD continue to impose substantial morbidity, mortality, and economic burdens on affected individuals and society. Consequently, exploring alternative therapeutic options capable of preventing and treating the sequelae of NEC and IBD has become a pressing necessity. In recent decades, extracellular vehicles (EVs) have emerged as a potential solution to modulate the pathogenic mechanism in these multifactorial and complex disorders. Despite the diverse array of proposed models, a comprehensive model to investigate and decelerate the progression of NEC and IBD remains to be established. To bridge the translational gap between preclinical studies and clinical applications, enhancements in the technical development of gut-on-a-chip models and EVs hold considerable promise.

Current Practices, Challenges, and Recommendations in Enteral Nutrition After Necrotizing Enterocolitis.

Necrotizing enterocolitis (NEC) is a neonatal disease with high mortality and morbidity. There is a lack of evidence-based recommendations on nutritional rehabilitation following NEC, and much of the current practice is guided by institutional policies and expert opinions. After a diagnosis of NEC, infants are exposed to an extended period of bowel rest and a prolonged course of antibiotics. Recognizing the patient characteristics that predict nutritional tolerance, early initiation of enteral nutrition, minimizing periods of bowel rest and antibiotic exposure, and standardization of dietary practices are the mainstay of post-NEC nutrition.

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Necrotizing enterocolitis (NEC), with the main manifestations of bloody stool, abdominal distension, and vomiting, is one of the leading causes of death in neonates, and early identification and diagnosis are crucial for the prognosis of NEC. The emergence and development of machine learning has provided the potential for early, rapid, and accurate identification of this disease. This article summarizes the algorithms of machine learning recently used in NEC, analyzes the high-risk predictive factors revealed by these algorithms, evaluates the ability and characteristics of machine learning in the etiology, definition, and diagnosis of NEC, and discusses the challenges and prospects for the future application of machine learning in NEC.

Neonatal complicated intraabdominal infection.

PURPOSE OF REVIEW: The purpose of this review is to summarize the treatment of complicated intraabdominal infections (cIAIs) in premature infants. RECENT FINDINGS: Recent work has continued to define the complex nature of cIAIs and necrotizing enterocolitis (NEC). This includes new findings on the microbiome, breast milk and risk factors associated with NEC. The treatment of cIAIs employs a combination of both surgical and medical treatment. Further look at what type and timing of surgical intervention is used as well as the ideal antibiotic regimen. Upcoming research is highlighted in future directions of NEC treatment. SUMMARY: cIAIs in premature infants is a challenging disease with more research needed to further delineate the pathophysiology and treatment options.

What animal model should I use to study necrotizing enterocolitis?

Unfortunately, we are all too familiar with the statement: "Necrotizing enterocolitis remains the leading cause of gastrointestinal surgical emergency in preterm neonates". It's been five decades since the first animal models of necrotizing enterocolitis (NEC) were described. There remains much investigative work to be done on identifying various aspects of NEC, ranging from the underlying mechanisms to treatment modalities. Experimental NEC is mainly focused on a rat, mouse, and piglet models. Our aim is to not only highlight the pros and cons of these three main models, but to also present some of the less-used animal models that have contributed to the body of knowledge about NEC. Choosing an appropriate model is essential to conducting effective research and answering the questions asked. As such, this paper reviews some of the variations that come with each model.

Stem cells as a therapeutic avenue for active and long-term complications of Necrotizing Enterocolitis.

Necrotizing enterocolitis (NEC) is a devastating neonatal intestinal disease associated with significant morbidity and mortality. Although decades of research have been dedicated to understanding the pathogenesis of NEC and developing therapies, it remains the leading cause of death among neonatal gastrointestinal diseases. Mesenchymal stem cells (MSCs) have garnered significant interest recently as potential therapeutic agents for the treatment of NEC. They have been shown to rescue intestinal injury and reduce the incidence and severity of NEC in various preclinical animal studies. MSCs and MSC-derived organoids and tissue engineered small intestine (TESI) have shown potential for the treatment of long-term sequela of NEC such as short bowel syndrome, neurodevelopmental delay, and chronic lung disease. Although the advances made in the use of MSCs are promising, further research is needed prior to the widespread use of these cells for the treatment of NEC.

New insights into the pathogenesis of necrotizing enterocolitis and the dawn of potential therapeutics.

Necrotizing enterocolitis (NEC) is a devastating gastrointestinal disorder in premature infants that causes significant morbidity and mortality. Research efforts into the pathogenesis of NEC have discovered a pivotal role for the gram-negative bacterial receptor, Toll-like receptor 4 (TLR4), in its development. TLR4 is activated by dysbiotic microbes within the intestinal lumen, which leads to an exaggerated inflammatory response within the developing intestine, resulting in mucosal injury. More recently, studies have identified that the impaired intestinal motility that occurs early in NEC has a causative role in disease development, as strategies to enhance intestinal motility can reverse NEC in preclinical models. There has also been broad appreciation that NEC also contributes to significant neuroinflammation, which we have linked to the effects of gut-derived pro-inflammatory molecules and immune cells which activate microglia in the developing brain, resulting in white matter injury. These findings suggest that the management of the intestinal inflammation may secondarily be neuroprotective. Importantly, despite the significant burden of NEC on premature infants, these and other studies have provided a strong rationale for the development of small molecules with the capability of reducing NEC severity in pre-clinical models, thus guiding the development of specific anti-NEC therapies. This review summarizes the roles of TLR4 signaling in the premature gut in the pathogenesis of NEC, and provides insights into optimal clinical management strategies based upon findings from laboratory studies.

Necrotizing Enterocolitis following Onasemnogene Abeparvovec for Spinal Muscular Atrophy: A Case Series.

Onasemnogene abeparvovec treats spinal muscular atrophy by delivering a functional SMN1 gene. Necrotizing enterocolitis typically occurs in preterm infants. We report 2 term infants diagnosed with spinal muscular atrophy who presented with necrotizing enterocolitis after onasemnogene abeparvovec infusion. We discuss potential etiologies and propose monitoring for necrotizing enterocolitis after onasemnogene abeparvovec therapy.

Necrotizing enterocolitis: recent advances in treatment with translational potential.

Necrotizing enterocolitis (NEC) is one of the most prevalent and devastating gastrointestinal disorders in neonates. Despite advances in neonatal care, the incidence and mortality due to NEC remain high, highlighting the need to devise novel treatments for this disease. There have been a number of recent advancements in therapeutic approaches for the treatment of NEC; these involve remote ischemic conditioning (RIC), stem cell therapy, breast milk components (human milk oligosaccharides, exosomes, lactoferrin), fecal microbiota transplantation, and immunotherapy. This review summarizes the most recent advances in NEC treatment currently underway as well as their applicability and associated challenges and limitations, with the aim to provide new insight into the paradigm of care for NEC worldwide.

Development of an international core outcome set for treatment trials in necrotizing enterocolitis-a study protocol.

AIM: Necrotizing enterocolitis (NEC) is the most lethal disease of the gastrointestinal tract of preterm infants. New and existing management strategies need clinical evaluation. Large heterogeneity exists in the selection, measurement, and reporting of outcome measures in NEC intervention studies. This hampers meta-analyses and the development of evidence-based management guidelines. We aim to develop a Core Outcome Set (COS) for NEC that includes the most relevant outcomes for patients and physicians, from moment of diagnosis into adulthood. This COS is designed for use in NEC treatment trials, in infants with confirmed NEC. METHODS: This study is designed according to COS-STAD (Core Outcome Set-STAndards for Development) recommendations and the COMET (Core Outcome Measures in Effectiveness Trials) Initiative Handbook. We obtained a waiver from the Ethics Review Board and prospectively registered this study with COMET (Study 1920). We will approach 125 clinicians and/or researchers from low-middle and high-income countries based on their scientific output (using SCIVAL, a bibliometric tool). Patients and parents will be approached through local patient organisations. Participants will be separated into three panels, to assess differences in priorities between former patients and parents (1. lay panel), clinicians and researchers involved in the neonatal period (2. neonatal panel) and after the neonatal period (3. post-neonatal panel). They will be presented with outcomes currently used in NEC research, identified through a systematic review, in a Delphi process. Eligible outcome domains are also identified from the patients and parents' perspectives. Using a consensus process, including three online Delphi rounds and a final face-to-face consensus meeting, the COS will be finalised and include outcomes deemed essential to all stakeholders: health care professionals, parents and patients' representatives. The final COS will be reported in accordance with the COS-Standards for reporting (COS-STAR) statement. CONCLUSIONS: Development of an international COS will help to improve homogeneity of outcome measure reporting in NEC, will enable adequate and efficient comparison of treatment strategies, and will help the interpretation and implementation of clinical trial results. This will contribute to high-quality evidence regarding the best treatment strategy for NEC in preterm infants.