Prevention of Parenteral Nutrition-associated Cholestasis Using Reduced Dose Soybean Lipid Emulsion: A Multicenter Randomized Trial.

INTRODUCTION: Reducing soybean lipid emulsion (SLE) dose may prevent parenteral nutrition-associated cholestasis (PNAC) but effects on growth and neurodevelopment are unknown. The purpose of this study was to evaluate the effect of reduced dose SLE on growth and neurodevelopment. METHODS: Surgical neonates at 4 centers were randomized to standard SLE (3 g/kg/day) or reduced SLE (1 g/kg/day) over a 12-week period. Bilirubin levels and growth parameters were measured baseline and weekly while on study. The effects of time and group on direct bilirubin and growth were evaluated with a linear mixed effects model. Neurodevelopmental outcomes were assessed at 12- and 24-months corrected gestational age. RESULTS: Twenty-one individuals were randomized (standard dose = 9, reduced dose = 12). Subjects in the reduced dose group had slower rates of direct bilirubin increase and overall levels decreased earlier than those in the standard dose group. There was a trend toward a faster direct bilirubin decrease in the reduced dose group (p = 0.07 at day 84). There were no differences in the rates of change in weight (p = 0.352 at day 84) or height Z-scores (p = 0.11 at day 84) between groups. One subject in the reduced dose group had abnormal neurodevelopmental testing at 24 months. CONCLUSIONS: Surgical neonates randomized to a reduced dose of SLE had improved trends in direct bilirubin levels without clinically significant differences in overall growth and neurodevelopment. TYPE OF STUDY: Randomized Controlled Trial. LEVEL OF EVIDENCE: II.

Lower extremity complications in children following femoral cannulation for extracorporeal membrane oxygenation.

INTRODUCTION: Extracorporeal membrane oxygenation cannulation strategies vary between adults and children. Femoral approach is common in adults and extremity morbidity is well-documented. Aside from limb ischemia, complications in children are theorized and have yet to be studied. This study aims to comprehensively evaluate implications of pediatric femoral cannulation. METHODS: This is a single-center retrospective review of children <21 years, undergoing femoral venoarterial (VA) or venovenous (VV) cannulation between 2015 and 2022. The primary outcome was incidence of lower extremity complications on ECMO (groin hematoma/hemorrhage, vascular thrombosis, North-South syndrome, compartment syndrome, limb loss). Secondary outcome was incidence of post-decannulation extremity complications (pseudoaneurysm, surgical site infection, vascular thrombosis, motor/sensory deficits). RESULTS: 29 children were cannulated via femoral approach. Most required VA support (89%). Common sites were right femoral artery (70.8%) and right femoral vein (56%). 18 patients (75%) had distal reperfusion cannulas (DPC) placed. Short-term lower extremity complication rate was 59%, most frequently groin hematoma/hemorrhage (30%) and North-South syndrome (19%). Compartment syndrome occurred in 3 patients (11%), though none suffered digit/limb loss. There were no significant differences in complications between cannulation approach (open vs percutaneous) or vessel laterality (ipsilateral vs contralateral). Of those decannulated (n = 15), median ECMO duration was 8 days. Following decannulation, 20% suffered pseudoaneurysm. Ten (63%) experienced ipsilateral motor weakness which resolved in 50% of patients at 1-month follow-up; 20% suffered sensory deficits all resolving by discharge. CONCLUSION: Approximately one third of children who underwent femoral cannulation suffered groin hematoma/hemorrhage and nearly 20% experienced North-South syndrome. Following decannulation, most had extremity weakness while sensory deficits were rarer. This marked risk of extremity morbidity prompts proactive inpatient monitoring and close surveillance after discharge.

Beyond Parity: Gender Diversity of National and International Pediatric Surgery Societal Leadership.

PURPOSE: Despite trends toward equal gender representation among medical school graduates, surgical trainees and fellows, diversity in higher levels of pediatric surgery is largely unstudied. This study aims to quantify gender diversity among leadership of pediatric surgical associations and societies across the globe. METHODS: National and international pediatric surgical organizations were identified from the websites of the American Pediatric Surgical Association (APSA) and World Federation of Associations of Pediatric Surgery (WOFAPS). Compositional gender data of current and past organizational leadership was collected by examining publicly available archives of executive membership rosters. If roster pictures were not available, member names were input into social media sites and other search engines to ensure accurate gender denotation. Univariate analyses of organizational metrics and aggregate data of 5-year time intervals were performed via Fischer's Exact Test with significance of p < 0.05. RESULTS: Nineteen pediatric surgical organizations were included for study analysis. Of 189 current organizational leaders, 50 (26.4%) are women. Eight organizations (42.1%) have less than 20% of leadership positions filled by women members, while two executive boards have no women members. Four organizations (22.2%) have a current woman seated as president/chairperson. Historical gender distribution stratified by organization demonstrates a range of 0-7.8% (p = 0.99), with one organization having yet to elect a woman president/chairperson. Longitudinally, women presidential representation remained consistently low (5-11%) across all time intervals from 1993 to 2022 (p = 0.35). CONCLUSIONS: Despite advances in diversity in medical school graduates, surgical training, and workforce recruitment, there are still significant disparities in gender representation within pediatric surgery societal leadership. LEVEL OF EVIDENCE: IV.

Children with large primary spontaneous pneumothoraxes may benefit from early operative intervention.

PURPOSE: The initial management of primary spontaneous pneumothoraxes (PSP) in children remains controversial, particularly regarding the timing of operative intervention. This study aimed to identify factors associated with failure of non-operative management of PSP. METHODS: A single-center, retrospective review was performed for patients presenting with PSP. Demographics and clinical predictors were collected. Patients successfully managed non-operatively were compared to failed non-operative management. Fischer exact and Mann-Whitney tests were used as appropriate. RESULTS: Fifty-seven pediatric patients were identified as having PSP. Four patients underwent initial surgical intervention, 60% (n = 34) were successfully managed non-operatively, while 33% (n = 19) failed non-operative management and underwent video-assisted thoracic surgery (VATS). Those who failed were more likely to have PSP > 2 cm on initial X-ray (79% vs. 44%, p = 0.021) and have a persistent air leak for > 48 h (47% vs 6%, p ≤ 0.001). LOS was greater in the failure group (11.5 ± 5.1 vs 3.1 ± 2.5, p ≤ 0.001) as well as higher complication rates (21% vs 0%, p = 0.013). CONCLUSION: Our findings suggest that patients presenting with PSP of > 2 cm or have a persistent air leak for > 48 h despite chest tube management are unlikely to be treated by chest tube alone and may benefit from earlier operative intervention.

NH2-terminal deletion of specific phosphorylation sites on PHOX2B disrupts the formation of enteric neurons in vivo.

Mutations in the paired-like homeobox 2 b (PHOX2B) gene are associated with congenital central hypoventilation syndrome (CCHS), which is a rare condition in which both autonomic dysregulation with hypoventilation and an enteric neuropathy may occur. The majority of patients with CCHS have a polyalanine repeat mutation (PARM) in PHOX2B, but a minority of patients have nonpolyalanine repeat mutations (NPARMs), some of which have been localized to exon 1. A PHOX2B-Y14X nonsense mutation previously generated in a human pluripotent stem cell (hPSC) line results in an NH2-terminus truncated product missing the first 17 or 20 amino acids, possibly due to translational reinitiation at an alternate ATG start site. This NH2-terminal truncation in the PHOX2B protein results in the loss of two key phosphorylation residues. Though the deletion does not affect the potential for PHOX2BY14X/Y14X mutant hPSC to differentiate into enteric neural crest cells (ENCCs) in culture, it impedes in vivo development of neurons in an in vivo model of human aganglionic small intestine.NEW & NOTEWORTHY A mutation that affects only 17-20 NH2-terminal amino acids in the paired-like homeobox 2 b (PHOX2B) gene hinders the subsequent in vivo establishment of intestinal neuronal cells, but not the in vitro differentiation of these cells.

Sprouty2 limits intestinal tuft and goblet cell numbers through GSK3ß-mediated restriction of epithelial IL-33.

Dynamic regulation of intestinal cell differentiation is crucial for both homeostasis and the response to injury or inflammation. Sprouty2, an intracellular signaling regulator, controls pathways including PI3K and MAPKs that are implicated in differentiation and are dysregulated in inflammatory bowel disease. Here, we ask whether Sprouty2 controls secretory cell differentiation and the response to colitis. We report that colonic epithelial Sprouty2 deletion leads to expanded tuft and goblet cell populations. Sprouty2 loss induces PI3K/Akt signaling, leading to GSK3ß inhibition and epithelial interleukin (IL)-33 expression. In vivo, this results in increased stromal IL-13+ cells. IL-13 in turn induces tuft and goblet cell expansion in vitro and in vivo. Sprouty2 is downregulated by acute inflammation; this appears to be a protective response, as VillinCre;Sprouty2F/F mice are resistant to DSS colitis. In contrast, Sprouty2 is elevated in chronic colitis and in colons of inflammatory bowel disease patients, suggesting that this protective epithelial-stromal signaling mechanism is lost in disease.

R-Spondin1 enhances wnt signaling and decreases weight loss in short bowel syndrome zebrafish.

BACKGROUND: R-spondins, including R-spondin 1 (RSPO1), are a family of Wnt ligands that help to activate the canonical Wnt/ß-catenin pathway, which is critical for intestinal epithelial cell proliferation and maintenance of intestinal stem cells. This proliferation underpins the epithelial expansion, or intestinal adaptation (IA), that occurs following massive bowel resection and short bowel syndrome (SBS). The purpose of this study was to identify if recombinant human RSPO1 (rhRSPO1) could be serially administered to SBS zebrafish to enhance cellular proliferation and IA. METHODS: Adult male zebrafish were assigned to four groups: sham + PBS, SBS + PBS, sham + rhRSPO1, and SBS + rhRSPO1. Sham fish had a laparotomy alone. SBS fish had a laparotomy with distal intestinal ligation and creation of a proximal stoma. Fish were weighed at initial surgery and then weekly. rhRSPO1 was administered post-operatively following either a one- or two-week dosing schedule with either 3 or 5 intraperitoneal injections, respectively. Fish were harvested at 7 or 14 days with intestinal segments collected for analysis. RESULTS: Repeated intraperitoneal injection of rhRSPO1 was feasible and well tolerated. At 7 days, intestinal epithelial proliferation was increased by rhRSPO1. At 14 days, SBS + rhRSPO1 fish lost significantly less weight than SBS + PBS fish. Measurements of intestinal surface area were not increased by rhRSPO1 administration but immunofluorescent staining for ß-catenin and gene expression for cyclin D1 was increased. CONCLUSIONS: Intraperitoneal injection of rhRSPO1 decreased weight loss in SBS zebrafish with increased ß-catenin + cells and cyclin D1 expression at 14 days, indicating improved weight maintenance might result from increased activation of the canonical Wnt pathway.

Remnant Intestinal Length Defines Intestinal Adaptation and Hepatic Steatosis: Two Zebrafish Models.

BACKGROUND: Short bowel syndrome (SBS) is a condition that results from inadequate intestinal absorptive capacity, usually after the loss of functional intestine. We have previously developed a severe model of SBS in zebrafish that demonstrated increased intestinal adaptation (IA) and epithelial proliferation in SBS zebrafish. However, many children with SBS do not have this extreme intestinal loss. Therefore, in this study, we developed a variation of this model to evaluate the effects of increasing intestinal length on IA and the complications of SBS. MATERIALS AND METHODS: After Institutional Animal Care and Use Committee approval, adult male zebrafish were assigned to three groups: sham (n = 30), S1-SBS (n = 30), and S3-SBS (n = 30). Sham surgery included ventral laparotomy alone. S1-SBS surgery consisted of laparotomy with creation of a proximal stoma at S1 (jejunostomy equivalent) and ligation at S4. S3-SBS surgery had stoma creation at S3 (ileostomy equivalent) and the same ligation. Fish were harvested at 14 d. Markers of IA were measured from proximal intestinal segments, and the liver was analyzed for development of hepatic steatosis. RESULTS: At 14 d, S3-SBS fish lost less weight than S1-SBS and had increased markers of IA compared with sham fish, which were decreased compared with S1-SBS fish. S3-SBS fish had decreased proximal intestinal inflammation compared with S1-SBS fish. S1-SBS fish developed extensive hepatic steatosis. Although S3-SBS fish have increased hepatic steatosis compared with sham fish, it is decreased compared with S1-SBS. CONCLUSIONS: Longer remnant intestine decreases the extent of IA, inflammation, and hepatic steatosis in a zebrafish model of SBS.

Broad-spectrum antibiotics alter the microbiome, increase intestinal fxr, and decrease hepatic steatosis in zebrafish short bowel syndrome.

Short bowel syndrome (SBS) is associated with changes in the intestinal microbiome and marked local and systemic inflammation. There is also a late complication of SBS, intestinal failure associated liver disease (IFALD) in which hepatic steatosis progresses to cirrhosis. Most patients with SBS arrive at massive intestinal resection after a contaminating intraabdominal catastrophe and have a history of exposure to broad-spectrum antibiotics. We therefore investigated whether the administration of broad-spectrum antibiotics in conjunction with SBS in zebrafish (ZF) would replicate these systemic effects observed in humans to identify potentially druggable targets to aid in the management of SBS and resulting IFALD. In zebrafish with SBS, broad-spectrum antibiotics altered the microbiome, decreased inflammation, and reduced the development of hepatic steatosis. After two weeks of broad-spectrum antibiotics, these fish exhibited decreased alpha diversity, with less variation in microbial community composition between SBS and sham fish. Additionally, administration of broad-spectrum antibiotics was associated with decreased expression of intestinal toll-like receptor 4 (tlr4), increased expression of the intestinal gene encoding the Farnesoid X receptor (fxr), decreased expression of downstream hepatic cyp7a1, and decreased development of hepatic steatosis. SBS in zebrafish reproducibly results in increased epithelial surface area as occurs in human patients who demonstrate intestinal adaptation, but antibiotic administration in zebrafish with SBS reduced these gains with increased cell death in the intervillus pocket that contains stem/progenitor cells. These alternate states in SBS zebrafish might direct the development of future human therapies.NEW & NOTEWORTHY In a zebrafish model that replicates a common clinical scenario, systemic effects of the administration of broad-spectrum antibiotics in a zebrafish model of SBS identified two alternate states that led to the establishment of fat accumulation in the liver or its absence. Broad-spectrum antibiotics given to zebrafish with SBS over 2 wk altered the intestinal microbiome, decreased intestinal and hepatic inflammation, and decreased hepatic steatosis.

Spleen Organoid Units Generate Functional Human and Mouse Tissue-Engineered Spleen in a Murine Model.

Introduction: Splenectomy is common after trauma or hematologic disease, and alters immune protection against pathogens, which may lead to fulminant infection with high mortality. Yet the spleen has demonstrable regenerative capacity and cells might be recovered and reimplanted at the time of injury or excision to avoid these risks. Methods: Tissue-engineered spleen (TESp) was generated from ActinGFP mice (mTESp) or human donor spleen (hTESp) through implantation of spleen organoid units (spleen OU), in NOD/SCID mice with concurrent splenectomy, on a biodegradable scaffold. Explants were evaluated and blood smears were obtained to investigate the presence of target cells or Howell-Jolly bodies, which are erythrocyte sequelae of asplenia. Results: TESp was generated from mouse (mTESp) and human (hTESp) donor cells with essential splenic components: red and white pulp with trabeculae. mTESp and hTESp demonstrated green fluorescent protein- or lamin-positive costaining with proliferating cell nuclear antigen, CD4, and CD11c, identifying proliferative donor cells and key immune components of the spleen of donor origin. Animals with hTESp and mTESP combined with splenectomy had significantly fewer Howell-Jolly bodies on blood smears than controls. Conclusion: TESp from mouse and human donor cells can be generated by 4 weeks and contains donor immune cells identified by CD4 and CD11c. TESp reduces postsplenectomy erythrocyte inclusions, indicating possible function. Impact Statement Overwhelming postsplenectomy infection is rare but highly mortal. Tissue-engineered spleen (TESp) was generated from murine (mTESp) and human (hTESp) donors and appeared histologically similar to native spleen. Both mTESp and hTESp demonstrated proliferative cells of donor spleen origin. Importantly, functional cells were demonstrated on imaging with a corresponding reduction in the number of erythrocyte inclusions in blood smears that are typically identified in patients with asplenia and indicate a lack of clearance by functional spleen tissue. Taken together, these findings indicate that this approach might be clinically relevant as a future human therapy.

Advances in fetal surgery.

Historically, the gold standard for the treatment of congenital malformations has been planned delivery at tertiary care center with attempted post-natal repair or amelioration of the lesion. Over the last few decades however, rapid advances in imaging and instrumentation technology combined with superior knowledge of fetal pathophysiology has led to the development of novel intrauterine interventions for most common fetal anomalies. Great success has already been seen the treatment of previous devastating anomalies such as myelomeningocele (MMC), congenital cystic malformations of the lung, twin-twin transfusion, and sacrococcygeal teratomas. Although still limited, these innovative techniques have unique potential to improve outcomes in the most devastating fetal anomalies.

The Reliability of a Novel Mobile 3-dimensional Wound Measurement Device.

BACKGROUND: Objective assessment of wound dimensions is essential for tracking progression and determining treatment effectiveness. A reliability study was designed to establish intrarater and interrater reliability of a novel mobile 3-dimensional wound measurement (3DWM) device. METHODS: Forty-five wounds were assessed by 2 raters using a 3DWM device to obtain length, width, area, depth, and volume measurements. Wounds were also measured manually, using a disposable ruler and digital planimetry. The intraclass correlation coefficient (ICC) was used to establish intrarater and interrater reliability. RESULTS: High levels of intrarater and interrater agreement were observed for area, length, and width; ICC = 0.998, 0.977, 0.955 and 0.999, 0.997, 0.995, respectively. Moderate levels of intrarater (ICC = 0.888) and interrater (ICC = 0.696) agreement were observed for volume. Lastly, depth yielded an intrarater ICC of 0.360 and an interrater ICC of 0.649. Measures from the 3DWM device were highly correlated with those obtained from scaled photography for length, width, and area (ρ = 0.997, 0.988, 0.997, P < 0.001). The 3DWM device yielded correlations of ρ = 0.990, 0.987, 0.996 with P < 0.001 for length, width, and area when compared to manual measurements. CONCLUSION: The 3DWM device was found to be highly reliable for measuring wound areas for a range of wound sizes and types as compared to manual measurement and digital planimetry. The depth and therefore volume measurement using the 3DWM device was found to have a lower ICC, but volume ICC alone was moderate. Overall, this device offers a mobile option for objective wound measurement in the clinical setting.