Direct thrombin inhibitors fail to reverse the negative effects of heparin on lung growth and function after murine left pneumonectomy.

Neonates with congenital diaphragmatic hernia (CDH) frequently require cardiopulmonary bypass and systemic anticoagulation. We previously demonstrated that even subtherapeutic heparin impairs lung growth and function in a murine model of compensatory lung growth (CLG). The direct thrombin inhibitors (DTIs) bivalirudin and argatroban preserved growth in this model. Although DTIs are increasingly used for systemic anticoagulation clinically, patients with CDH may still receive heparin. In this experiment, lung endothelial cell proliferation was assessed following treatment with heparin-alone or mixed with increasing concentrations of bivalirudin or argatroban. The effects of subtherapeutic heparin with or without DTIs in the CLG model were also investigated. C57BL/6J mice underwent left pneumonectomy and subcutaneous implantation of osmotic pumps. Pumps were preloaded with normal saline, bivalirudin, or argatroban; treated animals received daily intraperitoneal low-dose heparin. In vitro, heparin-alone decreased endothelial cell proliferation and increased apoptosis. The effect of heparin on proliferation, but not apoptosis, was reversed by the addition of bivalirudin and argatroban. In vivo, low-dose heparin decreased lung volume compared with saline-treated controls. All three groups that received heparin demonstrated decreased lung function on pulmonary function testing and impaired exercise performance on treadmill tolerance testing. These findings correlated with decreases in alveolarization, vascularization, angiogenic signaling, and gene expression in the heparin-exposed groups. Together, these data suggest that bivalirudin and argatroban fail to reverse the inhibitory effects of subtherapeutic heparin on lung growth and function. Clinical studies on the impact of low-dose heparin with DTIs on CDH outcomes are warranted.NEW & NOTEWORTHY Infants with pulmonary hypoplasia frequently require cardiopulmonary bypass and systemic anticoagulation. We investigate the effects of simultaneous exposure to heparin and direct thrombin inhibitors (DTIs) on lung growth and pulmonary function in a murine model of compensatory lung growth (CGL). Our data suggest that DTIs fail to reverse the inhibitory effects of subtherapeutic heparin on lung growth and function. Clinical studies on the impact of heparin with DTIs on clinical outcomes are thus warranted.

A Medium-Chain Fatty Acid Analogue Prevents Intestinal Failure-Associated Liver Disease in Preterm Yorkshire Piglets.

BACKGROUND & AIMS: At least 20%-30% of patients with intestinal failure receiving long-term parenteral nutrition will develop intestinal failure-associated liver disease (IFALD), for which there are few therapeutic options. SEFA-6179 is a first-in-class structurally engineered medium-chain fatty acid analogue that acts through GPR84, PPARα, and PPARγ agonism. We hypothesized that SEFA-6179 would prevent biochemical and histologic liver injury in a preterm piglet model of IFALD. METHODS: Preterm Yorkshire piglets were delivered by cesarean section, and parenteral nutrition was provided for 14 days via implanted central venous catheters. Animals were treated with either medium-chain triglyceride vehicle control or SEFA-6179. RESULTS: Compared to medium-chain triglyceride vehicle at day of life 15, SEFA-6179 prevented biochemical cholestasis (direct bilirubin: 1.9 vs <0.2 mg/dL, P = .01; total bilirubin: 2.7 vs 0.4 mg/dL, P = .02; gamma glutamyl transferase: 172 vs 30 U/L, P = .01). SEFA-6179 also prevented steatosis (45.6 vs 13.9 mg triglycerides/g liver tissue, P = .009), reduced bile duct proliferation (1.6% vs 0.5% area cytokeratin 7 positive, P = .009), and reduced fibrosis assessed by a masked pathologist (median Ishak score: 3 vs 1, P = 0.007). RNA sequencing of liver tissue demonstrated that SEFA-6179 broadly impacted inflammatory, metabolic, and fibrotic pathways, consistent with its in vitro receptor activity (GPR84/PPARα/PPARγ agonist). CONCLUSIONS: In a preterm piglet model of IFALD, SEFA-6179 treatment prevented biochemical cholestasis and steatosis and reduced bile duct proliferation and fibrosis. SEFA-6179 is a promising first-in-class therapy for the prevention and treatment of IFALD that will be investigated in an upcoming phase II clinical trial.

A Digestive Cartridge Reduces Parenteral Nutrition Dependence and Increases Bowel Growth in a Piglet Short Bowel Model.

OBJECTIVE: To determine whether the use of an immobilized lipase cartridge (ILC) to hydrolyze fats in enteral nutrition (EN) reduces parenteral nutrition (PN) dependence in a porcine model of short bowel syndrome with intestinal failure (SBS-IF). BACKGROUND: SBS-IF occurs after intestinal loss resulting in malabsorption and PN dependence. Limited therapeutic options are available for achieving enteral autonomy. METHODS: Eleven Yorkshire piglets underwent 75% jejunoileal resection and were randomized into control (n=6) and treatment (n = 5) groups. PN was initiated postoperatively and reduced as EN advanced if predefined clinical criteria were fulfilled. Animals were studied for 14 days and changes in PN/EN calories were assessed. Intestinal adaptation, absorption, and nutrition were evaluated at the end of the study (day 15). Comparisons between groups were performed using analysis of covariance adjusted for baseline. RESULTS: ILC animals demonstrated a 19% greater reduction in PN calories ( P < 0.0001) and higher mean EN advancement (66% vs 47% of total calories, P < 0.0001) during the 14-day experiment. Treatment animals had increased intestinal length (19.5 vs 0.7%, P =0.03) and 1.9-fold higher crypt cell proliferation ( P =0.02) compared with controls. By day 15, ILC treatment resulted in higher plasma concentrations of glucagon-like peptide-2 ( P = 0.02), eicosapentaenoic acid ( P < 0.0001), docosahexaenoic acid ( P = 0.004), vitamin A ( P = 0.02), low-density lipoprotein ( P = 0.02), and high-density lipoprotein ( P = 0.04). There were no differences in liver enzymes or total bilirubin between the two groups. CONCLUSIONS: ILC use in conjunction with enteral feeding reduced PN dependence, improved nutrient absorption, and increased bowel growth in a porcine SBS-IF model. These results support a potential role for the ILC in clinical SBS-IF.

Infusion Appointment Self-Management Among Adolescents With Inflammatory Bowel Disease.

OBJECTIVE: Adolescents and young adults with inflammatory bowel disease (IBD) are in vulnerable positions for lapses in care as they transition from pediatric to adult practices. As biologic agents become a mainstay of treatment for these patients, it is important to ensure that responsibility for tasks related to scheduling, remembering, and transporting to infusion appointments for intravenous biologics are mastered prior to transition. This ensures preservation of therapy and disease control. METHODS: We surveyed 236 adolescents and young adults with IBD aged 13-22 years receiving infusion-based biologic therapy at outpatient infusion visits at Boston Children's Hospital from February to May 2021. The questionnaire asked the ideal and actual ages that patients take responsibility for scheduling their infusion appointments, remembering their infusion appointments, and transporting to their infusion appointments. RESULTS: We received 168 completed survey questionnaires. The ideal reported mean age for independence was 17.9 ± 1.7 years across all 3 tasks. Among 80 patients 18 years and older, 44 (55%) were independently scheduling their appointments, 63 (79%) were keeping track of their appointments, and 43 (54%) were getting to their appointments independently. CONCLUSIONS: Adolescent and young adult patients with IBD ideally would independently manage biologic infusion related tasks prior to the age of 18 years, as this is the natural age that many move away from the homes of their parents/guardians. Our study demonstrates that just over half of patients 18 years or older independently manage their infusion appointments. This is an educational opportunity that has implications for health outcomes of patients with IBD.

Pancreatitis-Associated Medication Use in Hospitalized Pediatric and Young Adult Patients With Acute Pancreatitis.

OBJECTIVE: The objective of this study is (1) to describe the prevalence of pancreatitis-associated medication (PAM) use at admission and discharge in pediatric and young adult patients hospitalized with acute pancreatitis (AP) and (2) to describe the prevalence of PAM use at admission in patients classified as having idiopathic AP. STUDY DESIGN: A single-center retrospective study of patients <21 years who were hospitalized with AP or acute recurrent pancreatitis from March 2015 to July 2017 was performed. Charts were reviewed for demographic data, etiology of pancreatitis, comorbidities, and use of PAMs at admission and discharge. PAMs were defined and scored based on an evidence-based classification system, with class I PAMs having strongest evidence for causation. Standard descriptive statistics were used to report prevalence data. RESULTS: Our cohort was comprised of 119 patients; 50% of patients were using a PAM at admission and 67% were taking a PAM at discharge, reflecting a significant change (P = 0.0009); 44% of patients classified as having idiopathic pancreatitis were taking a PAM on admission, reflecting a possibly missed role of medication in their presentation. Comorbidities significantly associated with PAM use included seizure disorder (P = 0.005) and oncologic disease (P = 0.005). The most commonly used class I PAMs were omeprazole, trimethoprim-sulfamethazole, valproic acid, and 6-mercaptopurine. The increase in prevalence of PAM use at discharge compared to admission was partially driven by addition of omeprazole to the outpatient medication regimen during the hospital stay (P = 0.07). CONCLUSION: Medications likely play an under-recognized role in pediatric AP. The practice of using proton pump inhibitors in management of AP warrants further study.

Air Displacement Plethysmography is an Accurate and Feasible Noninvasive Measure of Fat-Free Mass in Children With Intestinal Failure.

BACKGROUND: The nutritional status of children with intestinal failure (IF) can be difficult to determine using body weight and currently available anthropometric techniques. Air displacement plethysmography (ADP) is a noninvasive measure of whole-body composition that measures body mass and volume, with a calculation of percent body fat (%BF) and fat-free mass (FFM) that may be useful during the provision of specialized nutrition. OBJECTIVES: To evaluate the validity and feasibility of measuring body composition in children with IF using ADP compared with deuterium dilution (DD), as well as secondarily with other measures of body composition, namely bioelectrical impedance analysis (BIA), dual-energy X-ray absorptiometry (DXA), and four-site skinfold anthropometry. METHODS: We conducted a prospective cohort study of 18 children recruited through the Center for Advanced Intestinal Rehabilitation at Boston Children's Hospital. Patients 2-17 years of age with IF dependent on parenteral nutrition (PN) for more than 90 days were included. Spearman rank correlation and Bland-Altman limits of agreement (LOA) analysis were used to compare ADP to 4 alternative measures of body composition. RESULTS: Eighteen children with IF, median age 7.1 [interquartile range (IQR) 5.4-9.3] years, 9 female (50%), and median residual bowel length 31 (IQR 22-85) cm were enrolled. Median PN energy intake was 46 (IQR 39-49) kcal/kg/day. Incomplete bladder emptying lead to invalid measures of DD in 4 subjects. Spearman correlation coefficients for %BF were low to moderate between ADP and DD ( r = 0.29), DXA ( r = 0.62), BIA ( r = 0.50), and skinfold ( r = 0.40). Correlations for FFM were high between ADP and these other measures (range 0.95-0.98). Comparing ADP with DD and skinfold measures, Bland-Altman analysis showed small mean bias (-1.9 and +1.5 kg) and acceptable 95% LOA ranges (10.7 and 22.9 kg), respectively, with larger bias (-10.7 and -7.7 kg) and LOA ranges (38.7 and 45.2 kg) compared to DXA and BIA. %BF by ADP and skinfold thickness were moderately correlated ( r = 0.43) with low bias (-0.2%) but very wide LOA (25.7%). CONCLUSIONS: Body composition via ADP is feasible and valid in children with IF as a measure of FFM but appears less suitable for the measurement of %BF. The technique holds promise as a noninvasive measure of body composition to assess the efficacy of nutritional, medical, and surgical interventions.

Deficiency in pigment epithelium-derived factor accelerates pulmonary growth and development in a compensatory lung growth model.

Children with hypoplastic lung disease associated with congenital diaphragmatic hernia (CDH) continue to suffer significant morbidity and mortality secondary to progressive pulmonary disease. Recently published work from our lab demonstrated the potential of Roxadustat (FG-4592), a prolyl hydroxylase inhibitor, as a treatment for CDH-associated pulmonary hypoplasia. Treatment with Roxadustat led to significantly accelerated compensatory lung growth (CLG) through downregulation of pigment epithelium-derived factor (PEDF), an anti-angiogenic factor, rather than upregulation of vascular endothelial growth factor (VEGF). PEDF and its role in pulmonary development is a largely unexplored field. In this study, we sought to further evaluate the role of PEDF in accelerating CLG. PEDF-deficient mice demonstrated significantly increased lung volume, total lung capacity, and alveolarization compared to wild type controls following left pneumonectomy without increased VEGF expression. Furthermore, Roxadustat administration in PEDF-deficient mice did not further accelerate CLG. Human microvascular endothelial lung cells (HMVEC-L) and human pulmonary alveolar epithelial cells (HPAEC) similarly demonstrated decreased PEDF expression with Roxadustat administration. Additionally, downregulation of PEDF in Roxadustat-treated HMVEC-L and HPAEC, a previously unreported finding, speaks to the potential translatability of Roxadustat from small animal studies. Taken together, these findings further suggest that PEDF downregulation is the primary mechanism by which Roxadustat accelerates CLG. More importantly, these data highlight the critical role PEDF may have in pulmonary growth and development, a previously unexplored field.

Presentation, Management, and Outcome of Congenital Portosystemic Shunts in Children: The Boston Children's Hospital Experience.

OBJECTIVES: Congenital portosystemic shunts (CPSS) are rare vascular malformations. We describe presentations, complications, associations, and outcomes of CPSS at Boston Children's Hospital (BCH). METHODS: This was a retrospective review of children with CPSS at BCH from 2000 to 2020. RESULTS: Twenty-nine patients had CPSS (17 girls): 14 extrahepatic (EH) and 15 intrahepatic (IH). At diagnosis, 15 were ≤5 days, 7 <1 year, and 7 >1 year (range 1-19). Median follow-up duration was 5.2 years (interquartile range [IQR] 1.6-10.9) in EH and 2.2 years (0.2-4.2) in IH CPSS. The most common presentation was antenatal ultrasound 13 (45%) followed by hyperammonemia 10 (34%), whereas 6 (21%) were asymptomatic. Complications were noted in 17 (12/14 EH vs 6/15 IH, P = 0.008). Associated anomalies were present in 25 (14/14 EH vs 11/15 IH, P = 0.10). Spontaneous closure was observed in 8 (28%) patients with IH CPSS, all <12 months of age. Ten patients underwent shunt closure 3 (30%) by interventional radiology (IR) and 5 (50%) by surgery, whereas 2 (20%) required both. After therapeutic closure; 8 had improvement, 1 had portal hypertension, and 1 had sepsis and thrombosis. The remaining 11 patients, 8 (42%) were followed without closure: 6 of 8 (75%) EH versus 2 of 11 (18%) IH ( P = 0.02), 2 lost follow-up and 1 with complicated EH CPSS died, unsuitable for therapeutic closure. CONCLUSIONS: CPSS may be asymptomatic or present with complications. Spontaneous closure of IH shunts may occur in infancy, thus therapeutic closure may be deferred until age ≥ 2 years. IR and surgical closure of CPSS are associated with improvement in the majority of cases.

Comparison of Aerodigestive and Nonaerodigestive Provider Responses to Clinical Case Vignettes.

OBJECTIVE: To evaluate differences in practice patterns between aerodigestive and nonaerodigestive providers in pediatric gastroenterology when diagnosing and treating common aerodigestive complaints. STUDY DESIGN: A questionnaire comprised of clinical vignettes with multiple-choice questions was distributed to both aerodigestive and nonaerodigestive pediatric gastroenterologists. Vignettes focused on management of commonly encountered general gastroenterology and aerodigestive issues, such as gastroesophageal (GE) reflux, aspiration, and feeding difficulties. Tests of equal proportions were used to compare rates of testing and empiric therapy within and across groups. Multivariate analysis was used to assess differences in response rates between aerodigestive and nonaerodigestive providers. RESULTS: A total of 88 pediatric gastroenterologists from 18 institutions completed the questionnaire. There were 35 aerodigestive gastroenterology providers and 53 nonaerodigestive gastroenterology providers. The nonaerodigestive group included 31 general gastroenterologists and 22 providers with self-identified subspecialty gastroenterology expertise. Aerodigestive specialists were more likely than nonaerodigestive gastroenterologists to pursue testing over empiric therapy in cases involving isolated respiratory symptoms (P < .05); aerodigestive providers were more likely to recommend pH-impedance testing, videofluoroscopic swallow studies, and upper gastrointestinal barium study (P < .05 for each test) depending on the referring physician. For vignettes involving infant GE reflux, both groups chose empiric treatments more frequently than testing (P < .001), although aerodigestive providers were more likely than nonaerodigestive providers to pursue testing like upper gastrointestinal barium studies (P < .05). CONCLUSIONS: Although some practice patterns were similar between groups, aerodigestive providers pursued more testing than nonaerodigestive providers in several clinical scenarios including infants with respiratory symptoms and GE reflux.

Low Adherence to Society Guidelines for the Management of Helicobacter Pylori Among Pediatric Gastroenterologists.

BACKGROUND: The revised ESPGHAN/NASPGHAN 2016 guideline on the diagnosis and management of Helicobacter pylori (H pylori) infection discourages a "test and treat" strategy. Instead, upper endoscopy (EGD) is recommended when a valid clinical indication is present. Likewise, new treatment recommendations for first-line therapies strongly encourage obtaining antimicrobial susceptibility before treatment. We conducted this study to assess the effect of revised guidelines on clinical practice at our center. METHODS: Retrospective chart review of patients with H pylori infection diagnosis either by serology, stool antigen test, urea breath test, or EGD at Boston Children's Hospital between January 2013 and July 2019. We compared demographic and clinical data between initial guideline and 2016 revision (January 2013 to November 2016) and period after revised guideline (December 2016 to July 2019). RESULTS: Two hundred and fifty-six patients were included. EGD was the initial diagnostic test in 49% (50/103, prerevised guideline) and in 52% (79/153, postrevised guideline). Biopsy culture was sent in 3% of patients for both periods (3/103 and 4/153, respectively). PPI-clarithromycin-amoxicillin triple therapy was the most common regimen in both periods. Clarithromycin use was lower in postrevised guideline period (P = 0.003) whereas the opposite was noted for metronidazole and tetracycline (P = 0.009 and P = 0.02, respectively). There was no significant difference in eradication rate between periods (86% vs 81%). CONCLUSIONS: Low adherence to the updated H pylori guideline recommendations was observed among pediatric gastroenterologists at our center with low use of gastric biopsy culture. The guideline revision was associated with avoidance of clarithromycin use as a second-line therapy, but no change in eradication rates. Future interventions should address the importance of obtaining gastric biopsy culture for antibiotic susceptibilities to guide therapy.

A Retrospective Review of Primary Percutaneous Endoscopic Gastrostomy and Laparoscopic Gastrostomy Tube Placement.

OBJECTIVES: The laparoscopic-assisted gastrostomy tube placement (LAP) has increasingly become the preferred method for placing gastrostomy tubes in infants and children. The goal of this retrospective review was to examine our institutional experiences with our transition from the percutaneous endoscopic gastrostomy (PEG) procedure to LAP technique. METHODS: All patients undergoing primary PEG or LAP gastrostomy at Boston Children's Hospital between January 2010 and June 2015 were identified. The primary aim was to compare complication rates within the first 6 months after tube placement; differences in total hospital procedural costs, hospital resource utilization, and postoperative gastroesophageal reflux disease were examined. RESULTS: Nine hundred and eighty-seven patients (442 PEG and 545 LAP gastrostomy tubes) were included. No differences in total complications within 6 months were seen. Patients undergoing PEG placement had more gastrostomy-related complications (PEG 30 [6.7%] vs LAP 13 [2.4%], P = 0.0007) and cellulitis (PEG 23 [5.1%] vs LAP 2 [0.4%], P = 0.03) within the first week of placement. Patients undergoing LAP procedures had more granulation tissue episodes (PEG 19 [4.4%] vs LAP 107 [19.8%], P = 0.005). No differences in emergency room visits, hospital readmissions, or postoperative gastroesophageal reflux disease were seen, although transition to a gastrojejunal tube was higher in patients undergoing LAP procedure (PEG 20 patients [4.6%] vs LAP 51 patients [9.5%], P = 0.0008). CONCLUSIONS: Total complications were similar between patients undergoing PEG versus LAP gastrostomy tube placement. Patients with the PEG procedure had more complications within the first week of placement versus patients with the LAP procedure had more granulation skin complications.

One-year Experience With Composite Intravenous Lipid Emulsion in Children on Home Parenteral Nutrition.

BACKGROUND: Composite lipid emulsion (CLE) composed of soybean oil, medium-chain triglycerides, olive oil, and fish oil is approved in the US for parenterally fed adults. For stable children discharged on home parenteral nutrition (HPN) without cholestasis (direct bilirubin > 2.0 mg/dL), CLE has theoretical benefits over soybean-based intravenous lipid emulsion due to reduced phytosterol exposure with higher calorie support to permit reduced glucose infusion rates (GIRs), omega-3 supplementation, and supplemental α-tocopherol. METHODS: In this prospective, single-center open-label research study, safety and efficacy outcomes were evaluated in patients on HPN younger than 18 years treated with CLE at 1 to 3 g ·â€Škg-1 ·â€Šday-1 over 12 months. The primary outcome was change in anthropometrics and GIRs compared with baseline. Secondary outcomes were changes in fatty acid profiles and liver function and enzyme tests compared with baseline. RESULTS: Fifty-seven subjects were treated with a median age of 7 years. The diagnosis was short bowel syndrome in 72%. Change in practice was associated with a decrease in mean GIRs from 17 to 14 mg ·â€Škg-1 ·â€Šh-1 at 4 to 6 months postbaseline and beyond with a coincidental decline in mean arachidonic acid and stable growth parameters. No significant adverse events were noted. CONCLUSIONS: CLE was safe and well-tolerated in stable children on HPN at 1 year, but further studies are needed in this population to appreciate long-term outcomes.

Packet Flow Based Reinforcement Learning MAC Protocol for Underwater Acoustic Sensor Networks.

Medium access control (MAC) is one of the key requirements in underwater acoustic sensor networks (UASNs). For a MAC protocol to provide its basic function of efficient sharing of channel access, the highly dynamic underwater environment demands MAC protocols to be adaptive as well. Q-learning is one of the promising techniques employed in intelligent MAC protocol solutions, however, due to the long propagation delay, the performance of this approach is severely limited by reliance on an explicit reward signal to function. In this paper, we propose a restructured and a modified two stage Q-learning process to extract an implicit reward signal for a novel MAC protocol: Packet flow ALOHA with Q-learning (ALOHA-QUPAF). Based on a simulated pipeline monitoring chain network, results show that the protocol outperforms both ALOHA-Q and framed ALOHA by at least 13% and 148% in all simulated scenarios, respectively.

Roxadustat (FG-4592) accelerates pulmonary growth, development, and function in a compensatory lung growth model.

Children with hypoplastic lung disease associated with congenital diaphragmatic hernia (CDH) continue to suffer significant morbidity and mortality secondary to progressive pulmonary disease. Current management of CDH is primarily supportive and mortality rates of the most severely affected children have remained unchanged in the last few decades. Previous work in our lab has demonstrated the importance of vascular endothelial growth factor (VEGF)-mediated angiogenesis in accelerating compensatory lung growth. In this study, we evaluated the potential for Roxadustat (FG-4592), a prolyl hydroxylase inhibitor known to increase endogenous VEGF, in accelerating compensatory lung growth. Treatment with Roxadustat increased lung volume, total lung capacity, alveolarization, and exercise tolerance compared to controls following left pneumonectomy. However, this effect was likely modulated not only by increased VEGF, but rather also by decreased pigment epithelium-derived factor (PEDF), an anti-angiogenic factor. Furthermore, this mechanism of action may be specific to Roxadustat. Vadadustat (AKB-6548), a structurally similar prolyl hydroxylase inhibitor, did not demonstrate accelerated compensatory lung growth or decreased PEDF expression following left pneumonectomy. Given that Roxadustat is already in Phase III clinical studies for the treatment of chronic kidney disease-associated anemia with minimal side effects, its use for the treatment of pulmonary hypoplasia could potentially proceed expeditiously.

Efficacy of Fecal Microbiota Transplantation for Clostridium difficile Infection in Children.

BACKGROUND & AIMS: Fecal microbiota transplantation (FMT) is commonly used to treat Clostridium difficile infection (CDI). CDI is an increasing cause of diarrheal illness in pediatric patients, but the effects of FMT have not been well studied in children. We performed a multi-center retrospective cohort study of pediatric and young adult patients to evaluate the efficacy, safety, and factors associated with a successful FMT for the treatment of CDI. METHODS: We performed a retrospective study of 372 patients, 11 months to 23 years old, who underwent FMT at 18 pediatric centers, from February 1, 2004, to February 28, 2017; 2-month outcome data were available from 335 patients. Successful FMT was defined as no recurrence of CDI in the 2 months following FMT. We performed stepwise logistic regression to identify factors associated with successful FMT. RESULTS: Of 335 patients who underwent FMT and were followed for 2 months or more, 271 (81%) had a successful outcome following a single FMT and 86.6% had a successful outcome following a first or repeated FMT. Patients who received FMT with fresh donor stool (odds ratio [OR], 2.66; 95% CI, 1.39-5.08), underwent FMT via colonoscopy (OR, 2.41; 95% CI, 1.26-4.61), did not have a feeding tube (OR, 2.08; 95% CI, 1.05-4.11), or had 1 less episode of CDI before FMT (OR, 1.20; 95% CI, 1.04-1.39) had increased odds for successful FMT. Seventeen patients (4.7%) had a severe adverse event during the 3-month follow-up period, including 10 hospitalizations. CONCLUSIONS: Based on the findings from a large multi-center retrospective cohort, FMT is effective and safe for the treatment of CDI in children and young adults. Further studies are required to optimize the timing and method of FMT for pediatric patients-factors associated with success differ from those of adult patients.

Optimizing Duration of Empiric Management of Suspected Central Line-Associated Bloodstream Infections in Pediatric Patients with Intestinal Failure.

OBJECTIVES: To assess whether a 24-hour length of hospitalization and empiric antibiotic therapy to exclude central line-associated bloodstream infection (CLABSI) in children with intestinal failure is potentially as safe as 48 hours, which is the duration most commonly used but not evidence based. STUDY DESIGN: A prospective single-institution observational cohort study was conducted among pediatric patients with intestinal failure from July 1, 2015, through June 30, 2018, to identify episodes of suspected CLABSI. The primary end point was time from blood sampling to positive blood culture. Secondary end points included presenting symptoms, laboratory test results, responses to a parent/legal guardian-completed symptom survey, length of inpatient stay, costs, and charges. RESULTS: Seventy-three patients with intestinal failure receiving nutritional support via central venous catheters enrolled; 35 were hospitalized with suspected CLABSI at least once during the study. There were 49 positive blood cultures confirming CLABSI in 128 episodes (38%). The median time from blood sampling to positive culture was 11.1 hours. The probability of a blood culture becoming positive after 24 hours was 2.3%. Elevated C-reactive protein and neutrophil predominance in white blood cell count were associated with positive blood cultures. Estimated cost savings by transitioning from a 48-hour to a 24-hour admission to rule-out CLABSI was $4639 per admission. CONCLUSIONS: A 24-hour duration of empiric management to exclude CLABSI may be appropriate for patients with negative blood cultures and no clinically concerning signs. A multi-institutional study would more robustly differentiate patients safe for discharge after 24 hours from those who warrant longer empiric treatment.

Abnormal 24-hour pH-impedance Testing Does Not Predict Reduced Quality of Life in Children With Reflux Symptoms.

OBJECTIVES: Symptoms of gastroesophageal reflux (GER) have been associated with reduced health-related quality of life (QOL) in children, though it is unclear whether reflux burden on objective diagnostic testing, such as 24-hour multichannel intraluminal impedance with pH (pH-MII) is associated with impaired QOL in children. Our aim was to identify predictors of QOL impairment based on the results of esophageal reflux testing. METHODS: In this prospective, cross-sectional study of children undergoing pH-MII and esophagogastroduodenoscopy (EGD) for evaluation of suspected gastroesophageal reflux disease, we collected validated questionnaires (Pediatric Gastroesophageal Symptom and Quality of Life Questionnaire [PGSQ], Pediatric Quality of Life Inventory 4.0 [PedsQL] and PedsQL Gastrointestinal Symptoms Module [GI PedsQL]) to determine the relationship between objective measures of GER, patient-reported symptoms and QOL outcomes. RESULTS: Of the 82 subjects, 38% of children had an abnormal pH-MII study. There were no significant differences in QOL scores on any questionnaire between patients with normal and abnormal pH-MII studies (P > 0.11). There was no correlation between individual pH-MII parameters and QOL scores. Subjects with gross esophagitis on EGD reported significantly worse QOL with lower total PedsQL (P = 0.002) and GI PedsQL (P = 0.03) scores. Microscopic esophagitis was not associated with differences in QOL scores (P > 0.32). CONCLUSIONS: There was no relationship between abnormalities on pH-MII testing and reduced QOL in children. These findings highlight the importance of considering other diagnoses beyond GERD as they may be significant drivers for QOL impairment.

Growth in Infants and Children With Intestinal Failure-associated Liver Disease Treated With Intravenous Fish Oil.

BACKGROUND: Infants with intestinal failure (IF) and IF-associated liver disease (IFALD) are at risk for poor somatic growth because of increased metabolic demands, inadequate intake, intestinal malabsorption, chronic liver disease and other comorbidities. There are limited data on the nutritional adequacy of intravenous fish oil lipid emulsion (FOLE) compared with standard soybean oil lipid emulsion (SOLE) in the setting of intestinal failure. AIMS: To describe growth patterns in a large cohort of infants with IFALD treated with FOLE. METHODS: We compared growth data from infants enrolled in a single-center, prospective FOLE study to published norms, as well as to a multicenter, historical cohort of infants with IF treated with SOLE. RESULTS: One hundred thirty-eight infants with IFALD were treated with FOLE and 108 with SOLE. Compared with normative growth curves from WHO and published preterm data, infants in both groups from 6 to 11 months postmenstrual age exhibited declines in mean weight- and length-for-age z scores. At 24 months postmenstrual age compared with WHO growth data, infants treated with FOLE had a mean (95% confidence interval [CI]) weight-for-age z-score of 0.13 (-0.18 to 0.45) and length-for-age z-score of 0.07 (-0.33 to 0.47). In comparison, at 24 months postmenstrual age, infants treated with SOLE had a mean weight for age z-score of -0.93 (-1.20 to -0.67) and mean length for age z-score of -2.33 (-2.75 to -1.91). Independent predictors of higher weight, length and head circumference z-scores included older postmenstrual age at baseline, fewer central line-associated blood stream infections, resolution of cholestasis, type of intravenous fat emulsion (FOLE vs SOLE) and female sex. CONCLUSIONS: Infants with IFALD treated with FOLE showed comparable somatic growth to those treated with SOLE in early infancy, and improved somatic growth up to 24 months of age, supporting its wider use in this patient population.

Barrett Esophagus and Intestinal Metaplasia of the Gastroesophageal Junction in Children: A Clinicopathologic Study.

OBJECTIVES: Barrett esophagus (BE) and intestinal metaplasia of gastroesophageal junction (IMGEJ) are rare in the pediatric population. This multi-institutional retrospective study evaluated the clinicopathologic characteristics and natural history of BE and IMGEJ in children. METHODS: Data from 20 BE patients (70% boys, mean age: 14.9 years) and 17 IMGEJ patients (71% boys, mean age: 14 years) were retrospectively obtained from chart review. Endoscopic and pathologic findings from index and follow-up endoscopies were analyzed. RESULTS: Most patients (70% BE and 59% IMGEJ) had underlying conditions which put them at risk for gastroesophageal reflux disease. Increased body mass index (BMI) was observed in patients without underlying conditions (BE: 30.1 ±â€Š9.8; IMGEJ: 23.9 ±â€Š6.3) compared with those with underlying conditions (BE: 19.6 ±â€Š7.8; IMGEJ: 16.4 ±â€Š2.1) (BE, P = 0.02; IMGEJ, P = 0.01). Incomplete intestinal metaplasia (IM) was the predominant histology seen in BE (80%) and IMGEJ patients (75%). Dysplasia and malignancy were not identified in the initial and follow-up biopsies. Concurrent gastric biopsies showed various findings (79% BE and 40% IMGEJ were normal), with 1 IMGEJ patient showing coexisting gastric IM (7%). Follow-up in 12 BE patients (mean follow-up time 51.6 months) showed 100% persistent endoscopic disease and 58% persistent IM histologically. Three of 6 IMGEJ patients (mean follow-up time 24 months) demonstrated endoscopic and histologic features consistent with BE on subsequent procedures. Moreover, a subset of BE (57%) and IMGEJ patients (67%) who underwent endoscopy before initial diagnosis showed nongoblet columnar mucosa above the anatomic gastroesophageal junction. CONCLUSIONS: Increased BMI may be a risk factor for BE and IMGEJ in pediatric patients without underlying conditions. Nongoblet columnar metaplasia and IMGEJ might represent incomplete forms of BE. Our data suggest that these patients should be closely monitored.

Transient elastography assessment of liver allograft fibrosis in pediatric transplant recipients.

TE measures liver stiffness to assess fibrosis. Its use in post-transplant patients was reported in few small pediatric studies. We evaluated TE ability to predict liver graft fibrosis in a large cohort while comparing it to the performance of APRI and FIB-4. We also investigated the effect of graft type on LSMs. Patients at Boston Children's Hospital who underwent LT and LSM ≤ 1 year from biopsy (2007-2018) were eligible. Ninety-four patients (45%M) aged 1-21 years (89% < 18 years; 13% < 2 years) were eligible. Median time between transplant/biopsy and LSM was 5.1 years and 52 days, respectively. Thirty-nine percent received whole-liver grafts, 54% TV grafts, and 6% as part of MV. At LSM, median ALT was 25 [IQR 16-33] IU/L. Twenty-one percent had METAVIR ≥ F2. LSM was statistically higher among those with significant fibrosis (METAVIR ≥ F2) compared to those with METAVIR F0/F1 (median [IQR] 7.5 [4.6, 13.6] vs 5.1 [4.0, 6.4] kPa, respectively) (P = .005 by Wilcoxon rank-sum test). APRI and FIB-4 distributions were not different across METAVIR stages. The AUROC for LSM was 0.71 (95% CI 0.56-0.85) with an optimal cut-point of 6.5 kPa. Graft type had no influence on the AUROC for LSM. TE is useful for assessing significant graft fibrosis in children and young adult LT recipients and performs better than APRI and FIB-4. TV grafts demonstrate similar correlation with histology as whole-liver grafts.