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Background: The presenting symptoms of patients with Hirschsprung's disease (HD) are a failure to pass meconium, abdominal distension, and bilious vomiting. The gold standard diagnosis is a rectal biopsy to confirm aganglionosis. The aim of our study was to describe the diagnostic pathway of Hirschsprung's disease at our institution and document the indication for a rectal biopsy. Methods: We have performed a prospective collection of all patients who underwent a rectal biopsy to exclude HD from December 2022 until September 2023 including. The following data were collected: patient's age, presenting symptoms, type of biopsy, failure rate, complications, and histopathological results. Results: We identified 33 patients who underwent 34 rectal biopsies at 0.6 years of age. A total of 17 patients had a rectal suction biopsy (RSB), and 17 patients underwent a partial thickness under general anaesthesia (GA). 1/17 (6%) patients had an inconclusive RSB and subsequently underwent a biopsy under GA. Constipation and chronic abdominal distension plus vomiting were the most common presenting symptoms throughout all ages. Five patients (15%) had a rectal biopsy that was positive for HD. Conclusion: A protocolised approach to the assessment of infants and children with suspected HD ensures the appropriate utilisation of invasive procedures such as biopsy. [ABSTRACT FROM AUTHOR]

Purpose: Patients with Hirschsprung disease affecting the splenic flexure or more proximal segments present a surgical challenge. Mobilizing the transverse colon to the pelvis during a pull-through may obstruct the distal ileum, or the length may be insufficient to reach the lower pelvis. This retrospective study aimed to describe two surgical techniques that facilitate mobilization of the transverse colon and their outcome. Methods: We included patients operated on between April 2017 and April 2024 and analyzed sex, comorbidities, type of pull- through, age at pull-through, history of previous surgeries, cause of the proximal transverse colon pull-through, technique used (Deloyers or Turnbull), complications , postoperative outcome and follow-up. The first technique used was the maneuver described by Turnbull. This operation creates a mesenteric defect and mobilizes the colon into this mesenteric window at the distal ileum level. The second technique was described by Deloyers and involves a 180-degree rotation of the right colon by dissecting the right colon attachment and the hepatocolic ligament. The cecum and the ileocecal valve are placed in the right upper quadrant, and the distal colon is mobilized into the pelvis. Results: We included 13 patients, 12 boys and 1 girl. Eight patients had previous surgeries in another hospital: five had an initial transverse colostomy, and three had an ileostomy. The remaining five had the initial operation in our hospital: two had an ileostomy, two had a colostomy, and one had a primary pull-through. The median age at pull-through was 16 months (4–59 months). We used the Turnbull technique in four patients whose aganglionosis was limited to the middle transverse colon. The Deloyers technique was used in the remaining patients, with ganglion cells in the proximal transverse colon. We left a protective ileostomy in five patients. The median follow-up was 4.5 years (3 months to 10 years). The stoma takedown is pending in one patient. Conclusion: The Turnbull and Deloyers techniques were helpful in patients with aganglionosis affecting the transverse colon. [ABSTRACT FROM AUTHOR]

Introduction A biopsy protocol for diagnosing Hirschsprung's disease (HD) in children using the anorectal line (ARL). Materials and Methods The ARL was adopted for diagnosing HD in 2016 using two excisional submucosal rectal biopsies performed at different levels, sequentially; the first just above the ARL and the second, further proximal (2-ARL). Currently, only the first-level biopsy is performed (1-ARL) and examined intraoperatively. Management was observation if normoganglionic, pull-through if aganglionic, and a second-level biopsy if hypoganglionic. Hypoganglionosis was considered physiologic if the second-level biopsy was normoganglionic and pathologic if hypoganglionic. Colon caliber change and bowel obstructive symptoms reflect the severity of hypoganglionosis. Results For 2-ARL (n = 54), results were: normoganglionosis (n = 31/54; 57.4%), aganglionosis (n = 19/54; 35.2%), and hypoganglionosis (n = 4/54; 7.4%); physiologic (n = 3/54; 5.6%) and pathologic (n = 1/54; 1.9%). Normoganglionosis and aganglionosis were always duplicated in 2-ARL (kappa = 1.0). For 1-ARL (n = 36), results were: normoganglionosis (n = 17/36; 47.2%), aganglionosis (n = 17/36; 47.2%), and hypoganglionosis (n = 2/36; 5.6%). Second-level biopsies were normoganglionic (physiologic: n = 1) and hypoganglionic (pathologic: n = 1). All normoganglionic cases, except one, resolved conservatively. All aganglionic cases had pull-through with HD confirmed on histopathology. Both pathologic hypoganglionic cases had caliber change and severe obstructive symptoms as definitive indications for pull-through with hypoganglionosis of the entire rectum confirmed on histopathology. Physiologic hypoganglionic cases were observed and currently have regular defecation. Conclusion Because the ARL is an objective functional, neurologic, and anatomic demarcation, normoganglionosis and aganglionosis can be diagnosed accurately with a single excisional biopsy. Only hypoganglionosis requires a second-level biopsy. [ABSTRACT FROM AUTHOR]

The enteric nervous system (ENS), the gut's intrinsic nervous system critical for gastrointestinal function and gut-brain communication, is believed to mainly originate from vagal neural crest cells (vNCCs) and partially from sacral NCCs (sNCCs). Resolving the exact origins of the ENS is critical for understanding congenital ENS diseases but has been confounded by the inability to distinguish between both NCC populations in situ. Here, we aimed to resolve the exact origins of the mammalian ENS. We genetically engineered mouse embryos facilitating comparative lineage-tracing of either all (pan-) NCCs including vNCCs or caudal trunk and sNCCs (s/tNCCs) excluding vNCCs. This was combined with dual-lineage tracing and 3-dimensional reconstruction of pelvic plexus and hindgut to precisely pinpoint sNCC and vNCC contributions. We further used coculture assays to determine the specificity of cell migration from different neural tissues into the hindgut. Both pan-NCCs and s/tNCCs contributed to established NCC derivatives but only pan-NCCs contributed to the ENS. Dual-lineage tracing combined with 3-dimensional reconstruction revealed that s/tNCCs settle in complex patterns in pelvic plexus and hindgut-surrounding tissues, explaining previous confusion regarding their contributions. Coculture experiments revealed unspecific cell migration from autonomic, sensory, and neural tube explants into the hindgut. Lineage tracing of ENS precursors lastly provided complimentary evidence for an exclusive vNCC origin of the murine ENS. sNCCs do not contribute to the murine ENS, suggesting that the mammalian ENS exclusively originates from vNCCs. These results have immediate implications for comprehending (and devising treatments for) congenital ENS disorders, including Hirschsprung's disease. [Display omitted] The enteric nervous system, the gut's "brain," originates from a single source of progenitor cells instead of 2, as previously believed, which greatly simplifies understanding developmental enteric nervous system disorders. [ABSTRACT FROM AUTHOR]

Hirschsprung's disease (HD) is characterized by a congenital absence of enteric ganglion cells in the intestine, posing challenges in diagnosis, particularly in pediatric patients. The gold standard, rectal suction biopsy (RSB), carries risks, prompting an exploration of non-invasive alternatives such as high-resolution anorectal manometry (HR-ARM) for HD screening. We conducted a retrospective analysis of 136 patients suspected of HD between 2018 and 2022, which were stratified into three age groups: ≤12 months, ≤24 months, and >24 months. Criteria for suspicion included delayed meconium passage, unresponsive chronic constipation, and abnormal prior test results. HR-ARM, supplemented by additional tests, confirmed 16 HD cases. HR-ARM exhibited 93.75% sensitivity, 89.47% specificity, 99.03% negative predictive value (NPV), and 55.56% positive predictive value (PPV). Notably, HR-ARM consistently performed well in patients ≤ 2 years old but demonstrated reduced efficacy in older children, which was likely due to complications from chronic constipation. This study underscores HR-ARM's promise as a non-invasive HD screening tool, especially in younger patients. However, its limitations in older children warrant consideration. Establishing standardized protocols, particularly for assessing the recto-anal inhibitory reflex, is crucial. Further research is imperative to optimize HR-ARM's diagnostic role across varied age groups in HD assessment. [ABSTRACT FROM AUTHOR]

We examined a case of congenital idiopathic megaesophagus (CIM) in a 5-wk-old female Gordon Setter puppy by means of contrast radiography, autopsy, histopathology, and immunohistochemistry. Clinical and radiologic findings included weight stagnation and marked generalized esophageal dilation with ventral displacement of the heart and lungs. These findings were confirmed at autopsy, and segments of the thoracic esophagus were sampled for histopathology. On histopathology, diffuse esophageal muscular atrophy, mucosal erosions, mononuclear inflammation, and a marked reduction in the number of myenteric plexus structures and number of ganglion cells were present (aganglionosis). The latter was determined immunohistochemically using an anti-peripherin antibody as the primary reagent, which provides a strong tool for the histologic confirmation of CIM. The histologic findings share some similarities to lesions associated with megaesophagus in Friesian foals, as well as esophageal achalasia and Hirschsprung disease in humans. [ABSTRACT FROM AUTHOR]

Hirschsprung’s disease (HD) is a common disease in our society that is frequently described in children with delayed passing bowel motion or intestinal obstruction symptoms. It is due to the absence of intramural plexus of the ganglion cells in the distal bowel. It can be classified further into clinical groups based on the length of the aganglionic segment. We describe a rare form of Hirschsprung’s disease, total intestinal aganglionosis (total absence of the ganglion cells in the bowel) and challenges in managing the disease in a developing country. [ABSTRACT FROM AUTHOR]

Background: The presenting symptoms of patients with Hirschsprung’s disease (HD) are a failure to pass meconium, abdominal distension, and bilious vomiting. The gold standard diagnosis is a rectal biopsy to confirm aganglionosis. The aim of our study was to describe the diagnostic pathway of Hirschsprung’s disease at our institution and document the indication for a rectal biopsy. Methods: We have performed a prospective collection of all patients who underwent a rectal biopsy to exclude HD from December 2022 until September 2023 including. The following data were collected: patient’s age, presenting symptoms, type of biopsy, failure rate, complications, and histopathological results. Results: We identified 33 patients who underwent 34 rectal biopsies at 0.6 years of age. A total of 17 patients had a rectal suction biopsy (RSB), and 17 patients underwent a partial thickness under general anaesthesia (GA). 1/17 (6%) patients had an inconclusive RSB and subsequently underwent a biopsy under GA. Constipation and chronic abdominal distension plus vomiting were the most common presenting symptoms throughout all ages. Five patients (15%) had a rectal biopsy that was positive for HD. Conclusion: A protocolised approach to the assessment of infants and children with suspected HD ensures the appropriate utilisation of invasive procedures such as biopsy.

Background and Aims: Hirschsprung's disease (HSD) remains a common cause of pediatric intestinal obstruction. Barium contrast enema (BE) is the primary imaging modality for the evaluation of clinically suspected cases. Here, we aimed to assess the diagnostic accuracy of BE in children with clinically suspected HSD when compared to a gold standard full‐thickness rectal biopsy (FTRB). Methods: We recruited and consecutively enrolled children with clinically suspected HSD at two tertiary teaching hospitals. Participants underwent BE imaging and two radiologists interpreted the findings independently. Participants further underwent FTRB by pediatric surgeons as the confirmatory test. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and receiver operating characteristics (ROC) with the area under the curve (AUC) were calculated on Stata version 14.2, taking FTRB as the standard. Results: We enrolled 55 cases, of which 49 completed the evaluation and were included in the final analysis. The median age was 9.4 months (interquartile range: 2–24], with a male‐to‐female ratio of 4.4:1. The sensitivity, specificity, PPV, and NPV of BE were 0.95 (95% confidence interval [CI] [0.81–0.99]), 0.73 (95% CI [0.39–0.94]), 0.92 (95% CI [0.82–0.97]), and 0.80 (95% CI [0.50–0.94]), respectively. On AUC, the diagnostic accuracy of BE compared to the confirmatory FTRB was 0.84 (95% CI [0.69–0.98]). The diagnostic accuracy was higher in neonates (ROC: 1.00) when compared to infants (ROC: 0.83) or those above 1 year of age (ROC: 0.798). HSD‐suggestive BE findings were associated with absence of ganglion cells on FTRB (χ2 = 23.301, p < 0.001). Inverted rectosigmoid ratio and transition zone were more sensitive in detecting HSD of 0.92 (95% CI [0.74–0.98]) and 0.81 (95% CI [0.63–0.92]), respectively. Conclusion: BE is sufficiently accurate in the diagnosis of children with HSD, suggesting BE would likely be used to inform surgical management in settings where confirmatory biopsy is lacking. However, clinical judgment is warranted in interpreting negative BE findings. [ABSTRACT FROM AUTHOR]

Aim of the study: The coexistence of Hirschsprung's disease (HD) with anorectal malformation (ARM) is rare but many surgeons still ask pathologists to look for ganglia in the terminal rectum or fistula. In this study, we aimed to highlight the rarity of this association and question the necessity of histological evaluation. Methods: After obtaining board review approval, rectal specimens of ARM patients who underwent corrective surgery in the last 8 years were re-analyzed by two blinded pathologists for the presence and structure of ganglia. Clinical and radiological data of patients retrieved from center records and correlated with histopathologic findings. Main results: 67 patients with ARM were identified, distal rectal specimen was obtained in 47. The median age at the time of surgery was 11 months (2 days–59 months). A normal pattern of ganglia was present in 51.1% (24/47), 29.7% (14/47) had aganglionosis and 19.1% (9/47) were inconclusive due to insufficient material. None of the aganglionic specimens showed other histological findings of HD. Patients were followed up regularly in the outpatient colorectal clinic for a median of 87 months (42–117 m). Only 6 experienced severe constipation (3 ganglionic, 2 no biopsy, 1 aganglionic), all of whom responded to a bowel management program, and none developed other manifestations of HD (abdominal distension, failure to thrive or enterocolitis) or required additional surgery. Conclusions: Our results strongly suggest that the association of ARM and HD is extremely rare and the practice of searching for ganglia in the distal rectum or fistula of ARM patients should be discouraged to avoid potential misdiagnosis and overtreatment. [ABSTRACT FROM AUTHOR]

Introduction: The classical surgical treatment of Hirschsprung’s Disease (HD) is by resection of the aganglionic segment of the distal intestine and bringing down the ganglionic segment by Modified Duhamel’s procedure or other pull-through operations. The assessment of the postoperative functional outcome and continence scoring systems are important considerations during follow-up of these children. In the present study, a scoring system was used to analyse the postoperative functional outcome of HD as there are very few studies, that have objectively assessed the same. Aim: To assess the functional outcome in children under six years of age, who underwent Modified Duhamel’s procedure for HD. Materials and Methods: This descriptive longitudinal, study was conducted in the Tertiary Teaching Institution at Government Medical College, Thiruvananthapuram, Kerala, India. The duration of the study was one year and nine months, from February 2017 to November 2018. Forty cases of biopsy proven HD, who underwent Modified Duhamel’s procedure were analysed. Postoperative follow-up was done at one, two, and three years after the definitive surgical procedure. Patients were classified as good, fair and poor outcome groups depending based on the Taylor-Duthies-Zachary continence scoring system. Statistical analysis was performed using Statistical Package for Social Sciences (SPSS) version 22.0. Pretest comparison of scores and p-value were analysed by Wilcoxon signed-rank test. A p-value

Abstract Background and Aims Hirschsprung's disease (HSD) remains a common cause of pediatric intestinal obstruction. Barium contrast enema (BE) is the primary imaging modality for the evaluation of clinically suspected cases. Here, we aimed to assess the diagnostic accuracy of BE in children with clinically suspected HSD when compared to a gold standard full‐thickness rectal biopsy (FTRB). Methods We recruited and consecutively enrolled children with clinically suspected HSD at two tertiary teaching hospitals. Participants underwent BE imaging and two radiologists interpreted the findings independently. Participants further underwent FTRB by pediatric surgeons as the confirmatory test. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and receiver operating characteristics (ROC) with the area under the curve (AUC) were calculated on Stata version 14.2, taking FTRB as the standard. Results We enrolled 55 cases, of which 49 completed the evaluation and were included in the final analysis. The median age was 9.4 months (interquartile range: 2–24], with a male‐to‐female ratio of 4.4:1. The sensitivity, specificity, PPV, and NPV of BE were 0.95 (95% confidence interval [CI] [0.81–0.99]), 0.73 (95% CI [0.39–0.94]), 0.92 (95% CI [0.82–0.97]), and 0.80 (95% CI [0.50–0.94]), respectively. On AUC, the diagnostic accuracy of BE compared to the confirmatory FTRB was 0.84 (95% CI [0.69–0.98]). The diagnostic accuracy was higher in neonates (ROC: 1.00) when compared to infants (ROC: 0.83) or those above 1 year of age (ROC: 0.798). HSD‐suggestive BE findings were associated with absence of ganglion cells on FTRB (χ2 = 23.301, p

Introduction: The Enteric Nervous System (ENS) contributes to the innervation of the gut and is considered the second brain in the gut. It is a part of the peripheral nervous system and the ganglionated plexus (GP) of enteric neurons, present in the layers of the digestive tract, is more complex than any other structure of the peripheral nervous system. The establishment of a valid standard method for quantitative analysis of the myenteric plexus has been a topic of debate among enteric neuropathologists and is essential for better characterisation of patients with gut dysmotility. Aim: To determine the histomorphometric analysis of the interganglion distance of the myenteric plexus in the entire large intestine of aborted human foetuses. Materials and Methods: A cross-sectional descriptive study was carried out in the Department of Anatomy at Pondicherry Institute of Medical Sciences, Pondicherry, India. The study duration was eight years and seven months, from October 2014 to May 2022. A total of 50 aborted human foetus samples were collected from Rajiv Gandhi Government Women and Children’s Hospital, Puducherry, India, from the Department of Obstetrics and Gynaecology. The age of the aborted human foetuses was determined based on Biparietal Diameter (BPD) and Crown Rump Length (CRL) and correlated with clinical history. The aborted human foetuses were assigned to two groups: group A (n=29), ≤20 Weeks of Gestation (WG), and group B (n=21), ≥20 WG. Nicotinamide Adenine Dinucleotide Phosphate (NADPH) diaphorase histochemistry, an enzyme histochemistry technique, was used to study the tissue preparations. Statistical significance was determined using Statistical Package for Social Sciences (SPSS) version 20.0, International Business Machines (IBM) corporation. The independent sample t-test was conducted for parametric analysis. Results: The interganglion distance was measured from the caecum (A1 segment) to the anal canal (A7 segment) in aborted foetuses of less than 20 WG. The mean values ranged from 78.86±38.09 μm to 126.94±23.87 µm in foetuses of less than 20 WG. The mean values ranged from 66.41±8.05 μm to 107.67±30.17 µm in aborted human foetuses of more than 20 WG. Conclusion: The anal canal showed a long interganglion distance. The average reference values were found to be helpful as a diagnostic tool for identifying disorders related to gut innervation and motility.

Highlights • To confirm ganglionic bowel wall in Hirschsprung’s disease, intra-operative frozen biopsy samples are required. This means a prolonged anesthesia time and a more immediate diagnostic method is warranted. • Muscle layers’ thicknesses differ between aganglionic and ganglionic bowel walls in children with Hirshsprung’s disease. These findings could be transferred to instant imaging techniques. • See the attached Supplementary Figure 2

Introduction: The classical surgical treatment of Hirschsprung's Disease (HD) is by resection of the aganglionic segment of the distal intestine and bringing down the ganglionic segment by Modified Duhamel's procedure or other pull-through operations. The assessment of the postoperative functional outcome and continence scoring systems are important considerations during follow-up of these children. In the present study, a scoring system was used to analyse the postoperative functional outcome of HD as there are very few studies, that have objectively assessed the same. Aim: To assess the functional outcome in children under six years of age, who underwent Modified Duhamel's procedure for HD. Materials and Methods: This descriptive longitudinal, study was conducted in the Tertiary Teaching Institution at Government Medical College, Thiruvananthapuram, Kerala, India. The duration of the study was one year and nine months, from February 2017 to November 2018. Forty cases of biopsy proven HD, who underwent Modified Duhamel's procedure were analysed. Postoperative follow-up was done at one, two, and three years after the definitive surgical procedure. Patients were classified as good, fair and poor outcome groups depending based on the Taylor-Duthies-Zachary continence scoring system. Statistical analysis was performed using Statistical Package for Social Sciences (SPSS) version 22.0. Pretest comparison of scores and p-value were analysed by Wilcoxon signed-rank test. A p-value <0.05 was considered as statistically significant. Results: The mean age of the study participants was 12.7±4.1 months and age ranges from three to 25 months. Median stool frequency per day after one, two, and three years of surgery, was 6.0, 4.0, and 3.0, respectively. The observed difference in median frequency between one and two year, one and three, and two year and three year was statistically significant (p<0.05). Median continence score to assess the anal sphincter control at one, two and three years after surgery were 2.3, 4.0 and 4.5, respectively. The observed difference in scores over successive years, was statistically significant (p<0.05). Conclusion: The functional outcome in patients, who underwent Duhamel's procedure was good and the postoperative issues like increased stool frequency, and sphincter control improved over successive years. [ABSTRACT FROM AUTHOR]

Introduction: Hirschsprung's disease (HD) occurs secondary to failed migration of neural crest cells in embryonic life and results in a dysfunctional, mechanically obstructed colon. Despite an increased occurrence amongst family members, predominantly amongst siblings, HD in twins is extremely rare with approximately 21 total cases documented in the literature. Case presentations: This case series includes 2 cases of concordant expression of HD in twins: one dizygotic set and the other monozygotic. This is contrary to prior studies which suggest that monozygotic twins more frequently exhibit disease discordance, where one twin is affected while the other is not, over disease concordance. In each case, the twins demonstrated either variability in presentation or location of pathology, which ultimately delayed diagnosis and further management. The complex etiology makes it difficult to predict the likelihood of disease inheritance. A comprehensive literature review is also included to consider the rarity of this occurrence and evaluate the variation of concordant disease expression. Conclusion: Further understanding of the inheritance pattern will help guide management and provide us with more information for genetic counseling.

Introduction: Impairment of both the central and peripheral nervous system is a major cause of mortality and disability. It varies from an affection of the brain to various types of enteric dysganglionosis. Congenital enteric dysganglionosis is characterized by the local absence of intrinsic innervation due to deficits in either migration, proliferation or differentiation of neural stem cells. Despite surgery, children’s quality of life is reduced. Neural stem cell transplantation seems a promising therapeutic approach, requiring huge amounts of cells and multiple approaches to fully colonize the diseased areas completely. A combination of successful expansion and storage of neural stem cells is needed until a sufficient amount of cells is generated. This must be combined with suitable cell transplantation strategies, that cover all the area affected. Cryopreservation provides the possibility to store cells for long time, unfortunately with side effects, i.e., upon vitality.Methods: In this study we investigate the impact of different freezing and thawing protocols (M1-M4) upon enteric neural stem cell survival, protein and gene expression, and cell function.Results: Freezing enteric nervous system derived neurospheres (ENSdN) following slow-freezing protocols (M1-3) resulted in higher survival rates than flash-freezing (M4). RNA expression profiles were least affected by freezing protocols M1/2, whereas the protein expression of ENSdN remained unchanged after treatment with protocol M1 only. Cells treated with the most promising freezing protocol (M1, slow freezing in fetal calf serum plus 10% DMSO) were subsequently investigated using single-cell calcium imaging. Freezing of ENSdN did not alter the increase in intracellular calcium in response to a specific set of stimuli. Single cells could be assigned to functional subgroups according to response patterns and a significant shift towards cells responding to nicotine was observed after freezing.Discussion: The results demonstrate that cryopreservation of ENSdN is possible with reduced viability, only slight changes in protein/gene expression patterns and without an impact on the neuronal function of different enteric nervous system cell subtypes, with the exception of a subtle upregulation of cells expressing nicotinergic acetylcholine receptors. In summary, cryopreservation presents a good method to store sufficient amounts of enteric neural stem cells without neuronal impairment, in order to enable subsequent transplantation of cells into compromised tissues.

Set theory faces two difficulties: formal definitions of sets/subsets are incapable of assessing biophysical issues; formal axiomatic systems are complete/inconsistent or incomplete/consistent. To overtake these problems reminiscent of the old-fashioned principle of individuation, we provide formal treatment/validation/operationalization of a methodological weapon termed "outer approach" (OA). The observer's attention shifts from the system under evaluation to its surroundings, so that objects are investigated from outside. Subsets become just "holes" devoid of information inside larger sets. Sets are no longer passive containers, rather active structures enabling their content's examination. Consequences/applications of OA include: a) operationalization of paraconsistent logics, anticipated by unexpected forerunners, in terms of advanced truth theories of natural language; b) assessment of embryonic craniocaudal migration in terms of Turing's spots; c) evaluation of hominids' social behaviors in terms of evolutionary modifications of facial expression's musculature; d) treatment of cortical action potentials in terms of collective movements of extracellular currents, leaving apart what happens inside the neurons; e) a critique of Shannon's information in terms of the Arabic thinkers' active/potential intellects. Also, OA provides an outer view of a) humanistic issues such as the enigmatic Celestino of Verona's letter, Dante Alighieri's "Hell" and the puzzling Voynich manuscript; b) historical issues such as Aldo Moro's death. Summarizing, we suggest that the safest methodology to quantify phenomena is to remove them from our observation and tackle an outer view, since mathematical/logical issues such as selective information deletion and set complement rescue incompleteness/inconsistency of biophysical systems. [ABSTRACT FROM AUTHOR]

Intestinal atresia and hirschsprung disease are two common causes of bowel obstruction in neonates; simultaneous occurrence is rare. This report delineates a 36‐week newborn with ileal atresia and total colonic hirschsprung who was referred to our unit due to failure of meconium passage during the first 48 h after birth. [ABSTRACT FROM AUTHOR]

ObjectiveThe 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).BackgroundWe 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

Hirschsprung disease (HD) is characterized by circumferential aganglionosis of the rectum with variable proximal bowel involvement. The underlying pathogenesis is due to failure of caudal migration of neural crest cells during pre-natal development, causing functional bowel obstruction. Definitive therapy is surgical resection; however, a subset of patients will require reoperation. An important cause of reoperation is the rare but distinct entity described as the ganglion cell "vanishing" phenomenon. In this phenomenon, affected patients have normal circumferential ganglion cells present at the proximal margin during primary resection. They undergo a variable asymptomatic period post-primary resection but ultimately develop recurrent symptoms. Upon reoperation, ganglion cells seemingly vanish and are no longer present in the previously functioning and ganglionated bowel proximal to the initial anastomotic site. To further characterize and investigate this poorly understood pathology, here we present 2 cases of HD patients who required reoperation. Our small series implicates that an immune component may contribute as patient 2 had a brisk neurotrophic eosinophilic infiltrate only present in the reoperation specimen. However, this was not observed in patient 1. Other possible etiologies include post-operative ischemia/hypoxia, visceral neuropathy, or signaling abnormalities within the residual ganglion cells themselves. [ABSTRACT FROM AUTHOR]

Background: In the validation of new imaging technology for children with Hirschsprung's disease (HSCR), basic anatomical parameters of the bowel wall must be established specifically for this patient group. Aim: To explore differences in histoanatomical layers of bowel wall, comparing ganglionic and aganglionic bowel walls, and to examine if the bowel wall thickness is linked to patient weight. Methods: This was an observational study of bowel specimens from children weighing 0–10 kg, operated on consecutively during 2018–2020. Ganglionic and aganglionic bowel walls were measured in digitalized microscopy images from 10 sites per trans-sectional specimen and compared regarding the thickness of their histoanatomical layers. Results: Bowel walls were measured in 21 children. Full bowel wall thickness did not differ between aganglionic and ganglionic bowel (2.20 vs 2.04; p = 0.802) while weight at surgery correlated positively with both ganglionic and aganglionic bowel wall thickness (r = 0.688 and 0.849, respectively), and age at surgery with ganglionic bowel wall thickness (r = 0.517). In aganglionic segments, the muscularis externa layer was thicker compared to that in ganglionosis (0.45 vs 0.31 mm, p = 0.012) whereas the muscularis interna was thinner (0.45 vs 0.62 mm, p < 0.001). A diagnostic index was identified whereby a lower ratio of muscularis interna/externa thickness followed by a thinner muscularis interna differed between aganglionic and ganglionic bowel in all specimens. Conclusion: Thicknesses of the bowel wall's muscle layers differ between aganglionic and ganglionic bowel walls in children with HSCR. These findings support a diagnostic index that could be validated for transfer to instant diagnostic imaging techniques. Level of evidence: Diagnostic: 3 Highlights: • To confirm ganglionic bowel wall in Hirschsprung's disease, intra-operative frozen biopsy samples are required. This means a prolonged anesthesia time and a more immediate diagnostic method is warranted. • Muscle layers' thicknesses differ between aganglionic and ganglionic bowel walls in children with Hirshsprung's disease. These findings could be transferred to instant imaging techniques. • See the attached Supplementary Figure 2 [ABSTRACT FROM AUTHOR]

Hirschsprung's disease (HSCR) is characterized by a lack of enteric nervous system ganglion cells (aganglionosis) in a variable extent of distal bowel. It is the commonest congenital bowel motility disorder and affected neonates usually present with distal intestinal obstruction in the first few days of life. Current treatment involves resection of the aganglionic bowel and a 'pull through' procedure to bring the normally innervated bowel down to the anal margin. Despite advances in surgery, outcomes can be poor especially in long-segment HSCR when more bowel than the rectosigmoid is aganglionic. Children with HSCR are more prone to enterocolitis and up to 75% have problems with incontinence or constipation. Some children require a long-term colostomy. This article aims to provide an overview of Hirschsprung's disease, outlining the aetiology of HSCR, and management of children with HSCR. [ABSTRACT FROM AUTHOR]

• National cohort of pediatric patients with Hirschsprung disease used to compare those with and without Down syndrome. • Patients with Down syndrome have delays in diagnosis and poorer outcomes than those with Hirschsprung disease alone. • Earlier suspicion of Hirschsprung disease in patients with Down syndrome may improve outcomes. Down syndrome (DS) is the most common abnormality associated with Hirschsprung disease (HD). It has been suggested patients with HD and DS have worse outcomes, however the literature is controversial. The Kids' Inpatient Database (KID) from 2003 to 2012 was used to identify newborns with HD. Demographics, hospital characteristics, and outcomes were compared among patients with and without DS using standard statistical tests. There were 481 patients identified with HD, of which 45 (9%) had DS. Patients with DS were older at the time of first rectal biopsy (6 [3–11] days vs. 4 [3–6] days, p = 0.012). There were no differences in operative versus non-operative management in patients with and without DS (p = 0.706). Hospital length of stay was longer in the DS cohort (22 [13–33] days vs. 15 [10–24] days, p = 0.019), and patients with DS were more likely to have a concomitant diagnosis of wound infection (<12% vs. 3%, p = 0.002) and necrotizing enterocolitis (<14% vs. 5%, p = 0.018). The mortality rate for patients with DS was four times higher than those without DS (< 5% vs. < 0.8%, p = 0.018). In this nationwide cohort of patients with Hirschsprung disease, those with Down syndrome experienced delays in diagnosis and worse outcomes. Level III. Treatment study, retrospective comparative study. [ABSTRACT FROM AUTHOR]

Introduction: Hypertrophic submucosal nerves, defined as ≥40 µm in diameter, are considered supportive of a diagnosis of HSCR, but the effect of age on nerve diameter has not been well-studied. We sought to determine the distribution of the largest nerve diameter in ganglionic rectal biopsies and the significance of hypertrophic submucosal nerves in the diagnosis of Hirschsprung disease (HSCR) based on age. Methods: Rectal biopsies performed in the evaluation of HSCR were retrospectively reviewed from 179 patients (151 ganglionic biopsies, 28 aganglionic biopsies), and the diameter of the largest submucosal nerve was measured. Results: In non-Hirschsprung disease (non-HSCR) biopsies, submucosal nerve diameter increased with age. In patients <1 year, the average diameter was 34.1 ± 11.6 µm but increased to 50.8 ± 17.3 µm after 1 year of age. Submucosal nerves ≥40 µm in diameter were significantly associated with HSCR across all ages [HSCR = 25/28 (89.3%) vs non-HSCR = 59/151 (39.1%), p < 0.0001] and remained significant in patients <1 year of age [HSCR = 22/24 (91.7%) vs non-HSCR = 19/91 (20.9%), p < 0.0001]. Conclusions: The diameter of submucosal nerves increases with age, and ≥40 µm nerves are common after 1 year of age. [ABSTRACT FROM AUTHOR]

Background & Aims: Defective rostrocaudal colonization of the gut by vagal neural crest cells (vNCCs) results in Hirschsprung's disease (HSCR), which is characterized by aganglionosis in variable lengths of the distal bowel. Skip segment Hirschsprung’s disease (SSHD), referring to a ganglionated segment within an otherwise aganglionic intestine, contradicts HSCR pathogenesis and underscores a significant gap in our understanding of the development of the enteric nervous system. Here, we aimed to identify the embryonic origin of the ganglionic segments in SSHD. Methods: Intestinal biopsy specimens from HSCR patients were prepared via the Swiss-roll technique to search for SSHD cases. NCC migration from the neural tube to the gut was spatiotemporally traced using targeted cell lineages and gene manipulation in mice. Results: After invading the mesentery surrounding the foregut, vNCCs separated into 2 populations: mesenteric NCCs (mNCCs) proceeded to migrate along the mesentery, whereas enteric NCCs invaded the foregut to migrate along the gut. mNCCs not only produced neurons and glia within the gut mesentery, but also continuously complemented the enteric NCC pool. Two new cases of SSHD were identified from 183 HSCR patients, and Ednrb-mutant mice, but not Ret-/- mice, showed a high incidence rate of SSHD-like phenotypes. Conclusions: mNCCs, a subset of vNCCs that migrate into the gut via the gut mesentery to give rise to enteric neurons, could provide an embryologic explanation for SSHD. These findings lead to novel insights into the development of the enteric nervous system and the etiology of HSCR.

Abstract Background In cases of Hirschsprung disease, complete and reproducible resection of the aganglionic bowel is ideal to achieve good postoperative bowel function. Reliable identification of the upper margin of the surgical anal canal, which is the squamous-columnar junction, is necessary during transanal pull-through. Here, we describe a novel staining technique using Lugol’s iodine stain to visualize the upper margin of the surgical anal canal. Methods Lugol’s iodine staining was performed in five patients with Hirschsprung disease treated using a single-stage laparoscopic transanal pull-through modified Swenson procedure. In two of these patients, endocytoscopic observation with ultra-high magnification was performed using methylene blue and crystal violet to mark the border of the squamous epithelium at 1 week before surgery. The alignment between the incisional line, which was revealed using Lugol’s iodine staining and endocytoscopic marking, was evaluated. Complications, including postoperative bowel dysfunction, were evaluated. Results In all cases, Lugol’s iodine staining produced a well-demarcated line. The endocytoscopic marking of the upper margin of the surgical anal canal was aligned with the line revealed by Lugol’s iodine staining. There were no complications associated with the transanal pull-through procedure, including postoperative bowel dysfunction. Conclusions Lugol’s iodine staining could be a safe and practical method to visualize the upper margin of the surgical anal canal intraoperatively. This finding may be useful for surgeons to make a consistent removal of the aganglionic bowel during surgery for Hirschsprung disease.

Abstract Background The diagnostic gold standard of Hirschsprung’s disease (HD) is based on the histopathological assessment of colorectal biopsies. Although data on cholinergic innervation and ganglion cell (GC) distribution exist, only few studies have examined these two key features together. We assessed the pattern of cholinergic innervation and the amount of GCs in colorectal specimens of 14 HD patients. Methods We established a semi-quantitative score for cholinergic innervation using acetylcholinesterase (AChE) enzyme histochemistry and quantitatively analyzed the number of GCs via NADH tetrazolium reductase (NADH) enzyme histochemistry. We examined both the entire length of the resected specimens as well as defined areas of the transition zone of both pathological and healthy appearing segment. Results High AChE score values were associated with absence of GCs, and AChE scores were inversely correlated with the number of GCs. Nevertheless, we observed several cases in which one of the two features revealed a normal distribution pattern, whereas the other still displayed pathological features. Conclusions Our data support the need for transmural colon biopsies, to enable the best evaluation of both cholinergic innervation and GCs for a reliable assessment of HD.

Hirschsprung's disease is a common cause of lower intestinal obstruction in newborns. It has variable postoperative outcomes affecting quality of life. The study was aimed at assessing postoperative bowel function in children with Hirschsprung's disease. It was conducted on 120 children operated for Hirschsprung's disease. A structured questionnaire for bowel function score was used and analyzed using relevant statistical tests. Of the 120 children in the study, 97 (80.8%) were male with 49 (40.8%) diagnosed during neonatal age and others by 2 years of age. Ninety-three (77.5%) of them had the classic type. Diversion colostomy was done in 104 (86.6%), and two-staged endorectal pullthrough was performed in 62 (72.5%) of cases with a 16% rate of retained aganglionosis. Postoperative continence was excellent in 46 (57%) and good in 26 (32%) with an incontinence rate of 11%. None of the outcome predictor showed significant influence. Optimal postoperative bowel function was obtained in the majority of patients with two-stage procedures, and the overall outcome of bowel function in children was not influenced by age, gender, level of aganglionosis, and type of procedure. Longer follow-up periods are required for definitive information., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objectives: Classical Hirschsprung disease (HD) is defined by the absence of ganglion cells in the rectosigmoid colon. The diagnosis is made from rectal biopsy, which reveals the aganglionosis and the presence of cholinergic hyperinnervation. However, depending on the method of rectal biopsy, the quality of the specimens and the related diagnostic accuracy varies substantially. To facilitate and objectify the diagnosis of HD, we investigated whether software-based identification of cholinergic hyperinnervation in digitalized histopathology slides is suitable for distinguishing healthy individuals from affected individuals., Methods: N = 190 samples of 112 patients who underwent open surgical rectal biopsy at our pediatric surgery center between 2009 and 2019 were included in this study. Acetylcholinesterase (AChE) stained slides of these samples were collected and digitalized via slide scanning and analyzed using two digital imaging software programs (HALO, QuPath). The AChE-positive staining area in the mucosal layers of the intestinal wall was determined. In the next step machine learning was employed to identify patterns of cholinergic hyperinnervation., Results: The area of AChE-positive staining was greater in HD patients compared to healthy individuals (p < 0.0001). Artificial intelligence-based assessment of parasympathetic hyperinnervation identified HD with a high precision (area under the curve [AUC] 0.96). The accuracy of the prediction model increased when nonrectal samples were excluded (AUC 0.993)., Conclusions: Software-assisted machine-learning analysis of AChE staining is suitable to improve the diagnostic accuracy of HD., (© 2024 The Author(s). Journal of Pediatric Gastroenterology and Nutrition published by Wiley Periodicals LLC on behalf of European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)