Intravenous lipid emulsions designed to meet preterm infant requirements increase plasma and tissue levels of docosahexaenoic acid and arachidonic acid in mice.

BACKGROUND & AIMS: Intravenous lipid emulsions used in preterm infants contain insufficient docosahexaenoic acid (DHA) and arachidonic acid (ARA) to support normal development, resulting in deficiencies that contribute to complications of prematurity and cognitive delay. We sought to investigate the effects of new intravenous lipid emulsions designed to contain sufficient DHA and ARA to meet preterm needs, while avoiding liver toxicity. METHODS: Three new lipid emulsions (NLE A-C) were laboratory-generated using high pressure homogenization. First, a long-term experiment evaluated the impact on plasma, liver, and frontal cortex fatty acid composition compared to commercially available lipid emulsions. Lipid emulsions were administered via daily orogastric gavage to four-week-old C57Bl/6 J mice. Next, liver toxicity was evaluated in a murine model of parenteral nutrition-induced hepatosteatosis. Mice were provided an ad lib fat-free high carbohydrate diet, with intravenous lipid emulsion administration every other day for 19 days. RESULTS: Administration of commercially available lipid emulsions (soybean oil, mixed oil, or fish oil) resulted in decreased plasma and tissue levels of DHA and/or ARA compared to a chow control. The new lipid emulsions demonstrated a dose-response effect in plasma and tissue concentration of DHA and ARA. NLE C (with an approximately even DHA:ARA ratio), compared to chow, maintained similar DHA (19.2 ± 0.3 vs. 19.3 ± 0.3%, P = 1.00) and ARA (10.4 ± 0.2 vs. 9.9 ± 0.2% ARA, P = 0.75) content in frontal cortex tissue. All three new lipid emulsions prevented biochemical liver injury and pathologist-assessed hepatosteatosis; soybean oil lipid emulsion and mixed oil lipid emulsion treatment resulted in hepatosteatosis in both experiments. CONCLUSION: Long-term treatment with the new lipid emulsions in juvenile mice resulted in increased plasma and tissue DHA and/or ARA content compared to currently available lipid emulsions. The new lipid emulsions also prevented hepatosteatosis and biochemical liver injury with enteral and parenteral administration.

Administration of 4% tetrasodium EDTA lock solution and central venous catheter complications in high-risk pediatric patients with intestinal failure: A retrospective cohort study.

BACKGROUND: Selection of central venous catheter (CVC) lock solution impacts catheter mechanical complications and central line-associated bloodstream infections (CLABSIs) in pediatric patients with intestinal failure. Disadvantages of the current clinical standards, heparin and ethanol lock therapy (ELT), led to the discovery of new lock solutions. High-risk pediatric patients with intestinal failure who lost access to ELT during a recent shortage were offered enrollment in a compassionate use trial with 4% tetrasodium EDTA (T-EDTA), a lock solution with antimicrobial, antibiofilm, and antithrombotic properties. METHODS: We performed a descriptive cohort study including 14 high-risk pediatric patients with intestinal failure receiving 4% T-EDTA as a daily catheter lock solution. CVC complications were documented (repairs, occlusions, replacements, and CLABSIs). Complication rates on 4% T-EDTA were compared with baseline rates, during which patients were receiving either heparin or ELT (designated as heparin/ELT). RESULTS: Patients initiated 4% T-EDTA at the time they were enrolled in the compassionate use protocol. Use of 4% T-EDTA resulted in a 50% reduction in CVC complications, compared with baseline rates on heparin/ELT (incidence rate ratio: 0.50; 95% CI, 0.25-1.004; P = 0.051). CONCLUSION: In a compassionate use protocol for high-risk pediatric patients with intestinal failure, the use of 4% T-EDTA reduced composite catheter complications, including those leading to emergency department visits, hospital admissions, additional procedures, and mortality. This outcome suggests 4% T-EDTA has benefits over currently available lock solutions.

Inpatient management of iron deficiency anemia in pediatric patients with inflammatory bowel disease: A single center experience.

BACKGROUND: Screening for iron deficiency anemia (IDA) is important in managing pediatric patients with inflammatory bowel disease (IBD). Concerns related to adverse reactions may contribute to a reluctance to prescribe intravenous (IV) iron to treat IDA in this population. AIM: To track the efficacy and safety of IV iron therapy in treating IDA in pediatric IBD patients admitted to our center. METHODS: A longitudinal observational cohort study was performed on 236 consecutive pediatric patients admitted to our tertiary IBD care center between September 2017 and December 2019. 92 patients met study criteria for IDA, of which 57 received IV iron, 17 received oral iron, and 18 were discharged prior to receiving iron therapy. RESULTS: Patients treated with IV iron during their hospitalization experienced a significant increase of 1.9 (± 0.2) g/dL in mean (± SE) hemoglobin (Hb) concentration by the first ambulatory follow-up, compared to patients who received oral iron 0.8 (± 0.3) g/dL or no iron 0.8 (± 0.3) g/dL (P = 0.03). One out of 57 (1.8%) patients that received IV iron therapy experienced an adverse reaction. CONCLUSION: Our findings demonstrate that treatment with IV iron therapy is safe and efficacious in improving Hb and iron levels in pediatric patients with IDA and active IBD.

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 pneumonectomy model to study flow-induced pulmonary hypertension and compensatory lung growth.

In newborns, developmental disorders such as congenital diaphragmatic hernia (CDH) and specific types of congenital heart disease (CHD) can lead to defective alveolarization, pulmonary hypoplasia, and pulmonary arterial hypertension (PAH). Therapeutic options for these patients are limited, emphasizing the need for new animal models representative of disease conditions. In most adult mammals, compensatory lung growth (CLG) occurs after pneumonectomy; however, the underlying relationship between CLG and flow-induced pulmonary hypertension (PH) is not fully understood. We propose a murine model that involves the simultaneous removal of the left lung and right caval lobe (extended pneumonectomy), which results in reduced CLG and exacerbated reproducible PH. Extended pneumonectomy in mice is a promising animal model to study the cellular response and molecular mechanisms contributing to flow-induced PH, with the potential to identify new treatments for patients with CDH or PAH-CHD.

Absorption of an engineered medium-chain fatty acid analogue in two short bowel syndrome minipig models.

BACKGROUND: Enteral drug therapy is challenging in short bowel syndrome with intestinal failure (SBS-IF) because of unpredictable absorption. SEFA-6179 is an enterally administered medium-chain fatty acid analogue under development for intestinal failure-associated liver disease. We investigate the pharmacokinetics of two SEFA-6179 formulations in two large-animal models of SBS-IF, including a new pseudojejunostomy model. METHODS: Twenty Yucatan minipigs were obtained. Half underwent pre-resection pharmacokinetic study with single-dose SEFA-6179 administration. All minipigs then underwent 90% jejunoileal resection, with either a jejunoileal anastomosis or bypass of the intraperitoneal colon with anastomosis just proximal to the rectum (pseudojejunostomy). On postoperative day 3, a single-dose pharmacokinetic study was performed. RESULTS: Both SBS-IF models were well tolerated. Compared with the jejunoileal anastomosis minipigs, pseudojejunostomy minipigs had a more severe malabsorptive phenotype with weight loss by postoperative day 4 (+0.1 vs -0.9 kg, P = 0.03) and liquid diarrhea (Bristol 5 vs Bristol 7, P = 0.0007). Compared with pre-resection minipigs, both jejunoileal and pseudojejunostomy minipigs had lower total plasma exposure of SEFA-6179 measured by area under the curve (jejunoileal: 37% less, P = 0.049; pseudojejunostomy: 74% less, P = 0.0001). Peak plasma concentration was also lower in the pseudojejunostomy group compared with pre-resection (65% less, P = 0.04), but not lower in the jejunoileal group (P = 0.47). CONCLUSION: In two SBS-IF minipig models, SEFA-6179 had substantially decreased absorption compared with pre-resection minipigs. Dose optimization for different intestinal anatomy and function may be required. We describe a new SBS-IF pseudojejunostomy model that may improve the translation of preclinical research to patients with SBS-IF who have enterostomies.

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.

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.

Ethanol lock therapy increases mechanical catheter complications in a pediatric intestinal failure population: A retrospective cohort study.

BACKGROUND: Ethanol lock therapy (ELT) decreases central line-associated bloodstream infections; however, the effect on mechanical catheter complications is unclear. In recent years, ELT has become unavailable for many patients, often resulting in high-risk patients switching back to heparin locks. We investigated the impact of ELT on mechanical catheter complications during this period. METHODS: We performed a retrospective cohort study of the Boston Children's Hospital intestinal rehabilitation program from January 1, 2018, to December 31, 2020. Pediatric patients with a central venous catheter requiring parenteral support for 3 months were included. The primary outcome was the composite rate of mechanical catheter complications (repairs and replacements). RESULTS: The pediatric intestinal failure cohort consisted of 122 patients. Forty-four percent received ELT for the entirety of the study period, 29% used only heparin locks, and 27% used ELT and heparin locks at different periods. During ELT use, there was 1.65 times the risk of mechanical catheter complications (composite outcome of repairs and replacements) compared with heparin locks (adjusted incidence rate ratio [aIRR] = 1.65, 95% CI = 1.18-2.31). Current ELT use was associated with 2.3 times the risk of catheter repairs (aIRR = 2.30, 95% CI = 1.36-3.89) but no significant increase in catheter replacement risk (aIRR = 1.41, 95% CI = 0.91-2.20). CONCLUSION: In the largest pediatric intestinal failure cohort evaluated to date, the use of ELT, compared with heparin locks, increased the risk of mechanical catheter complications. Mechanical complications carry morbidity requiring urgent clinic or emergency department visits and additional procedures. The investigation of alternative lock solutions is warranted.

Fat digestion using RELiZORB in children with short bowel syndrome who are dependent on parenteral nutrition: Protocol for a 90-day, phase 3, open labeled study.

BACKGROUND: Short bowel syndrome (SBS) is a leading cause of intestinal failure resulting in parenteral nutrition (PN) dependence and nutritional deficiencies. Long-term PN use is associated with the development of sepsis and intestinal failure-associated liver disease. Achieving enteral autonomy is the optimal way to prevent these complications. In SBS, the decreased intestinal length, bile acid deficiency, and rapid transit time contribute to fat malabsorption and continued PN dependence. We propose the use of an immobilized lipase cartridge (ILC; RELiZORB) that connects in-line with enteral feed tubing sets and is designed to breakdown the majority of fats provided in enteral nutrition (EN). Preclinical studies have demonstrated both improved fat and fat-soluble vitamin absorption with ILC use in a porcine model of SBS. To evaluate the clinical applicability of these findings, we designed a phase 3, open labeled, single center, clinical trial to determine the safety, tolerability, and efficacy of the RELiZORB enzyme cartridge when used daily with EN for 90 days. METHODS: The patient population will include PN dependent children with SBS, aged 2-18 years. The primary outcome is the change in PN calories from baseline, assessed weekly throughout the study. Changes in growth Z-scores, 72-hour fecal fat and coefficient of fat absorption, plasma fatty acids and fat-soluble vitamins will also be evaluated. Assessment of change in continuous outcomes will be made using the area under the curve, expressed as a percent change relative to baseline, calculated over study day 7 to 90 (AUC7-90). The incidence of adverse events will be monitored and summarized by system organ class. DISCUSSION: If successful, RELiZORB may offer a safe alternative to reducing PN dependence and achieving enteral autonomy in pediatric intestinal failure. These results would be clinically significant given the clear association between long-term PN use and complications in SBS. TRIAL REGISTRATION: ClinicalTrials.gov NCT03530852; registered on May 21st, 2018, last update posted on September 14th, 2022.

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.

Incidence and development of cholestasis in surgical neonates receiving an intravenous mixed-oil lipid emulsion.

BACKGROUND: Intestinal failure-associated liver disease (IFALD), initially manifesting as cholestasis, is a complication in neonates receiving parenteral nutrition (PN). Soybean oil lipid emulsion (SOLE), though implicated in IFALD, was the only US Food and Drug Administration (FDA)-approved initial intravenous lipid emulsion (ILE) for infants and children in the United States. A mixed-oil lipid emulsion (MOLE) gained popularity in patients at risk for IFALD and was recently FDA approved as an initial ILE in children. Given the presence of soybean oil in MOLE, we hypothesized that MOLE would not be effective at preventing cholestasis in surgical neonates. METHODS: Neonates with gastrointestinal surgical conditions necessitating PN for ≥14 days and receiving MOLE (SMOFlipid) from July 2016 to July 2019 were analyzed retrospectively. Unpaired and pair-matched historical surgical neonates treated with SOLE (Intralipid) served as controls. The primary outcome measure was development of cholestasis (direct bilirubin ≥2 mg/dl). RESULTS: Overall, 63% (10 of 16) of MOLE patients and 22% (30 of 136) of SOLE patients developed cholestasis after ≥14 days of therapy (P = 0.005). The latency to developing cholestasis was significantly shorter in MOLE patients compared with SOLE patients. CONCLUSION: In surgical neonates, MOLE may not prevent cholestasis and should not be considered hepatoprotective. Regardless of ILE source, all surgical neonates should be closely monitored for development of IFALD. To date, there is still no ILE able to prevent IFALD.

Gastrointestinal factors associated with risk of bronchiectasis in children.

OBJECTIVE: To evaluate gastrointestinal (GI) risk factors for bronchiectasis in children. We hypothesized that upper GI tract dysmotility would be associated with increased risk of bronchiectasis. STUDY DESIGN: Subjects in this retrospective cohort study included those evaluated for persistent pulmonary symptoms in the Aerodigestive Center at Boston Children's Hospital who underwent chest computed tomography (CT) between 2002 and 2019. To determine gastrointestinal predictors of bronchiectasis, baseline characteristics, comorbidities, enteral tube status, medications received, gastroesophageal reflux burden, adequacy of swallow function, esophageal dysmotility, gastric dysmotility, and neutrophil count on bronchoalveolar lavage (BAL) were compared between patients with and without bronchiectasis. Proportions were compared with Fisher's exact test and binary logistic regression with stepwise selection was used for multivariate analysis. ROC analyses were utilized to compare BAL neutrophils and bronchiectasis. RESULTS: Of 192 subjects, 24% were found to have evidence of bronchiectasis on chest CT at age 7.9 ± 0.5 years. Enteral tubes (OR 5.77, 95% CI 2.25-14.83, p < 0.001) and increased BAL neutrophil count (OR 5.79, 95% CI 1.87-17.94, p = 0.002) were associated with increased risk while neurologic comorbidities were associated with decreased risk (OR 0.24, 95% CI 0.09-0.66, p = 0.006). Gastroesophageal reflux was not found to be a significant risk factor. Neutrophil counts >10% had 72% sensitivity and 60% specificity for identifying bronchiectasis. CONCLUSIONS: Enteral tubes were associated with significantly increased risk of bronchiectasis but gastroesophageal reflux was not. Providers should consider obtaining chest CT to evaluate for bronchiectasis in children found to have unexplained elevated BAL neutrophil count.

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.

Direct thrombin inhibitors as alternatives to heparin to preserve lung growth and function in a murine model of compensatory lung growth.

Infants with congenital diaphragmatic hernia (CDH) may require cardiopulmonary bypass and systemic anticoagulation. Expeditious lung growth while on bypass is essential for survival. Previously, we demonstrated that heparin impairs lung growth and function in a murine model of compensatory lung growth (CLG). We investigated the effects of the direct thrombin inhibitors (DTIs) bivalirudin and argatroban. In vitro assays of lung endothelial cell proliferation and apoptosis were performed. C57BL/6 J mice underwent left pneumonectomy and subcutaneous implantation of osmotic pumps. Pumps were pre-loaded with normal saline (control), bivalirudin, argatroban, or heparin and outcomes were assessed on postoperative day 8. Heparin administration inhibited endothelial cell proliferation in vitro and significantly decreased lung volume in vivo, while bivalirudin and argatroban preserved lung growth. These findings correlated with changes in alveolarization on morphometric analysis. Treadmill exercise tolerance testing demonstrated impaired exercise performance in heparinized mice; bivalirudin/argatroban did not affect exercise tolerance. On lung protein analysis, heparin decreased angiogenic signaling which was not impacted by bivalirudin or argatroban. Together, this data supports the use of DTIs as alternatives to heparin for systemic anticoagulation in CDH patients on bypass. Based on this work, clinical studies on the impact of heparin and DTIs on CDH outcomes are warranted.

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.

Contrasting Social Media Use Between Young Adults With Inflammatory Bowel Disease and Type 1 Diabetes: Cross-sectional Study.

BACKGROUND: Social media is used by young adult patients for social connection and self-identification. OBJECTIVE: This study aims to compare the social media habits of young adults with inflammatory bowel disease (IBD) and type 1 diabetes (T1D). METHODS: This is a cross-sectional study of subjects from Boston Children's Hospital outpatient IBD and diabetes clinics. Patients above 18 years of age were invited to complete a brief anonymous survey, which asked about the various ways they use several social media platforms. RESULTS: Responses were received from 108 patients (92.5% response rate), evenly split across disease type. We found that 83% of participants spent at least 30 minutes per day on social media, most commonly on Instagram and Facebook. Although the content varied based on the platform, patients with IBD posted or shared content related to their disease significantly less than those with T1D (23% vs 38%, P=.02). Among Instagram users, patients with IBD were less likely to engage with support groups (22% vs 56%, P=.04). Among Twitter users, patients with IBD were less likely to seek disease information (77% vs 29%, P=.005). Among Facebook users, patients with IBD were less likely to post about research and clinical trials (31% vs 65%, P=.04) or for information seeking (49% vs 87%, P=.003). Patients with IBD were also less likely to share their diagnosis with friends or family in person. CONCLUSIONS: Young adults with IBD were less willing to share their diagnosis and post about or explore the disease on social media compared to those with T1D. This could lead to a sense of isolation and should be further explored.

Efficacy and Outcomes of Faecal Microbiota Transplantation for Recurrent Clostridioides difficile Infection in Children with Inflammatory Bowel Disease.

BACKGROUND: Children with inflammatory bowel disease [IBD] are disproportionally affected by recurrent Clostridioides difficile infection [rCDI]. Although faecal microbiota transplantation [FMT] has been used with good efficacy in adults with IBD, little is known about outcomes associated with FMT in paediatric IBD. METHODS: We performed a retrospective review of FMT at 20 paediatric centres in the USA from March 2012 to March 2020. Children with and without IBD were compared with determined differences in the efficacy of FMT for rCDI. In addition, children with IBD with and without a successful outcome were compared with determined predictors of success. Safety data and IBD-specific outcomes were obtained. RESULTS: A total of 396 paediatric patients, including 148 with IBD, were included. Children with IBD were no less likely to have a successful first FMT then the non-IBD affected cohort [76% vs 81%, p = 0.17]. Among children with IBD, patients were more likely to have a successful FMT if they received FMT with fresh stool [p = 0.03], were without diarrhoea prior to FMT [p = 0.03], or had a shorter time from rCDI diagnosis until FMT [p = 0.04]. Children with a failed FMT were more likely to have clinically active IBD post-FMT [p = 0.002] and 19 [13%] patients had an IBD-related hospitalisation in the 3-month follow-up. CONCLUSIONS: Based on the findings from this large US multicentre cohort, the efficacy of FMT for the treatment of rCDI did not differ in children with IBD. Failed FMT among children with IBD was possibly related to the presence of clinically active IBD.

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.