INTRODUCTION:Parenteral nutrition (PN) is life-saving for patients with intestinal malabsorption. Soybean oil lipid emulsions (SOLEs) administered as part of PN can cause liver injury that progresses to death or need for transplantation, partly due to high level of proinflammatory omega-6 (n6) polyunsaturated fatty acids. Fat-1 mice express an omega-3 (n3) fatty acid desaturase enzyme that converts n6 to n3 polyunsaturated fatty acids that have anti-inflammatory/anti-steatotic properties. MATERIALS AND METHODS:We hypothesized that fat-1 mice will have less severe fatty liver disease compared to C57Bl/6J mice when administered identical lipid doses (4 g/kg/d) of either SOLE or mixed-oil emulsion in a 19-d model of PN-induced hepatosteatosis. Chow-fed, age-matched mice served as controls. The primary outcome was hepatosteatosis severity assessed by histology and triglyceride assay. RESULTS:Compared to C57Bl/6J mice, fat-1 mice had reduced histologic hepatosteatosis and lower liver triglyceride levels for PN + saline (P = 0.005) and PN + SOLE (P = 0.02) groups. C57Bl/6J mice had higher n6:n3 ratios than fat-1 mice for chow (P < 0.001), PN + saline (P = 0.01), PN + mixed-oil emulsion (P = 0.001), and PN + SOLE (P < 0.001) groups. Fat-1 mice developed less severe fatty liver disease compared to C57Bl/6J mice in a PN steatosis model. CONCLUSIONS:In a murine model of PN-induced hepatosteatosis, fat-1 mice expressing an n3 fatty acid desaturase enzyme developed less severe fatty liver disease compared to C57Bl/6J mice administered identical doses of ILEs.

Parenteral nutrition (PN) is lifesaving for patients with short bowel syndrome and other gastrointestinal disorders, however long-term use may lead to complications including hepatosteatosis and sepsis. We have previously demonstrated the anti-steatotic, -fibrotic, and -inflammatory properties of SEFA-6179, an engineered medium-chain fatty acid analogue. We hypothesized that SEFA-6179 treatment would protect against endotoxin-induced liver injury in a murine model of PN-induced hepatosteatosis. C57Bl/6J mice were administered a high-carbohydrate liquid diet plus intravenous lipid emulsion (Intralipid, 4 g fat/kg/d) or intravenous saline for 19 days to induce hepatosteatosis. SEFA-6179 (100 mg/kg) or vehicle (MCT/medium-chain triglyceride) was administered via oral gavage for four days leading up to intraperitoneal challenge with lipopolysaccharide (15 mg/kg) or saline on day 19. Age-matched, chow-fed controls received the same treatments. The primary outcome was liver biomarkers: alanine aminotransferase and aspartate aminotransferase. Pro-inflammatory cytokines, IL-6, TNF-alpha, and monocyte chemoattractant protein (MCP1), were analyzed. Liver immunofluorescence staining was performed to evaluate macrophage phenotypes. In endotoxin-challenged mice, pre-treatment with SEFA-6179 lowered liver enzymes and pro-inflammatory cytokine levels compared to vehicle. On liver histology, SEFA-6179 pre-treatment led to greater polarization of M1/pro-inflammatory macrophages to an M2/anti-inflammatory phenotype compared to vehicle. SEFA-6179 is currently in Phase II clinical trials. These findings support the potential application of SEFA-6179 in high-risk, PN-dependent patients.

Preterm infants born in the saccular stage of lung development are at risk for developing bronchopulmonary dysplasia (BPD). Oxygen toxicity and volutrauma are identified as major contributors of BPD. Despite mitigation of these risks preterm infants continue to be affected by chronic lung disease. Heparin is commonly administered to preterm infants and is known to interfere with angiogenesis, a critical element of lung development. We previously demonstrated, in a murine model, that compensatory lung growth after left pneumonectomy is inhibited by heparin administration. Based on these results, we hypothesized that heparin would interfere with lung development in neonatal mice, which are born during the saccular phase of lung development. Newborn C57BL/6J mice received either therapeutic unfractionated heparin (UFH), low molecular weight heparin (LMWH) or normal saline (control) for the first week of life. At one month, both UFH and LMWH produced an emphysematous lung phenotype. Late administration of heparin, after the saccular phase did not impact lung function or growth. This data establishes the negative effects of UFH and LMWH during the critical period of postnatal lung development. Based on this work, clinical studies on the impact of heparin on lung development of newborn and preterm infants are warranted.

This single-center cross-sectional retrospective chart review sought to define the prevalence of neuropsychiatric (NP) disorders among children with non-alcoholic fatty liver disease (NAFLD) compared to the general population. The prevalence rate of NP disorders was determined at diagnosis among children evaluated from 2006 to 2016. The NP disorder prevalence rates were compared to those reported in the 2016 National Survey of Children’s Health (NSCH). 24.3% of 254 children with NAFLD reported to have at least 1 NP disorder compared to 16.9% of those in NSCH (relative risk [RR] = 1.44; P < .0001). More children had intellectual disability (ID) (4.5% vs 0.8%; RR = 5.43, P < .0001), depression (3.9% vs 2.2%; RR = 1.82, P = .0009), or autism spectrum disorder (ASD) (3.3% vs 2.0%; RR = 1.67, P = .047) in the Boston Children’s Hospital (BCH) NAFLD cohort. The prevalence of 1 NP disorder was 29.4% in our cohort compared to 22.3% in NSCH (RR = 1.32; P = .007). Children with NAFLD have a higher rate of NP disorders compared to the general population.

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.

BackgroundHuman milk and amino acid (AA) formulas are correlated with a shorter duration of parenteral nutrition (PN) dependence for infants with intestinal failure (IF). Literature to guide feeding practices beyond infancy in this population is limited. We aimed to assess PN dependence, growth patterns, and stool frequency in pediatric patients with IF who transitioned from AA or hydrolyzed formula to blenderized tube feedings (BTFs).MethodsWe performed a retrospective review among children with IF observed at Boston Children's Hospital from January 2014 to January 2019. Inclusion criteria were receipt of BTF for >= 3 months at a volume of >= 200 ml/day and >= 2 outpatient visits during the study period. Patients who received BTF in combination with another formula or food purees were excluded.ResultsTwelve children met criteria. Eleven had a small bowel resection with mean residual small bowel length of 51 +/- 47 cm. Two retained their ileocecal valve (ICV), and eight had colonic resection. All patients were dependent on PN with mean (SD) energy intake of 51 +/- 21 kcal/kg/day. After transition to BTF, three patients (25%) achieved enteral autonomy, and seven (58%) had a reduction in PN energy intake. Anthropometric data and stool frequency were generally unchanged.ConclusionThe transition from AA or hydrolyzed formula to BTF was associated with a substantial reduction in PN support in 12 children with IF. Stool frequency and growth parameters were not significantly changed. Our findings suggest that the use of BTF in older children with IF should be considered.

BackgroundSelection 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.MethodsWe 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).ResultsPatients 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).ConclusionIn 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.

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.

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.

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.

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.

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 (AUC 7-90 ). 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 21 st , 2018, last update posted on September 14 th , 2022.

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, PPARa, and PPAR? agonism. We hypothesized that SEFA6179 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/PPARa/PPAR? 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.

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.

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.

BackgroundEnteral 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.MethodsTwenty 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.ResultsBoth 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).ConclusionIn 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.

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.

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.

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.