The Novel MFG-E8-derived Oligopeptide, MOP3, Improves Outcomes in a Preclinical Murine Model of Neonatal Sepsis.

INTRODUCTION: Neonatal sepsis is a devastating inflammatory condition that remains a leading cause of morbidity and mortality. Milk fat globule-EGF-factor VIII (MFG-E8) is a glycoprotein that reduces inflammation, whereas extracellular cold-inducible RNA binding protein (eCIRP) worsens inflammation. This study aimed to determine the therapeutic potential of a novel MFG-E8-derived oligopeptide 3 (MOP3) designed to clear eCIRP and protect against inflammation, organ injury, and mortality in neonatal sepsis. METHODS: C57BL6 mouse pups were injected intraperitoneally with cecal slurry (CS) and treated with MOP3 (20 µg/g) or vehicle. 10 h after injection, blood, lungs, and intestines were collected for analyses, and in a 7-day experiment, pups were monitored for differences in mortality. RESULTS: MOP3 treatment protected septic pups from inflammation by reducing eCIRP, IL-6, TNFα, and LDH. MOP3 reduced lung and intestinal inflammation and injury as assessed by reductions in tissue mRNA levels of inflammatory markers, histopathologic injury, and apoptosis in lung and intestines. MOP3 also significantly improved 7-day overall survival for CS-septic mouse pups compared to vehicle (75% vs. 46%, respectively). CONCLUSION: Deriving from MFG-E8 and designed to clear eCIRP, MOP3 protects against sepsis-induced inflammation, organ injury, and mortality in a preclinical model of neonatal sepsis, implicating it as an exciting potential new therapeutic. LEVEL OF EVIDENCE: Level 1.

Delphi Process for Validation of Fluid Treatment Algorithm for Critically Ill Pediatric Trauma Patients.

INTRODUCTION: While intravenous fluid therapy is essential to re-establishing volume status in children who have experienced trauma, aggressive resuscitation can lead to various complications. There remains a lack of consensus on whether pediatric trauma patients will benefit from a liberal or restrictive crystalloid resuscitation approach and how to optimally identify and transition between fluid phases. METHODS: A panel was comprised of physicians with expertise in pediatric trauma, critical care, and emergency medicine. A three-round Delphi process was conducted via an online survey, with each round being followed by a live video conference. Experts agreed or disagreed with each aspect of the proposed fluid management algorithm on a five-level Likert scale. The group opinion level defined an algorithm parameter's acceptance or rejection with greater than 75% agreement resulting in acceptance and greater than 50% disagreement resulting in rejection. The remaining were discussed and re-presented in the next round. RESULTS: Fourteen experts from five Level 1 pediatric trauma centers representing three subspecialties were included. Responses were received from 13/14 participants (93%). In round 1, 64% of the parameters were accepted, while the remaining 36% were discussed and re-presented. In round 2, 90% of the parameters were accepted. Following round 3, there was 100% acceptance by all the experts on the revised and final version of the algorithm. CONCLUSIONS: We present a validated algorithm for intavenous fluid management in pediatric trauma patients that focuses on the de-escalation of fluids. Focusing on this time point of fluid therapy will help minimize iatrogenic complications of crystalloid fluids within this patient population.

A novel opsonic eCIRP inhibitor for lethal sepsis.

Sepsis is a life-threatening inflammatory condition partly orchestrated by the release of various damage-associated molecular patterns such as extracellular cold-inducible RNA-binding protein (eCIRP). Despite advances in understanding the pathogenic role of eCIRP in inflammatory diseases, novel therapeutic strategies to prevent its excessive inflammatory response are lacking. Milk fat globule-epidermal growth factor-VIII (MFG-E8) is critical for the opsonic clearance of apoptotic cells, but its potential involvement in the removal of eCIRP was previously unknown. Here, we report that MFG-E8 can strongly bind eCIRP to facilitate αvß3-integrin-dependent internalization and lysosome-dependent degradation of MFG-E8/eCIRP complexes, thereby attenuating excessive inflammation. Genetic disruption of MFG-E8 expression exaggerated sepsis-induced systemic accumulation of eCIRP and other cytokines, and consequently exacerbated sepsis-associated acute lung injury. In contrast, MFG-E8-derived oligopeptide recapitulated its eCIRP binding properties, and significantly attenuated eCIRP-induced inflammation to confer protection against sepsis. Our findings suggest a novel therapeutic approach to attenuate eCIRP-induced inflammation to improve outcomes of lethal sepsis.

A multicenter evaluation of pediatric emergency department injury visits during the COVID-19 pandemic.

BACKGROUND: Injuries, the leading cause of death in children 1-17 years old, are often preventable. Injury patterns are impacted by changes in the child's environment, shifts in supervision, and caregiver stressors. The objective of this study was to evaluate the incidence and proportion of injuries, mechanisms, and severity seen in Pediatric Emergency Departments (PEDs) during the COVID-19 pandemic. METHODS: This multicenter, cross-sectional study from January 2019 through December 2020 examined visits to 40 PEDs for children < 18 years old. Injury was defined by at least one International Classification of Disease-10th revision (ICD-10) code for bodily injury (S00-T78). The main study outcomes were total and proportion of PED injury-related visits compared to all visits in March through December 2020 and to the same months in 2019. Weekly injury visits as a percentage of total PED visits were calculated for all weeks between January 2019 and December 2020. RESULTS: The study included 741,418 PED visits for injuries pre-COVID-19 pandemic (2019) and during the COVID-19 pandemic (2020). Overall PED visits from all causes decreased 27.4% in March to December 2020 compared to the same time frame in 2019; however, the proportion of injury-related PED visits in 2020 increased by 37.7%. In 2020, injured children were younger (median age 6.31 years vs 7.31 in 2019), more commonly White (54% vs 50%, p < 0.001), non-Hispanic (72% vs 69%, p < 0.001) and had private insurance (35% vs 32%, p < 0.001). Injury hospitalizations increased 2.2% (p < 0.001) and deaths increased 0.03% (p < 0.001) in 2020 compared to 2019. Mean injury severity score increased (2.2 to 2.4, p < 0.001) between 2019 and 2020. Injuries declined for struck by/against (- 4.9%) and overexertion (- 1.2%) mechanisms. Injuries proportionally increased for pedal cycles (2.8%), cut/pierce (1.5%), motor vehicle occupant (0.9%), other transportation (0.6%), fire/burn (0.5%) and firearms (0.3%) compared to all injuries in 2020 versus 2019. CONCLUSIONS: The proportion of PED injury-related visits in March through December 2020 increased compared to the same months in 2019. Racial and payor differences were noted. Mechanisms of injury seen in the PED during 2020 changed compared to 2019, and this can inform injury prevention initiatives.

Gut microbiome and necrotizing enterocolitis: Understanding the connection to find a cure.

Necrotizing enterocolitis (NEC), a cause of death among premature babies, has defied therapeutics for decades. Bacterial analyses have expanded insights into NEC pathophysiology and roles of the gut microbiome. We discuss the contribution of the gut microbiome and potential therapeutics, notably lactadherin, that may promote gut homeostasis to alleviate NEC.

Gastrointestinal Dysfunction Criteria in Critically Ill Children: The PODIUM Consensus Conference.

CONTEXT: Prior criteria to define pediatric multiple organ dysfunction syndrome (MODS) did not include gastrointestinal dysfunction. OBJECTIVES: Our objective was to evaluate current evidence and to develop consensus criteria for gastrointestinal dysfunction in critically ill children. DATA SOURCES: Electronic searches of PubMed and EMBASE were conducted from January 1992 to January 2020, using medical subject heading terms and text words to define gastrointestinal dysfunction, pediatric critical illness, and outcomes. STUDY SELECTION: Studies were included if they evaluated critically ill children with gastrointestinal dysfunction, performance characteristics of assessment/scoring tools to screen for gastrointestinal dysfunction, and assessed outcomes related to mortality, functional status, organ-specific outcomes, or other patient-centered outcomes. Studies of adults or premature infants, animal studies, reviews/commentaries, case series with sample size ≤10, and non-English language studies with inability to determine eligibility criteria were excluded. DATA EXTRACTION: Data were abstracted from each eligible study into a standard data extraction form along with risk of bias assessment by a task force member. RESULTS: The systematic review supports the following criteria for severe gastrointestinal dysfunction: 1a) bowel perforation, 1b) pneumatosis intestinalis, or 1c) bowel ischemia, present on plain abdominal radiograph, computed tomography (CT) scan, magnetic resonance imaging (MRI), or gross surgical inspection, or 2) rectal sloughing of gut mucosa. LIMITATIONS: The validity of the consensus criteria for gastrointestinal dysfunction are limited by the quantity and quality of current evidence. CONCLUSIONS: Understanding the role of gastrointestinal dysfunction in the pathophysiology and outcomes of MODS is important in pediatric critical illness.

The Pediatric Trauma Society Annual Meeting: An Analysis of Scholarly Output From the First 5 Years.

BACKGROUND: The Pediatric Trauma Society (PTS) is a multidisciplinary organization, with scientific presentations at its annual meeting addressing trauma care from prehospital through rehabilitation. OBJECTIVE: The purpose of this study was to identify and describe the scholarly areas of focus of presentations at the annual meeting over the society's first 5 years and evaluate research dissemination. METHODS: Data were collected on abstracts presented between 2014 and 2018, including titles, authors, and abstract classification. PubMed and Google Scholar searches identified abstracts that resulted in publications. Journal impact factors were identified. RESULTS: Over 5 years, 491 of 635 (77.3%) abstracts were accepted. The number of submitted and accepted abstracts increased, but the acceptance rate was stable (range = 72.1%-81.2%, p = NS [nonsignificant]). The most frequently accepted categories included "Epidemiology," "Abdominal or Thoracic Trauma," and "Neurosurgery or Traumatic Brain Injury (TBI)," whereas "Trauma Nursing" and "Quality Improvement" were less common. Among the 2014-2016 abstracts, 55.4% of podium and 24.3% of poster presentations were published. Abstracts categorized as "Epidemiology," "Education & Injury Prevention," and "Neurosurgery or TBI" were commonly presented but uncommonly published. The median journal impact factor of publications was 2.1 and 2.0 for podium and poster presentations, respectively (ranging from 0.11 to 10.25). CONCLUSION: Most of the scholarly effort presented at the PTS remains unpublished. Published work is mainly in low-impact factor journals. Mentorship in the publication process and encouragement of multidisciplinary collaboration within the society are needed to address limitations in the number and potential impact of the scientific content of the annual meeting. This type of analysis is relevant not only to the PTS but also to any professional society seeking to improve its impact.

Limiting hospital resources for acute appendicitis in children: Lessons learned from the U.S. epicenter of the COVID-19 pandemic.

INTRODUCTION: The COVID-19 pandemic resulted in the suspension of nonemergent surgeries throughout New York. Our tertiary care children's hospital pivoted towards a brief trial of intravenous (IV) antibiotic therapy in all patients in order to limit operating room (OR) utilization and avoid prolonged hospital stays. We describe our pandemic-based strategy for non-operative management (NOM) of appendicitis but with a limited duration of IV antibiotics. METHODS: We performed a retrospective study of children treated for acute appendicitis at our center from 3/31/2020 to 5/3/2020 during the peak of the New York pandemic. We compared appendicitis volume to similar months in prior years. We evaluated failure of NOM, length of stay, and compared characteristics of children we successfully treated with our expanded NOM protocol to previously published inclusion criteria for NOM. RESULTS: 45.5% of children (25/55) with acute appendicitis underwent NOM. Of the 30 who underwent surgery, 13 had complicated appendicitis while 17 had simple appendicitis. Three patients were COVID-positive, although none had respiratory symptoms. The majority of patients presenting with acute appendicitis (78.2%) did not meet previously published criteria for NOM. CONCLUSIONS: We treated a similar volume of children with acute appendicitis during the pandemic compared to prior years. We applied non-operative management to nearly half our patients, even as we expanded inclusion criteria for NOM to reduce OR utilization, but limited the duration of the antibiotic trial to avoid prolonged hospital stays. TYPE OF STUDY: Retrospective study. LEVEL OF EVIDENCE: IV.

Targeting the eCIRP/TREM-1 interaction with a small molecule inhibitor improves cardiac dysfunction in neonatal sepsis.

BACKGROUND: Neonatal sepsis and the associated myocardial dysfunction remain a leading cause of infant mortality. Extracellular cold-inducible RNA-binding protein (eCIRP) acts as a ligand of triggering receptor expressed on myeloid cells-1 (TREM-1). M3 is a small CIRP-derived peptide that inhibits the eCIRP/TREM-1 interaction. We hypothesize that the eCIRP/TREM-1 interaction in cardiomyocytes contributes to sepsis-induced cardiac dysfunction in neonatal sepsis, while M3 is cardioprotective. METHODS: Serum was collected from neonates in the Neonatal Intensive Care Unit (NICU). 5-7-day old C57BL/6 mouse pups were used in this study. Primary murine neonatal cardiomyocytes were stimulated with recombinant murine (rm) CIRP with M3. TREM-1 mRNA and supernatant cytokine levels were assayed. Mitochondrial oxidative stress, ROS, and membrane potential were assayed. Neonatal mice were injected with rmCIRP and speckle-tracking echocardiography was conducted to measure cardiac strain. Sepsis was induced by i.p. cecal slurry. Mouse pups were treated with M3 or vehicle. After 16 h, echocardiography was performed followed by euthanasia for tissue analysis. A 7-day survival study was conducted. RESULTS: Serum eCIRP levels were elevated in septic human neonates. rmCIRP stimulation of cardiomyocytes increased TREM-1 gene expression. Stimulation of cardiomyocytes with rmCIRP upregulated TNF-α and IL-6 in the supernatants, while this upregulation was inhibited by M3. Stimulation of cardiomyocytes with rmCIRP resulted in a reduction in mitochondrial membrane potential (MMP) while M3 treatment returned MMP to near baseline. rmCIRP caused mitochondrial calcium overload; this was inhibited by M3. rmCIRP injection impaired longitudinal and radial cardiac strain. Sepsis resulted in cardiac dysfunction with a reduction in cardiac output and left ventricular end diastolic diameter. Both were improved by M3 treatment. Treatment with M3 attenuated serum, cardiac, and pulmonary levels of pro-inflammatory cytokines compared to vehicle-treated septic neonates. M3 dramatically increased sepsis survival. CONCLUSIONS: Inhibition of eCIRP/TREM-1 interaction with M3 is cardioprotective, decreases inflammation, and improves survival in neonatal sepsis. Trial registration Retrospectively registered.

Inhibition of a triggering receptor expressed on myeloid cells-1 (TREM-1) with an extracellular cold-inducible RNA-binding protein (eCIRP)-derived peptide protects mice from intestinal ischemia-reperfusion injury.

BACKGROUND: Intestinal ischemia-reperfusion injury results in morbidity and mortality from both local injury and systemic inflammation and acute lung injury. Extracellular cold-inducible RNA-binding protein is a damage associated molecular pattern that fuels systemic inflammation and potentiates acute lung injury. We recently discovered a triggering receptor expressed on myeloid cells-1 serves as a novel receptor for extracellular cold-inducible RNA-binding protein. We developed a 7-aa peptide, named M3, derived from the cold-inducible RNA-binding protein, which interferes with cold-inducible RNA-binding protein's binding to a triggering receptor expressed on myeloid cells-1. Here, we hypothesized that M3 protects mice against intestinal ischemia-reperfusion injury. METHODS: Intestinal ischemia was induced in C57BL/6 mice via clamping of the superior mesenteric artery for 60 minutes. At reperfusion, mice were treated intraperitoneally with M3 (10 mg/kg body weight) or normal saline vehicle. Mice were killed 4 hours after reperfusion and blood and lungs were collected for various analysis. A 24-hours survival after intestinal ischemia-reperfusion was assessed. RESULTS: Serum levels of organ injury markers aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and lactate were increased with intestinal ischemia-reperfusion, while treatment with M3 significantly decreased their levels. Serum, intestinal, and lung levels of proinflammatory cytokines and chemokines were also increased by intestinal ischemia-reperfusion, and treatment with M3 significantly reduced these values. Intestinal ischemia-reperfusion caused significant histological intestinal and lung injuries, which were mitigated by M3. Treatment with M3 improved the survival from 40% to 80% after intestinal ischemia-reperfusion. CONCLUSION: Inhibition of triggering receptor expressed on myeloid cells-1 by an extracellular cold-inducible RNA-binding protein-derived small peptide (M3) decreased inflammation, reduced lung injury, and improved survival in intestinal ischemia-reperfusion injury. Thus, blocking the extracellular cold-inducible RNA-binding protein-triggering receptor expressed on myeloid cells-1 interaction is a promising therapeutic avenue for mitigating intestinal ischemia-reperfusion injury.

Pediatric Robotic Surgery.

Pediatric robotic-assisted surgery is quickly gaining traction in pediatric surgical disciplines but presents unique challenges as compared to adult robotic surgery. Small abdominal and thoracic cavities limit working space and operative indications differ from the adult population. This article describes the development of pediatric robotic-assisted surgery, discusses technical limitations and benefits, and reviews training considerations particular to robotic surgery. Applications and published outcomes of common procedures in urology, general and thoracic surgery, otolaryngology, and pediatric surgical oncology are described. Finally, costs and the anticipated future direction of pediatric robotic-assisted surgery are discussed.

Extracellular CIRP as an endogenous TREM-1 ligand to fuel inflammation in sepsis.

Extracellular cold-inducible RNA-binding protein (eCIRP) is a recently discovered damage-associated molecular pattern. Understanding the precise mechanism by which it exacerbates inflammation is essential. Here we identified that eCIRP is a new biologically active endogenous ligand of triggering receptor expressed on myeloid cells-1 (TREM-1), fueling inflammation in sepsis. Surface plasmon resonance revealed a strong binding affinity between eCIRP and TREM-1, and fluorescence resonance energy transfer assay confirmed eCIRP's interaction with TREM-1 in macrophages. Targeting TREM-1 by its siRNA or a decoy peptide, LP17, or by using TREM-1-/- mice dramatically reduced eCIRP-induced inflammation. We developed a potentially novel 7-aa peptide derived from human eCIRP, M3, which blocked the interaction of TREM-1 and eCIRP. M3 suppressed inflammation induced by eCIRP or agonist TREM-1 antibody cross-linking in murine macrophages or human peripheral blood monocytes. M3 also inhibited eCIRP-induced systemic inflammation and tissue injury. Treatment with M3 further protected mice from sepsis, improved acute lung injury, and increased survival. Thus, we have discovered a potentially novel TREM-1 ligand and developed a new peptide, M3, to block eCIRP-TREM-1 interaction and improve outcomes in sepsis.

EAST multicenter trial of simulation-based team training for pediatric trauma: Resuscitation task completion is highly variable during simulated traumatic brain injury resuscitation.

BACKGROUND: Best practices for benchmarking the efficacy of simulation-based training programs are not well defined. This study sought to assess feasibility of standardized data collection with multicenter implementation of simulation-based training, and to characterize variability in pediatric trauma resuscitation task completion associated with program characteristics. METHODS: A prospective multicenter observational cohort of resuscitation teams (N = 30) was used to measure task completion and teamwork during simulated resuscitation of a child with traumatic brain injury. A survey was used to measure center-specific trauma volume and simulation-based training program characteristics among participating centers. RESULTS: No task was consistently performed across all centers. Teamwork skills were associated with faster time to computed tomography notification (r = -0.51, p < 0.01). Notification of the operating room by the resuscitation team occurred more frequently in in situ simulation than in laboratory-based simulation (13/22 versus 0/8, p < 0.01). CONCLUSIONS: Multicenter implementation of a standardized pediatric trauma resuscitation simulation scenario is feasible. Standardized data collection showed wide variability in simulated resuscitation task completion.

Management and outcomes of peripancreatic fluid collections and pseudocysts following non-operative management of pancreatic injuries in children.

BACKGROUND: Peripancreatic fluid collection and pseudocyst development is a common sequela following non-operative management (NOM) of pancreatic injuries in children. Our purpose was to review management strategies and assess outcomes. METHODS: A multicenter, retrospective review was conducted of children treated with NOM following blunt pancreatic injury at 22 pediatric trauma centers between the years 2010 and 2015. Organized fluid collections were called "acute peripancreatic fluid collection" (APFC) if identified < 4 weeks and "pseudocyst" if > 4 weeks following injury. Data analysis included descriptive statistics Wilcoxon rank-sum, Kruskal-Wallis and t tests. RESULTS: One hundred patients with blunt pancreatic injury were identified. Median age was 8.5 years (range 1-16). Forty-two percent of patients (42/100) developed organized fluid collections: APFC 64% (27/42) and pseudocysts 36% (15/42). Median time to identification was 12 days (range 7-42). Most collections (64%, 27/42) were observed and 36% (15/42) underwent drainage: 67% (10/15) percutaneous drain, 7% (1/15) needle aspiration, and 27% (4/15) endoscopic transpapillary stent. A definitive procedure (cystogastrostomy/pancreatectomy) was required in 26% (11/42). Patients with larger collections (≥ 7.1 cm) had longer time to resolution. Comparison of outcomes in patients with observation vs drainage revealed no significant differences in TPN use (79% vs 75%, p = 1.00), hospital length of stay (15 vs 25 median days, p = 0.11), time to tolerate regular diet (12 vs 11 median days, p = 0.47), or need for definitive procedure (failure rate 30% vs 20%, p = 0.75). CONCLUSIONS: Following NOM of blunt pancreatic injuries in children, organized fluid collections commonly develop. If discovered early, most can be observed successfully, and drainage does not appear to improve clinical outcomes. Larger size predicts prolonged recovery. LEVEL OF EVIDENCE: III STUDY TYPE: Case series.

Safe phlebotomy reduction in stable pediatric liver and spleen injuries.

PURPOSE: Pediatric blunt solid organ injury management based on hemodynamic monitoring rather than grade may safely reduce resource expenditure and improve outcomes. Previously we have reported a retrospectively validated management algorithm for pediatric liver and spleen injuries which monitors hemodynamics without use of routine phlebotomy. We hypothesize that stable blunt pediatric isolated splenic/liver injuries can be managed safely using a protocol reliant on vital signs and not repeat hemoglobin levels. METHODS: A prospective multi-institutional study was performed at three pediatric trauma centers. All pediatric patients from 07/2016-12/2017 diagnosed with liver or splenic injuries were identified. If appropriate for the protocol, only a baseline hemoglobin was obtained unless hemodynamic instability as defined in an age-appropriate fashion was determined by treating physician discretion. Descriptive statistics were conducted. RESULTS: One hundred four patients were identified of which 38 were excluded from the protocol. There was a significant difference in abnormal shock index, pediatric age-adjusted (SIPA) values, hematocrit, and percentage of patients with hemoglobin less than 10 between the excluded and included patients. Of the 66 patients managed on the protocol, four patients had to be removed, two each on day one and day two. Of those four patients, only one required intervention. There were no mortalities. CONCLUSION: A phlebotomy limiting protocol may be a safe option for stable pediatric splenic and liver injuries cared for in a pediatric trauma center with the resources for rapid intervention should the need arise. The differences in groups highlight the importance of utilizing this protocol in the correct patient population. Reduced phlebotomy offers the potential for reduced resource expenditure without any evidence of increased morbidity or mortality. LEVEL OF EVIDENCE: Level IV.

Decreased Pediatric Trauma Length of Stay and Improved Disposition With Implementation of Lewin's Change Model.

Although often cared for nonoperatively, trauma is a surgical disease managed by surgical services in a multidisciplinary manner. The American College of Surgeons Committee on Trauma (ACS COT) emphasizes this as part of the ACS COT verification process and expects nonsurgical service admission rate of less than 10%. In this project, we developed a collaborative care model captained by surgical services with medical service consultation to achieve this goal for optimal care of injured patients. The project was conducted at a freestanding pediatric trauma center undergoing verification as a Level 1 ACS COT pediatric trauma center. The trauma registry was utilized to obtain nonsurgical service admission rate from January 2011 to June 2015. Lewin's 3-Step Model was utilized to guide change. Adherence to the new ACS standards was continually tracked and fallouts were addressed on an individual basis. Overall compliance was reported routinely through trauma and hospital quality programs. Individual successes and accomplishments were recognized and reinforced. At the inception of the project, nonsurgical admission rate was 30%. Implementation of Lewin's 3-Step Model nonsurgical admission rate decreased to 3%, representing a reduction of 27%. In addition, a 21% reduction in hospital length of stay, 3.78-3 days, was demonstrated with no change in 30-day readmission rate. Lewin's change model facilitated culture change to achieve ACS COT standards and reduced nonsurgical admissions to less than 10%. Reduction in hospital length of stay supports an improvement in the efficiency of care when directed by the pediatric trauma surgery team.

Neonatal intestinal dysbiosis in necrotizing enterocolitis.

Necrotizing Enterocolitis (NEC) is one of the most devastating gastrointestinal diseases in neonates, particularly among preterm infants in whom surgical NEC is the leading cause of morbidity. NEC pathophysiology occurs in the hyper-reactive milieu of the premature gut after bacterial colonization. The resultant activation of the TLR4 pathway appears to be a strongly contributing factor. Advancements in metagenomics may yield new clarity to the relationship between the neonatal intestinal microbiome and the development of NEC. After a century without effective directed treatments, microbiome manipulation offers a promising therapeutic target for the prevention and treatment of this devastating disease.