Genomic Contributors to Esophageal Atresia and Tracheoesophageal Fistula: A 12 Year Retrospective Review.

OBJECTIVE: To evaluate genetic testing utilization and diagnostic yield in infants with esophageal atresia (EA)/tracheoesophageal fistula (TEF) over the past 12 years to inform future practices and individualize prognostication and management. STUDY DESIGN: A retrospective cohort study was performed for all infants with EA or EA/TEF hospitalized between January 2011 and January 2023 at a quaternary children's hospital. For each infant, demographic information, prenatal and postnatal history, and genetic testing were reviewed. RESULTS: There were 212 infants who were classified as follows: 1) complex/syndromic with EA/TEF plus an additional major anatomic anomaly (n = 114, of which 74 met VACTERL criteria); 2) isolated/nonsyndromic EA/TEF (n = 88) and 3) isolated/nonsyndromic EA (n = 10). A range of genetic tests were sent with varying diagnostic rates including karyotype analysis in 12 (all with complex/syndromic phenotypes and all positive), chromosomal microarray analysis in 189 (114 of whom were complex/syndromic with an overall diagnostic rate of 3/189), single gene testing for CHD7 in 18 (4 positive), and exome analysis in 37 complex/syndromic patients (8 positive). CONCLUSIONS: EA/TEF with and without additional anomalies is genetically heterogeneous with a broad range of associated phenotypes. While the genetic etiology of EA/TEF with or without VACTERL remains largely unknown, genome wide testing (exome or genome) including copy number analysis is recommended over chromosomal microarray testing. We anticipate that expanded genetic/genomic testing modalities such as RNA sequencing and tissue specific molecular testing are needed in this cohort to improve our understanding of the genomic contributors to EA/TEF.

Pediatric thoracic cage fractures - mind the sternum: A retrospective analysis of the ACS-TQIP database.

BACKGROUND: The thoracic cage is an anatomical entity formed by the thoracic spine, ribs, and sternum. As part of this osteoligamentous complex, the sternum contributes substantially to the stability of the thoracic spine. This study investigates the influence of a concomitant sternal fracture (SF) on the treatment and hospital course of pediatric patients with a thoracic vertebral fracture (TVF). METHODS: The Trauma Quality Improvement Program (TQIP) datasets from 2016-2020 were reviewed. Patients aged 0-19 with TVF with or without SF following blunt trauma were identified using the abbreviated injury scale (AIS) codes and selected for further data collection. Patients with transverse or spinous process fractures or incomplete data were excluded. Data collected included demographics, mechanisms of injury, clinical variables, procedures, intensive care unit (ICU) admission and length of stay (LOS), total LOS and in-hospital mortality. Continuous variables were analyzed with Wilcoxon Rank Sum test, categorical variables with Chi-squared test. RESULTS: A total of 13,434 patients were identified, of which 10,292 had isolated TVF (TVF), 788 TVF and concomitant SF (TVF + SF), 2,225 isolated SF (excluded), and 126 incomplete data (excluded). Motor vehicle collisions were the most common mechanism of injury in both groups (TVF: 75%, TVF + SF: 88%), followed by falls (TVF: 23%, TVF + SF: 12%). Spinal cord injuries were more common among TVF + SF patients (6.4% vs 4%). Median injury severity score (17 vs. 12), age (17 vs. 15 years), LOS (5 vs. 3 days), and mortality (5.6% vs. 2.3%) were significantly higher and the need for operative treatment (69% vs. 56%) and ICU admission (53% vs 36%) significantly more frequent in patients with TVF + SF. CONCLUSIONS: Concomitant SF occur in 7% of all pediatric patients with TVF and are associated with increased morbidity and mortality. This combination of injuries is likely the result of greater energy transmission and injury potential. LEVEL OF EVIDENCE: Level IV, Therapeutic/ Care management.

Trends in Histrelin Implantation at a Pediatric Tertiary Care Center.

INTRODUCTION: Determine procedural outcomes and identify changing trends of utilization among patients undergoing histrelin implantation at a large pediatric tertiary care center over 15 y. METHODS: Retrospective review of all patients undergoing histrelin implantation between January 2008 and April 2022. RESULTS: A total of 746 patients underwent 1794 unique procedures (1364 placements/replacements, 430 removals). Procedures were performed in the clinic (1071, 60%), sedation unit (630, 35%), and operating room (93, 5%). A total of 14 (0.8%) complications were identified, including two patients that required early implant removal and one patient requiring antibiotics. Implants were placed for central precocious puberty (CPP, 579) or gender dysphoria (GD, 167). Cohort included 25.9% males and 74.1% females with mean age of implantation of 9.48 y (SD: 2.34, range: 1.05-17.34). The GD group is comprised of 52.4% males and 47.6% females, compared to 18.3% males and 81.7% females in the CPP. Significant difference was identified for mean age at placement by indication (CPP 8.65 y versus GD 12.34, P < 0.001). New patient referrals and implant procedures increased significantly over 14 y. Yearly frequency of patients receiving implants for CPP and GD increased significantly (P < 0.001), with proportion of GD patients increasing from 7% to 32%. CONCLUSIONS: Histrelin procedures have increased in frequency overall with the greater increase noted in the GD cohort. The development of a streamlined process and a dedicated team have enabled histrelin procedures to be safely performed in the clinic setting for most, with a very low complication rate.

Settling the Score: Injury Severity Score Fails to Capture Nuances in Pediatric Trauma.

OBJECTIVES: Recent work has questioned the accuracy of the Injury Severity Score (ISS) and the Abbreviated Injury Scale (AIS) in the pediatric population. We sought to determine mortality rates in pediatric trauma patients at ISSs considered "severe" in adults and whether mortality would vary substantially between adults and children sustaining injuries with the same AIS. METHODS: Univariate logistic regression was used to generate mortality rates associated with ISS scores, for children (<16 years of age) and adults, using the 2016 National Trauma Data Bank. Mortality rates at an ISS of 15 were calculated in both groups. We similarly calculated ISS scores associated with mortality rates of 10%, 25%, and 50%. Receiver operating characteristic curves were constructed to compare the discriminative ability of ISS to predict mortality after blunt and penetrating injuries in adults and children. Mortality rates associated with 1 or more AIS 3 injuries per body region were defined. RESULTS: There were 855,454 cases, 86,414 (10.1%) of which were children. The ISS associated with 10%, 25%, and 50% mortality were 35, 44, and 53, respectively, in children; they were 27, 38, and 48 in adults. At an ISS of 15, pediatric mortality was 1.0%; in adults, it was 3.1%. A 3.1% mortality rate was not observed in children until an ISS of 25. On receiver operating characteristic analysis, the ISS performed better in children compared with adults (area under the curve, 0.965 vs 0.860 [P < 0.001]). Adults consistently suffered from higher mortality rates than did children with the same number of severe injuries to a body region, and mortality varied widely between specific selected AIS 3 injuries. CONCLUSIONS: Although the ISS predicts mortality well, children have lower mortality than do adults for the same ISS, and therefore, the accepted definition of severe injury is not equivalent between these 2 cohorts. Mortality risk is highly dependent on the specific nature of the injury, with large variability in outcomes despite identical AIS scores.

Pneumatosis intestinalis in children beyond the neonatal period: is it always benign?

PURPOSE: The significance and management of pediatric pneumatosis intestinalis (PI) remains poorly defined. We sought to add clarity in children beyond the neonatal period. METHODS: Pediatric patients 3 months-18 years admitted to a quaternary children's hospital with a diagnosis of PI were included in this retrospective study. Pathologic PI was defined as irreversible, transmural intestinal ischemia. RESULTS: 167 children were identified with PI. Of these children, 155 (92.8%) had benign PI and 12 (7.2%) developed pathologic PI. The most common underlying diagnosis for pathologic PI was global developmental delay (75%), although we identified a spectrum of underlying diagnoses at risk for PI. Physical exam notable for abdominal distension (p = 0.023) or guarding (p = 0.028), and imaging with portal venous gas (p < 0.001) or bowel distension (p = 0.001) were significantly associated with pathologic PI. Only 6.6% of all children underwent an operation. For those undergoing non-surgical management of benign PI, 75% of children received antibiotics and average duration of bowel rest was 6.8 days. CONCLUSIONS: PI in children is primarily a benign phenomenon and often does not warrant surgical intervention. Bowel rest and antibiotics are therapeutic strategies frequently used in the treatment of this finding.

Arterial Fat Embolism in a Pediatric Patient with Femur Fracture: A Case Report.

CASE: Here, we present the case of a pediatric polytrauma patient found to have lower extremity intra-arterial fat embolism causing ischemic necrosis and ultimately necessitating below-the-knee amputation. CONCLUSION: Fat embolism, a common complication of long bone fractures in adults, can be associated with significant morbidity. Although rare, it should be considered among the possible etiologies for a pulseless limb after trauma. Early fracture stabilization may prevent fat embolism and fat embolism syndrome; however, there is no known definitive treatment, and management is supportive.

Use of angioembolization in pediatric polytrauma patients: WITH BLUNT SPLENIC INJURYAngioembolization in Pediatric Blunt Splenic Injury.

BACKGROUND/PURPOSE: We sought to analyze the use of angioembolization (AE) after pediatric splenic injuries at adult and pediatric trauma centers (ATCs/PTCs). METHODS: The National Trauma Data Bank (2010-2015) was queried for patients (<18 years) who experienced blunt splenic trauma. Multivariate logistic regression was used to determine the association of AE with splenectomy. Propensity score matching was used to explore the relationship between trauma center designation and AE utilization. RESULTS: 14,027 encounters met inclusion criteria. 514 (3.7%) patients underwent AE. When compared to PTCs, patients were older, had a higher ISS, and more often presented in shock at ATCs (p<0.001 for all). Regression models demonstrated no difference in mortality between cohorts. Odds of splenectomy were lower for patients undergoing AE (OR 0.16 [CI: 0.08-0.31]), however this effect was mostly driven by utilization at ATCs. Using a 1:1 propensity score matching model, patients treated at ATCs were 4 times more likely to undergo AE and 7 times more likely to require a splenectomy compared to PTCs (p<0.001). Over 6 years, PTCs performed only 27 splenectomies and 23 AEs (1.1% and 0.9%, respectively). CONCLUSIONS: AE was associated with improved splenic salvage at ATCs in select patients but appeared overutilized when compared to outcomes at PTCs. PTCs accomplished a higher splenic salvage rate with a lower AE utilization. LEVEL OF EVIDENCE: III - Retrospective cohort study.

Same-day discharge after laparoscopic appendectomy for non-perforated appendicitis is safe and cost effective.

AIM OF THE STUDY: To compare the outcomes and hospital charges of patients who underwent laparoscopic appendectomy for non-perforated appendicitis and were discharged home either shortly after the operation after being admitted for overnight observation. METHODS: Postoperative (30-day) emergency department (ED) visits, hospital readmissions, and reoperations were compared between patients who were discharged shortly after surgery (same-day discharge [SDD] group) and patients who were discharged after spending one night in the hospital (overnight observation group). STUDY PERIOD: July/2015 to June/2019. Patients with perforated appendicitis and/or who spent > 1 night in the hospital were excluded from the study. RESULTS: We did 1957 laparoscopic appendectomies within the 4-year study period. After excluding all non-eligible cases, 930 patients were included in the overnight observation group, and 511 in the SDD group. Mean age and mean operative time were similar in both groups: 11.5 (SD 3.6)/11.8 (SD 3.5) years, and 35 (SD 13)/33 (SD 12) minutes, respectively. There were 24 (2.6%) ED visits within the overnight observation group. Sixteen patients (1.7%) were discharged from the ED, and 8 (0.9%) required a re-admission. There were 11 (2.1%; P = 0.61) ED visits within the SDD group. Six patients (1.1%; P = 0.41) were discharged from the ED, and 5 (1%; P = 0.82) required a readmission. Six of the 11 ED visits within the SDD group occurred on the 5th postoperative day or later, whereas five (1%) occurred within the first 3 days post appendectomy. These five patients would have likely benefited from an overnight admission and were erroneously discharged on the same day of the appendectomy. There were no reoperations in the overnight observation group, but there were 3 reoperations in the SDD group (0.6%, P = 0.01). The reasons for the reoperations (two bowel obstructions and one bowel perforation) were in no way related to the time of the original discharge. The mean hospital charges per patient in the SDD group and the overnight observation group were significantly different: $32,450 and $35,420, respectively (> 9% margin, P < 0.01). CONCLUSION: Healthy children who undergo laparoscopic appendectomy for non-perforated appendicitis can be discharged home during the same day of the operation after a short period of observation. This approach is safe and does not result in more postoperative ED visits or hospital readmissions. In addition, there is a significant financial benefit when patients are discharged early. LEVEL-OF-EVIDENCE: Level III-retrospective comparative treatment study.

Mortality After Adolescent Firearm Injury: Effect of Trauma Center Designation.

PURPOSE: To determine the incidence and outcomes of firearm injuries in adolescents and the effect of trauma center (TC) designation on their mortality. METHODS: The National Trauma Data Bank (2010-2016) was queried for all encounters involving adolescents aged 13-16 years with firearm injuries. Multivariable logistic regression was employed to determine the association of covariates with mortality (α = .05). Propensity score matching was also used to explore the relationship between TC designation and mortality. RESULTS: A total of 9,029 adolescents met inclusion criteria. Patients aged 15 and 16 years compromised 77.8% of the cohort and were more often male (87.9% vs. 80.6%, p < .001), black (63.8% vs. 56.1%, p < .001), injured in the abdomen (25.4% vs. 22.4%, p = .007) or extremities (62.3% vs. 56.7%, p < .001), and incurred severe injuries (54.5% vs. 50.9%, p = .004) versus 13- and 14-year-old patients. Younger patients were more often injured in the head/neck (23.8% vs. 20.5%, p = .001). Multivariable logistic regression demonstrated no difference in mortality between age groups. Poor neurologic presentation, severe injury, abdominal, chest, and head injuries were all associated with an increased odds of death. Odds of mortality were 2.88 times higher at adult TCs compared to pediatric TCs (CI: 1.55-5.36, p = .001). However, using a 1:1 propensity score matching model, no difference in mortality was found between TC types (p = NS). CONCLUSIONS: Variability exists in outcomes for adolescents after firearm injuries. Understanding and identifying the potential differences between pediatric and adult TCs managing adolescent firearm victims may improve survival in all treatment venues, but these data support patients being treated at the closest available TC.

Pediatric firearm mortality in the United States, 2010 to 2016: A National Trauma Data Bank analysis.

BACKGROUND: Pediatric firearm injury is a leading cause of death for U.S. children. We sought to further characterize children who die from these injuries using a validated national database. METHODS: The National Trauma Data Bank 2010 to 2016 was queried for patients aged 0 to 19 years old. International Classification of Diseases external cause of injury codes were used to classify patients by intent. Differences between groups were analyzed using χ or Mann-Whitney U tests. Patterns over time were analyzed using nonparametric tests for trend. Multivariable logistic regression was used to investigate associations between the above factors and mortality. RESULTS: There were a total of 45,288 children with firearm injuries, 12.0% (n = 5,412) of whom died. Those who died were younger and more often white than survivors. Mortality was associated with increased injury severity, shock on presentation, and polytrauma (p < 0.001 for all). There was an increasing trend in the proportion of self-inflicted injuries over the study period (p < 0.001), and mortality from these self-inflicted injuries increased concordantly (35.3% in 2010 to 47.8% in 2016, p = 0.001). Location of severe injuries had significant different mortality rates, ranging from 51.3% of head injuries to 3.9% in the extremities. In the multivariable model, treatment at a pediatric trauma center was protective against mortality, with odds ratios of 2.10 (confidence interval, 1.64-2.68) and 1.80 (confidence interval, 1.39-2.32) for death at adult and dual-designated trauma centers, respectively. This finding was confirmed in age-stratified cohorts. CONCLUSION: Proportions of self-inflicted pediatric firearm injury in the National Trauma Data Bank increased from 2010 to 2016, as did mortality from self-inflicted injury. Because mortality is highest in this subpopulation, prevention and treatment efforts should be prioritized in this group of firearm-injured children. LEVEL OF EVIDENCE: Epidemiological study, level V.

Primary sigmoidectomy and appendicostomy for chronic idiopathic constipation.

PURPOSE: To present our experience in patients with chronic idiopathic constipation complicated by megarectosigmoid and fecal incontinence who underwent a primary sigmoidectomy and appendicostomy. METHODS: We reviewed eight patients referred to the Colorectal Center from 2014 to 2016 with chronic idiopathic constipation and undergoing a sigmoidectomy and appendicostomy. We analyzed the previous medical treatment, indications for the surgical procedure, and outcomes. RESULTS: Age at operation was 5-19 years. Time with constipation was 4-15 years. All patients received multiple laxatives, mainly polyethylene glycol, and all had severe social problems. Four patients have autism. The indication for surgery was an unsuccessful laxative trial, refusal to continue with rectal enemas or both, and social fear of continued fecal incontinence. Post-operatively, all patients were having daily bowel movements without fecal accidents. CONCLUSION: Selected patients with chronic idiopathic constipation complicated by megarectosigmoid and fecal incontinence can obtain great benefit from primary sigmoidectomy and appendicostomy.

Survival and tolerability of liver radioembolization: a comparison of elderly and younger patients with metastatic colorectal cancer.

AIM: To evaluate the outcomes among elderly (≥70 years) and younger patients (<70 years) with liver-dominant metastatic colorectal cancer (mCRC) who received radioembolization (RE) as salvage therapy. METHODS: A retrospective review of 107 consecutive patients with unresectable mCRC treated with RE after failing first- and second-line chemotherapy. RESULTS: From 2002 to 2012, 44 elderly and 63 younger (<70 years) patients received RE. Patients had similar previous extensive chemotherapy and liver-directed interventions. Using modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria, either a stable or a partial radiographical response was seen in 65.8% of the younger compared with 76.5% of the elderly patients. RE was equally well tolerated in both groups and common procedure-related adverse events were predominantly grade 1-2 and of short duration. No significant difference was found with regard to overall median survival between younger [8.4 months; 95% confidence interval (CI) = 6.2-10.6] or elderly patients (8.2 months; 95% CI = 5.9-10.5, P = 0.667). The presence of extrahepatic disease at the time of RE was associated with a significantly worse median survival in both groups. CONCLUSION: Radioembolization appears to be as well tolerated and effective for the elderly as it is for younger patients with mCRC. Age alone should not be a discriminating factor for the use of radioembolization in the management of mCRC patients.

Hepatocyte-specific high-mobility group box 1 deletion worsens the injury in liver ischemia/reperfusion: a role for intracellular high-mobility group box 1 in cellular protection.

UNLABELLED: High-mobility group box 1 (HMGB1) is an abundant chromatin-associated nuclear protein and released into the extracellular milieu during liver ischemia-reperfusion (I/R), signaling activation of proinflammatory cascades. Because the intracellular function of HMGB1 during sterile inflammation of I/R is currently unknown, we sought to determine the role of intracellular HMGB1 in hepatocytes after liver I/R. When hepatocyte-specific HMGB1 knockout (HMGB1-HC-KO) and control mice were subjected to a nonlethal warm liver I/R, it was found that HMGB1-HC-KO mice had significantly greater hepatocellular injury after I/R, compared to control mice. Additionally, there was significantly greater DNA damage and decreased chromatin accessibility to repair with lack of HMGB1. Furthermore, lack of hepatocyte HMGB1 led to excessive poly(ADP-ribose)polymerase 1 activation, exhausting nicotinamide adenine dinucleotide and adenosine triphosphate stores, exacerbating mitochondrial instability and damage, and, consequently, leading to increased cell death. We found that this was also associated with significantly more oxidative stress (OS) in HMGB1-HC-KO mice, compared to control. Increased nuclear instability led to a resultant increase in the release of histones with subsequently more inflammatory cytokine production and organ damage through activation of Toll-like receptor 9. CONCLUSION: The lack of HMGB1 within hepatocytes leads to increased susceptibility to cellular death after OS conditions.

Histones activate the NLRP3 inflammasome in Kupffer cells during sterile inflammatory liver injury.

Cellular processes that drive sterile inflammatory injury after hepatic ischemia/reperfusion (I/R) injury are not completely understood. Activation of the inflammasome plays a key role in response to invading intracellular pathogens, but mounting evidence suggests that it also plays a role in inflammation driven by endogenous danger-associate molecular pattern molecules released after ischemic injury. The nucleotide-binding domain, leucine-rich repeat containing protein 3 (NLRP3) inflammasome is one such process, and the mechanism by which its activation results in damage and inflammatory responses following liver I/R is unknown. In this article, we report that both NLRP3 and its downstream target caspase-1 are activated during I/R and are essential for hepatic I/R injury, because both NLRP3 and caspase-1 knockout mice are protected from injury. Furthermore, inflammasome-mediated injury is dependent on caspase-1 expression in liver nonparenchymal cells. Although upstream signals that activate the inflammasome during ischemic injury are not well characterized, we show that endogenous extracellular histones activate the NLRP3 inflammasome during liver I/R through TLR9. This occurs through TLR9-dependent generation of reactive oxygen species. This mechanism is operant in resident liver Kupffer cells, which drive innate immune responses after I/R injury by recruiting additional cell types, including neutrophils and inflammatory monocytes. These novel findings illustrate a new mechanism by which extracellular histones and activation of NLRP3 inflammasome contribute to liver damage and the activation of innate immunity during sterile inflammation.

Cellular-specific role of toll-like receptor 4 in hepatic ischemia-reperfusion injury in mice.

UNLABELLED: Ischemia-reperfusion (I/R) injury is a process whereby an initial hypoxic insult and subsequent return of blood flow leads to the propagation of innate immune responses and organ injury. The necessity of the pattern recognition receptor, Toll-like receptor (TLR)4, for this innate immune response has been previously shown. However, TLR4 is present on various cell types of the liver, both immune and nonimmune cells. Therefore, we sought to determine the role of TLR4 in individual cell populations, specifically, parenchymal hepatocytes (HCs), myeloid cells, including Kupffer cells, and dendritic cells (DCs) subsequent to hepatic I/R. When HC-specific (Alb-TLR4(-/-) ) and myeloid-cell-specific (Lyz-TLR4(-/-) ) TLR4 knockout (KO) mice were subjected to warm hepatic ischemia, there was significant protection in these mice, compared to wild type (WT). However, the protection afforded in these two strains was significantly less than global TLR4 KO (TLR4(-/-) ) mice. DC-specific TLR4(-/-) (CD11c-TLR4(-/-) ) mice had significantly increased hepatocellular damage, compared to WT mice. Circulating levels of high-mobility group box 1 (HMGB1) were significantly reduced in Alb-TLR4(-/-) mice, compared to WT, Lyz-TLR4(-/-) , CD11c-TLR4(-/-) mice and equivalent to global TLR4(-/-) mice, suggesting that TLR4-mediated HMGB1 release from HCs may be a source of HMGB1 after I/R. HCs exposed to hypoxia responded by rapidly phosphorylating the mitogen-activated protein kinases, c-Jun-N-terminal kinase (JNK) and p38, in a TLR4-dependent manner; inhibition of JNK decreased release of HMGB1 after both hypoxia in vitro and I/R in vivo. CONCLUSION: These results provide insight into the individual cellular response of TLR4. The parenchymal HC is an active participant in sterile inflammatory response after I/R through TLR4-mediated activation of proinflammatory signaling and release of danger signals, such as HMGB1.