BACKGROUND:The enteric nervous system (ENS), which arises from enteric neural crest cells (ENCCs), plays important roles in many aspects of gastrointestinal tract function, including motility, secretions, blood flow and hormone release. Defects in ENS development could lead to a broad range of disorders, including Hirschsprung's disease (HSCR), which is characterized by missing nerve cells in the distal segment of the colon. Here, we identify EMB as an evolutionarily conserved regulator of ENS development. METHODS:We first examined EMB expression in human and mouse intestines using scRNA-seq data and immunofluorescence staining. To investigate its role in ENS development, we constructed Emb-knockout zebrafish and mouse models. To explore the underlying mechanisms, we focused on ENCCs and analyzed their proliferation and migration using migration assays in explant guts and organoid cultures. Finally, we assessed rare EMB variants in a cohort of HSCR patients. RESULTS:In zebrafish, loss of emb leads to a decrease number of enteric neurons and impaired intestinal transit ability. In mice, knockout of Emb causes HSCR-like phenotypes and defects. In vitro experiments, including explant mouse gut and organoid cultures, show that EMB is required for both the proliferation and migration of ENCCs. Mechanistically, EMB binds to and recruits the phosphatase complex PP2A to the cellular membrane to facilitate the activation of PI3K-AKT pathway, thereby promoting ENCCs development. Indeed, application of PI3K or AKT agonists partially restores the ENS developmental defects in zebrafish emb mutants. Furthermore, rare variants of EMB may potentially contribute to the pathology of HSCR in humans. CONCLUSIONS:EMB is required for ENS development by regulating the proliferation and migration of the ENCCs. Mechanistically, EMB recruits PP2A to the cell membrane, reducing cytoplasmic dephosphorylation activity and promoting the activation of the PI3K signaling pathway.

Background: Lobectomy resection is the standard treatment for patients with congenital pulmonary airway malformation (CPAM). However, accurate localization of CPAM lesions and avoiding excessive resection of normal lung tissue are one of the critical issues that can impact postoperative pulmonary function. Indocyanine green (ICG) can be adopted in lung preservation surgery, to minimize damage to normal lung tissue during thoracoscopic pneumonectomy. Objective: To demonstrate the potential benefits of aerosol inhalation of ICG followed by thoracoscopic precision pneumonectomy for the treatment of CPAM. Methods: From January 2023 to March 2024, we prospectively collected clinical data from 34 pediatric patients diagnosed with CPAM and treated with thoracoscopic surgery. Patients inhaled ICG aerosol solution (0.5 mg/kg) approximately 30e60 min before the operation. During surgery, fluorescence thoracoscopy was used to clearly locate the lesion boundaries and achieve precise resection. Results: All patients successfully underwent thoracoscopic precise resection of CPAM lesions without conversion to open surgery. The mean operation time was 100.3 +/- 24.6 min, and the mean intraoperative blood loss was 30.5 +/- 25.6 mL. The mean total length of hospital stay (tLOS) was 6.6 +/- 3.2 days. No adverse reactions to ICG were observed. Postoperative complications included one case of pneumothorax (5.9 %) and three cases of subcutaneous emphysema (17.6 %), all of which resolved without special intervention. Follow-up CT scans and pulmonary function tests conducted 6 months post-surgery demonstrated the absence of residual or recurrent lesions and notable enhancement in pulmonary function. Conclusion: Preliminary results indicated that the treatment of CPAM with aerosolized ICG followed by thoracoscopic precise pneumonectomy is safe and feasible. (c) 2024 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

Hirschsprung's disease (HSCR) is a congenital enteric neuropathic disorder characterized by high heritability (>80%) and polygenic inheritance (>20 genes). The previous genome-wide association studies (GWAS) identified several common variants associated with HSCR and demonstrated increased predictive performance for HSCR risk in Europeans using a genetic risk score, there remains a notable gap in knowledge regarding Chinese populations. We conducted whole exome sequencing in a HSCR case cohort in Chinese. By using the common controls (505 controls from 1KG EAS and 10 588 controls from ChinaMAP), we conducted GWAS for the common variants in the exome and gene-based association for rare variants. We further validated the associated variants and genes in replicated samples and in vitro and vivo experiments. We identified one novel gene PLK5 by GWAS and suggested 45 novel putative genes based the gene-based test. By using genetic variant at RET and PLK5, we constructed a genetic risk score that could identify the individuals with very high genetic risk for HSCR. Compared with patients with zero or one risk allele from the three variants, the risk for HSCR was 36.61 times higher with six alleles. In addition, we delineated a HSCR risk gene landscape that encompasses 57 genes, which explains 88.5% and 54.5% of HSCR in Chinese and European, respectively. In summary, this study improved the understanding of genetic architecture of HSCR and provided a risk prediction approach for HSCR in the Chinese.

Background: Biliary atresia (BA) is a severe pediatric biliary disorder characterized by the progressive obstruction of liver bile ducts. In the absence of treatment, fibrosis advances rapidly in most affected children. In recent years, there has been significant progress in the management of BA, but many challenges remain. This guideline provides expert opinions on the screening, diagnosis, treatment, and follow-up of BA, aiming to assist and guide clinical practice. Methods: The guideline steering group, guideline development group, and guideline review group were formed to formulate clinical questions, develop recommendations, and draft guidelines using the GRADE Grid method, nominal group technique (NGT), and Delphi voting method. Three offline meetings were held on November 5, 2022, June 10, 2023, November 10, 2023, and October 27, 2024, respectively, to vote on the recommendations and solicit comments and suggestions from all participating experts. All experts from the United States, Europe, and Asia contributed significantly to this consensus guideline. Results: After summarizing high-quality literature on clinically encountered issues such as early screening, complementary checkup, treatments, follow-up, vaccinations, growth, development, and neurocognition, 23 observations were made and strength of recommendations were given. Conclusions: International guidelines for BA can guide surgeons, patients, medical societies, hospital administrators, and relevant community groups in their current practice. The diagnosis and treatment of BA remains controversial internationally and more research evidence is needed.

Preoperative undernutrition is prevalent among children with Hirschsprung disease (HSCR). To evaluate whether preoperative nutritional support reduces the incidence of postoperative HSCR-associated enterocolitis (HAEC), we conducted a prospective, multicenter, open-label randomized controlled trial. The trial was initiated on January 1, 2021 and completed on October 31, 2022. It was carried out across seven tertiary hospitals in China. A total of 110 patients admitted for pull-through surgery for HSCR were enrolled. Eligible participants were randomly assigned 1:1 via a centralized web-based randomization system ( www.cbdps.com ), which generated the allocation sequence. Specifically, 55 patients were allocated to the preoperative nutritional support (PNS) group and 55 to the standard medical care (SMC) group. Surgeons and patients were not blinded to group assignment. The primary outcome was the incidence of HAEC at 3 months after surgery. At 3 months postoperatively, the incidence of HAEC in the PNS group was significantly lower compared to the SMC group. Specifically, the HAEC incidence was 7.27% (4/55) for the PNS group versus 29.09% (16/55) for the SMC group. This resulted in an absolute risk reduction of 21.82% (95% confidence interval: -35.64% to -7.99%; p = 0.003). No adverse events were documented. These results demonstrate that preoperative nutritional support substantially reduces early HAEC incidence in pediatric HSCR patients following pull-through surgery. Trial Registration: ClinicalTrials.gov NCT04598841.

To evaluate the efficacy of laparoscopy combined with intraoperative choledochoscopy in treating choledochal cysts and preventing postoperative complications. This single-center retrospective study included 208 patients with Todani type I choledochal cysts treated laparoscopically from January 2016 to January 2023. Patients undergoing open surgery were excluded. Of these, 138 cases were treated with 6 Fr catheter irrigation (Group A), while 70 cases underwent intraoperative choledochoscopy for thorough irrigation and stone extraction (Group B). All patients were followed up for at least 18 months. Data collected included age at operation, gender, cyst diameter, preoperative manifestations, and postoperative outcomes. Statistical analysis was performed using Student’s t-test for continuous data and Fisher’s exact test for categorical data, with P < 0.05 indicating significance. Clinical data of 187 cases were analyzed after excluding 21 lost to follow-up. No significant differences were found between Group A (n = 124) and Group B (n = 63) in age at operation (35.4 ± 17.2 months vs. 38.9 ± 19.6 months, P = 0.875), gender distribution (male:female ratio 34:90 vs. 13:50, P = 0.891), cyst diameter (25.6 ± 17.8 mm vs. 23.1 ± 17.5 mm, P = 0.758), or preoperative stone presence (54/124 vs. 25/63, P = 0.918). However, Group B had significantly lower incidence of residual/recurrent stones (1/63 vs. 14/124, P = 0.021) and postoperative pancreatitis (1/63 vs. 7/124, P = 0.044). At 6-month follow-up, intrahepatic bile duct dilation was significantly lower in Group B (0/63 vs. 6/124, P = 0.038), and hospital stay was shorter (9.1 ± 2.2 days vs. 10.7 ± 2.1 days, P = 0.003) without significant increase in total medical expenses (39059.6 ± 4115.3 RMB vs. 38422.8 ± 3341.6 RMB, P = 0.291). Laparoscopy combined with intraoperative choledochoscopy is feasible and effective in clearing biliary stones, preventing postoperative complications such as pancreatitis and bile duct dilation, and identifying hepatic duct stenosis in choledochal cyst treatment.

PURPOSE:Congenital pulmonary airway malformation (CPAM) is a developmental lung malformation that seriously endangers children's health. The objective of this study was to investigate the etiology of CPAM by observing changes at the molecular and cellular levels. METHODS:Patient clinical data were collected and analyzed. Tissue samples were collected from CPAM lesions and marginal normal lung tissue during CPAM surgery. The samples were subjected to hematoxylin and eosin (H&E) staining for pathological analysis. Tissue RNA was isolated for RNA sequencing, and the differentially expressed genes (DEGs) were enriched for Gene Ontology (GO) analysis. The cytoskeletal and cell subtypes were subjected to immunofluorescence staining. RESULTS:RNA sequencing of 7 CPAM patients revealed 1252 DEGs, with 1041 upregulated and 211 downregulated. GO analysis revealed that biological processes related to cilium organization and movement were strongly enriched. Protein-protein interaction (PPI) network analysis highlighted genes such as CCDC65, DNAH5, DNAH11, DNAH12, CFAP43, CFAP70, PIH1D3, RSPH4A and DNAH6 as potentially important in CPAM. Immunofluorescence staining revealed abnormalities in cytoskeleton and cilia, and a reduction in the number of alveolar epithelial type II (AEC II) cells in CPAM lesions compared with normal lung tissue. CONCLUSION:Our study revealed a significant increase in cytoskeletal and cilia expression, along with a marked reduction in AEC II. These abnormalities provide potential insights into the etiology of CPAM and may guide the development of improved diagnostic and therapeutic strategies.

Investigate the safety and efficacy of preoperative atomization inhalation of indocyanine green (ICG) solution in precise lesion resection of pediatric thoracoscopic intralobar pulmonary sequestration. A multicenter 1:1 matched case-control study was adopted, to compare the safety and efficacy of the ICG group (preoperative atomization inhalation of 0.5 mg/kg ICG solution) with traditional group (no preoperative atomization inhalation of ICG solution). The baseline, intraoperative, and postoperative recovery conditions of the two groups were observed. Outpatient follow-up visits were conducted 3 to 6 months after surgery, including lung CT scans and pulmonary ventilation function tests. 134 patients were included in the study. The ICG group included 67 patients, and the traditional surgery group included 67 patients matched at a ratio of 1:1 according to age and lesion location. There were no reports of deaths or adverse reactions. The postoperative chest drainage tube indwelling time [(53.19 ± 8.15) hours vs. (73.25 ± 15.51) hours, P < 0.001] and postoperative hospital stay [(4.81 ± 1.84) days vs. (6.72 ± 1.31) days, P < 0.001] were shorter in the ICG group than in the traditional group. More importantly, the postoperative pulmonary function in the ICG group was better than that in the traditional group. No residual lesions were found in the postoperative CT examination of both groups. The innovative application of atomization inhalation of ICG provides the possibility for precise localization and lesion resection of pediatric thoracoscopic intralobar pulmonary sequestration. This maximizes the preservation of normal lung parenchyma, better improves postoperative pulmonary function, and shortens postoperative recovery time.

Objective and design: Hirschsprung disease-associated enterocolitis (HAEC) is a common life-threatening complication of Hirschsprung disease (HSCR). We aimed to investigate the effectiveness, long-term safety and the underlying mechanisms of Mesenchymal stem cells (MSCs) based therapy for HAEC. Material or subjects: Specimens from HSCR and HAEC patients were used to assess the inflammatory condition. Ednrb knock-out mice was used as HAEC model. MSCs was intraperitoneally transplanted into HAEC mice. The therapy effects, long-term outcome, safety and toxicity and the mechanism of MSCs on the treatment of HAEC were explored in vivo and in vitro. Results: Intestinal M1 macrophages infiltration and severe inflammation condition were observed in HAEC. After the injection of MSCs, HAEC mice showed significant amelioration of the inflammatory injury and inhibition of M1 macrophages infiltration. The expression levels of pro-inflammatory cytokines (TNF- a and IFN- g ) were decreased and anti-inflammatory cytokines (IL-10 and TGF- b ) were increased. In addition, we found that effective MSCs homing to the inflamed colon tissue occurred without long-term toxicity response. However, COX-2 inhibitor could diminish the therapeutic effects of MSCs. Using MSCs and macrophages co-culture system, we identified that MSCs could alleviate HAEC by inhibiting M1 macrophages activation through COX-2-dependent MAPK/ERK signaling pathway. Conclusions: MSCs ameliorate HAEC by reducing M1 macrophages polarization via COX-2 mediated MAPK/ERK signaling pathway, thus providing novel insights and potentially promising strategy for the treatment or prevention of HAEC. (c) 2024 Elsevier Inc. All rights reserved.

Hirschsprung disease (HSCR) is a congenital anomaly of the intestine caused by the developmental absence of the enteric nervous system, which results in variable lengths of intestinal dysfunction and requires surgical intervention.[1] Due to the complex etiology, multiple surgical procedures and postoperative complications, the diagnosis and treatment strategies of HSCR have always been the focus of pediatric surgeons around the world. Seventy pediatric surgical experts with rich clinical experience from almost all national and provincial children’s medical centers in China constituted the Chinese Research Group of Hirschsprung disease (CRGHSCR). All members discussed and compiled the disagreements concerning the diagnosis, treatment [Supplementary File, https://links.lww.com/CM9/B890], and perioperative management of HSCR based on existing evidence from previous articles, in combination with the latest high-quality evidence. The current consensus statement is aimed at standardizing the diagnostic and surgical strategies, and emphasizing postoperative rehabilitation training, to systematically improve postoperative recovery and to improve the quality of life in long-term follow-up. The consensus was reached through a total of three rounds of discussions between February 2019 and June 2022. A modified Delphi method was used for as many reiterative rounds as necessary. The quality of evidence and recommendations were evaluated according to the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system. Diagnosis of HSCR Meconium is delayed 24 h after birth in approximately 90% of HSCR patients.[1] The symptoms of premature infants with HSCR are similar to those of full-term infants. Recommendation 1: HSCR should be considered for all neonates who fail to pass meconium within 24 h after birth. (Grade 1A) Digital rectal examination (DRE) is an important method for screening HSCR. It is also a simple method for the differential diagnosis of anorectal malformations. Recommendation 2: DRE can exclude anorectal malformations and screen for HSCR. (Grade 1B) In contrast enema (CE) test, the most intuitive manifestation of HSCR is the transition zone (TZ) between the narrow distal segment without ganglion cells and dilated proximal colon with normal ganglion cells. In a systematic review, CE had a mean sensitivity of 70% (95% confidence interval [CI]: 64–76%) and a mean specificity of 83% (95% CI: 74–90%) for the diagnosis of HSCR.[2] Recommendation 3: Preoperative CE can detect the TZ and provide information, which can be beneficial to determine the lesion range in HSCR. (Grade 1A) Anorectal manometry (ARM) is used to evaluate the voluntary and involuntary properties of the anorectum. One of the most important manometry assessment indicators for anorectal function is the recto-anal inhibitory reflex (RAIR). In a systematic review, the mean sensitivity and mean specificity of ARM were 91% (95% CI: 85–95%) and 94% (95% CI: 89–97%), respectively.[2] However, in a subgroup analysis of the diagnostic accuracy of ARM in infants younger than 6 months, ARM had a lower sensitivity of 88% and specificity of 89%.[3] Recommendation 4: ARM can be a routine method for the preoperative diagnosis of HSCR. (Grade 1A) The preoperative diagnosis of HSCR mainly depends on the histopathological analysis of rectal biopsies, including rectal suction biopsy (RSB) and full-thickness rectal biopsy (FTRB). A systematic review demonstrated that the mean sensitivity of RSB was 96.84% (95% CI: 95.57–97.47%), and the mean specificity was 99.42% (95% CI: 99.17–99.57%), but 8.46% (95% CI: 7.55–9.46%) repeated RSB was required due to insufficient specimens. Systematic review showed that the conclusive rates of RSB and FTRB did not significantly differ.[4] Commonly used histological staining methods include hematoxylin and eosin (HE), enzyme histochemical staining for acetylcholinesterase (AChE), and immunohistochemical staining for calretinin. In a systematic review and meta-analysis, HE staining alone and AChE alone obtained pooled proportions of 89% (95% CI: 83–93%) and 95% (95% CI: 90–99%) conclusive results, respectively. In addition, 89% (95% CI: 81–95%) in the HE + AChE group and 94% (95% CI: 89–98%) in the HE with calretinin with or without AChE group were found.[4] Recommendation 5: RSB or FTRB should be used as the gold standard for the preoperative diagnosis of HSCR, but consensus on the preferred histological staining method is lacking. (Grade 1A) Intraoperative frozen sections are commonly used to identify ganglion cells at the resection margin of the bowel. Generally, the most commonly cited features of TZ are partial circumferential aganglionosis (absent myenteric and/or submucosal ganglion cells in a contiguous eighth of the circumference), myenteric hypoganglionosis (as defined above of ≥1/8 circumference), and submucosal nerve hypertrophy (e.g., >2 submucosal nerves with >40 μm-thickness in one high-power field).[5] Recommendation 6: Intraoperative frozen sections could be used to guide the length of bowel resection. (Grade 1D) At present, establishing ideal guidelines for diagnosing neonatal HSCR remains challenging. Although a recent study showed that the sensitivity and specificity of CE examination exceeded 80% and 90% for neonatal HSCR, respectively, it is less reliable in the neonatal period than in older children.[6] Furthermore, the accuracy of CE in neonatal total colonic aganglionosis (TCA) is only approximately 25%.[7] Typically, ARM is still used as a screening tool for HSCR, although the accuracy of ARM in the diagnosis of HSCR in neonates varies among the literatures.[3] As for rectal biopsies, infants ≤3 months of age (43.5%) had a significantly higher risk of inconclusive results than infants >3 months of age (25.7%).[8] Recommendation 7: Neonates with clinical symptoms of suspected HSCR can be screened using CE and ARM, and histopathological evaluation, such as RSB or FTRB, is the most important examination for diagnosing neonatal HSCR. (Grade 2C) Preoperatively radiological patterns of TCA in CE examination include microcolon, a question mark-shaped colon, or a lack of distinct features in an otherwise normal colon. In clinical practice, multisite biopsies on the terminal ileum and whole colon during primary exploratory laparotomy are recommended to confirm the diagnosis if TCA is suspected. Recommendation 8: If TCA is suspected, a multisite biopsy involving the terminal ileum and whole colon during primary surgery is needed. (Grade 2D) Surgery for HSCR Compared with multistage surgery, the single-stage pull-through procedure has the prominent advantages of shortening the length of hospital stay, reducing the number of operations, decreasing hospitalization costs, and avoiding complications of enterostomy. Recommendation 9: A single-stage pull-through procedure is recommended; however, for patients with complicated conditions, a multistage operation should be performed. (Grade 1C) In recent decades, the primary pull-through approach for HSCR has gradually transformed from traditional laparotomy to minimally invasive surgeries (MIS), such as robot or laparoscopic techniques and transanal endorectal pull-through (TERPT). Evidence from a meta-analysis indicated that compared with laparotomy, laparoscopic-assisted pull-through is associated with less visible scarring, enhanced postoperative recovery, and shorter hospitalization time.[9] Recommendation 10: Generally, the TERPT or laparoscopy approach is recommended for short-segment HSCR, and the laparoscopy or laparotomy approach is recommended for long-segment HSCR or TCA. (Grade 1B) Whether primary pull-through should be performed in neonates remains controversial. In a recent meta-analysis, Westfal et al[10] suggested that patients with short-segment HSCR who were less than 2.5 months of age at the time of TERPT had higher rates of postoperative complications, such as soiling and anastomosis problems, including stricture and leak. Recommendation 11: Single-stage pull-through is not recommended in the neonatal period. (Grade 2B) Successful treatment of TCA using a single-stage laparoscopic technique has been reported. The opposite view tends to multi-stage operation, which is helpful to perform multi-site biopsies in the initial exploration operation to detect the range of the affected intestines. More importantly, multi-stage surgery reduces the risk of severe perianal irritant dermatitis and provides a window of time for behavioral training, which can improve patients’ ability to control defecation after definite operation. Recommendation 12: For TCA patients, staged ileostomy with multi-site biopsies before definite operation is preferred, and a single-stage operation is not recommended. (Grade 2D) Perioperative Management Effective colonic emptying is believed to reduce the risk of postoperative anastomotic leakage and Hirschsprung disease associated enterocolitis (HAEC). European Reference Network for rare Inherited and Congenital Anomalies (ERNICA) guidelines recommended preoperative saline rectal irrigation to overcome functional bowel obstruction and to enable enteral feeding.[11] Recommendation 13: Preoperative rectal irrigation is required; it is beneficial to recovery after the pull-through procedure. (Grade 1D) Malnutrition has been identified as a risk factor for postoperative recurrent HAEC, and it is related to long-term quality of life.[12] Recently, according to a multi-center cross-sectional study conducted in China screening for undernutrition in children with HSCR, moderate to severe malnutrition rate was as high as 18.1%.[13] In a multicenter random controlled trial (RCT), Tang et al[14] reported that preoperative nutritional intervention improved the nutritional status of HSCR patients in the early postoperative period and promoted postoperative recovery. Recommendation 14: HSCR patients with malnutrition should receive personalized nutritional intervention before the pull-through procedure, including enteral nutrion (EN) or parenteral nutrition (PN). (Grade 1C) In a multicenter RCT, early postoperative EN helped to reduce insulin resistance and promote intestinal peristalsis, which help to improve the nutritional status of HSCR patients after pull-through.[14] Recommendation 15: Postoperative early oral feeding should be encouraged. (Grade 1B) As a part of the continuous nursing management strategy of HSCR, postoperative behavioral intervention involves dietary adjustment and toilet training. In a prospective RCT, Wang et al[15] demonstrated that such a postoperative rehabilitation protocol can reduce the recurrence rate of postoperative HAEC and improve the defecation control and quality of life of HSCR patients during long-term follow-up. Recommendation 16: Postoperative behavioral interventions, including dietary adjustment and toilet training, could improve HSCR patients’ quality of life in long-term follow-up. (Grade 1C) Clinical practice indicates that the application of anal dilatation is based on different anastomosis methods, and the main indication is anastomotic stenosis. Recommendation 17: Postoperative regular anal dilation in the short term is beneficial to the recovery of HSCR. (Grade 2D) It is important to insist on structural follow-up for HSCR patients after pull-through procedures. Recommendation 18: HSCR patients need regular long-term follow-up after the pull-through procedure. (Grade 1C) Conflicts of interst None.

During enteric nervous system (ENS) development, pioneering wavefront enteric neural crest cells (ENCCs) initiate gut colonization. However, the molecular mechanisms guiding their specification and niche interaction are not fully understood. We used single-cell RNA sequencing and spatial transcriptomics to map the spatiotemporal dynamics and molecular landscape of wavefront ENCCs in mouse embryos. Our analysis shows a progressive decline in wavefront ENCC potency during migration and identifies transcription factors governing their specification and differentiation. We further delineate key signaling pathways (ephrin-Eph, Wnt-Frizzled, and Sema3a-Nrp1) utilized by wavefront ENCCs to interact with their surrounding cells. Disruptions in these pathways are observed in human Hirschsprung's disease gut tissue, linking them to ENS malformations. Additionally, we observed region-specific and cell-type-specific transcriptional changes in surrounding gut tissues upon wavefront ENCC arrival, suggesting their role in shaping the gut microenvironment. This work offers a roadmap of ENS development, with implications for understanding ENS disorders.

Abstract Background The prevalence of malnutrition is unknown in patients with Hirschsprung disease. Undernutrition is associated with poor clinical outcomes. This study aims to describe the nutrition status among patients with Hirschsprung disease at admission. Methods We retrospectively used data from children with Hirschsprung disease admitted to three pediatric surgery centers in China from January 2016 to December 2020. The weight‐for‐age z scores (WAZ), height‐for‐age z scores (HAZ), and body mass index‐for‐age z scores (BAZ) were calculated as the reference for nutrition risk according to the World Health Organization child growth standards. The nutrition status of enrolled children was described and nutrition risk in each clinical characteristic was compared. The association between nutrition status and clinical outcomes was analyzed using univariate and multivariate logistic regression. Results A total of 624 patients were included in this study. The mean WAZ, HAZ, and BAZ of all patients was −0.64 ± 1.40, −0.45 ± 1.78, and −0.43 ± 1.50, respectively. Moderate to severe overall undernutrition was 16.3% (102/624). We found that WAZ and BAZ were significantly reduced with the length of aganglionic segments (P = 0.001). Children who had a definitive surgery at 3 years of age or older had significantly lower HAZ (P = 0.001). A multivariate regression model assessing postoperative Hirschsprung‐associated enterocolitis showed that the WAZ was one of the independent risk factors (P = 0.001). Conclusion Undernutrition is prevalent among children with Hirschsprung disease. Nutrition assessment to identify individuals at risk of undernutrition for further intervention is necessary.

BACKGROUND:Cholangitis is common in patients with biliary atresia following Kasai portoenterostomy (KPE). The prompt use of empiric antibiotics is essential due to the lack of identified microorganisms. The authors aimed to validate a severity grading system to guide empiric antibiotic therapy in the management of post-KPE cholangitis.MATERIALS AND METHODS:This multicenter, prospective, randomized, open-label study recruited patients with post-KPE cholangitis and was conducted from January 2018 to December 2019. On admission, patients were categorized into mild, moderate, and severe cholangitis according to the severity grading system. Patients in the mild cholangitis group were randomized to receive cefoperazone sodium tazobactam sodium (CSTS) or meropenem (MEPM). Patients with severe cholangitis were randomized to treatment with MEPM or a combination of MEPM plus immunoglobulin (MEPM+IVIG). Patients with moderate cholangitis received MEPM.RESULTS:The primary endpoint was duration of fever (DOF). Secondary outcomes included blood culture, length of hospital stay, incidence of recurrent cholangitis, jaundice clearance rate, and native liver survival (NLS). For mild cholangitis, DOF, and length of hospital stay were similar between those treated with CSTS or MEPM (all P >0.05). In addition, no significant difference in recurrence rate, jaundice clearance rate, and NLS was observed between patients treated with CSTS and MEPM at 1-month, 3-month, and 6-month follow-up. In patients with moderate cholangitis, the DOF was 36.00 (interquartile range: 24.00-48.00) h. In severe cholangitis, compared with MEPM, MEPM+IVIG decreased DOF and improved liver function by reducing alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, and direct bilirubin at 1-month follow-up. However, recurrence rate, jaundice clearance rate, and NLS did not differ significantly between MEPM+IVIG and MEPM at 1-month, 3-month, and 6-month follow-up.CONCLUSIONS:In patients with post-KPE cholangitis, MEPM is not superior to CSTS for the treatment of mild cholangitis. However, MEPM+IVIG treatment was associated with better short-term clinical outcomes in patients with severe cholangitis.

Background: Inflammatory myofibroblastic tumor (IMT) infrequently involves the sigmoid colon, and has not previously been described in an infant sigmoid colon. Case report: An inflammatory myofibroblastic tumor arose from the sigmoid colon of an 11-month-old boy, confirmed by anaplastic lymphoma kinase (ALK), smooth muscle actin (SMA) and desmin immunohistochemical staining. The patient recovered well after complete resection of the tumor. Discussion: Sigmoid IMT can occur in infancy. This eighth case is the youngest so far. The child did well after surgical resection.

Objective:To employ body weight as a reference index for nutritional risk screening to assess the nutritional status of hospitalized children with Hirschsprung disease (HSCR) and provide evidence-based rationales for clinical nutritional management.Methods:From January 2006 to December 2019, clinical data were reviewed for 472 hospitalized HSCR children. There were 386 boys and 86 girls with a median age of 10(0-120) months. Weight-for-age z score (WAZ) was calculated as an evaluation index of nutritional status using a standardized growth curve of height and weight of WHO 2006 as a reference. And WAZ < -2 was defined as moderate-to-severe malnutrition. To assess the overall nutritional status of HSCR children and compare the nutritional risk differences in children with different age of onset, different clinical types of HSCR and whether or not receiving conservative treatment.Results:The overall WAZ was (-0.81±1.56) and moderate-to-severe malnutrition accounted for 18.2%(86/472). According to diagnostic age, they were divided into 5 groups of ≤6 months, 6 months < age ≤12 months, 12 months < age≤24 months, 24 months < age ≤60 months and >60 months. The median body weight was 6.0, 8.0, 10.0, 13.7 and 21.7 kg. And WAZ of five groups were (-0.68±1.47), (-0.70±1.45), (-0.92±1.67), (-1.15±1.79) and (-1.29±1.51) respectively and there was no significant inter-group difference ( P=0.15). WAZ of children with different clinical types, namely short-segment, common, long-segment and pancolonic, were (-0.62±1.53), (-0.81±1.47), (-1.06±1.75), and (-2.20±1.79) respectively and the difference was statistically significant ( P=0.001). No significant differences existed in the incidence of WAZ or moderate-to-severe malnutrition between recipients and non-recipients of conservative treatment ( P>0.05). The results of correlation analysis hinted at a significant weak correlation between WAZ and whether or not postoperative enteritis occurring (r=0.21, P=0.001). Conclusions:Malnutrition is a prevalent condition among HSCR children. And clinical classification of HSCR is a influencing factor of malnutrition risk. Moderate-to-severe malnutrition is a significant influencing factor of occurrence of postoperative complications. Weight-for-age Z score may be employed as a simple and easy screening tool. Nutritional assessment should be performed and appropriate and timely nutritional intervention offered to children at a risk of malnutrition.

Background Preoperative evaluation of the dysganglionic bowel segment is critical for establishing the optimal resection strategy for Hirschsprung’s disease (HSCR), which facilitates patient outcomes. Objective We set out to determine the utility of the 24-h delayed film of barium retention in predicting the length of dysganglionic bowel segment in HSCR. Materials and methods A retrospective study of patients with clinically suspicious HSCR who underwent a preoperative 24-h delayed film of barium enema and were surgically treated from January 2015 to December 2019 was conducted. Results Two hundred and 58 patients were enrolled in this study. The sensitivity, specificity, positive and negative predictive values (NPVs) of the 24-h delayed film of barium enema to predict the neuropathological segment were 89.1, 91.5, 91.3, and 89.4%, respectively. The Youden index was 80.6%, with a kappa value of 0.806 (P < 0.001). The correlation rate between barium retention level and pathological results was 72.7% (16/22) when aganglionosis was restricted within the mid-distal rectum (short-segment type), increasing to 92.0% (46/50) and 93.5% (174/186) for patients that had aganglionosis extended beyond the mid-distal rectum (classical type) and sigmoid colon (long-segment type), respectively. Lastly, patients younger than 3 months showed a lower correlation rate (72.2%) compared to patients aged 3–12 months (91.0%) and > 12 months (92.6%). Conclusions Our investigation of the 24-h delayed film of barium enema performed for patients suspected of having HSCR indicated that the barium retention level remains crucial in predicting dysganglionic bowel segment, which contributes to the decision-making for surgical physicians.

Purpose: Radical surgery is the most effective treatment for Hirschsprung's disease. However, some children still have symptoms of intestinal dysfunction such as constipation, abdominal distension, and recurrent enterocolitis after operation. The purpose of this study was to evaluate treatment outcomes of postoperative intestinal dysfunction in children with Hirschsprung's disease by using the principle of "anorectal balance". Methods: The clinical data of postoperative intestinal dysfunction in children with Hirschsprung's disease in the single treatment group from July 2019 to July 2021 were retrospectively analyzed. All the enrolled children underwent botulinum toxin injection (2.5 U/kg); 3 to 6 months later, the injection was performed again; the children who had received more than two botulinum toxin injections underwent the internal sphincter myectomy. Anorectal manometry was performed routinely after operation, and abdominal distension and defecation were recorded. Results: A total of thirty children with postoperative intestinal dysfunction underwent radical surgery for Hirschsprung's disease were included in this study. Symptoms of constipation, abdominal distension and enterocolitis were improved after botulinum toxin injections in most children compared to before surgery (P < 0.01). After re-injection of botulinum toxin in twelve children, the frequency of defecation increased, the anal resting pressure decreased, and the clinical symptoms were relieved again (P < 0.05). Eleven children underwent internal sphincter myectomy, and the symptoms of constipation, abdominal distension and enterocolitis were significantly improved after the operation (P < 0.01). Conclusion: Botulinum toxin injection and internal sphinctermyectomy based on the principle of "anorectal balance" can effectively reduce the resting pressure of the anus and relieve intestinal dysfunction, and have satisfactory clinical effect.

Abstract Purpose: This study aims to investigate risk factors of BE, ARM and acetylcholinesterase staining related to failure of treatments and diagnostic value of Hirschsprung’s disease (HSCR) or intractable constipation (IC). Methods: A single-center retrospective cohort study of children with constipation was conducted. All patients were followed up until significant improvement of defecation. Patients initially received general/conservative treatment or surgery. Upgraded treatments were adopted if the initial treatment failed. The risk factors including transitional zone, barium residue, absence of recto-anal inhibitory reflex (RAIR) and acetylcholinesterase staining. A p value <0.1 or <0.05 was considered to be statistically significant in Logistic regression. Chi-square test was used to calculate the sensitivity and specificity when analyzing the diagnostic value.Results: This study enrolled 4869 cases. Acetylcholinesterase staining +++ had the highest risk (OR, 177.613[95%CI 92.178~273.526]) leading to failure of general treatment, followed by absence of RAIR ((OR, 158.786[95%CI 92.178~273.526]) and severe barium residue (OR, 153.829[70.004~338.028]). The leading risk factors causing failure of conservative therapy were severe barium residue (OR, 15.530[95%CI 5.337~45.191]) and acetylcholinesterase staining +++ (OR, 13.242[6.657~26.337]). In children ≤3 years, the transitional zone, absence of RAIR and acetylcholinesterase staining ++/+++ had similar specificity (80.0%, 75.6% and 73.3%), whereas the acetylcholinesterase staining ++/+++ had the highest sensitivity (95.5%). The sensitivity was generally lower in children ＞ 3 years, however the specificity was similar between each age group.Conclusion: This real-world study validates that the performance of 3 examinations is of great significance in guiding upgrading treatments, predicting clinical outcomes and identifying HSCR and IC.Trial Number: NCT02216994 (registered on October 27, 2014)

Background and AimWe evaluated the clinical features of neonatal Hirschsprung's disease (HD)-associated bowel perforation (perforated HD) and investigated risk factors related to it.MethodsWe retrospectively collected clinical data of neonates (<1 month of age) with perforated HD from multicenters in China from January 2006 to December 2019. A total of 142 patients (6.7%) with perforated HD were enrolled in the study. A 1:2 matching method was used to compare the clinical information of HD patients with and without bowel perforation during the neonatal period. The risk factors for bowel perforation were identified using univariate and multivariate logistic risk regression analyses.ResultsPerforation site was present in the proximal ganglionic bowel in 101 (71.1%) cases and the distal aganglionosis segment in 41 (28.9%) cases. Adjacent marginal tissue from the perforated intestine revealed varying degrees of inflammatory cell infiltration, and the severity of enterocolitis was higher in the proximal ganglionic bowel than in the distal aganglionosis segment (p < 0.05). In the univariable and multivariable logistic analyses, clinical symptoms, such as vomiting (adjusted OR = 2.06, 95% CI: 2.01–2.88, p < 0.05), and inflammation index in hematologic tests, such as neutrophil proportion (adjusted OR = 1.09, 95% CI: 1.05–1.33, p < 0.05) and CRP (adjusted OR = 2.13, 95% CI: 1.01–3.27, p < 0.05) were associated with increased risk for perforated HD.ConclusionClinical Hirschsprung disease-associated enterocolitis (HAEC) highly correlated with perforated HD. Timely treatment of HAEC should be appropriate therapeutic approaches to prevent perforated HD.