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Background and Objective: Minimally invasive surgery (MIS) has been widely utilized to manage congenital gastrointestinal (GI) anomalies in children during the last two decades. Currently, MIS has a proven track-record for its feasibility and provides multiple benefits including better cosmesis, less trauma, and faster recovery in neonates and infants. However, it remains controversial whether MIS provides better definitive outcomes in pediatric patients with GI anomalies, especially among neonates. We aim to review the recent developments of MIS in infants with GI defects, assisting surgeons in making decisions and improving patient outcomes., Methods: A comprehensive literature search of PubMed and Web of Science's core collection was performed using terms of MIS techniques and congenital GI anomalies., Key Content and Findings: This review summarizes recent evidence-based advances of MIS in infants with congenital GI defects and potential future strategies based on evidence. Better cosmetic results, less postoperative pain, and an accelerated recovery have been shown to be common advantages of MIS relative to open approaches. Technical hurdles and metabolic disturbance were reported to be the main reasons for the decisions of open approach., Conclusions: Advanced techniques of MIS have made more precise manipulations and better outcomes possible, even for newborns. At the same time, surgeons should not be afraid to use an open approach in certain circumstances due to technical limitations or patient tolerance. The difficulty infants face in expressing their true feelings underscores the need for systematic and objective assessment tools to evaluate surgical outcomes., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-23-611/coif). The authors have no conflicts of interest to declare., (2024 Translational Pediatrics. All rights reserved.)

Purpose: Necrotizing enterocolitis (NEC), an inflammatory intestinal disease common in premature infants, has been associated with the development of lung damage. Toll-like receptor 4 has been shown to regulate inflammation in the NEC lungs, however, other important inflammatory mechanisms have not been thoroughly investigated. In addition, we reported that milk-derived exosomes were able to attenuate intestinal injury and inflammation in experimental NEC. This study aims to (i) investigate the role of the NLRP3 inflammasome and NF-κB pathway in regulating lung damage during experimental NEC; and (ii) evaluate the therapeutic potential of bovine milk exosomes in reducing lung inflammation and injury during NEC., Methods: NEC was induced by gavage feeding of hyperosmolar formula, hypoxia, and lipopolysaccharide administration in neonatal mice from postnatal days 5-9. Exosomes were obtained by ultracentrifugation of bovine milk and administered during each formula feed., Results: The lung of NEC pups showed increased inflammation, tissue damage, NLRP3 inflammasome expression, and NF-κB pathway activation, which were attenuated upon exosome administration., Conclusion: Our findings suggest that the lung undergoes significant inflammation and injury following experimental NEC which are attenuated by bovine milk-derived exosomes. This emphasizes the therapeutic potential of exosomes not just on the intestine but also on the lung., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Family-involved care in the neonatal intensive care unit (NICU) helps to alleviate neonatal anxiety and promotes breastmilk intake, body growth and neurological development, but its effect on reducing the incidence of neonatal sepsis is not known. We conducted a systematic review and meta-analysis of randomized controlled trials (RCT) to evaluate whether neonates receiving family care have a lower incidence of neonatal sepsis compared to neonates receiving standard NICU care., Methods: MEDLINE, Embase, Web of Science, and CENTRAL were searched for RCTs that compared preterm neonates receiving family care vs. standard NICU care. From 126 articles that were identified and screened, 34 full-text articles were assessed for eligibility, and 5 RCTs were included. The primary outcome was the development of sepsis. The RevMan 5.4 software was used to conduct the Meta-analysis., Results: The metanalysis, based on 5 RCTs demonstrated that neonates receiving family-involved care had significantly lower incidence of sepsis (12.0% vs. 16.3%), increased body weight, and reduced length of hospital stay compared to those receiving standard NICU care., Conclusion: This study suggests that family-involved care in NICU can (i) reduce the incidence of neonatal sepsis, (ii) improve growth, and (iii) reduce the length of hospital stay. This study highlights the need for evaluating whether family-involved care improves other neonatal outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Ganji, Alganabi, Yamoto, Chusilp, Pierro and Li.)

Objective: The aim of this study was to define controlled outcomes for bowel function and quality of life (QoL) after transanal rectal mucosectomy and partial internal anal sphincterectomy pull-through (TRM-PIAS, A modified Swenson procedure) for Hirschsprung disease (HD)., Background: We have previously shown that a novel modification of transanal rectal mucosectomy and partial internal anal sphincterectomy (TRM-PIAS, A modified procedure) for Hirschsprung disease have the advantage of low postoperative Hirschsprung associated enterocolitis. The controlled long-term follow-up studies evaluating Bowel Function Score (BFS) and Pediatric Quality of Life Inventory (PedsQoL, age <18 years) remain unclear., Methods: Between Jan 2006 and Jan 2016, 243 Patients underwent TRM-PIAS older than 4 years were included, while experienced redo surgery because of complication were excluded. Patients were compared with age- and gender-matched 244 healthy children each randomly selected from the 405 general population. The enrollee was investigated for questionnaires on BFS and PedsQoL., Results: One hundred and ninety-nine (81.9%) patients' representatives for the entire study population responded. The mean age of patients was 84.4 months (48-214 months). Compared with controls, patients reported impairment of hold back defecation, fecal soiling, and the urge to defecate ( P  < 0.05), and no significantly different in fecal accidents, constipation and social problems. With advancing age, the total BFS of HD patients improved, with a tendency close to the normal level beyond 10 years old. But, after grouped according to presence or absence of HAEC, the non-HAEC group experienced more dramatic improvement with age increasing., Conclusions: Compared with matched peers, significant impairment of fecal control prevails after TRM-PIAS in HD patients, but bowel function improve with age and recovery faster than conventional procedure. It should be emphasized that post-enterocolitis is a high-risk factor for delayed recovery., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Zhang, Li, Li, Alganabi and Li.)

Introduction:  The optimal timing of delivery for pregnancies complicated by prenatally diagnosed gastroschisis remains controversial. Therefore, the aim of this study was to find whether elective or expectant delivery is associated with improved neonatal outcome., Materials and Methods:  MEDLINE and Embase databases were searched for studies up to 2021 that reported timing of delivery for prenatally diagnosed gastroschisis. A systematic review and meta-analysis were then performed in group 1: moderately preterm (gestational age [GA]: 34-35 weeks) elective delivery versus expectant management after GA 34-35 weeks; and group 2: near-term (GA: 36-37 weeks) elective delivery versus expectant management after GA 36-37 weeks. The following clinical outcomes were evaluated: length of stay (LOS), total parenteral nutrition (TPN) days, bowel morbidity (atresia, perforation, and volvulus), sepsis, time of first feeding, short gut syndrome and respirator days, and mortality., Results:  Two randomized controlled trials (RCT)s and eight retrospective cohort studies were included, comprising 629 participants. Moderately preterm elective delivery failed to improve clinical outcomes. However, near-term elective delivery significantly reduced bowel morbidity (7.4 vs. 15.4%, relative risk = 0.37; 95% confidence interval [CI]: 0.18, 0.74; p  = 0.005; I2 = 0%) and TPN days (mean difference =-13.44 days; 95% CI: -26.68, -0.20; p  = 0.05; I2 = 45%) compared to expectant delivery. The mean LOS was 39.2 days after near-term delivery and 48.7 days in the expectant group ( p  = 0.06)., Conclusion:  Based on the data analyzed, near-term elective delivery (GA 36-37 weeks) appears to be the optimal timing for delivery of pregnancies complicated by gastroschisis as it is associated with less bowel morbidity and shorter TPN days. However, more RCTs are necessary to better validate these findings., Competing Interests: None declared., (Thieme. All rights reserved.)

Background: Intestinal ischemia and reperfusion (IR) injury like that seen in midgut volvulus can be life-threatening in the pediatric population. Human breast milk-derived exosomes (HMDEs) can prevent intestinal inflammation in experimental necrotizing enterocolitis and other intestinal diseases. The aim of this study is to investigate the effects of HMDEs on intestinal damage related to IR injury., Methods: Exosomes were isolated from human breast milk by ultracentrifugation then confirmed by Nanoparticle tracking analysis and detection of exosome membrane markers. 2-weeks old Sprague Dawley rats were randomly divided into 4 groups: a) Sham (n = 8) with laparotomy alone, b) Sham with HMDEs administration by gavage (n = 8), c) Intestinal IR injury (n = 8) by occlusion of the superior mesenteric artery (SMA) for 30 min followed by reperfusion, and d) Intestinal IR by SMA occlusion with HMDEs administration by gavage (n = 8). Six hours after laparotomy, animals were euthanized, and the ilea (10 cm to cecum) were harvested. Mucosal injury was scored histologically. The intestines were further examined for inflammatory cytokine TNFα, and epithelial proliferation marker Ki67., Results: Compared to sham, the small intestine of IR rats had more intestinal damage, increased expression of inflammatory cytokine TNFα and decreased intestinal proliferation. HMDEs significantly counteracted all these changes., Conclusions: Human breast milk-derived exosomes protect the intestine against damage by IR injury. This beneficial effect is associated with decreased intestinal inflammation and enhanced epithelial proliferation. This study implicates the potential novel application of HMDEs in preventing intestinal damage in infants with intestinal IR injury., (Copyright © 2022. Published by Elsevier Inc.)

Purpose: Necrotizing enterocolitis (NEC) is a gastrointestinal disease in neonates that is associated with immune-mediated intestinal inflammation. Remote ischemic conditioning (RIC) applied to a limb has been shown to be protective against experimental NEC. In this study, we explore the immune cell-mediated response involved in NEC and the immunomodulatory effects of RIC in an experimental mouse model of the disease., Methods: NEC was induced in C57BL/6 mice (ethical approval #58119) pups on postnatal day5 (p5) using gavage hyperosmolar formula, lipopolysaccharide, and hypoxia. RIC consisted of 4 cycles of 5 min ischemia followed by 5 min reperfusion of the right hindlimb during NEC induction on p6 and p8. Breastfed mice were used as control. The mice were sacrificed on p9, with ileal tissue evaluated for inflammatory cytokines and by characterization of T-cell populations., Results: NEC mice had increased number of CD4 + cells indicating an accumulation of T-cells in the mesenchyme of the NEC ileum. Compared to control, NEC pups had upregulated expression pro-inflammatory cytokines (GATA3, IFNγ, IL1β, IL6, IL17, IL22, and TNFα) and reduced anti-inflammatory cytokine (TGFβ). In NEC, there was also a shift in the balance of Treg/Th17 cells towards Th17. Compared to NEC alone, RIC during the course of NEC resulted in reduction of pro-inflammatory cytokines (GATA3, IFNγ, IL1β, IL6, IL17, IL22, and TNFα), increase in anti-inflammatory cytokine TGFβ and concomitant shift back of Th17 cells towards Treg cells., Conclusion: In experimental NEC, remote ischemic conditioning reduces the production of pro-inflammatory markers and increases the production of anti-inflammatory markers. In addition, during NEC, RIC reverses the imbalance of Treg/Th17 providing support for its effect on cell-mediated inflammation. RIC is a non-invasive physical maneuver that can have a significant beneficial effect in reducing the inflammation seen in NEC., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Scope: Necrotizing enterocolitis (NEC) is a devastating gastrointestinal emergency affecting preterm infants. Breastmilk protects against NEC, partly due to human milk oligosaccharides (HMOs). HMO compositions are highly diverse, and it is unclear if anti-NEC properties are specific to carbohydrate motifs. Here, this study compares intestinal epithelial transcriptomes of five synthetic HMOs (sHMOs) and examines structure-function relationships of HMOs on intestinal signaling., Methods and Results: This study interrogates the transcriptome of Caco-2Bbe1 cells in response to five synthetic HMOs (sHMOs) using RNA sequencing: 2'-fucosyllactose (2'-FL), 3-fucosyllactose (3FL), 6'-siallyllactose (6'-SL), lacto-N-tetraose (LNT), lacto-N-neotetraose (LNnT). Protection against intestinal barrier dysfunction and inflammation occurred in an HMO-dependent manner. Each sHMO exerts a unique set of host transcriptome changes and modulated unique signaling pathways. There is clustering between HMOs bearing similar side chains, with little overlap in gene regulation which is shared by all sHMOs. Interestingly, most sHMOs protect pups against NEC, exerting divergent mechanisms on intestinal cell morphology and inflammation., Conclusions: These results demonstrate that while structurally distinct HMOs impact intestinal physiology, their mechanisms of action differ. This finding establishes the first structure-function relationship of HMOs in the context of intestinal cell signaling responses and offers a functional framework by which to screen and design HMO-like compounds., (© 2021 Wiley-VCH GmbH.)

Background: Stem cell therapy has been proven to rescue intestinal injury and stimulate intestinal regeneration in necrotizing enterocolitis (NEC). Specifically, stem cells derived from amniotic fluid (AFSCs) and mesenchymal stem cells (MSCs) derived from bone marrow have shown promising results in the treatment of experimental NEC. This study aims to examine the effects of AFSCs and MSCs on the prevention of intestinal injury during experimental NEC., Methods: Supernatants from AFSC and MSC cultures were collected to perform proteomic analysis. Prior to NEC induction, mice received intraperitoneal injections of phosphate-buffered saline (PBS), 2 × 10 6 AFSCs, or 2 × 10 6 MSCs., Results: We found that AFSCs grew faster than MSCs. Proteomic analysis indicated that AFSCs are primarily involved in cell development and growth, while MSCs are involved in immune regulation. Administering AFSCs before NEC induction decreased NEC severity and mucosal inflammation. Intestinal proliferation and endogenous stem cell activation were increased after AFSC administration. However, administering MSCs before NEC induction had no beneficial effects., Conclusions: This study demonstrated that AFSCs and MSCs have different protein release profiles. AFSCs can potentially be used as a preventative strategy for neonates at risk of NEC, while MSCs cannot be used., Impact: AFSCs and MSCs have distinct protein secretory profiles, and AFSCs are primarily involved in cell development and growth, while MSCs are involved in immune regulation. AFSCs are unique in transiently enhancing healthy intestinal epithelial cell growth, which offers protection against the development of experimental NEC. The prevention of NEC via the administration of AFSCs should be evaluated in infants at great risk of developing NEC or in infants with early signs of NEC., (© 2021. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Purpose: Necrotizing enterocolitis (NEC) is one of the most distressing gastrointestinal emergencies affecting neonates. Amniotic fluid stem cells (AFSC) improve intestinal injury and survival in experimental NEC but are difficult to administer. In this study, we evaluated whether conditioned medium (CM) derived from human AFSC have protective effects., Methods: Three groups of C57BL/6 mice were studied: (i) breast-fed mice as control; (ii) experimental NEC mice receiving PBS; and (iii) experimental NEC mice receiving CM. NEC was induced between post-natal days P5 through P9 via: (A) gavage feeding of hyperosmolar formula four-time a day; (B) 10 minutes hypoxia prior to feeds; and (C) lipopolysaccharide administration on P6 and P7. Intra-peritoneal injections of either PBS or CM were given on P6 and P7. All mice were sacrificed on P9 and terminal ileum were harvested for analyses., Results: CM treatment increased survival and reduced intestinal damage, decreased mucosal inflammation (IL-6; TNF-α), neutrophil infiltration (MPO), and apoptosis (CC3), and also restored angiogenesis (VEGF) in the ileum. Additionally, CM treated mice had increased levels of epithelial proliferation (Ki67) and stem cell activity (Olfm4; Lgr5) compared to NEC+PBS mice, showing restored intestinal regeneration and recovery during NEC induction. CM proteomic analysis of CM content identified peptides that regulated immune and stem cell activity., Conclusions: CM derived from human AFSC administered in experimental NEC exhibited various benefits including reduced intestinal injury and inflammation, increased enterocyte proliferation, and restored intestinal stem cell activity. This study provides the scientific basis for the use of CM derived from AFSC in neonates with NEC., Competing Interests: RM, SR, PD, and KP are stockholder of Micregen Ltd, this relationship had no effect on study design, analysis, or interpretation of results, and this does not alter our adherence to PLOS ONE policies on sharing data and materials. All other authors declared they had no conflict of interest.

Purpose: Extrahepatic portal vein obstruction (EHPVO) is a major cause of non-cirrhotic portal hypertension in children. Surgical procedures for EHPVO include portosystemic shunts (PSS) and meso-Rex bypass (MRB). We conducted a systematic review and meta-analysis to compare the effectiveness of MRB versus PSS in EHPVO patients., Methods: A systematic literature search was performed using four databases. Articles reporting EHPVO and comparing patients who received MRB and PSS were included in the analysis., Results: We retrieved 851 papers, of which five observational studies met the inclusion criteria. There was no difference in shunt complications, mortality, or gastrointestinal bleeding after surgery between MRB and PSS in the meta-analysis. MRB had increased shunt complications compared with PSS in the non-comparative studies. MRB had a potential advantage over PSS in long-term prognosis in one comparative study. Overall, the quality of the evidence was low., Conclusions: Based on available data, our meta-analysis indicates that MRB does not increase shunt complications, mortality, or gastrointestinal bleeding after surgery. The present study did not reveal superiority for either MRB or PSS. The paucity of well conducted trials in this area justifies future multicenter studies and studies that examine long-term outcomes., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Surgical site infections (SSIs) are the most common healthcare-associated infections in patients undergoing surgery. Various randomised control trials (RCTs) indicate that laparoscopic procedures can be associated with better outcomes compared to open procedures. However, how open versus laparoscopic approaches compare across various paediatric procedures with respect to SSI rate remains poorly defined. In this review, we examined RCTs that directly compare SSI rates after open versus laparoscopic operations for appendicitis, gastro-esophageal reflux, inguinal hernia, and pyloric stenosis. MEDLINE, Embase, and Web of Science were searched for RCTs comparing four types of open versus laparoscopic operations in children. The operations included appendectomy, fundoplication for gastro-esophageal reflux, inguinal hernia repair, or pyloromyotomy. 364 records were identified and screened, 54 full-text articles were assessed for eligibility, and 17 RCTs were included in the analysis. SSI rate was the primary outcome. Operative time and length of stay (LOS) were the secondary outcomes. A meta-analysis was conducted using RevMan 5.4 software. Laparoscopic appendectomy had a lower SSI rate than open appendectomy (odds ratio of 2.22 [1.19, 4.15] p = 0.01). Laparoscopic fundoplication for gastro-esophageal reflux, inguinal hernia repair, or pyloromyotomy for pyloric stenosis were not associated with lower SSI rate compared to open surgery. Operative time was shorter in open fundoplication (- 71.22 min [- 89.79,  - 52.65] p < 0.00001) than laparoscopic fundoplication. There was no significant difference in operative time of any of the other procedures. There was no significant difference in LOS between open and laparoscopic procedures for all types of operations analysed. Based on the findings of this review, it is recommended to utilise the laparoscopic approach over the open approach to reduce SSI risk in paediatric appendectomy.

This protocol describes a novel technique to investigate the microcirculation dynamics underlying the pathology in the small intestine of neonatal mice using two-photon laser-scanning microscopy (TPLSM). Recent technological advances in multi-photon microscopy allow intravital analysis of different organs such as the liver, brain and intestine. Despite these advances, live visualization and analysis of the small intestine in neonatal rodents remain technically challenging. We herein provide a detailed description of a novel method to capture high resolution and stable images of the small intestine in neonatal mice as early as postnatal day 0. This imaging technique allows a comprehensive understanding of the development and blood flow dynamics in small intestine microcirculation., Competing Interests: Competing interestsThe authors have no conflict of interest to declare., (Copyright © 2021 The Authors; exclusive licensee Bio-protocol LLC.)

Purpose: Necrotizing enterocolitis (NEC) is a severe neonatal gastrointestinal disease that can cause damage to remote organs. Previous studies have shown that inflammatory and oxidative injury occur in the liver during NEC. Mitochondrial DNA (mtDNA) plays an important role in hepatic injuries of many other diseases. We aimed to investigate the mechanism of mitochondrial dysfunction in hepatic oxidative injury during NEC., Methods: NEC was induced in C57BL/6 mice (approval: 44032) by hypoxia, gavage feeding with hyperosmolar formula, and lipopolysaccharide administration from postnatal days 5 to 9 (n = 15). Two additional groups with hypoxia only (n = 10) and hypoxia and hyperosmolar formula (n = 13) were also examined. Breastfed pups were used as control (n = 15). Liver was harvested on postnatal day 9. Gene expressions of mtDNA markers cytochrome c oxidase subunit 3 (COX3), cytochrome b (CYTB) and NADH-ubiquinone oxidoreductase chain 1 (ND1) were measured by real-time qPCR. Mitochondrial morphology marker HSP60 and oxidative stress marker NRF2 were detected by immunofluorescence staining and compared between NEC and control. Data were presented as mean ± SD and compared using Student's t test; p < 0.05 was considered significant., Results: Gene expression of mtDNA markers (COX3, CYTB, and ND1) were significantly decreased in the liver of NEC mice relative to control, hypoxia alone, and hypoxia with hyperosmolar formula. Immunofluorescence showed depletion of HSP60 indicating decreased mitochondria in NEC liver relative to control. Furthermore, a higher protein expression of NRF2 was observed indicating higher oxidative stress in NEC liver relative to control., Conclusions: Intestinal injury in experimental NEC leads to a systemic inflammatory response affecting the liver. Hepatic oxidative injury in NEC is characterized by decreased mitochondria and mtDNA depletion. This study provides insight into the mechanism of liver injury in NEC.

Aim of the Study: Midgut volvulus is a potentially life-threatening condition which is based on intestinal ischemia and reperfusion (I/R) injury. Remote ischemia conditioning (RIC) applied to a limb can protect distant organs such as heart and kidney. The aims of this study were to investigate the effect of RIC on a model of midgut volvulus and to explore its underlying mechanism of action., Methods: Six-weeks old C57BL/6 mice were studied: (a) sham (n = 4): laparotomy alone. (b) Intestinal I/R injury (n = 5): occlusion of the superior mesenteric artery (SMA) for 45 min followed by reperfusion. (c) Intestinal I/R (as in group above) with RIC immediately after reperfusion (n = 5). RIC consisted of 4 cycles of 5 min hind limb ischemia followed by 5 min reperfusion. 24-h after laparotomy, animals were euthanized, and the small intestine (same distance from cecum) was harvested. The intestine was examined for inflammatory cytokines (TNF-α and IL-6), epithelial proliferation marker Ki67 and stem cell marker Lgr5 expression., Main Results: Compared to sham, the small intestine of IR mice had more intestinal damage, increased expression of inflammatory cytokines, decreased intestinal proliferation and stem cell activity. RIC significantly counteracted all these changes., Conclusions: Remote ischemia conditioning avoids intestinal damage due to I/R injury. This beneficial effect is associated with decreased intestinal inflammation and enhanced intestinal regeneration. This study implicates that RIC is a novel non-invasive intervention to reduce the intestinal damage occurring in midgut volvulus.

Purpose: Delayed enteral feeding (DEF) contributes to postoperative complications among children undergoing intestinal surgery. Various recent studies indicate the benefits of early enteral nutrition after intestinal surgery in adults. This systematic review and meta-analysis evaluates whether early enteral feeding (EEF) is beneficial in children who underwent intestinal anastomosis., Methods: MEDLINE, PubMed, the Cochrane Library, and Web of Science databases were searched for RCTs that addressed the effect of EEF in children (younger than 18 years old) undergoing intestinal anastomosis. EEF was defined as starting enteral feeding before the 3rd postoperative day. Studies were selected based on predetermined inclusion and exclusion criteria. A meta-analysis was performed using RevMan 5.3 to estimate odds ratios (ORs) or mean differences (MDs) with 95% confidence intervals (CIs)., Results: Four RCT studies met the inclusion criteria, comprising 97 cases with EEF and 89 cases with DEF. Enteral feeding started significantly earlier in the EEF group compared to the DEF group (MD = - 2.80; 95% CI - 3.11 to - 2.49; p < 0.00001). Postoperative anastomotic leak rate was unchanged between EEF and DEF groups (OR = 0.86; 95% CI 0.17-4.46; p = 0.86). The EEF group had a shorter length of hospital stay (MD = - 3.38; 95% CI - 4.29 to - 2.48; p < 0.00001), earlier time to bowel movement return (MD = - 0.57; 95% CI - 0.79 to - 0.35; p < 0.00001), lower incidence of surgical infection (OR = 0.27; 95% CI 0.08-0.90; p = 0.03), and faster tolerance of full enteral feeding (MD = - 2.00; 95% CI - 3.01 to - 2.79; p < 0.00001). Incidence of fever (OR = 0.37; 95% CI 0.10-1.31; p = 0.12), emesis, and abdominal distention (OR = 0.63; 95% CI 0.13-3.16; p = 0.58) were not different between the two groups., Conclusions: Early enteral feeding after intestinal anastomosis in children does not increase the risk of postoperative anastomotic leak, fever, emesis, and abdominal distention. However, early enteral feeding is beneficial as it promotes the return of bowel function, reduces the length of hospital stay and the incidence of surgical infection in comparison to delayed enteral feeding.

Pediatric surgeon scientists in Canada and broadly North America occupy a unique role balancing both clinical practice and surgical research. The path to becoming an academic pediatric surgeon scientist is one that is lengthy but highly rewarding. There are excellent opportunities for young surgeons to become academic pediatric surgeons represented by the Doctor of Medicine (MD) / Doctor of Philosophy (PhD) and the Surgeon Scientist Training Programs (SSTP). Meeting the demands for clinical practice often takes precedence over research training in healthcare, leading to a potential shortage of academic pediatric surgeons in Canada and North America. This shortage often leads to increased reliance on international research collaborations and imported talent to continue to advance the field. Protecting the research academic time is essential to a fruitful progression in academic pediatric surgery., (Copyright © 2021. Published by Elsevier Inc.)

Scope: Necrotizing enterocolitis (NEC) is a devastating gastrointestinal emergency and currently the leading cause of mortality in preterm infants. Recent studies show that human milk oligosaccharides (HMOs) reduce the frequency and incidence of NEC; however, the molecular mechanisms for their protection are largely unexplored., Methods and Results: To address this gap, a genome-wide profiling of the intestinal epithelial transcriptome in response to HMOs using RNA-sequencing is performed. It is found that HMOs alter the host transcriptome in 225 unique target genes pertaining to cell proliferation and differentiation, including upregulation of stem cell differentiation marker HMGCS2. To validate these results, differentiation in Caco-2Bbe1 (Caco-2) intestinal cells is verified by Alcian Blue staining and transepithelial electrical resistance (TER) recordings. Furthermore, an in vivo model of NEC is also employed whereby neonatal pups are gavage fed HMOs. Interestingly, HMOs-fed pups show enhanced cell MUC2 differentiation and HMGCS2 expression., Conclusions: These findings demonstrate HMOs protect against NEC in part by altering the differentiation of the crypt-villus axis. In addition, this study suggests that pooled HMOs directly induce a series of biological processes, which provide mechanistic insights to how HMOs protect the host intestine., (© 2020 Wiley-VCH GmbH.)

Purpose: Intestinal absorption in premature infants occurs via direct epithelial cellular endocytosis and degradation by intracellular lysosomes. Autophagy is a mechanism by which cytoplasmic organelles contribute to lysosomal degradation. However, excessive autophagy can lead to cell death. The purpose of this study was to investigate whether autophagy and endocytosis are present in the small intestinal mucosa during experimental necrotizing enterocolitis (NEC)., Methods: NEC was induced by gavage feeding of hyperosmolar formula, lipopolysaccharide and hypoxia between P5 and P9 (ethical approval 44032). Breastfed mice were used as control. Distal ileum was harvested on P5, P7 and P9 and analyzed for intestinal epithelial cellular morphology as well as autophagy/lysosomal activity, and cell death. Groups were compared using Student's t test., Results: During NEC, giant lysosomes were present in the intestinal villi, with some exceeding their degradation ability leading to their rupture. The NEC group had significantly increased inflammation and autophagy activity, decreased lysosome activity, and increased apoptosis compared to control., Conclusions: NEC induction causes excessive autophagy and endocytosis leading to lysosomal overloading, lysosomal membrane permeabilization and rupture which results in cell death. These novel findings may help to clarify the pathogenesis of NEC. Reduction of lysosome overload and assisting in their degradation capability may reduce the burden of NEC.

Necrotizing enterocolitis (NEC) is a devastating intestinal disease primarily affecting preterm neonates and causing high morbidity, high mortality, and huge costs for the family and society. The treatment and the outcome of the disease have not changed in recent decades. Emerging evidence has shown that stimulating the Wnt/β-catenin pathway and enhancing intestinal regeneration are beneficial in experimental NEC, and that they could potentially be used as a novel treatment. Amniotic fluid stem cells (AFSC) and AFSC-derived extracellular vesicles (EV) can be used to improve intestinal injury in experimental NEC. However, the mechanisms by which they affect the Wnt/β-catenin pathway and intestinal regeneration are unknown. In our current study, we demonstrated that AFSC and EV attenuate NEC intestinal injury by activating the Wnt signaling pathway. AFSC and EV stimulate intestinal recovery from NEC by increasing cellular proliferation, reducing inflammation and ultimately regenerating a normal intestinal epithelium. EV administration has a rescuing effect on intestinal injury when given during NEC induction; however, it failed to prevent injury when given prior to NEC induction. AFSC-derived EV administration is thus a potential emergent novel treatment strategy for NEC.

Purpose: Necrotizing Enterocolitis (NEC) is a devastating neonatal disease with a high mortality rate. Fecal Microbiota Transplantation (FMT) has been used to treat a variety of gastrointestinal diseases. We aimed to investigate the role of FMT in NEC., Methods: NEC was induced by hypoxia, LPS, and hyperosmolar gavage feeding between postnatal days P5 and P9 (n = 8). Breastfed mice were used as control (n = 7). FMT (30 μl/g) was administered by gavage or enema at P6 during NEC induction. Distal ileum was harvested on P9. Disease severity was evaluated by H&E staining. Gene expression of inflammatory markers IL6 and TNFa was measured. Expression of intestinal barrier function was investigated by measuring Claudin-7. Microbiota composition in ileum and colon was analyzed by quantitative PCR., Results: FMT by gavage further increased terminal ileum inflammation and did not improve the histological damage owing to experimental NEC. Conversely, FMT by enema decreased intestinal inflammation and improved histology of the NEC-like injury in the ileum. In addition, compared with NEC alone, FMT by enema increased Claudin-7 expression indicating an improvement in barrier function. These beneficial effects occurred despite no change in microbiota., Conclusion: Our results show that FMT by enema may be an effective strategy to reduce NEC progression as it attenuates intestinal inflammation and enhances intestinal barrier function. FMT by enema is a potential novel treatment for NEC., Level of Evidence: Level IV, Evidence from well-designed case-control or cohort studies., (Copyright © 2020. Published by Elsevier Inc.)

Purpose: Butyrate is a short-chain fatty acid produced in the intestine. It is controversial whether butyrate is protective or destructive for the intestinal epithelium in the development of diseases like necrotizing enterocolitis (NEC), and its mechanism of action remains unclear. We aimed to determine the effect of butyrate on the intestinal epithelium by studying its effects on intestinal epithelial cells (IEC-18) exposed to injury and in vivo by investigating the effects on the intestine in an experimental model of NEC., Methods: A) In vitro study: Butyrate was given to normal IEC-18 to determine the dose triggering injury. Based on above results, low dose butyrate (1 mM) was given to H 2 O 2 -injured cells to determine its effect against inflammation. B) In vivo study: NEC was induced by hypoxia and gavage feeding between postnatal day P5 and P9 (n = 8). Breastfed mice were used as control (n = 7). Butyrate (150 mM) was administered by enema on P6 in NEC (n = 6). Distal ileum was harvested on P9., Results: High dose (16 mM) butyrate upregulated inflammatory marker IL-6, while low dose butyrate protected cells from injury by reducing IL-6 expression. Similarly, compared with NEC alone, NEC mice who received butyrate had reduced intestinal damage, reduced IL-6 and NF-ĸB expression, and increased intestinal tight junction marker Claudin-7., Conclusion: Butyrate has opposite effects depending on the dose administered. Butyrate can protect cells from H 2 O 2 -induced injury and can in vivo protect the intestine from NEC. This beneficial effect is because of downregulation of inflammation and enhancement of intestinal barrier., (Copyright © 2020. Published by Elsevier Inc.)

Ischemia/reperfusion (I/R) is implicated in the pathogenesis of various acute intestinal injuries. Amniotic fluid stem cells (AFSC) are beneficial in experimental intestinal diseases. Tumor necrosis factor-induced protein 6 (TSG-6) has been shown to exert anti-inflammatory effects. We aimed to investigate if AFSC secreted TSG-6 reduces inflammation and rescues intestinal I/R injury. The superior mesenteric artery of 3-week-old rats was occluded for 90 minutes and green fluorescent protein-labeled AFSC or recombinant TSG-6 was injected intravenously upon reperfusion. AFSC distribution was evaluated at 24, 48, and 72 hours after I/R. AFSC and TSG-6 effects on the intestine were assessed 48 hours postsurgery. Intestinal organoids were used to study the effects of TSG-6 after hypoxia-induced epithelial damage. After I/R-induced intestinal injury, AFSC migrated preferentially to the ileum, the primary site of injury, through blood circulation. Engrafted AFSC reduced ileum injury, inflammation, and oxidative stress. These AFSC-mediated beneficial effects were dependent on secretion of TSG-6. Administration of TSG-6 protected against hypoxia-induced epithelial damage in intestinal organoids. Finally, TSG-6 attenuated intestinal damage during I/R by suppressing genes involved in wound and injury pathways. This study indicates that AFSC or TSG-6 have the potential of rescuing the intestine from the damage caused by I/R., (© 2020 Federation of American Societies for Experimental Biology.)

Purpose: Activation of calcium/calmodulin-dependent protein kinase IV (CaMKIV) has been shown to increase intestinal injury and inhibit epithelial cell proliferation in dextran sulfate sodium (DSS)-induced colitis mice. However, the role of CaMKIV in necrotizing enterocolitis (NEC) is unknown. We aimed to study the expression and activation of CaMKIV in experimental NEC., Methods: Following ethical approval, NEC (n = 10) was induced in C57BL/6 mouse pups by hypoxia, gavage hyperosmolar formula feeding and lipopolysaccharide from postnatal days P5 to 9. Breastfed pups served as control (n = 10). Mouse pups were sacrificed on P9 and the terminal ileum was harvested. Gene NEC injury was scored blindly by three independent investigators. CaMKIV, CREM and IL17 gene expression, and CaMKIV and pCaMKIV protein expression were assessed. The data were compared using Mann-Whitney U test. P < 0.05 was considered significant., Results: Intestinal injury was induced in the NEC mice and confirmed by histological scoring and inflammatory cytokine IL6. CaMKIV and its downstream target genes of CREM and IL17 were significantly elevated in NEC mice relative to control. Similarly, phosphorylated-CaMKIV (pCaMKIV), the active form of CaMKIV, was more notably expressed in the NEC ileal tissue relative to control ileal tissue. Elevated pCaMKIV protein expression was also confirmed by western blot., Conclusion: CaMKIV expression and activation are upregulated in experimental NEC suggesting a potential contributing factor in the pathogenesis of NEC.

Introduction:  There is a need to develop sensitive markers to diagnose or monitor the severity of intestinal damage in necrotizing enterocolitis (NEC). Mitochondrial deoxyribonucleic acid (mtDNA) is increased in the intestine and blood of adults in response to intestinal ischemia and can trigger secondary organ damage. We hypothesize that mtDNA is increased during experimental NEC and that mtDNA levels are correlated to the degree of intestinal injury., Materials and Methods:  NEC was induced in C57BL/6 mice ( n  = 18) (approval: 44032) by gavage feeding with hyperosmolar formula, hypoxia, and lipopolysaccharide administration from postnatal day (P) 5 to 9. Breastfed pups served as control ( n  = 15). Blood was collected by cardiac puncture and terminal ileum was harvested on P9. Reverse transcription quatitative polymerase chain reaction was used to measure mtDNA (markers COX3, CYTB, ND1) and inflammatory cytokines (interleukin 6 [IL-6] and tumor necrosis factor-α[TNF-α]) in blood and ileum. Intestinal injury was scored blindly by four investigators and classified as no/minor injury (score 0 or 1) or NEC (score ≥2)., Results:  mtDNA is significantly increased in gut and blood of NEC mice ( p  < 0.05). Furthermore, mtDNA increases in intestine and blood proportionally to the degree of intestinal injury as indicated by a positive correlation with histological scoring and inflammation ( r  = 0.6; p  < 0.05) (expression of IL-6 and TNF-α)., Conclusion:  Following NEC intestinal injury, mtDNA is released from the intestine into circulation. The blood level of mtDNA is related to the degree of intestinal injury. mtDNA can be a novel marker of intestinal injury and can be useful for monitoring the progression of NEC., Competing Interests: None declared., (Georg Thieme Verlag KG Stuttgart · New York.)

Purpose: The purpose of this study was to investigate (i) postoperative course of apple-peel atresia (APA), (ii) long-term follow-up of APA children, and (iii) risk factors for poor prognosis., Methods: We conducted a retrospective review of 39 APA neonates treated at our institution between 2008 and 2017. Patient characteristics, operative details, postoperative course, long-term outcomes, and prognostic factors were analyzed., Results: Of the 39 APA neonates, 30 (76.9%) were born preterm, and 20 (51.3%) were diagnosed prenatally. All patients underwent primary anastomosis within the first week after birth: 10 laparoscopic-assisted (25.6%) and 29 open (74.4%). Postoperative complications occurred in 28 patients (71.8%), of which 20 (71.4%) developed cholestasis. Survival at hospital discharge was 94.9%. Median parenteral nutrition period was 59 days. Reoperation was required in 7 children (17.9%) owing to anastomotic obstruction (n = 3) and adhesive intestinal obstruction (n = 4). 32 children (82.1%) were followed up for an average of 5.7 years, of which 23 children (71.9%) showed normal growth and development. APA patients with low birth weight and associated anomalies had significantly worse outcomes., Conclusion: Most of the patients with apple-peel atresia have excellent long-term outcomes, though initial postoperative complications are common. Low birth weight and the presence of associated anomalies are independent prognostic factors in APA., Type of Study: Prognosis study (case series)., Level of Evidence: Level IV., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: Autophagy is a natural mechanism aimed to degrade and recycle cellular components within cells. Previous studies reported that autophagy in the intestinal epithelium can be activated and that excessive autophagy can have negative consequences. However, the mechanism by which autophagy is regulated during intestinal epithelial injury remains unclear. This study aimed to investigate the mechanism of autophagy regulation during intestinal epithelial cells (IEC) injury., Methods: Rat IEC18 were exposed to hypoxia and Lipopolysaccharide (LPS) (200 μg/ml) to induce injury. IEC18 were treated with autophagy initiation inhibitor, Wortmannin or with autophagy degradation inhibitor, Bafilomycin A1 were added for 24 h. We assessed the number and diameter of autophagic vacuoles, Cell viability, inflammation and apoptosis., Results: Hypoxia and LPS administration increased the number and diameter of autophagic vacuoles in IEC18. Wortmannin administration reduced the number and diameter of autophagic vacuoles. On the contrary, Bafilomycin A1 administration increased the number of autophagic vacuoles. Cell viability increased following administration of Wortmannin and decreased following administration of Bafilomycin A1., Conclusions: We found that accumulation of autophagic vacuoles which characterize excessive or incomplete autophagy was detrimental to cell survival. This was shown by an increase in the number and size of the autophagic vacuoles with Bafilomycin A1treatment after hypoxia and LPS stressors relative to hypoxia and LPS alone. Conversely, there was a decrease in the number of autophagic vacuoles with Wortmannin treatment after hypoxia and LPS stressors relative to hypoxia and LPS alone. Therefore, reducing autophagosomes accumulation may represent a novel therapeutic strategy for intestinal injury.

Background and Purpose: Excessive inflammatory cell infiltration and accumulation in the intestinal mucosa are pathological features of necrotizing enterocolitis (NEC) leading to intestinal barrier disruption. Vasoactive intestinal peptide (VIP) is a potent anti-inflammatory agent that regulates intestinal epithelial barrier homeostasis. We previously demonstrated that VIP-ergic neuron expression is decreased in experimental NEC ileum, and this may be associated with inflammation and barrier compromise. We hypothesize that exogenous VIP administration has a beneficial effect in NEC., Methods: NEC was induced in C57BL/6 mice by gavage feeding, hypoxia, and lipopolysaccharide administration between postnatal day (P) 5 and 9. There were four studied groups: Control (n = 6): Breast feeding without stress factors; Control + VIP (n = 5): Breast feeding + intraperitoneal VIP injection once a day from P5 to P9; NEC (n = 9): mice exposed to NEC induction; NEC + VIP (n = 9): NEC induction + intraperitoneal VIP injection. Terminal ileum was harvested on P9. NEC severity, intestinal inflammation, (IL-6 and TNFα), and Tight junctions (Claudin-3) were evaluated., Results: NEC severity and intestinal inflammation were significantly decreased in NEC + VIP compared to NEC. Tight junction expression was significantly increased in NEC + VIP compared to NEC., Conclusion: VIP administration has a beneficial therapeutic effect in NEC by reducing inflammation and tight junction disruption., (Copyright © 2019. Published by Elsevier Inc.)

Necrotizing enterocolitis (NEC) is a devastating neonatal disease characterized by acute intestinal injury. Intestinal stem cell (ISC) renewal is required for gut regeneration in response to acute injury. The Wnt/β-catenin pathway is essential for intestinal renewal and ISC maintenance. We found that ISC expression, Wnt activity and intestinal regeneration were all decreased in both mice with experimental NEC and in infants with acute active NEC. Moreover, intestinal organoids derived from NEC-injured intestine of both mice and humans failed to maintain proliferation and presented more differentiation. Administration of Wnt7b reversed these changes and promoted growth of intestinal organoids. Additionally, administration of exogenous Wnt7b rescued intestinal injury, restored ISC, and reestablished intestinal epithelial homeostasis in mice with NEC. Our findings demonstrate that during NEC, Wnt/β-catenin signaling is decreased, ISC activity is impaired, and intestinal regeneration is defective. Administration of Wnt resulted in the maintenance of intestinal epithelial homeostasis and avoidance of NEC intestinal injury.

Background: Laparoscopic repair has become the preferred option for the treatment of pediatric hernias. Recently, laparoscopic operations have also been conducted in pediatric recurrent hernia cases. Laparoscopic percutaneous extraperitoneal closure (LPEC) is a simple and reliable minimally invasive procedure for pediatric inguinal hernia repair. However, it is still unclear whether LPEC is an ideal procedure for recurrent inguinal hernias in children. The aim of this study is to evaluate the efficacy of LPEC in the treatment of pediatric recurrent inguinal hernias. Patients and Methods: We retrospectively reviewed all children with primary inguinal hernia repairs in our hospital from 2016 to 2017 and analyzed the outcomes of recurrent inguinal hernia repairs with LPEC. Results: There were 1703 children with 1985 indirect inguinal hernias: 1549 were laparoscopic (91.0%) and 154 open (9.0%). Thirty-five (2.1%) of these children had recurrent inguinal hernia with no difference in prevalence between laparoscopic and open ( P  = .24). One case was bilateral. LPEC was performed successfully in all children with recurrent inguinal hernias. There were no severe intra- or postoperative complications in any of the recurrent cases. No children had inguinal hernia recurrence at follow-up (8 months-2 years). Conclusions: LPEC of the internal ring is a reliable and effective minimally invasive technique for the treatment of recurrent inguinal hernia in children.

Necrotizing enterocolitis is a devastating intestinal disease affecting preterm infants. In spite of ongoing research and advancement in neonatal care, mortality remains high, especially in infants with advanced disease. The mechanism of disease development, the progression of intestinal injury, and management remain areas of ongoing research and controversy. In this review, we examine our current understanding of the disease, its epidemiology, the risk factors associated with the development of the disease, and its pathophysiology. We also describe current management and new emerging research highlighting potential future directions., Competing Interests: No competing interests were disclosed.No competing interests were disclosed.No competing interests were disclosed.

Aim of Study: The repair of esophageal atresia (EA) carries an increased risk of anastomotic leak and stricture formation, especially in patients with anastomotic tension. To minimize this risk, pediatric surgeons perform elective post-operative muscle paralysis, positive-pressure ventilation, and head flexion (PVF) to reduce movement and tension at the anastomosis. We systematically reviewed and analyzed the effect of post-operative PVF on reducing anastomotic complications., Methods: Embase, MEDLINE, Web of Science, and PubMed databases were used to conduct searches. Articles reporting pediatric EA undergoing primary anastomosis, anastomotic complications, and comparisons between patients who received post-operative PVF to those who did not were included. Odds ratios (OR) for all post-operative anastomotic complications were calculated using random effects modelling., Main Results: Three of the 2268 papers retrieved met inclusion criteria (all retrospective cohort studies). There were no randomized controlled trials. Post-operative PVF showed a significant reduction in anastomotic leak (OR 0.07; 95% CI 0.01-0.35) when compared to no PVF. Stricture formation was not statistically different between groups. Potential sources of bias include patient allocation., Conclusions: Based on available data, our analysis indicates PVF may reduce anastomotic post-operative leak. To confirm these results, a prospective study with clearer definitions of treatment allocation should be performed.

Aim of the Study: To investigate (1) the indications for reoperation after neonatal Ladd's procedure, (2) the type of reoperation and (3) its outcome., Methods: We reviewed all neonatal Ladd's procedures in our hospital from 2003 to 2017 and the outcomes of reoperation in these patients., Main Results: 252 neonates had Ladd's procedure: 59 were laparoscopic (23.4%) and 193 open (76.6%). 15 (6.0%) required reoperation with no difference between laparoscopic and open (p = 0.12). Overall, the indications for reoperation were: adhesive intestinal obstruction (n = 10, 4.0%), recurrent midgut volvulus (n = 4, 1.6%), and missed diagnosis of associated anomaly (n = 1, 0.4%). The incidence of recurrent midgut volvulus was higher after laparoscopic Ladd's procedure (3/59; 5.1%) compared to open Ladd's procedure (1/193; 0.5%) (p = 0.04). Adhesive intestinal obstruction developed after both open (8/193, 4.1%) or laparoscopic Ladd's procedure (2/59, 3.3%). The duration of reoperation and the length of post-operative hospital stay were 63.4 ± 27.1 min and 10.1 ± 5.2 days, respectively. After reoperation, there were no post-operative complications. All children were well at follow-up (6 months-14 years)., Conclusions: In neonates, laparoscopic Ladd's procedure compared to the open Ladd's procedure is associated with a significantly higher risk of recurrent volvulus. The risk of developing this potentially dangerous complication after laparoscopic Ladd's procedure raises doubts about the effectiveness and safety of the laparoscopic approach in neonates.

We report a case of a 48-year-old male who presented with hematuria of at least 10 years, and has a daughter with hematuria as well. The patient has a history of degenerative hearing loss, decreased vision and cataract formation, but no diabetes, hypertension or proteinuria. A full serology and urology workup was negative for any abnormality. A kidney biopsy for the patient revealed a diagnosis of Alport syndrome but was unable to rule out thin basement membrane disease. The biopsy was inconclusive in making the diagnosis but the patient's clinical presentation led to the diagnosis of Alport syndrome. The patient's 10-year-old daughter also has hematuria with no clear etiology but now can subsequently be anticipatorily managed for Alport syndrome progression. Due to the rarity of the disease, diagnosis is often missed or delayed by primary care providers especially when no associated proteinuria has yet developed. This can lead to confusion and misdiagnosis with thin basement membrane disease, a generally benign hematuria without kidney failure progression. Additionally, biopsy can be inconclusive in these patients, relying on the physician's history and physical examination findings to diagnose. It is important to appropriately diagnose Alport syndrome not only to manage the patient's rate of kidney failure progression but also allow for a higher degree of suspicion, screening and intervention in the patient's family members. Both the inconclusive nature of kidney biopsies and the usefulness of diagnosis for family member screening are often overlooked in medical literature but are explored in this case.