Prospective evaluation of ultrasound features of magnesium-based bioabsorbable screw resorption in pediatric fractures.

OBJECTIVE: Bioabsorbable magnesium-based alloy screws release gas upon resorption. The resulting findings in the adjacent soft tissues and joints may mimic infection. The aim of the study was to evaluate the ultrasound (US) findings in soft tissues and joints during screw resorption. METHODS: Prospectively acquired US studies from pediatric patients treated with magnesium screws were evaluated for screw head visibility, posterior acoustic shadowing, twinkling artifact, foreign body granuloma, gas (soft tissue, intra-articular), alterations of the skin and subcutaneous fat, perifascial fluid, localized fluid collections, hypervascularization, and joint effusion. RESULTS: Sixty-six US studies of 28 pediatric patients (nfemale = 9, nmale = 19) were included. The mean age of the patients at the time of surgery was 10.84 years; the mean time between surgery and ultrasound was 128.3 days (range = 6-468 days). The screw head and posterior acoustic shadowing were visible in 100% of the studies, twinkling artifact in 6.1%, foreign body granuloma in 92.4%, gas locules in soft tissue in 100% and intra-articular in 18.2%, hyperechogenicity of the subcutaneous fat in 90.9%, cobblestoning of the subcutaneous fat in 24.2%, loss of normal differentiation between the epidermis/dermis and the subcutaneous fat in 57.6%, localized fluid collection in 9.9%, perifascial fluid in 12.1%, hypervascularization in 27.3%, and joint effusion in 18.2%. CONCLUSION: US findings in pediatric patients treated with magnesium screws strongly resemble infection, but are normal findings in the setting of screw resorption. CLINICAL RELEVANCE STATEMENT: Bioabsorbable magnesium-based alloy screws release gas during resorption. The resulting US findings in the adjacent soft tissues and joints in pediatric patients may mimic infection, but are normal findings. KEY POINTS: • Bioabsorbable magnesium-based alloy screws release gas upon resorption. • The resulting ultrasound findings in children's soft tissues and joints closely resemble those of soft tissue infection or osteosynthesis-associated infection. • Be familiar with these ultrasound findings in order to avoid inadvertently misdiagnosing a soft tissue infection or osteosynthesis-associated infection.

Editorial for the Special Issue "Current Development of Pediatric Minimally Invasive Surgery" of the Journal Children.

Dear colleagues, [...].

Mobile Dressing Trolleys Improve Satisfaction and Logistics on Pediatric Surgery Wards.

BACKGROUND: Evidence-based data on the effect of dressing trolleys on children's postoperative recovery are not available. The aim of this study was to evaluate a specific pediatric surgical dressing trolley on patient and caregiver satisfaction, as well as temporal and logistical aspects of the dressing change procedures. METHODS: In a prospective observational non-randomized study, a total of 100 dressing changes were observed before (group 1) and after (group 2) the introduction of a pediatric surgical dressing trolley and the satisfaction, time and logistical factors were recorded on site. RESULTS: The median preparation time, the duration of the dressing change and the total time decreased significantly from group 1 to group 2 by 1:11 min (p < 0.001); 1:56 min (p = 0.05) and 5:09 min (p = 0.001), respectively. The patient's room was left significantly less often in group 2 to retrieve missing bandages. The median satisfaction of the medical staff increased by 12% in group 2 (p < 0.001). The satisfaction of the parents increased by 2.5% in group 2 (p = 0.042), and that of the nursing staff increased by 9.25% in group 2 (p = 0.015). CONCLUSIONS: Our results demonstrate the positive effects of a dressing trolley for pediatric surgical dressing changes by minimizing postoperative handling and manipulation of the child. It improves time and logistical factors as well as the satisfaction of those involved, which may lead to a faster recovery.

The Alexis Laparoscopic System as Minimally Invasive Surgical Technique in Operative Management of Huge Cystic Ovarian Tumors in Children and Young Adolescents: A Case Report.

BACKGROUND: The use of the Alexis wound protector-retractor (AWPR) could further improve the laparoscopic techniques for safely removing huge ovarian tumors in children. CASE: A 15-year-old patient presented to our emergency department with a history of weeks of persistent abdominal pain. Clinical examination and magnetic resonance imaging demonstrated a 25 × 21 × 21 cm cystic mass arising from the left ovary. An en block unilateral oophorectomy and salpingectomy with the use of a medium-sized AWPR was performed without complications. The patient was discharged on the second postoperative day. CONCLUSION: The AWPR is a safe and effective tool in treating such children and adolescents with huge ovarian tumors, preserving fertility, minimizing the postoperative pain and hospital stay, and providing an excellent cosmetic outcome.

Evaluation of the Versius Robotic System for Infant Surgery-A Study in Piglets of Less than 10 kg Body Weight.

BACKGROUND: We were able to demonstrate the feasibility of a new robotic system (Versius, CMR Surgical, Cambridge, UK) for procedures in small inanimate cavities. The aim of this consecutive study was to test the Versius® system for its feasibility, performance, and safety of robotic abdominal and thoracic surgery in piglets simulating infants with a body weight lower than 10 kg. METHODS: A total of 24 procedures (from explorative laparoscopy to thoracoscopic esophageal repair) were performed in 4 piglets with a mean age of 12 days and a mean body weight of 6.4 (7-7.5) kg. Additional urological procedures were performed after euthanasia of the piglet. The Versius® robotic system was used with 5 mm wristed instruments and a 10 mm 3D 0° or 30° camera. The setup consisted of the master console and three to four separate arms. The performance of the procedure, the size, position, and the distance between the ports, the external and internal collisions, and complications of the procedures were recorded and analyzed. RESULTS: We were able to perform all surgical procedures as planned. We encountered neither surgical nor robot-associated complications in the live model. Whereas all abdominal procedures could be performed successfully under general anesthesia, one piglet was euthanized early before the thoracic interventions, likely due to pulmonary inflammatory response. Technical limitations were based on the size of the camera (10 mm) being too large and the minimal insertion depth of the instruments for calibration of the fulcrum point. CONCLUSIONS: Robotic surgery on newborns and infants appears technically feasible with the Versius® system. Software adjustments for fulcrum point calibration need to be implemented by the manufacturer as a result of our study. To further evaluate the Versius® system, prospective trials are needed, comparing it to open and laparoscopic surgery as well as to other robotic systems.

Prospective Evaluation of Magnetic Resonance Imaging Features of Magnesium-Based Alloy Screw Resorption in Pediatric Fractures.

BACKGROUND: The resorption of magnesium-based alloy bioabsorbable screws results in the release of hydrogen gas, which can mimic infection and enter the growth plate. The screw itself and the released gas may also affect image quality. OBJECTIVE: The evaluation of magnetic resonance imaging (MRI) findings during the most active phase of screw resorption is the objective, with particular focus on the growth plate and to assess for the presence of metal-induced artifacts. MATERIAL AND METHODS: In total, 30 prospectively acquired MRIs from 17 pediatric patients with fractures treated with magnesium screws were assessed for the presence and distribution of intraosseous, extraosseous, and intra-articular gas; gas within the growth plate; osteolysis along the screw; joint effusion; bone marrow edema; periosteal reaction; soft tissue edema; and metal-induced artifacts. RESULTS: Gas locules were found in the bone and soft tissues in 100% of the examinations, intra-articular in 40%, and in 37% of unfused growth plates. Osteolysis and the periosteal reaction were present in 87%, bone marrow edema in 100%, soft tissue edema in 100%, and joint effusion in 50% of examinations. Pile-up artifacts were present in 100%, and geometric distortion in 0% of examinations. Fat suppression was not significantly impaired in any examination. CONCLUSIONS: Gas and edema in the bone and soft tissues are normal findings during the resorption of magnesium screws and should not be misinterpreted as infection. Gas can also be detected within growth plates. MRI examinations can be performed without metal artifact reduction sequences. Standard fat suppression techniques are not significantly affected.

Zygote Diameter and Total Cytoplasmic Volume as Useful Predictive Tools of Blastocyst Quality.

Introduction According to the Embryo Protection Act, the selection of embryos with the greatest potential for successful implantation in Germany must be performed in the pronucleus stage. The main aim of this study was to identify morphokinetic parameters that could serve as noninvasive biomarkers of blastocyst quality in countries with restrictive reproductive medicine laws. Materials and Methods The sample comprised 191 embryos from 40 patients undergoing antagonist cycles for intracytoplasmic sperm injection. Blastocysts were cultured in an EmbryoScope chamber and video records were validated to determine the post-injection timing of various developmental stages, cleavage stages, and blastocyst formation. The Gardner and Schoolcraft scoring system was used to characterize blastocyst quality. Results Morphokinetic data showed that the zygote diameter and total cytoplasmic volume were significantly different between good and poor blastocysts quality groups, where zygotes, which formed better blastocyst quality, had smaller diameter and smaller total cytoplasmic volume. Zygotes with more rapid pronuclear disappearance developed in better-quality blastocysts. Differences between good- and poor-quality blastocysts were also observed for late-stage parameters and for the spatial arrangement of blastomere where tetrahedral embryos more frequently forming good-quality blastocyst compare to the non-tetrahedral. Conclusions The study findings could be used to enhance embryo selection, especially in countries with strict Embryo Law Regulations. Further studies, including those in which the implantation potential and pregnancy rate are considered, are warranted to confirm these preliminary results.

Minimally Invasive Bimanual Fetal Surgery-A Review.

BACKGROUND: The aim of this review is to discuss experimental and clinical techniques and interventions of fetal surgery which have been performed minimally invasively by the means of a three-port approach for the fetoscope and instruments for the left and right hand of the surgeon (bimanual minimally invasive fetal surgery). METHODS: a print and electronic literature search was performed; the titles and abstracts were screened and included reports were reviewed in a two-step approach. First, reports other than minimally invasive fetal surgery were excluded, then a full text review and analysis of the reported data was performed. RESULTS: 17 reports were included. The heterogeneity of the included reports was high. Although reports on human fetoscopic surgical procedures can be found, most of them do not pick out bimanual fetal surgery as a central theme but rather address interventions applying a fetoscope with a working channel for a laser fiber, needle or flexible instrument. Most reports were on experimentation in animal models, the human application of minimally invasive fetoscopic bimanual surgery is rare and has at best been explored for the prenatal treatment of spina bifida. Some reported bimanual fetoscopic procedures were performed on the exteriorized uterus via a maternal laparotomy and can therefore not be classified as being truly minimally invasive. DISCUSSION: our results demonstrate that minimally invasive fetoscopic bimanual surgery is rare, even in animal models, excluding many other techniques and procedures that are loosely termed 'minimally invasive fetal surgery' which we suggest to better label as 'interventions'. Thus, more research on percutaneous minimally invasive bimanual fetoscopic surgery is warranted, with the aim to reduce the maternal, uterine and fetal trauma for correction of congenital malformations.

Robotically Assisted Surgery in Children-A Perspective.

The introduction of robotically assisted surgery was a milestone for minimally invasive surgery in the 21st century. Currently, there are two CE-approved robotically assisted surgery systems for use and development in pediatrics. Specifically, tremor filtration and optimal visualization are approaches which can have enormous benefits for procedures in small bodies. Robotically assisted surgery in children might have advantages compared to laparoscopic or open approaches. This review focuses on the research literature regarding robotically assisted surgery that has been published within the past decade. A literature search was conducted to identify studies comparing robotically assisted surgery with laparoscopic and open approaches. While reported applications in urology were the most cited, three other fields (gynecology, general surgery, and "others") were also identified. In total, 36 of the publications reviewed suggested that robotically assisted surgery was a good alternative for pediatric procedures. After several years of experience of this surgery, a strong learning curve was evident in the literature. However, some authors have highlighted limitations, such as high cost and a limited spectrum of small-sized instruments. The recent introduction of reusable 3 mm instruments to the market might help to overcome these limitations. In the future, it can be anticipated that there will be a broader range of applications for robotically assisted surgery in selected pediatric surgeries, especially as surgical skills continue to improve and further system innovations emerge.

Radiographic features of magnesium-based bioabsorbable screw resorption in paediatric fractures.

BACKGROUND: Resorption of magnesium-based alloy bioabsorbable screws produces hydrogen gas, which can be mistaken as a sign of infection and may affect the physis or fixed bone fragment. OBJECTIVE: We evaluated the temporal and spatial occurrence of gas and the occurrence of a breakage of the fixed bone fragment or screw following magnesium screw fixation. MATERIALS AND METHODS: Radiographs of paediatric patients treated with magnesium screws were retrospectively reviewed. Temporal occurrence and distribution of gas in the bone, the physis and soft tissues, breakage of the screw or fixed bone fragment and joint effusion were assessed. RESULTS: One hundred and three radiographs in 35 paediatric patients were reviewed (mean age: 10.6 years). Follow-up ranged from 1 to 730 days. Gas in the bone increases up to week 5, remains constant up to week 16 and then decreases. Gas in soft tissues, intra-articular gas and joint effusions gradually reduce over time. In 1/23 (4.3%) patients with an open physis, gas intrusion into the physis occurred. Breakage of the bone fragment fixated by the screw was observed in 4/35 (11.4%) patients within the first 6 weeks. Screw breakage was observed in 16/35 (45.7%) patients, with a median time to first detection of 300 days. CONCLUSION: Gas bubbles in bone and soft tissue are normal findings in the context of screw resorption and should not be confused with soft-tissue infection or osteomyelitis. Gas is rarely visible in the physis. Breakage of the fixed bone fragment and/or screw can occur.

Making Hardware Removal Unnecessary by Using Resorbable Implants for Osteosynthesis in Children.

INTRODUCTION: Following osteosynthesis, children generally require a second surgery to remove the hardware. This becomes unnecessary, by using resorbable implants. Limiting the number of required surgeries and their associated risks, this technique provides critical aspects of minimally invasive surgery. This review focuses on resorbable implants for osteosynthesis for the treatment of fractures in children and discusses their clinical features. METHOD: We provide an overview of the two most common technologies used in resorbable osteosynthesis materials: polymer- and magnesium-based alloys. Clinical examples of osteosynthesis are presented using polymer-based ActivaTM products and magnesium-based Magnezix® products. RESULTS: Polymer-based implants demonstrate surgical safety and efficacy. Due to their elasticity, initial placement of polymer-based products may demonstrate technical challenges. However, stability is maintained over the course of healing. While maintaining good biocompatibility, the rate of polymer-resorption may be controlled by varying the composition of polyesters and copolymers. Similarly, magnesium-based implants demonstrate good mechanical stability and resorption rates, while these characteristics may be controlled by varying alloy components. One of the significant shortcomings of magnesium is that metabolism results in the production of hydrogen gas. Both technologies provide equally good results clinically and radiographically, when compared to non-resorbable implants. CONCLUSION: Resorbable osteosynthesis materials demonstrate similar therapeutic results as conventional materials for osteosynthesis. Resorbable implants may have the potential to improve patient outcomes, by sparing children a second surgery for hardware removal.

Current Development of Minimally Invasive Repair of Pectus Excavatum (MIRPE).

For decades, open surgical repair was the only available method to treat congenital and acquired chest wall deformities (CWDs). In 1998, D. Nuss described a minimally invasive procedure for surgical repair of Pectus excavatum (PE). Today, the Nuss procedure is performed with increasing frequency worldwide and considered as the "gold standard". After its introduction, the method experienced numerous modifications such as routine thoracoscopy and/or sternal elevation, increasing safety of the procedure. Placement of multiple bars and/or the so called cross-bar technique were introduced to correct complex CWDs. Standardized pain management, the introduction of cryo-analgesia and a standardized postoperative physiotherapy program including deep breathing exercises facilitate the establishment of an enhanced recovery after surgery (ERAS) process. However, the widespread use of the minimally invasive repair of pectus excavatum (MIRPE) procedure has been associated with a significant number of serious complications. Furthermore, several studies report near-fatal complications, not only during bar placement, but also during bar removal. This review focuses upon the most relevant modifications, including recent published surgical techniques of MIRPE, in order to describe current developments in the field.

Fetal Surgery for Gastroschisis-A Review with Emphasis on Minimally Invasive Procedures.

(1) Background: The morbidity of gastroschisis is defined by exposure of unprotected intestines to the amniotic fluid leading to inflammatory damage and consecutive intestinal dysmotility, the viscero-abdominal disproportion which results in an abdomen too small to incorporate the herniated and often swollen intestine, and by associated pathologies, such as in complex gastroschisis. To prevent intestinal damage and to provide for growth of the abdominal cavity, fetal interventions such as amnio exchange, gastroschisis repair or covering have been evaluated in several animal models and human trials. This review aims to evaluate the reported techniques for the fetal treatment of gastroschisis by focusing on minimally invasive procedures. (2) Methods: We conducted a systematic database search, quality assessment and analyzed relevant articles which evaluate or describe surgical techniques for the prenatal surgical management of gastroschisis in animal models or human application. (3) Results: Of 96 identified reports, 42 eligible studies were included. Fetal interventions for gastroschisis in humans are only reported for EXIT procedures and amnio exchange. In animal models, particularly in the fetal sheep model, several techniques of open or minimally invasive repair of gastroschisis or covering the intestine have been described, with fetoscopic covering being the most encouraging. (4) Discussion: Although some promising minimally invasive techniques have been demonstrated in human application and animal models, most of them are still associated with relevant fetal morbidity and mortality and barely appear to be currently applicable in humans. Further research on specific procedures, instruments and materials is needed before any human application.

Evaluation of the Versius Robotic Surgical System for Procedures in Small Cavities.

BACKGROUND: The Versius® is a recently approved robotic surgical system for general surgery procedures in adults. Before any application in children, data of its feasibility and safety in small cavities has to be compiled, beginning with inanimate models. Therefore, the aim of this preclinical study was to assess the Versius® system for its performance in small boxes simulating small body cavities. METHODS: In total, 8 cardboard boxes of decreasing volumes (15.75 L to 106 mL) were used. The procedures, two single stitches with two square knots each, were performed in every box, starting in the largest and consecutively exchanging the box to the next smaller one. The evaluation included procedure time, port placement and pivot point setup, arrangement of the robotic arms and instrumentation, amount of internal and external instrument-instrument collisions and instrument-box collisions. RESULTS: All procedures could be successfully performed in all boxes. The procedure time decreased due to the learning curve in the first four boxes (15.75 to 1.87 L) and consecutively increased from boxes of 1.22 L up to the smallest box with the dimensions of 4.4 × 4.9 × 4.9 cm3. This may be based on the progress of complexity of the procedures in small cavities, which is also depicted by the synchronous increase of the internal instrument-instrument and instrument-box collisions. CONCLUSION: With the use of the Versius® robotic surgical system, we were able to perform robotic reconstructive procedures, such as intracorporal suturing and knot tying, in cavities as small as 106 mL. Whether this system is comparable or even superior to conventional laparoscopic surgery in small cavities, such as in children, has to be evaluated. Furthermore, before any application in newborns or infants, ongoing evaluation of this system should be performed in a live animal model.

Colectomy Followed by J-Pouch Reconstruction to Correct Total Colonic Aganglionosis.

BACKGROUND: Patients suffering from complete colonic aganglionosis (TCA) require the best surgical care possible. Only a few studies reported J-Pouch repair as the primary reconstructive surgery in TCA patients. This study adds to the current literature a thorough clinical and functional outcomes group. METHODS: Between 2011 and 2021, medical records of Hirschsprung disease (HD) patients who underwent J-Pouch reconstruction during infancy (n = 12) were reviewed. In close follow-up, bowel function and satisfaction with operation results were evaluated. The median age at the time of J-Pouch reconstruction was 16 months, and covering ileostomies were closed four months later. There were no postoperative problems. After the final repair, Pouch-related problems (PRP) occurred in 27% of the children and were treated conservatively. There was no histological evidence of pouchitis in any of the individuals. The median 24-h stooling frequency was 4-5 at the latest follow-up 51 months following enterostomy closure. CONCLUSIONS: The current study's findings support the existing literature and advocate for J-pouch repair in TCA patients. However, more research will be needed to determine the best time to undergo pouch surgery and ileostomy closure in TCA patients.

Robotic infant surgery with 3 mm instruments: a study in piglets of less than 10 kg body weight.

No data exist concerning the appication of a new robotic system with 3 mm instruments (Senhance®, Transenterix) in infants and small children. Therefore, the aim of this study was to test the system for its feasibility, performance and safety of robotic pediatric abdominal and thoracic surgery in piglets simulating infants with a body weight lower than 10 kg. 34 procedures (from explorative laparoscopy to thoracoscopic esophageal repair) were performed in 12 piglets with a median age of 23 (interquartile range: 12-28) days and a median body weight of 6.9 (6.1-7.3) kg. The Senhance® robotic system was used with 3 mm instruments, a 10 mm 3D 0° or 30° videoscope and advanced energy devices, the setup consisted of the master console and three separate arms. The amount, size, and position of the applied ports, their distance as well as the distance between the three operator arms of the robot, external and internal collisions, and complications of the procedures were recorded and analyzed. We were able to perform all planned surgical procedures with 3 mm robotic instruments in piglets with a median body weight of less than 7 kg. We encountered two non-robot associated complications (bleeding from the inferior caval and hepatic vein) which led to termination of the live procedures. Technical limitations were the reaction time and speed of robotic camera movement with eye tracking, the excessive bending of the 3 mm instruments and intermittent need of re-calibration of the fulcrum point. Robotic newborn and infant surgery appears technically feasible with the Senhance® system. Software adjustments for camera movement and sensitivity of the fulcrum point calibration algorithm to adjust for the increased compliance of the abdominal wall of infants, therefore reducing the bending of the instruments, need to be implemented by the manufacturer as a result of our study. To further evaluate the Senhance® system, prospective trials comparing it to open, laparoscopic and other robotic systems are needed.

Risk factors for mortality in preterm infants with necrotizing enterocolitis: a retrospective multicenter analysis.

It is difficult to predict the risk of mortality in necrotizing enterocolitis (NEC). This study aimed at identifying risk factors for severe NEC (Bell stage III) and mortality in preterm children with NEC. In this multicenter retrospective study, we analyzed multiple data from 157 premature children with confirmed NEC in the period from January 2007 to October 2018. We performed univariate, multivariate, stepwise logistic regression, and receiver operator characteristics (ROC) analyses. We were able to demonstrate that low Apgar scores (notably at 1' and 5'), low hemoglobin concentration (Hgb), and high lactate level at disease onset and during disease correlated with NEC severity and mortality (P < 0.05, respectively). Severe NEC was related to congenital heart disease (CHD - OR 2.6, CI95% 1.2-5.8, P 0.015) and patent ductus arteriosus (PDA - OR 3.3, CI95% 1.6-6.9, P 0.0012), whereas death was related to the presence of PDA (OR 5.5, CI95% 2.3-14, P < 0.001).Conclusion: Low Apgar scores, low Hgb, high lactate levels, and the presence of CHD or PDA correlated with severe NEC or mortality in children with NEC. What is Known: • It remains difficult to predict which infant that suffers from necrotizing enterocolitis at risk of death. • Several clinical and laboratory parameters tools to predict fatal outcome in NEC. What is New: • The following laboratory parameters were associated with the risk of death from NEC: Hemoglobin concentration, base excess and lactate level. • The following clinical variables were associated with the risk of death from NEC: Apgar scores, as well as the presence of congenital heart disease and patent ductus arteriosus.

Stereological Lung Parameters After Fetoscopic Abdominal Decompression of Congenital Diaphragmatic Hernia in an Ovine Model: A Pilot Study.

Background: Fetoscopic endoluminal tracheal occlusion (FETO) improves lung maturation in severe cases of congenital diaphragmatic hernia (CDH) but it does not ameliorate lung compression by herniated abdominal organs. Surgically opening the fetal abdomen (abdominal decompression [AD]) reduces the intrathoracic pressure by diverting the abdominal organs into the amniotic cavity-a probable causal therapy for lung hypoplasia and pulmonary hypertension in CDH. Open surgical abdominal decompression has been reported: we describe a minimally invasive approach in an ovine model of CDH as a probable fetoscopic intervention. Materials and Methods: Eight fetuses were included, 2 were kept as HEALTHY controls. A CDH (left side, liver down) was created by open fetal surgery at midgestation in 6 fetuses, 2 were taken as CDH controls. Fetoscopic abdominal decompression (fAD) was performed 21 days later in 4 animals. The fetuses were retrieved at the end of gestation and evaluated by lung stereology. Results: fAD led to a near total evacuation of the thoracic cavity in 2 of the 4 animals. Fetuses with CDH had a lower total volume and fraction of alveolar air space, a lower volume fraction of the parenchyma, and an increase of the volume fraction of the alveolar septa and atelectasis, as well as an increased mean thickness of alveolar septa compared with HEALTHY fetuses. Fetuses treated with abdominal decompression showed an improvement of stereological parameters. Conclusions: In spite of relevant limitations (pilot study, small groups, spontaneous closure of the abdominal incision) we were able to demonstrate that abdominal decompression for CDH can be performed by fetoscopy. Our results support the hypothesis of causally improving lung development by abdominal decompression, thus implying increased survival in extreme cases of CDH. A refinement of the fetoscopic techniques and direct comparison to FETO appears warranted.

Lack of Mucosal Cholinergic Innervation Is Associated With Increased Risk of Enterocolitis in Hirschsprung's Disease.

BACKGROUND & AIMS: Hirschsprung's disease (HSCR) is a congenital intestinal motility disorder defined by the absence of enteric neuronal cells (ganglia) in the distal gut. The development of HSCR-associated enterocolitis remains a life-threatening complication. Absence of enteric ganglia implicates innervation of acetylcholine-secreting (cholinergic) nerve fibers. Cholinergic signals have been reported to control excessive inflammation, but the impact on HSCR-associated enterocolitis is unknown. METHODS: We enrolled 44 HSCR patients in a prospective multicenter study and grouped them according to their degree of colonic mucosal acetylcholinesterase-positive innervation into low-fiber and high-fiber patient groups. The fiber phenotype was correlated with the tissue cytokine profile as well as immune cell frequencies using Luminex analysis and fluorescence-activated cell sorting analysis of colonic tissue and immune cells. Using confocal immunofluorescence microscopy, macrophages were identified in close proximity to nerve fibers and characterized by RNA-seq analysis. Microbial dysbiosis was analyzed in colonic tissue using 16S-rDNA gene sequencing. Finally, the fiber phenotype was correlated with postoperative enterocolitis manifestation. RESULTS: The presence of mucosal nerve fiber innervation correlated with reduced T-helper 17 cytokines and cell frequencies. In high-fiber tissue, macrophages co-localized with nerve fibers and expressed significantly less interleukin 23 than macrophages from low-fiber tissue. HSCR patients lacking mucosal nerve fibers showed microbial dysbiosis and had a higher incidence of postoperative enterocolitis. CONCLUSIONS: The mucosal fiber phenotype might serve as a prognostic marker for enterocolitis development in HSCR patients and may offer an approach to personalized patient care and new therapeutic options.

Cholinergic Signaling Attenuates Pro-Inflammatory Interleukin-8 Response in Colonic Epithelial Cells.

Infants affected by Hirschsprung disease (HSCR), a neurodevelopmental congenital disorder, lack ganglia of the intrinsic enteric nervous system (aganglionosis) in a variable length of the colon, and are prone to developing severe Hirschsprung-associated enterocolitis (HAEC). HSCR patients typically show abnormal dense innervation of extrinsic cholinergic nerve fibers throughout the aganglionic rectosigmoid. Cholinergic signaling has been reported to reduce inflammatory response. Consequently, a sparse extrinsic cholinergic innervation in the mucosa of the rectosigmoid correlates with increased inflammatory immune cell frequencies and higher incidence of HAEC in HSCR patients. However, whether cholinergic signals influence the pro-inflammatory immune response of intestinal epithelial cells (IEC) is unknown. Here, we analyzed colonic IEC isolated from 43 HSCR patients with either a low or high mucosal cholinergic innervation density (fiber-low versus fiber-high) as well as from control tissue. Compared to fiber-high samples, IEC purified from fiber-low rectosigmoid expressed significantly higher levels of IL-8 but not TNF-α, IL-10, TGF-ß1, Muc-2 or tight junction proteins. IEC from fiber-low rectosigmoid showed higher IL-8 protein concentrations in cell lysates as well as prominent IL-8 immunoreactivity compared to IEC from fiber-high tissue. Using the human colonic IEC cell line SW480 we demonstrated that cholinergic signals suppress lipopolysaccharide-induced IL-8 secretion via the alpha 7 nicotinic acetylcholine receptor (a7nAChR). In conclusion, we showed for the first time that the presence of a dense mucosal cholinergic innervation is associated with decreased secretion of IEC-derived pro-inflammatory IL-8 in the rectosigmoid of HSCR patients likely dependent on a7nAChR activation. Owing to the association between IL-8 and enterocolitis-prone, fiber-low HSCR patients, targeted therapies against IL-8 might be a promising immunotherapy candidate for HAEC treatment.