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We aim to evaluate recurrence rates of gallstone pancreatitis in children undergoing early vs interval cholecystectomy.A multicenter, retrospective review of pediatric patients admitted with gallstone pancreatitis from 2010 through 2017 was performed. Children were evaluated based on timing of cholecystectomy. Early cholecystectomy was defined as surgery during the index admission, whereas the delayed group was defined as no surgery or surgery after discharge. Outcomes, recurrence rates, and complications were evaluated.Of 246 patients from 6 centers with gallstone pancreatitis, 178 (72%) were female, with mean age 13.5 ± 3.2 years and a mean body mass index of 28.9 ± 15.2. Most (90%) patients were admitted with mild pancreatitis (Atlanta Classification). Early cholecystectomy was performed in 167 (68%) patients with no difference in early cholecystectomy rates across institutions. Delayed group patients weighed less (61 kg vs. 72 kg, p = 0.003) and were younger (12 vs. 14 years, p = 0.001) than those who underwent early cholecystectomy. However, there were no differences in clinical, radiological, or laboratory characteristics between groups. There were 4 (2%) episodes of postoperative recurrent pancreatitis in the early group compared with 22% in the delayed group. More importantly, when cholecystectomy was delayed more than 6 weeks from index discharge, recurrence approached 60%. There were no biliary complications in any group.Cholecystectomy during the index admission for children with gallstone pancreatitis reduces recurrent pancreatitis. Recurrence proportionally increases with time when patients are treated with a delayed approach.

We aimed to assess predictors of length of stay for simple gastroschisis utilizing the NSQIP-Pediatric Database.The NSQIP-P Participant Use Data File was queried to identify patients with simple gastroschisis. We defined short length of stay (LOS) as patients discharged home ≤ 30 days from birth. We compared patients with short LOS versus prolonged LOS 30 days. Predictors and outcomes were evaluated.There were 888 patients with simple gastroschisis identified. Half of patients had LOS ≤ 30 days. Patients with LOS ≤ 30 were younger at repair (median age 1 day vs. 3 days, p = 0.0001), had higher birth weight (median 2.5 kg vs. 2.4 kg, p = 0.0001), and were less premature (37 week vs. 36 weeks, p = 0.0001). However, only gestational age and weight at birth were significant predictors of LOS on multivariate analysis (p = 0.0001). Prolonged LOS patients had more instances of ventilation, oxygen supplementation, sepsis (n = 2/446 or 0.4% vs. n = 9/442 or 2%, p = 0.003), bleeding/transfusion (n = 7/446 or 1.6% vs. n = 43/442 or 9.7%, p = 0.0001), line infections (n = 1/446 or 0.2% vs. n = 12/442, p = 0.001), and reoperations (n = 9/446 or 2% vs. n = 26/442 or 5.9%, p = 0.003).Prematurity and birth weight are significant predictors of length of stay in simple gastroschisis patients. Prenatal counseling should continue to be one of the main factors to improve the outcomes for patients with gastroschisis. Type of study Retrospective cohort study. Level of evidence Level IV.

Trisomy 18 is associated with a wide range of potentially fatal congenital conditions. Historically, clinical attitudes on treatment have been ambiguous, with palliative care as the standard of care. The aim of our study was to provide a descriptive analysis of surgical outcomes in patients with trisomy 18.We identified patients with trisomy 18 aged 0-18 years using the NSQIP-Pediatric database from 2012 to 2017 and analyzed demographics, surgery types, and perioperative characteristics of patients with trisomy 18 patients undergoing surgical intervention. Additionally, a case-match analysis was performed to assess surgical outcome differences.A total of 310 patients with trisomy 18 were identified. Thirty-one percent were5 years of age and 73% were female. The most common surgical types were general surgery procedures (57.4%), followed by orthopedics (18.1%) and ENT (10.3%). Operations performed increased from 8% (2012) to 26% (2017), and only 23% of patients had previous cardiac surgery. Majority of patients had no prior history of malignancy (95%) and 5% had a tracheostomy placed. Discharge to home was achieved in 74% of patients, with a median total hospital length of stay of 5 days (IQR 17). Furthermore, 90% survived over 30 days from the operation. Thirty-two patients had readmissions and the most common reasons were dehydration, gastrostomy infection or malfunction. Surgical site infections occurred in3% of patients. No differences in complications, length of stay, reoperations, and readmissions were identified by case-match analysis.In this data set, patients with trisomy 18 undergoing noncardiac surgical procedures experience excellent surgical outcomes with minimal morbidity and low mortality. Most patients more than a year of age will experience similar outcomes to patients without trisomy 18.Treatment study (retrospective comparative study) LEVEL OF EVIDENCE: Level III.

Objective: The nation's aging population presents novel perioperative challenges. Potential benefits of operative interventions must be scrutinized in relation to recoverable quality of life. The purpose of this study is to evaluate common risk calculators used for medical decision making in a nonagenarian patient population. Methods: Retrospective medical record review was performed on patients 90 years or older who underwent operative interventions requiring anesthesia at a large academic medical center between January 1, 2013, and December 31, 2017. GraphPad 8.2.1 was used for statistical analysis. Results: Significant differences were found when data were stratified by age for elective versus emergent cases (P value < .0001), ability to return to baseline function (P value = .0062), and mortality (P value < .0001). Significant differences were found in emergent and elective cases, ability to return to baseline function, readmissions, and mortality (all P values < .0001) when stratified by American Society of Anesthesiologists score. Ability of patients to return to baseline functionality after intervention was influenced by their preintervention level of functionality (P value = .0008). American College of Surgeons and Portsmouth Physiologic and Operative Severity Score for Enumeration of Mortality and Morbidity risk calculators underestimated the need for rehabilitation and overestimated mortality for this population (all P values < .0001). Conclusion: Perioperative cares of the extreme geriatric population are complex and should be approached collaboratively. Rehabilitation and postoperative assistance resources should be assessed and used fully. Input from palliative care teams should be sought appropriately. End-of-life and escalation-of-care discussions should ideally be organized prior to emergent interventions. Frailty and risk calculators should be used and considered for formal implementation into the preoperative workflow.

Reports of incidental pneumomediastinum in infants secondary to inflicted trauma are limited. A retrospective review of infants with pneumomediastinum and history of inflicted trauma was performed. A comprehensive literature review was performed. Three infants presented with pneumomediastinum associated with inflicted trauma. Mean age was 4.6 weeks. All patients underwent diagnostic studies, as well as a standardized evaluation for nonaccidental trauma. All patients with pneumomediastinum were resolved at follow-up. Review of the literature identified other cases with similar presentations with related oropharyngeal injuries. Spontaneous pneumomediastinum in previously healthy infants may be associated with inflicted injuries. Clinicians should be aware of the possibility of an oropharyngeal perforation related to this presentation.

Surgical removal of the intestine, lifesaving in catastrophic gastrointestinal disorders of infancy, can result in a form of intestinal failure known as short bowel syndrome (SBS). Bloodstream infections (BSIs) are a major challenge in pediatric SBS management. BSIs require frequent antibiotic therapy, with ill-defined consequences for the gut microbiome and childhood health. Here, we combine serial stool collection, shotgun metagenomic sequencing, multivariate statistics and genome-resolved strain-tracking in a cohort of 19 patients with surgically-induced SBS to show that antibiotic-driven intestinal dysbiosis in SBS enriches for persistent intestinal colonization with BSI causative pathogens in SBS. Comparing the gut microbiome composition of SBS patients over the first 4 years of life to 19 age-matched term and 18 preterm controls, we find that SBS gut microbiota diversity and composition was persistently altered compared to controls. Commensals including Ruminococcus, Bifidobacterium, Eubacterium, and Clostridium species were depleted in SBS, while pathobionts (Enterococcus) were enriched. Integrating clinical covariates with gut microbiome composition in pediatric SBS, we identified dietary and antibiotic exposures as the main drivers of these alterations. Moreover, antibiotic resistance genes, specifically broad-spectrum efflux pumps, were at a higher abundance in SBS, while putatively beneficial microbiota functions, including amino acid and vitamin biosynthesis, were depleted. Moreover, using strain-tracking we found that the SBS gut microbiome harbors BSI causing pathogens, which can persist intestinally throughout the first years of life. The association between antibiotic-driven gut dysbiosis and enrichment of intestinal pathobionts isolated from BSI suggests that antibiotic treatment may predispose SBS patients to infection. Persistence of pathobionts and depletion of beneficial microbiota and functionalities in SBS highlights the need for microbiota-targeted interventions to prevent infection and facilitate intestinal adaptation.

Background & Aims The small intestine (SI) displays regionality in nutrient and immunological function. Following SI tissue loss (as occurs in short gut syndrome, or SGS), remaining SI must compensate, or “adapt”; the capacity of SI epithelium to reprogram its regional identity has not been described. Here, we apply single-cell resolution analyses to characterize molecular changes underpinning adaptation to SGS. Methods Single-cell RNA sequencing was performed on epithelial cells isolated from distal SI of mice following 50% proximal small bowel resection (SBR) vs sham surgery. Single-cell profiles were clustered based on transcriptional similarity, reconstructing differentiation events from intestinal stem cells (ISCs) through to mature enterocytes. An unsupervised computational approach to score cell identity was used to quantify changes in regional (proximal vs distal) SI identity, validated using immunofluorescence, immunohistochemistry, qPCR, western blotting, and RNA-FISH. Results Uniform Manifold Approximation and Projection-based clustering and visualization revealed differentiation trajectories from ISCs to mature enterocytes in sham and SBR. Cell identity scoring demonstrated segregation of enterocytes by regional SI identity: SBR enterocytes assumed more mature proximal identities. This was associated with significant upregulation of lipid metabolism and oxidative stress gene expression, which was validated via orthogonal analyses. Observed upstream transcriptional changes suggest retinoid metabolism and proximal transcription factor Creb3l3 drive proximalization of cell identity in response to SBR. Conclusions Adaptation to proximal SBR involves regional reprogramming of ileal enterocytes toward a proximal identity. Interventions bolstering the endogenous reprogramming capacity of SI enterocytes—conceivably by engaging the retinoid metabolism pathway—merit further investigation, as they may increase enteral feeding tolerance, and obviate intestinal failure, in SGS., Graphical abstract

Receptor tyrosine kinases (RTKs) are important drug targets for cancer and immunological disorders. Crystal structures of individual RTK domains have contributed greatly to the structure-based drug design of clinically used drugs. Low-resolution structures from electron microscopy are now available for the RTKs, EGFR, PDGFR, and Kit. However, there are still no high-resolution structures of full-length RTKs due to the technical challenges of working with these complex, membrane proteins. Here, we review what has been learned from structural studies of these three RTKs regarding their mechanisms of ligand binding, activation, oligomerization, and inhibition. We discuss the implications for drug design. More structural data on full-length RTKs may facilitate the discovery of druggable sites and drugs with improved specificity and effectiveness against resistant mutants.

Receptor tyrosine kinases (RTKs) are important drug targets for cancer and immunological disorders. Crystal structures of individual RTK domains have contributed greatly to the structure-based drug design of clinically used drugs. Low-resolution structures from electron microscopy are now available for the RTKs, EGFR, PDGFR, and Kit. However, there are still no high-resolution structures of full-length RTKs due to the technical challenges of working with these complex, membrane proteins. Here, we review what has been learned from structural studies of these three RTKs regarding their mechanisms of ligand binding, activation, oligomerization, and inhibition. We discuss the implications for drug design. More structural data on full-length RTKs may facilitate the discovery of druggable sites and drugs with improved specificity and effectiveness against resistant mutants.

BackgroundShort bowel syndrome (SBS) results from significant loss of small intestinal length. In response to this loss, adaptation occurs, with Epidermal Growth Factor Receptor (EGFR) being a key driver. Besides enhanced enterocyte proliferation, we have revealed that adaptation is associated with angiogenesis. Further, we have found that small bowel resection (SBR) is associated with diminished oxygen delivery and elevated levels of hypoxia-inducible factor 1-alpha (HIF1α).MethodsWe ablated EGFR in the epithelium and endothelium as well as HIF1α in the epithelium, ostensibly the most hypoxic element. Using these mice, we determined the effects of these genetic manipulations on intestinal blood flow after SBR using photoacoustic microscopy (PAM), intestinal adaptation and angiogenic responses. Then, given that endothelial cells require a stromal support cell for efficient vascularization, we ablated EGFR expression in intestinal subepithelial myofibroblasts (ISEMFs) to determine its effects on angiogenesis in a microfluidic model of human small intestine.ResultsDespite immediate increased demand in oxygen extraction fraction measured by PAM in all mouse lines, were no differences in enterocyte and endothelial cell EGFR knockouts or enterocyte HIF1α knockouts by POD3. Submucosal capillary density was also unchanged by POD7 in all mouse lines. Additionally, EGFR silencing in ISEMFs did not impact vascular network development in a microfluidic device of human small intestine.ConclusionsOverall, despite the importance of EGFR in facilitating intestinal adaptation after SBR, it had no impact on angiogenesis in three cell types-enterocytes, endothelial cells, and ISEMFs. Epithelial ablation of HIF1α also had no impact on angiogenesis in the setting of SBS.

The development and physiologic role of small intestine (SI) vasculature is poorly studied. This is partly due to a lack of targetable, organ-specific markers for in vivo studies of two critical tissue components: endothelium and stroma. This challenge is exacerbated by limitations of traditional cell culture techniques, which fail to recapitulate mechanobiologic stimuli known to affect vessel development. Here, we construct and characterize a 3D in vitro microfluidic model that supports the growth of patient-derived intestinal subepithelial myofibroblasts (ISEMFs) and endothelial cells (ECs) into perfused capillary networks. We report how ISEMF and EC-derived vasculature responds to physiologic parameters such as oxygen tension, cell density, growth factors, and pharmacotherapy with an antineoplastic agent (Erlotinib). Finally, we demonstrate effects of ISEMF and EC co-culture on patient-derived human intestinal epithelial cells (HIECs), and incorporate perfused vasculature into a gut-on-a-chip (GOC) model that includes HIECs. Overall, we demonstrate that ISEMFs possess angiogenic properties as evidenced by their ability to reliably, reproducibly, and quantifiably facilitate development of perfused vasculature in a microfluidic system. We furthermore demonstrate the feasibility of including perfused vasculature, including ISEMFs, as critical components of a novel, patient-derived, GOC system with translational relevance as a platform for precision and personalized medicine research.

Objective: The nation’s aging population presents novel perioperative challenges.Potential benefits of operative interventions must be scrutinized in relation to recoverable quality of life (QOL). The purpose of this study is to evaluate common risk calculators utilized for medical decision making in a nonagenarian patient population. Methods: Retrospective chart review was performed on patients 90 or older who underwent operative interventions requiring anesthesia at a large academic medical center between January 1, 2013 and December 31, 2017. GraphPad-8.2.1 was used for statistical analysis. Results: Significant differences were found when data was stratified by age for elective versus emergent cases (p-value

The purpose of our study was to compare outcomes of infants with spontaneous intestinal perforation (SIP) treated with primary peritoneal drain versus primary laparotomy.We performed a multi-institution retrospective review of infants with diagnosis of SIP from 2012 to 2016. Clinical characteristics and outcomes were compared between infants treated with primary peritoneal drain vs infants treated with laparotomy.We identified 171 patients treated for SIP (drain n = 110 vs. laparotomy n = 61). There were no differences in maternal or prenatal characteristics. There were no clinically significant differences in vital signs, white blood cell or platelet measures, up to 48 h after intervention. Patients who were treated primarily with a drain were more premature (24.9 vs. 27.2 weeks, p 0.001) and had lower median birth weight (710 g vs. 896 g, p 0.001). No significant differences were found in complications, time to full feeds, length of stay (LOS) or mortality between the groups. Primary laparotomy group had more procedures (median number 1 vs. 2, p = 0.002). There were 32 (29%) primary drain failures whereby a laparotomy was ultimately needed.SIP treated with primary drain is successful in the majority of patients with no significant differences in outcomes when compared to laparotomy with stoma.III.