Background: Endoscopic retrograde cholangiopancreatography (ERCP) is increasingly utilized for management of biliary disorders in children and adolescents. Practice patterns surrounding cholangioscopy in pediatric patients, however, are largely uncharacterized. Methods: We retrospectively analyzed all ERCPs in which cholangioscopy was performed on patients 18 and under at our tertiary care children’s hospital from 2015 to 2020 using our institution’s paper and electronic medical record system. Patient demographics, procedure indications, interventions, and associated adverse events were analyzed. Results: Over the study period, 307 ERCPs were performed on 282 patients at our children’s hospital. Cholangioscopy was performed in 36 procedures (11.7%) using the SpyGlass cholangioscope (Boston Scientific). Antibiotics to cover biliary organisms were administered to all patients precholangioscopy. Mean patient age was 13.6 years (range 7–18 years). The 2 most common indications for cholangioscopy included electrohydraulic lithotripsy for biliary stone disease and evaluation of biliary stricture (with incidental finding of biliary web in 2 patients and retained suture material in 2 patients). Adverse events were less prevalent in patients who underwent cholangioscopy relative to those who underwent ERCP. 0/36 (0%) developed post-ERCP pancreatitis, one patient had self-limited melena (possible self-limited postsphincterotomy bleeding). Patient care was enhanced by cholangioscopy in 30/36 (83.3%) of these patients. Conclusions: These data attest to the safety and clinical utility of cholangioscopy in children and adolescents. Cholangioscopy was performed in just over 11% of pediatric patients who underwent ERCP at our academic medical center—rates similar to those reported in adult patients. The radiation-sparing nature of cholangioscopy, coupled with these data supporting its safety, make it particularly appealing for use in children. Further multi-institution evaluation of the utility, safety, and range of indications for cholangioscopy in other practice settings would be of great interest and help guide endoscopic care.

Objectives To analyze outcome and utilization trends over time of pediatric endoscopic retrograde cholangiopancreatography (ERCP) in an all-capture US population-level study. Study design Using the National Inpatient Sample (2005-2014) and National Readmission Database (2010-2014), we identified pediatric (age <20 years) hospitalizations during which ERCP was performed and assessed ERCP-associated readmissions. International Classification of Diseases, Ninth Revision, Clinical Modification codes were used to identify hospitalization diagnoses, comorbidities, and patient/hospital characteristics. Multivariate logistic regression analyses were performed to determine significant predictors (P < .05) of 30-day readmission. Results A total of 11 060 hospitalized pediatric patients underwent ERCP between 2005 and 2014. Most were female (n = 8859; 81%), aged 14-20 years (n = 9342; 84%), and white (n = 4230; 45%). Most (85%) of ERCPs were therapeutic, and leading indications were biliary (n = 5350; 48%) and pancreatitis (n = 3218; 29%). Thirteen pecent of patients were readmitted post-ERCP. Odds for 30-day readmission were highest for patients with a history of liver transplantation, age 0-4 years, male sex, and obesity (P < .001 for each). Patients in both urban teaching and urban hospitals had much lower odds than those in rural hospitals for prolonged length of stay associated with ERCP. Conclusions These data represent a comprehensive study of nationwide trends in age-specific volumes and outcomes following ERCP in the pediatric population and provide important insights into trends in pediatric pancreaticobiliary disease management, as well as practice setting, patient characteristics, and patient comorbidities associated with pediatric post-ERCP outcomes, including readmission and length of stay.

Direct-acting antivirals (DAAs) have revolutionized hepatitis C virus (HCV) infection treatment with high efficacy rates in adults and in children older than 3 years old. Data on using DAAs in pediatrics are limited. We present the youngest infant reported to receive DAAs, who cleared her HCV infection on DAAs before a successful liver transplant (LT) for carbamoyl phosphate synthetase 1 (CPS-1) deficiency and achieved sustained virologic resistance (SVR) 12 weeks post-LT. CASE REPORT Our patient presented with a hyperammonemic crisis after birth. Genetic testing confirmed CPS-1 deficiency. The genetics team referred her for an LT evaluation due to metabolic crises and long-term neurocognitive deficits risk. Her mother had chronic HCV. During the transplant evaluation, we noted a persistent elevation in alanine aminotransferase and aspartate aminotransferase levels with preserved synthetic function (Fig. 1). She was found to be HCV antibody positive with HCV ribonucleic acid (RNA) polymerase chain reaction (PCR) at 289,000 IU/mL (normal range: undetectable) (Fig. 1). She had HCV genotype (GT) 3 with negative hepatitis B and human immunodeficiency virus testing. A multidisciplinary team agreed to list her for LT due to repeated metabolic crises and to treat her HCV infection before LT. Informed consent was obtained.FIGURE 1: Trend of hemoglobin, viral load, and liver enzymes with timeline events. ALT = alanine aminotransferase; AST = aspartate aminotransferase; HCV = hepatitis C virus; PCR = polymerase chain reaction.She started DAAs when she was 8 months old and 9.1 kg. A combination of daclatasvir (DCV) 30 mg daily, sofosbuvir (SOF) 200 mg daily, and ribavirin (RBV) 15 mg · kg−1 · day−1 divided into 2 doses was approved by the insurance company for off-label use. DCV was lowered to 15 mg daily based on pharmacokinetic modeling data (Table 1) (1). She was monitored for safety with weekly complete blood counts and biochemical profiles in the first 4 weeks of treatment. There was an increase in her hemoglobin immediately post-LT due to a transfusion requirement during transplant (Fig. 1). She tolerated the medications without side effects and no dose reduction of RBV. TABLE 1 - Pharmacokinetics of simulated daclatasvir (DCF) single dosing of 30 and 60 mg in pediatric patients, ages 9 to 12 months old (1) DCF single dosage amount 30 mg 60 mg Geometric mean C max 4785 ng/mL 9759 ng/mL Geometric mean area under curve (AUC) 45,804 ng/mLXhour 96,085 ng/mLXhour HCV eradication was delayed with undetectable HCV RNA PCR level at week 9 of therapy. She underwent an LT on week 17 of therapy. DAAs were held for 5 days postoperatively due to ileus then resumed. She received basiliximab, high-dose steroids, and tacrolimus for post-LT immunosuppression. She completed treatment 4 weeks after LT for a total of 21 weeks of treatment. She continued with negative HCV RNA PCR 12 weeks after the completion of therapy (SVR 12). Aspartate aminotransferase and alanine aminotransferase have remained normal post-SVR (Fig. 1). DISCUSSION Five million children have HCV infection mainly due to maternal transmission with 25% to 50% of these infants having spontaneous clearance by the age of 3 years (2). Our patient had GT3 acquired through vertical transmission and this genotype is associated with more severe complications (3). SOF-RBV therapy is the only treatment recommended for GT3 in children older than 12 years. The current recommendations are to hold treatment for children younger than 12 years unless persistent transaminitis or significant fibrosis is present (2). Children who undergo LT for HCV infection have higher rates of graft failure, cirrhosis, and mortality (4). Treatment of HCV infection pre-LT is preferred due to the complications seen in adults treating post-LT: drug interactions, increased recurrence rate, and lower efficacy rates (5). Due to the urgency of the LT to prevent future metabolic crises in CPS-1 deficiency and the poorer outcomes associated with HCV infection post-LT, our multidisciplinary team determined treatment to clear HCV infection before LT would provide the best potential outcome for this patient compared to treatment after LT or postponement of LT until HCV eradication, either spontaneous or with treatment. In ongoing trials in children 3 to 17 years old, DAAs have demonstrated high efficacy and a good safety profile (6,7). Before our case, the youngest patient to receive DAAs was a 1-year-old with biliary atresia and HCV infection GT type 1b treated with SOF/ledipasvir/RBV for 5 weeks pre-LT and 7 weeks post-LT successfully. DAAs were also effective in a 4-year-old after stem cell transplant (8). The combination of daclatasvir (DCF)/SOF/RBV was chosen due to their approval from the FDA for > 18 years of age and availability in dosage forms appropriate for our patient's weight with high efficacy for GT3 (2). Other fixed dose combinations were considered but were less efficacious for GT3 or could not be adjusted for weight. Due to the urgency of the LT with possible adverse neurologic sequelae, our patient could not wait for enrollment into an investigational drug trial. Although our patient tested negative for DCV resistance, we elected to include RBV to maximize treatment efficacy due to the lack of salvage treatment options. The dosing regimen was based on studies in children <17 kg at 3 to 12 years of age with HCV infection GT2 and 3. Our patient received 200 mg of SOF based on the recommendations of the manufacturer and the convenience of splitting the readily available 400 mg tablet. Our patient was started on DCV 30 mg orally daily because it was the lowest dosage strength available. DCV was lowered to 15 mg oral daily based on pharmacokinetic modeling data (1). The RBV dosing of 15 mg · kg−1 · day−1 divided twice daily is based on ongoing studies with children ages 3 to 12 years old (6). Given the limited data with treatment in infants, therapy was continued for a total of 21 weeks until the authorization of DAAs ended. We chose to continue DCF/SOF/RBV post-LT despite the potential for drug interactions to maximize the opportunity for SVR. DAAs can be a safe, effective treatment option for children younger than 3 years old with HCV infection or children with a metabolic condition before and after LT. Further data are necessary to generalize these results. We acknowledge spontaneous clearance in our patient is possible. Hopefully, future therapies will be available without RBV. DAAs should be considered a treatment option for young infants and children, particularly in cases where viral clearance offers improved outcomes.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a fatal disorder characterized by progressive gastrointestinal dysmotility, peripheral neuropathy, leukoencephalopathy, skeletal myopathy, ophthalmoparesis, and ptosis. MNGIE stems from deficient thymidine phosphorylase activity (TP) leading to toxic elevations of plasma thymidine. Hematopoietic stem cell transplant (HSCT) restores TP activity and halts disease progression but has high transplant-related morbidity and mortality. Liver transplant (LT) was reported to restore TP activity in two adult MNGIE patients. We report successful LT in four additional MNGIE patients, including a pediatric patient. Our patients were diagnosed between ages 14 months and 36 years with elevated thymidine levels and biallelic pathogenic variants in TYMP. Two patients presented with progressive gastrointestinal dysmotility, and three demonstrated progressive peripheral neuropathy with two suffering limitations in ambulation. Two patients, including the child, had liver dysfunction and cirrhosis. Following LT, thymidine levels nearly normalized in all four patients and remained low for the duration of follow-up. Disease symptoms stabilized in all patients, with some manifesting improvements, including intestinal function. No patient died, and LT appeared to have a more favorable safety profile than HSCT, especially when liver disease is present. Follow-up studies will need to document the long-term impact of this new approach on disease outcome. Take Home Message: Liver transplantation is effective in stabilizing symptoms and nearly normalizing thymidine levels in patients with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) and may have an improved safety profile over hematopoietic stem cell transplant.

Background: Endoscopic retrograde cholangiopancreatography (ERCP) is a fluoroscopy and endoscopy-based procedure important for diagnosis and management of pediatric pancreaticobiliary disorders. Patient, procedure, endoscopist, and facility characteristics have been shown to influence ERCP complexity and procedure outcomes as well as fluoroscopy utilization in adults; however, the extent to which this is true in pediatric patients remains under-studied and there are minimal data regarding fluoroscopy utilization in pediatric ERCP. Methods: We retrospectively analyzed ERCPs performed on patients <18 years of age at our tertiary care children's hospital from 2002 to 2017 using our institution's paper and electronic medical record system along with a prospectively maintained radiation exposure database. Procedure complexity was graded using the Stanford Fluoroscopy Complexity Score and the American Society of Gastrointestinal Endoscopy Complexity scale. High-volume endoscopists (HVE) were defined as having a cumulative annual ERCP volume >100 and low-volume endoscopists (LVE) as <100 (pediatric + adult) ERCPs/year. Results: Three hundred eighty-five ERCPs performed on 321 patients were included in this analysis. The mean patient age was 13.4 years (+/- 4.2 years), 77% were index ERCPs (native ampullas), and 81% were performed with therapeutic intent (87% for biliary indication and 13% for pancreatic indication). Fluoroscopy times (FTs) varied between procedures and providers. Median FT was 4.85 (+/- 2.68) minutes. Endoscopist annual ERCP volume was the strongest predictor of FT (P < 0.001). In addition to endoscopist volume, procedure-specific predictors of increased FT included pancreatic indication for the procedure, biliary or pancreatic duct stricture, patient age 16 years at the time of ERCP (P < 0.01 for each), and native ampulla. ERCP complexity rating based on the Stanford Fluoroscopy Complexity Score correlated with FT. Conclusions: Radiation exposure is higher than desirable for pediatric ERCP and varies with endoscopist as well as patient and procedure-specific factors. HVE perform ERCP with lower FT relative to LVE even though HVE procedure complexity was higher. The Stanford Fluoroscopy Score predicted FT for pediatric ERCP, but the ASGE ERCP complexity scale did not. Adaptation and refinement of pediatric-specific ERCP complexity scales including factors, such as patient size and age and indications/interventions more consistent with those encountered in pediatrics could be beneficial.

Abstract Background Oral vancomycin (OV) in primary sclerosing cholangitis (PSC) has been evaluated as a potential therapeutic agent. We report the long-term biochemical course and outcomes of patients with PSC treated with OV. Methods Patients were enrolled in 2 open-label clinical trials (ClinicalTrials.gov Identifier: NCT01802073 and NCT01322386) and offered OV at 50 mg/kg/day in 3 divided doses if weight <30kg, and 500 mg 3 times/day if weight ≥30kg. Patients with biliary strictures requiring stenting or awaiting liver transplant were excluded. Liver biochemistry, MRCP and histology were documented at baseline and while on OV. The primary outcome was a decrease in elevated gamma glutamyl transferase (GGT), alkaline phosphatase (ALP), and/or alanine aminotransferase (ALT) from baseline. Results 30 subjects were enrolled, and 29 additional subjects who learned of the clinical trial requested OV (total n = 59; median age was 13.5 years [range, 1.5–44 years]; 64.4% were male; and 94.9% had inflammatory bowel disease [IBD]). The median treatment duration was 2.7 years (range, 0.2–14 years). Ninety-six percent (57/59), 81.3% (48/59), and 94.9% (56/59) experienced reduction of GGT, ALP, and ALT, respectively. Furthermore, 39% (23/59), 22% (13/59), and 55.9% (33/59) experienced normalization of GGT, ALP, and ALT, respectively, within the first 6 months of OV treatment. One patient underwent liver transplantation 8 years after beginning OV treatment, and one developed biliary strictures requiring endoscopic intervention. OV was well-tolerated by patients, and no patient developed treatment-related adverse events. Conclusion In PSC, OV was well-tolerated and was associated with improvement in liver chemistry. A randomized placebo-controlled clinical trial is warranted.

Background and Aims: Endoscopic procedures are important for diagnosis and management of many gastrointestinal, liver, and biliary conditions in children. Therapeutic endoscopy procedures, including endoscopic retrograde cholangiopancreatography (ERCP), are performed less frequently in children relative to adults. A formal study to evaluate institutional volumes and practice patterns for advanced therapeutic pediatric endoscopy procedures has, however, not been previously undertaken. Methods: A self-administered 16-question (5-minute) online survey assessing practice patterns for performance of pediatric endoscopy procedures was distributed to all registered North American Society for Pediatric Gastroenterology, Hepatology and Nutrition programs. Results were analyzed using descriptive statistics and thematic analysis of free-text comments. Results: Respondents from 82.9% of North American Society for Pediatric Gastroenterology, Hepatology and Nutrition centers completed this survey. Responses revealed that esophagogastroduodenoscopy/colonoscopy are performed at the vast majority of centers (>90%), with most performing >50/year. Therapeutic endoscopy procedures are performed less frequently in the pediatric population, with 18.97% reporting that ERCP is not performed at their institution. Where ERCP is performed, 91.38% reported <25/year. Endoscopic ultrasound is not performed at more than half (53.33%) of institutions. Approximately 71.67% of respondents do not believe their institution's current arrangement for performing pediatric therapeutic endoscopy procedures is adequate. Conclusions: Although the range of endoscopic procedures performed in children parallels that performed in adults, there are notable differences in pediatric and adult gastroenterologists' endoscopy training and procedure volumes. Our results and respondent comments suggest that pediatric patients would benefit from a partnership between pediatric and adult gastroenterologists, with adult gastroenterologists performing more complex therapeutic endoscopic procedures.

Esophageal atresia (EA) with tracheoesophageal fistula (TEF) is a rare congenital malformation with a “blind-ending” esophageal pouch and aberrant connection between the airway and esophagus. The incidence of EA-TEF is reportedly 1 in 2500 to 4000 live births (1). Prenatal diagnosis of EA-TEF is rare, but the condition is usually symptomatic within the first hours of life. Repair of EA-TEFs often occurs in the first 24 to 48 hours of life, once the infant is stable and associated malformations have been excluded. Survival rates in patients who undergo repair is between 85% and 95%, with reported in-hospital mortality rate of 5.4% (2). There are multiple short- and long-term complications after EA-TEF repair, including anastomotic leak, gastroesophageal reflux (GER), trachomalacia, esophageal motility dysfunction, and anastomotic stricture (incidence of 8%–59%) (3). Complications from poorly managed or undiagnosed GER and esophagitis can also lead to strictures. The standard of care for managing esophageal strictures is dilation, classically through fluoroscopic-guided balloon dilation. Strictures tend to recur and require serial dilations. In 2010, Serhal et al (4) published a 5-year review of 62 children who had undergone EA-TEF repair; 37% of patients developed anastomotic strictures, most within the first year of life (mean age, 149 days). Strictures in this group resolved after an average of 3.2 dilations per patient. Advances in recent years have expanded the options for evaluating and treating esophageal strictures. We present the first reported case of balloon dilation of TEF-related stricture in a child without the use of fluoroscopy, utilizing the Esophageal Treatment Functional Lumen Imaging Probe (EsoFLIP). CASE REPORT Presentation Our patient is an 8-year-old boy born with proximal EA and a distal TEF, or type C EA-TEF, who underwent repair in infancy. His postoperative course was complicated by multiple esophageal anastomotic strictures, recurrent pneumonia, and eosinophilic esophagitis. He had 6 previous dilations of esophageal strictures because of dysphagia. On presentation, he had developed recurrent dysphagia to solid food, weight loss, and cough. He underwent an esophagram at an outside facility 2 months prior that showed a mid-esophageal stricture (6 mm diameter) with proximal esophageal distention. Technology Endoluminal Functional Lumen Imaging Probe (EndoFLIP; Crospon, Galway, Ireland) is a novel device for endoscopic evaluation of gastrointestinal strictures. The esophageal-treatment iteration of this device, EsoFLIP, has both diagnostic and therapeutic capabilities. Using electrode arrays, voltage measurements are used to calculate impedance along the catheter and derive precise cross-sectional areas (CSA) and diameters (5). EsoFLIP takes measurements every 5 mm along the length of the 8 cm catheter, and can also dilate strictures with real-time feedback of the luminal diameter. EndoFLIP has been safely used in adults with GER, dysphagia, eosinophilic esophagitis, and those undergoing per-oral endoscopic myotomy (POEM) (6). EsoFLIP has recently been shown feasible for adults with achalasia, allowing for safe dilation without the use of fluoroscopy (7). In pediatrics, the system has had limited use, partly because of the novelty of advanced endoscopic surgeries within this population (8). The diagnostic features of the EndoFLIP catheter have been used to measure the diameter and CSA of the gastroesophageal junction following POEM for achalasia (9). To date, there is no published data on EsoFLIP use for therapeutic dilation of esophageal strictures in pediatric patients. Procedure The procedure was performed under general anesthesia after obtaining informed consent. Initial endoscopy revealed an esophageal stricture beginning at the anastomosis, 20 cm from the incisors. The scope was passed through the stricture, revealing evidence of mild distal mucosal inflammation consistent with GER as a contributing factor in the stricture. A 20-mL dilating EsoFLIP was then delivered into the esophagus alongside the endoscope. Under direct visualization, the EsoFLIP was placed across the stricture. Diagnostic measurements were obtained. The stricture measured 2.5 cm in length; minimum diameter of 9.7 mm. Using the dilating function of the EsoFLIP, the balloon was initially dilated to 11 mm, and then to 12.2 mm (Fig. 1). The balloon was maintained at that volume for 1 minute, allowing for additional stretching of the esophagus. Postdilation endoscopy showed no evidence of bleeding. A contrast esophagram was performed after the dilation procedure; there was no evidence of perforation. The patient tolerated the procedure well and was discharged on the same day. He showed improvement in his dysphagia by 2 weeks, and complete resolution of his dysphagia and food intolerance at 3 months.FIGURE 1: Impedance-based measurements of esophageal diameter with pre- (left) and post-dilation (right) measurements. Stricture dilated from minimal diameter of 9.7 to 12.2 mm.DISCUSSION The EsoFLIP system provides several benefits that are particularly promising for pediatric patients with strictures. The system provides precise measurements of pre- and post-dilation CSA and diameter. Although the pre-dilation esophagram 2 months prior demonstrated a 6-mm stricture, the EsoFLIP enables more precise measurements by dynamically filling the lumen in real time. The added information can potentially help to standardize dilations and improve care. The most significant narrowing from this stricture was encountered just past the anastomosis, and was likely exacerbated by reflux. Although dysphagia and motility issues are common in patients after TEF-repair even without strictures, the symptomatic improvement in our patient after dilation argues that the stricture was contributing to his dysphagia. The impedance technology can significantly reduce the radiation exposure in pediatric patients, who often require multiple dilations to resolve strictures. Though there was an on-table esophagram performed at the end of this case, there was no radiation exposure during the dilation. A chest radiograph done after the procedure could be of equivalent clinical value for ruling out perforation. There is a growing body of evidence describing the correlation between childhood radiation exposure from diagnostic medical imaging and subsequent cancers (10). This technology can drastically reduce radiation risk in a population who is at high risk for repeat radiation exposure. CONCLUSIONS Surgical repair of AE-TEF can cause numerous long-term complications, including benign esophageal strictures secondary to anastomotic narrowing, GER, and esophagitis. EndoFLIP technology has been used in pediatric patients for diagnosis of strictures previously; however, this is the first report of a therapeutic dilation of an esophageal stricture after TEF-repair. The precision dilation without radiation exposure has the potential to improve the standard of care of pediatric patients. As training in and experience with advanced endoscopic surgery increases within the pediatric surgery community, FLIP technology can provide additional quality and safety in patient care.

Purpose of study: Patients with neonatal urea cycle defects (UCDs) typically experience severe hyperammonemia during the first days of life, which results in serious neurological injury or death. Long-term prognosis despite optimal pharmacological and dietary therapy is still poor. The combination of intravenous sodium phenylacetate and sodium benzoate (Ammonul (R)) can eliminate nitrogen waste independent of the urea cycle. We report attempts to improve outcomes for males with severe ornithine transcarbamylase deficiency (OTCD), a severe X-linked condition, via prenatal intravenous administration of Ammonul and arginine to heterozygous carrier females of OTCD during labor. Methods used: Two heterozygote OTCD mothers carrying male fetuses with a prenatal diagnosis of OTCD received intravenous Ammonul, arginine and dextrose-containing fluids shortly before birth. Maintenance Ammonul and arginine infusions and high-caloric enteral nutrition were started immediately after birth. Ammonul metabolites were measured in umbilical cord blood and the blood of the newborn immediately after delivery. Serial ammonia and biochemical analyses were performed following delivery. Summary of results: Therapeutic concentrations of Ammonul metabolites were detected in umbilical cord and neonatal blood samples. Plasma ammonia and glutamine levels in the postnatal period were within the normal range. Peak ammonia levels in the first 24-48 h were 53 mcmol/l and 62 mcmol/l respectively. The boys did not experience neurological sequelae secondary to hyperammonemia and received liver transplantation at ages 3 months and 5 months. The patients show normal development at ages 7 and 3 years. Conclusion: Prenatal treatment of mothers who harbor severe OTCD mutations and carry affected male fetuses with intravenous Ammonul and arginine, followed by immediate institution of maintenance infusions after delivery, results in therapeutic levels of benzoate and phenylacetate in the newborn at delivery and, in conjunction with high-caloric enteral nutrition, prevents acute hyperammonemia and neurological decompensation. Following initial medical management, early liver transplantation may improve developmental outcome.

Background: Achalasia is a primary esophageal motility disorder characterized by aperistalsis of the esophagus and failed relaxation of the lower esophageal sphincter that presents rarely in childhood. The peroral endoscopic myotomy (POEM) procedure is an emerging treatment for achalasia in adults that has recently been introduced into pediatric surgical practice. Methods: This is a prospective case series of all children referred to Stanford University Lucile Packard Children's Hospital with manometry-confirmed achalasia who underwent a POEM procedure from 2014 to 2016. Results: We enrolled 10 subjects ranging in age from 7 to 17 years (M = 13.4). The mean pre- and 1-month post-procedure Eckardt scores were 7 (SD = 2.5) and 2.4 (SD = 2) (p <0.001), respectively. The median procedure time for the entire cohort was 142 min (range 60-259 min) with ongoing improvement with increased experience (R-2 = 0.6, p = 0.008). There were no major adverse events. Conclusion: The POEM procedure can be successfully completed in children for the treatment of achalasia with demonstrated short-term post-operative improvement in symptoms. The adoption of advanced endoscopic techniques by pediatric surgeons may enable development of unique intraluminal approaches to congenital anomalies and other childhood diseases. (C) 2017 Elsevier Inc. All rights reserved.

Neonatal cholestasis is a potentially life-threatening condition requiring prompt diagnosis. Mutations in several different genes can cause progressive familial intrahepatic cholestasis, but known genes cannot account for all familial cases. Here we report four individuals from two unrelated families with neonatal cholestasis and mutations in NR1H4, which encodes the farnesoid X receptor (FXR), a bile acid-activated nuclear hormone receptor that regulates bile acid metabolism. Clinical features of severe, persistent NR1H4-related cholestasis include neonatal onset with rapid progression to end-stage liver disease, vitamin K-independent coagulopathy, low-to-normal serum gamma-glutamyl transferase activity, elevated serum alpha-fetoprotein and undetectable liver bile salt export pump (ABCB11) expression. Our findings demonstrate a pivotal function for FXR in bile acid homeostasis and liver protection.

Long-term IS in transplant patients has significant morbidity, poorer quality of life, and substantial economic costs. TOL, defined as graft acceptance without functional impairment in the absence of IS, has been achieved in some pediatric LT recipients. Using mass cytometry, peripheral blood immunotyping was performed to characterize differences between tolerant patients and patients who are stable on single-agent IS. Single-cell mass cytometry was performed using blood samples from a single-center pediatric LT population of operationally tolerant patients to comprehensively characterize the immune cell populations in the tolerant state compared with patients on chronic low-dose IS. Specific T-cell populations of interest were confirmed by flow cytometry. This high-dimensional phenotypic analysis revealed distinct immunoprofiles between transplant populations as well as a CD4+ TOT (CD4+ CD5+ CD25+ CD38-/lo CD45RA) that correlates with tolerance in pediatric LT recipients. In TOL patients, the TOT was significantly increased as compared to patients stable on low levels of IS. This TOT cell was confirmed by flow cytometry and is distinct from classic Treg cells. These results demonstrate the power of mass cytometry to discover significant immune cell signatures that have diagnostic potential.

Blood ammonia and glutamine levels are used as biomarkers of control in patients with urea cycle disorders (UCDs). This study was undertaken to evaluate glutamine variability and utility as a predictor of hyperammonemic crises (HACs) in UCD patients.Methods: The relationships between glutamine and ammonia levels and the incidence and timing of HACs were evaluated in over 100 adult and pediatric UCD patients who participated in clinical trials of glycerol phenylbutyrate.Results: The median (range) intra-subject 24-hour coefficient of variation for glutamine was 15% (8-29%) as compared with 56% (28%-154%) for ammonia, and the correlation coefficient between glutamine and concurrent ammonia levels varied from 0.17 to 0.29. Patients with baseline (fasting) glutamine values >900 mu mol/L had higher baseline ammonia levels (mean [SD]: 39.6 [26.2] mu mol/L) than patients with baseline glutamine <= 900 mu mol/L (26.6 [18.0] mu mol/L). Glutamine values >900 prnol/L during the study were associated with an approximately 2-fold higher HAC risk (odds ratio [OR] = 1.98; p = 0.173). However, glutamine lost predictive significance (OR = 1.47; p = 0.439) when concomitant ammonia was taken into account, whereas the predictive value of baseline ammonia >= 1.0 upper limit of normal (ULN) was highly statistically significant (OR = 4.96; p = 0.013). There was no significant effect of glutamine >900 mu mol/L on time to first HAC crisis (hazard ratio [HR] = 1.14; p = 0.813), but there was a significant effect of baseline ammonia >= 1.0 ULN (HR = 4.62; p = 0.0011).Conclusions: The findings in this UCD population suggest that glutamine is a weaker predictor of HACs than ammonia and that the utility of the predictive value of glutamine will need to take into account concurrent ammonia levels. (C) 2015 The Authors. Published by Elsevier Inc.

BACKGROUND:Little prospectively collected data are available comparing the dietary intake of urea cycle disorder (UCD) patients to UCD treatment guidelines or to healthy individuals. OBJECTIVE:To examine the protein and calorie intakes of UCD subjects who participated in clinical trials of glycerol phenylbutyrate (GPB) and compare these data to published UCD dietary guidelines and nutritional surveys. DESIGN:Dietary data were recorded for 45 adult and 49 pediatric UCD subjects in metabolic control during participation in clinical trials of GPB. Protein and calorie intakes were compared to UCD treatment guidelines, average nutrient intakes of a healthy US population based on the National Health and Nutrition Examination Survey (NHANES) and Recommended Daily Allowances (RDA). RESULTS:In adults, mean protein intake was higher than UCD recommendations but lower than RDA and NHANES values, while calorie intake was lower than UCD recommendations, RDA and NHANES. In pediatric subjects, prescribed protein intake was higher than UCD guidelines, similar to RDA, and lower than NHANES data for all age groups, while calorie intake was at the lower end of the recommended UCD range and close to RDA and NHANES data. In pediatric subjects height, weight, and body mass index (BMI) Z-scores were within normal range (- 2 to 2). CONCLUSIONS:Pediatric patients treated with phenylbutyrate derivatives exhibited normal height and weight. Protein and calorie intakes in adult and pediatric UCD subjects differed from UCD dietary guidelines, suggesting that these guidelines may need to be reconsidered.

Background: Health care outcomes have been increasingly assessed through health-related quality of life (HRQoL) measures. While the introduction of nitrogen-scavenging medications has improved survival in patients with urea cycle disorders (UCDs), they are often associated with side effects that may affect patient compliance and outcomes.Methods: Symptoms commonly associated with nitrogen-scavenging medications were evaluated in 100 adult and pediatric participants using a non-validated UCD-specific questionnaire. Patients or their caregivers responded to a pre-defined list of symptoms known to be associated with the use of these medications. Responses were collected at baseline (while patients were receiving sodium phenylbutyrate [NaPBA]) and during treatment with glycerol phenylbutyrate (GPB).Results: After 3 months of GPB dosing, there were significant reductions in the proportion of patients with treatment-associated symptoms (69% vs. 46%; p < 0.0001), the number of symptoms per patient (2.5 vs. 1.1; p < 0.0001), and frequency of the more commonly reported individual symptoms such as body odor, abdominal pain, nausea, burning sensation in mouth, vomiting, and heartburn (p < 0.05). The reduction in symptoms was observed in both pediatric and adult patients. The presence or absence of symptoms or change in severity did not correlate with plasma ammonia levels or NaPBA dose.Conclusions: The reduction in symptoms following 3 months of open-label GPB dosing was similar in pediatric and adult patients and may be related to chemical structure and intrinsic characteristics of the product rather than its effect on ammonia control. (C) 2015 Elsevier Inc. All rights reserved.

BACKGROUND:In solid organ transplant patients, non-participation in all aspects of the medical regimen is a prevalent problem associated with adverse consequences particularly in the adolescent and young adult (AYA) age group. This study is the first to evaluate the feasibility, utility and impact of a text messaging (TM) intervention to improve participation in laboratory testing in adolescent liver transplant patients.METHODS:AYA patients, aged 12 to 21 years, were recruited for a prospective pilot trial evaluating a TM intervention delivered over a 1-year period. The intervention involved automated TM reminders with feedback administered according to a prescribed laboratory testing frequency. Participation rate in laboratory testing after the intervention was compared to the year prior. Patient responses and feedback by text and survey were used to assess feasibility, acceptability and use of the intervention.RESULTS:Forty-two patients were recruited and 33 patients remained enrolled for the study duration. Recipients of the TM intervention demonstrated a significant improvement in participation rate in laboratory testing from 58% to 78% (P<.001). This rate was also significantly higher than in non-intervention controls (P=.003). There was a high acceptability, response rate and a significant correlation with reported versus actual completion of laboratory tests by TM.CONCLUSIONS:TM reminders significantly improved participation in laboratory testing in AYA liver transplant patients. The intervention demonstrated feasibility, acceptability, and use with a high proportion of patients who engaged in and perceived a benefit from using this technology.