Fetal lung regeneration using stem cell-derived extracellular vesicles: A new frontier for pulmonary hypoplasia secondary to congenital diaphragmatic hernia.

The poor outcomes of babies with congenital diaphragmatic hernia (CDH) are directly related to pulmonary hypoplasia, a condition characterized by impaired lung development. Although the pathogenesis of pulmonary hypoplasia is not fully elucidated, there is now evidence that CDH patients have missing or dysregulated microRNAs (miRNAs) that regulate lung development. A prenatal therapy that supplements these missing/dysregulated miRNAs could be a strategy to rescue normal lung development. Extracellular vesicles (EVs), also known as exosomes when of small dimensions, are lipid-bound nanoparticles that can transfer their heterogeneous cargo (proteins, lipids, small RNAs) to target cells to induce biological responses. Herein, we review all studies that show evidence for stem cell-derived EVs as a regenerative therapy to rescue normal development in CDH fetal lungs. Particularly, we report studies showing that administration of EVs derived from amniotic fluid stem cells (AFSC-EVs) to models of pulmonary hypoplasia promotes fetal lung growth and maturation via transfer of miRNAs that are known to regulate lung developmental processes. We also describe that stem cell-derived EVs exert effects on vascular remodeling, thus possibly preventing postnatal pulmonary hypertension. Finally, we discuss future perspectives and challenges to translate this promising stem cell EV-based therapy to clinical practice.

The role of sonography in differentiating congenital intrinsic duodenal anomalies from midgut malrotation: emphasizing the new signs of duodenal and gastric wall thickening and hyperechogenicity.

BACKGROUND: The clinical and plain radiographic differentiation of congenital intrinsic duodenal anomalies (atresia, web, stenosis) from intestinal malrotation is not always clear. Although sonography has been documented as an important diagnostic tool in the differentiation of these two entities, its role is still not widely appreciated and it is still not universally utilized in this clinical setting. OBJECTIVE: To assess the usefulness of sonographic features of the duodenal and gastric wall in the differentiation of congenital intrinsic duodenal anomalies from midgut malrotation in a large series of neonates and to compare them with other features on abdominal radiographs, ultrasound and upper gastrointestinal series. MATERIALS AND METHODS: Using the surgical database at our tertiary pediatric hospital, we identified neonates who had surgically proven congenital intrinsic duodenal anomalies or malrotation over a period of 15 years (2000-2015). We reviewed imaging findings in both groups of neonates (blinded to the final diagnosis) with attention to the echogenicity and thickness of the wall of the duodenum and stomach, the relationship between the superior mesenteric artery and vein, the position of the third portion of the duodenum and the presence of the whirlpool sign. Findings were compared between the groups using the unpaired t-test and Fisher exact test. RESULTS: We included 107 neonates in the study, 40 with a congenital intrinsic duodenal anomaly, 49 with malrotation (36 with volvulus) and 18 with a combination of both. Duodenal and gastric wall thickening and hyperechogenicity were significantly more common in the group with a congenital intrinsic duodenal anomaly compared to those with malrotation (P<0.0001). Conversely, an abnormal relationship between the superior mesenteric artery and vein, abnormal position of the third part of the duodenum, and the whirlpool sign were significantly more common in neonates with malrotation than in those with congenital intrinsic duodenal anomalies (P<0.0001). CONCLUSION: Duodenal or gastric wall thickening, and increased wall echogenicity are helpful sonographic features in the differentiation of congenital intrinsic duodenal anomalies from malrotation. Evaluation of the duodenal and gastric wall should thus be added to the features routinely assessed on ultrasound examinations in the clinical setting of suspected duodenal obstruction in the neonate.

Experimental necrotizing enterocolitis induces neuroinflammation in the neonatal brain.

BACKGROUND: Necrotizing enterocolitis (NEC) is an inflammatory gastrointestinal disease primarily affecting preterm neonates. Neonates with NEC suffer from a degree of neurodevelopmental delay that is not explained by prematurity alone. There is a need to understand the pathogenesis of neurodevelopmental delay in NEC. In this study, we assessed the macroscopic and microscopic changes that occur to brain cell populations in specific brain regions in a neonatal mouse model of NEC. Moreover, we investigated the role of intestinal inflammation as part of the mechanism responsible for the changes observed in the brain of pups with NEC. METHODS: Brains of mice were assessed for gross morphology and cerebral cortex thickness (using histology). Markers for mature neurons, oligodendrocytes, neural progenitor cells, microglia, and astrocytes were used to quantify their cell populations in different regions of the brain. Levels of cell apoptosis in the brain were measured by Western blotting and immunohistochemistry. Endoplasmic reticulum (ER) stress markers and levels of pro-inflammatory cytokines (in the ileum and brain) were measured by RT-qPCR and Western blotting. A Pearson test was used to correlate the levels of cytokines (ELISA) in the brain and ileum and to correlate activated microglia and astrocyte populations to the severity of NEC. RESULTS: NEC pups had smaller brain weights, higher brain-to-body weight ratios, and thinner cortices compared to control pups. NEC pups had increased levels of apoptosis and ER stress. In addition, NEC was associated with a reduction in the number of neurons, oligodendrocytes, and neural progenitors in specific regions of the brain. Levels of pro-inflammatory cytokines and the density of activated microglia and astrocytes were increased in the brain and positively correlated with the increase in the levels pro-inflammatory cytokines in the gut and the severity of NEC damage respectively. CONCLUSIONS: NEC is associated with severe changes in brain morphology, a pro-inflammatory response in the brain that alters cell homeostasis and density of brain cell populations in specific cerebral regions. We show that the severity of neuroinflammation is associated with the severity of NEC. Our findings suggest that early intervention during NEC may reduce the chance of acute neuroinflammation and cerebral damage.

Intraoperative acidosis and hypercapnia during thoracoscopic repair of congenital diaphragmatic hernia and esophageal atresia/tracheoesophageal fistula.

BACKGROUND: Intraoperative hypercapnia and acidosis have been associated with thoracoscopic repair of both congenital diaphragmatic hernia and esophageal atresia/tracheoesophageal fistula. AIM: The aim of the present study was to investigate whether thoracoscopic repair of congenital diaphragmatic hernia or esophageal atresia/tracheoesophageal fistula was associated with acidosis and hypercapnia in a large group of neonates, and to analyze the effects of acidosis and hypercapnia on early postoperative outcomes. METHODS: We reviewed the charts of neonates who underwent open or thoracoscopic congenital diaphragmatic hernia or esophageal atresia/tracheoesophageal fistula repair (2004-2014). Patients with available intraoperative arterial gas values were included. Data (PaCO2 : mm Hg) were compared using paired/unpaired tests and are reported as difference [95% confidence interval]. RESULTS: Congenital diaphragmatic hernia: 187 neonates underwent open (n=153) or thoracoscopic (n=34) repair. Intraoperative arterial gas values were recorded in 96 open and in 23 thoracoscopic operations. Both groups had similar preoperative pH and PaCO2 , and developed intraoperative acidosis (open -0.08 [-0.11, -0.05] P<.001, thoracoscopic -0.14 [-0.24, -0.04] P=.01) and hypercapnia (open: 7.8 [3.2, 12.4], P=.002; thoracoscopic: 20.2 [-2.5, 43, P=.07). Intraoperatively, neonates undergoing thoracoscopic repair developed lower pH than those having open surgery (-0.06 [-0.01, -0.10] P=.018), but maintained similar levels of PaCO2 (-4.0 [-9.0, 4.4] P=.39). Esophageal atresia/tracheoesophageal fistula: 205 neonates underwent open (n=180) or thoracoscopic (n=25) repair. Intraoperative arterial gas values were recorded in 62 open and in 14 thoracoscopic operations. Both groups had similar preoperative pH and PaCO2 , and developed intraoperative acidosis (open: -0.09 [-0.14, -0.04], P<.001; thoracoscopic: 0.21 [-0.28, -0.14], P<.001) and hypercapnia (open: 9.2 [2.6, 15.7] P=.008; thoracoscopic: 15.2 [1.6, 28.7], P=.03). Intraoperatively, neonates undergoing thoracoscopic repair developed lower pH than those having open surgery (difference 0.08 [0.01, 0.15], P=.02) but maintained similar levels of PaCO2 (difference -1 [-9, 3], P=.35). CONCLUSION: Neonates undergoing operative repair of congenital diaphragmatic hernia and esophageal atresia/tracheoesophageal fistula develop intraoperative acidosis and hypercapnia, regardless of the approach used. However, this phenomenon is more severe during thoracoscopic repair. Novel modalities to reduce intraoperative gas derangements, particularly during thoracoscopic repair, need to be established.

A spectrum of intestinal injury models in neonatal mice.

PURPOSE: To compare the degree of necrotizing enterocolitis (NEC)-like damage under different stress conditions in neonatal mice. METHODS: 5-day-old C57BL/6 mice were assigned to: (A) breastfed and no stress factors; (B) breastfed+maternal separation (3 h daily); (C) breastfed+hypoxia+lipopolysaccharide (LPS-4 mg/kg/day); (D) hyperosmolar formula+hypoxia+LPS. Mice were killed at 9 days of life. Ileum and colon were stained for hematoxylin/eosin and blindly assessed. A scoring ≥2 was considered NEC. Data were compared using one-way ANOVA and reported as median (range). RESULTS: Ileum-Mucosal injury was mild in group B (0.0-1). Hypoxia+LPS induced greater injury in group C (1.6, 1-2.5; p < 0.0001 to B) and D (2, 0.5-3.5; p < 0.0001 to B). There were no differences between group C and D (p = n.s.). There were no cases of NEC in group A or B, whereas NEC was present in 36 % group C and 68 % group D mice. Colon-a similar degree of mucosal injury was observed among group B (2, 1-3), C (1.7, 0-3) and D (1.5, 1-3; p = n.s.). NEC was present in 75 % of group B, 50 % of group C and 86 % of group D. CONCLUSION: These models establish a spectrum of intestinal injury and are useful to investigate the variability of neonatal intestinal diseases, such as NEC.

Are paediatric operations evidence based? A prospective analysis of general surgery practice in a teaching paediatric hospital.

BACKGROUND/AIM: Paediatric surgical practice should be based upon solid scientific evidence. A study in 1998 (Baraldini et al., Pediatr Surg Int) indicated that only a quarter of paediatric operations were supported by the then gold standard of evidence based medicine (EBM) which was defined by randomized controlled trials (RCTs). The aim of the current study was to re-evaluate paediatric surgical practice 16 years after the previous study in a larger cohort of patients. METHODS: A prospective observational study was performed in a tertiary level teaching hospital for children. The study was approved by the local research ethics board. All diagnostic and therapeutic procedures requiring a general anaesthetic carried out over a 4-week period (24 Feb 2014-22 Mar 2014) under the general surgery service or involving a general paediatric surgeon were included in the study. Pubmed and EMBASE were used to search in the literature for the highest level of evidence supporting the recorded procedures. Evidence was classified according to the Oxford Centre for Evidence Based Medicine (OCEBM) 2009 system as well as according to the classification used by Baraldini et al. Results was compared using Χ (2) test. P < 0.05 was considered statistically significant. RESULTS: During the study period, 126 operations (36 different types) were performed on 118 patients. According to the OCEBM classification, 62 procedures (49 %) were supported by systematic reviews of multiple homogeneous RCTs (level 1a), 13 (10 %) by individual RCTs (level 1b), 5 (4 %) by systematic reviews of cohort studies (level 2a), 11 (9 %) by individual cohort studies, 1 (1 %) by systematic review of case-control studies (level 3a), 14 (11 %) by case-control studies (level 3b), 9 (7 %) by case series (type 4) and 11 procedures (9 %) were based on expert opinion or deemed self-evident interventions (type 5). High level of evidence (OCEBM level 1a or 1b or level I according to Baraldini et al. PSI 1998) supported 75 (60 %) operations in the current study compared to 18 (26 %) in the study of 1998 (P < 0.0001). CONCLUSION: The present study shows that nowadays a remarkable number of paediatric surgical procedures are supported by high level of evidence. Despite this improvement in evidence-based paediatric surgical practice, more than a third of the procedures still lack sufficient evidence-based literature support. More RCTs are warranted to support and direct paediatric surgery practice according to the principals of EBM.

Outcome of right-sided diaphragmatic hernia repair: a multicentre study.

AIM: Right-sided congenital diaphragmatic hernia (R-CDH) occurs in 14 to 25% of all CDH cases. The current literature comparing the outcome of R-CDH vs left CDH (L-CDH) is inconsistent, with some studies reporting higher and others lower mortality in R-CDH compared to L-CDH. The aim of our multicentre study was to analyse characteristics and outcome of R-CDH. METHODS: We retrospectively reviewed the medical records of 178 consecutive infants with CDH who underwent surgical repair of CDH at three European tertiary pediatric surgical centres from three different countries between 2000 and 2009. The analysis focused on demographic data, morbidity and mortality in R-CDH compared with L-CDH. RESULTS: Out of a total of 178 children, 32 (18.0%) right-sided and 146 (82.0 %) left-sided cases of CDH were identified. Prenatal diagnosis was made in 8 R-CDH vs 67 L-CDH (25.0 vs 45.9%, p = 0.030). Median gestational age in R-CDH was 39 weeks (range 29-42 weeks) and 39 weeks in L-CDH (range 28-43 weeks, p = 0.943). Median birth weight in R-CDH was 3233 g (range 905-4480 g) and in L-CDH was 3060 g (range 1065-5240 g, p = 0.184). Major associated anomalies were present in 19 R-CDH vs 46 L-CDH (59.4 vs 31.5%, p = 0.003). Extracorporeal membrane oxygenation (ECMO) was required in 3 R-CDH vs 19 L-CDH (9.4 vs 13.0%, p = 0.571). A diaphragmatic patch was used in 13 R-CDH and 59 L-CDH (40.6 vs 40.4%, p = 0.982). Fundoplication for GERD was required in 1 R-CDH and 19 L-CDH (3.1 vs 13.0 %, p = 0.109). No significant differences were observed in recurrence rate (9.4 vs 8.9%, p = 0.933). Postoperative mortality rate was significantly higher in R-CDH compared to L-CDH (21.9 vs 8.2%, p = 0.023). In R-CDH, prenatal diagnosis and patch repair correlated with mortality by univariate regression (p = 0.005 and p = 0.019). CONCLUSION: This multicentre study shows that prenatal diagnosis and patch repair were associated with an increased mortality rate in R-CDH. However, the morbidity following repair of R-CDH was not significantly different from that in L-CDH in survivors.

Early maternal separation induces alterations of colonic epithelial permeability and morphology.

BACKGROUND: Early maternal separation could lead to significant intestinal barrier and epithelial dysfunction. However, the exact mechanism remains to be elucidated and need to be investigated. METHODS: Neonatal C57BL/6 mice were subjected to maternal separation: Maternal separation (MS) daily 3 h between postnatal day (PND) 5-9, single separation (SS) 3 h on PND 9 and no separation (NS). Colon and ileum permeability was measured by Ussing chamber. Severity of morphological changes in the colon was evaluated by blinded grading of histological stained sections. RESULTS: Trans-epithelial resistance of colon and ileum did not change indicating that the tissues remained intact during the course of the experiment. Permeability of trans-cellular tracer Horseradish peroxidase (HRP) was significantly increased in the colon of MS compared to SS and NS (p < 0.05 for SS and p < 0.001 for NS), but there was no difference in para-cellular permeability of fluorescein isothiocyanate-conjugated dextran (FD4). However, there was no change in permeability of both HRP and FD4 in the ileum. MS and SS groups had marked intestinal epithelium morphology changes in comparison to controls (p < 0.05). CONCLUSION: These preliminary observations indicate that neonatal maternal separation increases colonic trans-cellular permeability. This increase may be caused by the change of the transmural colonic morphology. The underlying mechanism is unknown and further investigation is necessary as it is of relevance to the development of early intestinal diseases such as necrotizing enterocolitis.

Neonatal Intestinal Segmental Volvulus: What Are the Differences with Midgut Volvulus?

OBJECTIVE: Intestinal volvulus in the neonate is a surgical emergency caused by either midgut volvulus (MV) with intestinal malrotation or less commonly, by segmental volvulus (SV) without intestinal malrotation. The aim of our study was to investigate if MV and SV can be differentiated by clinical course, intraoperative findings, and postoperative outcomes. METHODS: Using a defined search strategy, two investigators independently identified all studies comparing MV and SV in neonates. PRISMA guidelines were followed, and a meta-analysis was performed using RevMan 5.3. RESULTS: Of 1,026 abstracts screened, 104 full-text articles were analyzed, and 3 comparative studies were selected (112 patients). There were no differences in gestational age (37 vs. 36 weeks), birth weight (2,989 vs. 2,712 g), and age at presentation (6.9 vs. 3.8 days). SV was more commonly associated with abnormal findings on fetal ultrasound (US; 65 vs. 11.6%; p < 0.00001). Preoperatively, SV was more commonly associated with abdominal distension (32 vs. 77%; p < 0.05), whereas MV with a whirlpool sign on ultrasound (57 vs. 3%; p < 0.01). Bilious vomiting had similar incidence in both (88 ± 4% vs. 50 ± 5%). Intraoperatively, SV had a higher incidence of intestinal atresia (2 vs. 19%; p < 0.05) and need for bowel resection (13 vs. 91%; p < 0.00001). There were no differences in postoperative complications (13% MV vs. 14% SV), short bowel syndrome (15% MV vs. 0% SV; data available only from one study), and mortality (12% MV vs. 2% SV). CONCLUSION: Our study highlights the paucity of studies on SV in neonates. Nonetheless, our meta-analysis clearly indicates that SV is an entity on its own with distinct clinical features and intraoperative findings that are different from MV. SV should be considered as one of the differential diagnoses in all term and preterm babies with bilious vomiting after MV was ruled out-especially if abnormal fetal US and abdominal distension is present.

European Pediatric Surgeons' Association Survey on Timing of Inguinal Hernia Repair in Premature Infants.

AIM: This article evaluates the practice patterns of European Pediatric Surgeons' Association (EUPSA) members regarding the timing of inguinal hernia (IH) repair in premature infants. METHODS: Online survey containing 29 questions distributed to EUPSA members during January 2023. RESULTS: A total of 180 responds were received. Overall, IH repair prior to discharge was favored by 60% of respondents when there was a history of incarceration and 56% when there was not. In the case of very/extremely premature infants (< 32 weeks) with no history of incarceration, fewer (43%) respondents postpone the surgery until after discharge. The majority of respondents cited the risk of incarceration as the reason for advocating surgery prior to discharge, whereas a reduced risk of apnea was the most cited reason for respondents who prefer delayed surgery. Open approach under general anesthesia was favored by 54% of respondents, with 27% of them preferring open approach with spinal anesthesia. Laparoscopic surgery for premature infants is used in 11% while 7% of them preferred in all premature infants including extremely/very premature ones. Contralateral side evaluation was never done by 40% of respondents and 29% only performed it only during laparoscopic repair. The majority of respondents (77%) indicated that they have an overnight stay policy for premature infants < 45 weeks of gestation. CONCLUSION: There is variation in the practice patterns of pediatric surgeons in the treatment of IH in premature infants. Due to the concern for the high risk of incarceration, IH repair before discharge was the most prevalent practice. Lower risk of postoperative apnea was cited as the most common reason for delaying surgery. Randomized studies are required to establish the optimal timing for IH repair in premature infants.

Fetal hypoplastic lungs have multilineage inflammation that is reversed by amniotic fluid stem cell extracellular vesicle treatment.

Antenatal administration of extracellular vesicles from amniotic fluid stem cells (AFSC-EVs) reverses features of pulmonary hypoplasia in models of congenital diaphragmatic hernia (CDH). However, it remains unknown which lung cellular compartments and biological pathways are affected by AFSC-EV therapy. Herein, we conducted single-nucleus RNA sequencing (snRNA-seq) on rat fetal CDH lungs treated with vehicle or AFSC-EVs. We identified that intra-amniotically injected AFSC-EVs reach the fetal lung in rats with CDH, where they promote lung branching morphogenesis and epithelial cell differentiation. Moreover, snRNA-seq revealed that rat fetal CDH lungs have a multilineage inflammatory signature with macrophage enrichment, which is reversed by AFSC-EV treatment. Macrophage enrichment in CDH fetal rat lungs was confirmed by immunofluorescence, flow cytometry, and inhibition studies with GW2580. Moreover, we validated macrophage enrichment in human fetal CDH lung autopsy samples. Together, this study advances knowledge on the pathogenesis of pulmonary hypoplasia and further evidence on the value of an EV-based therapy for CDH fetuses.

The Role of Exosomes in the Treatment, Prevention, Diagnosis, and Pathogenesis of COVID-19.

The novel coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), continues to be a major health concern. In search for novel treatment strategies against COVID-19, exosomes have attracted the attention of scientists and pharmaceutical companies worldwide. Exosomes are small extracellular vesicles, secreted by all types of cells, and considered as key mediators of intercellular communication and stem-cell paracrine signaling. Herein, we reviewed the most recent literature about the role of exosomes as potential agents for treatment, prevention, diagnosis, and pathogenesis of COVID-19. Several studies and ongoing clinical trials have been investigating the anti-inflammatory, immunomodulatory, and reparative effects of exosomes derived from mesenchymal stem/stromal cells for COVID-19-related acute lung injury. Other studies reported that exosomes play a key role in convalescent plasma therapy for COVID-19, and that they could be of use for the treatment of COVID-19 Kawasaki's-like multisystem inflammatory syndrome and as drug delivery nanocarriers for antiviral therapy. Harnessing some advantageous aspects of exosome biology, such as their endogenous origin, capability of crossing biological barriers, high stability in circulation, and low toxicity and immunogenicity, several companies have been testing exosome-based vaccines against SARS-CoV-2. As they carry cargos that mimic the status of parent cells, exosomes can be isolated from a variety of sources, including plasma, and employed as biomarkers of COVID-19. Lastly, there is growing evidence supporting the role of exosomes in COVID-19 infection, spread, reactivation, and reinfection. The lessons learned using exosomes for COVID-19 will help determine their efficacy and applicability in other clinical conditions.

First national survey on opioids prescribing practices of Canadian pediatric surgeons.

PURPOSE: Prescription opioid misuse has become a public health concern globally. In Canada, little is known about the national prescription patterns in children. The purpose of the present study was to evaluate the opioid prescribing practices of pediatric surgeons in Canada. METHODS: Following ethical approval, an electronic questionnaire was administered to all pediatric surgeons currently practicing in Canada. Questions included surgeon practice information, patterns of opioid prescription at discharge based on the type of surgery, type of opioid prescribed, and availability of training for surgeons/families. RESULTS: Fifty-eight questionnaires were completed (response rate: 84%) by surgeons from 8 out of 8 Canadian provinces with pediatric surgery coverage. 33% of responders prescribed opioids (most commonly morphine) for day surgeries and 73% of Pediatric Surgeons prescribed opioids for major surgeries. Most responders (84%) declared that at their institution there was no formal training for residents/fellows in pain control and opioid prescribing. Similarly, 57% reported no education for families about opioids at discharge. CONCLUSION: This first national survey on opioid prescribing practices across Canada reveals that opioids were prescribed to pediatric patients following a broad range of minor and major surgical procedures. Moreover, there seems to be a lack of education for surgeons and families about opioid use. TYPE OF STUDY: Descriptive, cross-sectional, practice survey. LEVEL OF EVIDENCE: Level 5.

Activation of Wnt signaling by amniotic fluid stem cell-derived extracellular vesicles attenuates intestinal injury in experimental necrotizing enterocolitis.

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

First Population-Based Report of Infants with Congenital Diaphragmatic Hernia: 30-Day Outcomes from the American College of Surgeons National Quality Improvement Program.

AIM: The American College of Surgeons has developed a registry, the National Quality Improvement Program Pediatric (NSQIP-P), that provides participating centers with high-quality surgical outcome data for children. Herein, we aimed to analyze for the first time the short-term outcomes of live-born infants with congenital diaphragmatic hernia (CDH) registered on this large North American database. METHODS: During 2015 to 2016, up to 101 participating centers uploaded 95 perioperative data points on the NSQIP-P database for patients that underwent surgical repair of CDH. The demographics, peri-, and post-operative data (up to 30 days following surgical repair) of infants with CDH were reviewed. Binary logistic regression was performed to test associations between risk factors and mortality. MAIN RESULTS: There were 432 (61% male) infants, who underwent CDH surgical repair during the study period. The prematurity rate (gestational age < 37 weeks) was 17%. The majority of infants (82%) had cardiac risk factors identified (72% were reported as major/severe). Extracorporeal membrane oxygenation (ECMO) was employed in 13% of patients prior to surgery. The majority of infants (83%) were ventilated preoperatively, and 34% received inotropes. Median age at surgery was 5 (0-74) days. CDH repair was attempted via thoracoscopy in 18% (n = 79) infants, but with a high rate of conversion to open surgery (n = 32, 41%). The postoperative 30-day mortality rate was 9%. At binary logistic regression, major cardiac risk factors (odds ratio [OR], 1.7 [0.9-3.2], p = 0.095), Appearance, Pulse, Grimace, Activity, and Respiration at 1 minute (OR, 0.7 per unit [0.5-0.8], p < 0.005), and birth weight (OR, 0.5 per kg [0.2-1.0], p < 0.05) were retained in the final model as significantly associated with mortality. CONCLUSION: This is the first report on CDH outcomes from the NSQIP-P database. Utilization of ECMO was low compared with single-center studies from North America. The early postoperative mortality rate of babies with CDH considered suitable for surgery remains high.

Impaired Wnt/ß-catenin pathway leads to dysfunction of intestinal regeneration during necrotizing enterocolitis.

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

Open Versus Laparoscopic Approach for Morgagni's Hernia in Infants and Children: A Systematic Review and Meta-Analysis.

INTRODUCTION: The laparoscopic repair of Morgagni's hernia (MH) has been reported to be safe and feasible. However, it is still unclear whether laparoscopy is superior to open surgery in repairing MH. MATERIALS AND METHODS: Using a defined search strategy, three investigators independently identified all comparative studies reporting data on open and laparoscopic MH repair in patients <18 years of age. Case reports and opinion articles were excluded. Meta-analysis was conducted according to PRISMA guidelines and using RevMan 5.3. Data are expressed as mean ± SD. RESULTS: Systematic review - Of 774 titles/abstracts screened, 51 full-text articles were analyzed. Three studies were included (92 patients), with 53 (58%) open approaches and 39 (42%) laparoscopy. Meta-analysis - The length of surgery was shorter in laparoscopy (50.5 ± 17.0 min) than in open procedure (90.0 ± 15.0 min; P < .00001). Laparoscopy shortened the length of hospital stay (2.1 ± 1.4 days) versus open surgery (4.5 ± 2.1 days; P < .00001). There was no difference with regards to complications (laparoscopy: 8.8% ± 5.5%, open: 9.4% ± 1.6%; P = .087) and recurrences (laparoscopy: 2.9% ± 5.0%, open: 5.7% ± 1.8%; P = .84). DISCUSSION: Comparative studies indicate that laparoscopic MH repair can be performed in infants and children. Laparoscopy is associated with shortened length of surgery and hospital stay in comparison to open procedure. Prospective randomized studies would be needed to confirm present data.

A critical review of recent clinical practice guidelines on management of cryptorchidism.

BACKGROUND/PURPOSE: Limited efforts have been made in assessing the qualities of clinical practice guidelines (CPGs) on cryptorchidism (UDT). This appraisal aims to determine the quality of recent CPGs on the management of UDT. METHODS: After systematic literature search, all English-based CPGs providing recommendations for the management of UDT from 2012 to 2017 were reviewed. Using the AGREE II (Appraisal of Guidelines and Research Evaluation) instrument, eligible CPGs were independently appraised by 5 reviewers. Domain scores were calculated and summarized. Intraclass coefficient (ICC) was used to assess for interrater reliability. RESULTS: Five CPGs from Agency for Healthcare Research and Quality (AHRQ), American Urological Association (AUA), British Association of Pediatric Surgeons/British Association of Urologic Surgeons (BAPS/BAUS), Canadian Urological Association (CUA), and European Association of Urology/European Society for Pediatric Urology (EAU/ESPU) were assessed. There was a solid agreement (ICC: 0.749) among the 5 reviewers (p<0.001). Most recommendations for diagnostic and treatment approaches were consistent across CPGs. For most guidelines, the domains of 'clarity of presentation,' 'scope and purpose,' 'stakeholder involvement,' and 'rigor of development' were high, while 'applicability' was low. CONCLUSION: Most guidelines on UDT score high in the AGREE II domains and have consistent recommendations. To improve the 'applicability' domain, future guidelines should improve on aspects that facilitate implementation of the recommendations. TYPE OF STUDY: Systematic review. LEVEL OF EVIDENCE: V (based on the lowest level of evidence utilized by the assessed guidelines).

Pentalogy of Cantrell: Is Echocardiography Sufficient in the Neonatal Period?

Pentalogy of Cantrell is a rare syndrome that is characterized by varying degrees of midline wall defects and congenital cardiac anomalies. A left ventricular diverticulum (LVD) is defined as partial ectopia cordis, can be part of the pentalogy of Cantrell, and can put the patient at risk of severe complications. Early diagnosis and ligation/resection of the LVD is important to prevent complications. We report on a case of pentalogy of Cantrell, in which a LVD was diagnosed only at 2 months of age despite preceding pre- and postnatal echocardiography. We conclude that in the suspicion of pentalogy of Cantrell, either complete or incomplete, cardiac magnetic resonance imaging should be performed, when possible, to avoid the potential complication of a herniating ventricular diverticulum.