Category-Based Toxicokinetic Evaluations of Data-Poor Per- and Polyfluoroalkyl Substances (PFAS) using Gas Chromatography Coupled with Mass Spectrometry.

Concern over per- and polyfluoroalkyl substances (PFAS) has increased as more is learned about their environmental presence, persistence, and bioaccumulative potential. The limited monitoring, toxicokinetic (TK), and toxicologic data available are inadequate to inform risk across this diverse domain. Here, 73 PFAS were selected for in vitro TK evaluation to expand knowledge across lesser-studied PFAS alcohols, amides, and acrylates. Targeted methods developed using gas chromatography-tandem mass spectrometry (GC-MS/MS) were used to measure human plasma protein binding and hepatocyte clearance. Forty-three PFAS were successfully evaluated in plasma, with fraction unbound (fup) values ranging from 0.004 to 1. With a median fup of 0.09 (i.e., 91% bound), these PFAS are highly bound but exhibit 10-fold lower binding than legacy perfluoroalkyl acids recently evaluated. Thirty PFAS evaluated in the hepatocyte clearance assay showed abiotic loss, with many exceeding 60% loss within 60 min. Metabolic clearance was noted for 11 of the 13 that were successfully evaluated, with rates up to 49.9 µL/(min × million cells). The chemical transformation simulator revealed potential (bio)transformation products to consider. This effort provides critical information to evaluate PFAS for which volatility, metabolism, and other routes of transformation are likely to modulate their environmental fates.

Successful Medical-Surgical Management of Intracardiac Thrombosis and Pulmonary Pseudoaneurysms in an Adolescent With Hughes-Stovin Syndrome.

We present an adolescent male with a single intracardiac mass and pulmonary emboli, complicated by peripheral venous thrombosis and subsequent development of pulmonary pseudoaneurysms, leading to diagnosis of Hughes-Stovin syndrome. Remission was achieved with cyclophosphamide, corticosteroids, and pseudoaneurysm resection and maintained with infliximab and methotrexate.

Evaluation of Per- and Polyfluoroalkyl Substances (PFAS) In Vitro Toxicity Testing for Developmental Neurotoxicity.

Per- and polyfluoroalkyl substances (PFAS) are a diverse set of commercial chemicals widely detected in humans and the environment. However, only a limited number of PFAS are associated with epidemiological or experimental data for hazard identification. To provide developmental neurotoxicity (DNT) hazard information, the work herein employed DNT new approach methods (NAMs) to generate in vitro screening data for a set of 160 PFAS. The DNT NAMs battery was comprised of the microelectrode array neuronal network formation assay (NFA) and high-content imaging (HCI) assays to evaluate proliferation, apoptosis, and neurite outgrowth. The majority of PFAS (118/160) were inactive or equivocal in the DNT NAMs, leaving 42 active PFAS that decreased measures of neural network connectivity and neurite length. Analytical quality control indicated 43/118 inactive PFAS samples and 10/42 active PFAS samples were degraded; as such, careful interpretation is required as some negatives may have been due to loss of the parent PFAS, and some actives may have resulted from a mixture of parent and/or degradants of PFAS. PFAS containing a perfluorinated carbon (C) chain length ≥8, a high C:fluorine ratio, or a carboxylic acid moiety were more likely to be bioactive in the DNT NAMs. Of the PFAS positives in DNT NAMs, 85% were also active in other EPA ToxCast assays, whereas 79% of PFAS inactives in the DNT NAMs were active in other assays. These data demonstrate that a subset of PFAS perturb neurodevelopmental processes in vitro and suggest focusing future studies of DNT on PFAS with certain structural feature descriptors.

Implementation of enhanced recovery protocols reduces opioid use in pediatric laparoscopic cholecystectomy surgery.

PURPOSE: Enhanced recovery protocols [ERPs] standardize care and have been demonstrated to improve surgical quality in adults. We retrospectively compared outcomes before and after implementation of ERPs in children undergoing elective laparoscopic cholecystectomy [ELC] surgery. METHODS: A pediatric-specific ERP was implemented for children undergoing ELC at one [C1] of the two Pediatric Surgical Centers in July 2016. We retrospectively reviewed 606 patients undergoing ELC between July 2014 and December 2019. Of these, 206 patients underwent ELC prior to ERP implementation [Pre-ERP] were compared to 400 patients undergoing ELC managed in the post-ERP implementation period (between January 2017 and December 2019), 21 of which were managed by enhanced recovery protocol. Primary Outcomes included immediate peri-operative and post-operative narcotic use in mean morphine equivalents [MME], narcotics at discharge, complications, nurse calls and returns to system [RTS]. RESULTS: There was a significant decrease in opioid use both post-operatively and at time of discharge in the ERP managed cohort. The MME use during the post-operative period was 0.85 in the in ERP-compliant patients compared to 6.40 in the non-compliant group (p < 0.027). Eighty-six percent of ERP-compliant patients in the study required no narcotics at discharge, which was statistically significant when compared to ERP non-compliant cohort (p < 0.0001). There was also no change in RTS, nurse calls or complications. In addition, in the post-ERP period (2017-2019), a dominant proportion of patients at C1 partially complied with the ERP, resulting in a statistically significantly decrease of opioid use between sites in the post-op period (6.54 vs 10.57 MME) post-ERP (p < 0.001). Similar effects were noted in discharge narcotics. CONCLUSION: The use of pediatric-specific ERP in children undergoing ELC is safe, effective, and provides compassionate pain control while leading to a reduction in opioid use peri-operatively and at discharge. This improvement occurred without changes in RTS, nursing calls or complications. LEVEL OF EVIDENCE: Level III; Retrospective study.

Dual Balloon Catheter: A Novel Laparoscopic Common Bile Duct Exploration Device.

Introduction: Choledocholithiasis is a disease process that can be managed by laparoscopic common bile duct exploration at the time of cholecystectomy. However, it can be negatively perceived by surgeons as lengthening procedure time and adding technical complexity. Materials and Methods: We have created a dual balloon biliary intervention catheter designed to make common duct exploration efficient, simple, and safe. The device consists of two balloons, one compliant and one noncompliant, to perform initial cholangiography, dilate the sphincter, and occlude the proximal duct for distal power flushing of stones. The catheter design facilitates a stepwise, over the wire progression of interventions with a singular device. Results: The catheter has been successfully deployed in a porcine feasibility model and the dual balloon concepts reduced to practice using currently available devices. Conclusion: Laparoscopic common bile duct exploration is a safe and effective way to treat choledocolithiasis. The Dual Balloon Catheter is a novel device that allows for duct occlusion for cholangiogram and power flushing in conjunction with duct and sphincter dilation.

Impedance planimetry (EndoFLIP) assisted laparoscopic esophagomyotomy in pediatric population.

INTRODUCTION: Functional lumen imaging probe (EndoFLIP) is a diagnostic technology that assesses esophageal cross-sectional area via impedance planimetry during controlled volumetric distention. The purpose of this study is to evaluate the utility of EndoFLIP intraoperatively during laparoscopic esophagomyotomy. METHODS: We performed a retrospective cohort study reviewing all patients undergoing EndoFLIP assisted laparoscopic esophagomyotomy for achalasia between January and December 2021 (n = 10). Twenty-two patients with achalasia that underwent traditional laparoscopic esophagomyotomy between July 2014 and September 2019 served as a comparison. Primary outcome evaluated was resolution of symptoms at discharge. Secondary outcomes included change in distensibility index (DI), operative time, length of stay, time to regular diet, and reinterventions. RESULTS: All patients managed with EndoFLIP assistance had resolution of dysphagia and postprandial vomiting following intervention. Mean change in DI was 5.32 mm2/mmHg with a myotomy length of 3.6 cm. Operative time was shorter in the EndoFLIP cohort (97 min versus 185 min, p = <0.001). Study patients did not undergo an antireflux operation. There was no difference in length of stay or time to soft diet between groups. All patients were discharged on postoperative day 1 tolerating a mechanical soft diet. No acid suppressive medications were prescribed during the observation period. One patient required dilation for recurrent symptoms and one required reoperation for mucosal leak. CONCLUSION: EndoFLIP assisted laparoscopic esophagomyotomy results in similar short-term outcomes to traditional surgical technique. EndoFLIP allows for focused myotomy length and a shorter operative time. LEVEL OF EVIDENCE: III.

Congenital Central Hypoventilation Syndrome: Optimizing Care with a Multidisciplinary Approach.

Congenital central hypoventilation syndrome (CCHS) is a rare genetic disorder affecting respiratory control and autonomic nervous system function caused by variants in the paired-like homeobox 2B (PHOX2B) gene. Although most patients are diagnosed in the newborn period, an increasing number of patients are presenting later in childhood, adolescence, and adulthood. Despite hypoxemia and hypercapnia, patients do not manifest clinical features of respiratory distress during sleep and wakefulness. CCHS is a lifelong disorder. Patients require assisted ventilation throughout their life delivered by positive pressure ventilation via tracheostomy, noninvasive positive pressure ventilation, and/or diaphragm pacing. At different ages, patients may prefer to change their modality of assisted ventilation. This requires an individualized and coordinated multidisciplinary approach. Additional clinical features of CCHS that may present at different ages and require periodic evaluations or interventions include Hirschsprung's disease, gastrointestinal dysmotility, neural crest tumors, cardiac arrhythmias, and neurodevelopmental delays. Despite an established PHOX2B genotype and phenotype correlation, patients have variable and heterogeneous clinical manifestations requiring the formulation of an individualized plan of care based on collaboration between the pulmonologist, otolaryngologist, cardiologist, anesthesiologist, gastroenterologist, sleep medicine physician, geneticist, surgeon, oncologist, and respiratory therapist. A comprehensive multidisciplinary approach may optimize care and improve patient outcomes. With advances in CCHS management strategies, there is prolongation of survival necessitating high-quality multidisciplinary care for adults with CCHS.

Implementation of enhanced recovery protocols reduces opioid use in pediatric laparoscopic Heller myotomy surgery.

BACKGROUND: Enhanced recovery protocols (ERPs) are effective means of standardizing and improving the quality of surgical care in adults. Our purpose was to retrospectively compare outcomes before and after implementation of ERPs in children undergoing laparoscopic Heller myotomy for achalasia. METHODS: A pediatric-specific ERP was used for children undergoing laparoscopic Heller myotomy starting July 2017 at two pediatric surgery centers within a single metropolitan healthcare system. A retrospective review of 8 patients undergoing Heller myotomies between July 2014 and July 2017 was performed as a control. This cohort was compared to 14 patients managed post-ERP implementation (2017-2020). Outcomes of interest investigated included opioid use during admission, narcotics at discharge, time to regular diet, length of stay (LOS), and readmissions. RESULTS: There was a significant decrease in opioid use both while in the hospital and at time of discharge. Mean morphine equivalent use was 4.50 mg in the pre-ERP cohort and 1.97 mg in the post-ERP cohort. Furthermore, 8 out of 14 (57%) patients in the post-ERP cohort received no opioids during the admission compared with only 2 out of 8 (25%) patients in the pre-ERP cohort. Only 1 out of 14 (7.14%) patients in the post-ERP cohort was discharged with a prescription for opioid medication while 6 out of 8 (75%) in the pre-ERP cohort were discharged with an opiate prescription. CONCLUSIONS: The use of ERP in children undergoing laparoscopic Heller myotomy surgery is safe and effective and leads to a reduction in opioid use during admission and at discharge. LEVELS OF EVIDENCE: Level III.

Minimally invasive surgery of the pancreas: a narrative review of current practice.

Minimally invasive surgery has moved from the fringe of pediatric surgery to the mainstream to address a variety of problems. Pancreatic pathology, though uncommon and complex, is frequently amenable to laparoscopic intervention. Indications for pediatric pancreatic operative intervention includes trauma, congenital hyperinsulinemia and neoplasm. Children may require distal pancreatectomy, subtotal pancreatectomy, enucleation, lateral pancreaticojejunostomy and pancreaticoduodenectomy. Of these operations, all but pancreaticoduodenectomy have been successfully described in children using a minimally invasive approach. Traumatic transection of the main pancreatic duct may require operative intervention if endoscopic techniques are unsuccessful. Distal pancreatectomy has been successfully utilized in this circumstance. Additionally, near total pancreatectomy may also be performed laparoscopically although successful reports are limited. Enucleation, especially with the use of intraoperative ultrasound may avoid a large laparotomy for isolated benign masses. Finally, chronic pancreatitis resulting in a dilated main pancreatic duct may benefit from a lateral pancreaticojejunostomy. This operation has also successfully been performed in children. Included is a review of pediatric pancreatic minimally invasive operations paired with corresponding pathology.

Mutation Analysis and Disease Features at Presentation in a Multi-Center Cohort of Children With Monogenic Cholestasis.

OBJECTIVES: To advance our understanding of monogenic forms of intrahepatic cholestasis. METHODS: Analyses included participants with pathogenic biallelic mutations in adenosine triphosphate (ATP)-binding cassette subfamily B member 11 (ABCB11) (bile salt export pump; BSEP) or adenosine triphosphatase (ATPase) phospholipid transporting 8B1 (ATP8B1) (familial intrahepatic cholestasis; FIC1), or those with monoallelic or biallelic mutations in adenosine triphosphate (ATP)-binding cassette subfamily B member 4 (ABCB4) (multidrug resistance; MDR3), prospectively enrolled in the Longitudinal Study of Genetic Causes of Intrahepatic Cholestasis (LOGIC; NCT00571272) between November 2007 and December 2013. Summary statistics were calculated to describe baseline demographics, history, anthropometrics, laboratory values, and mutation data. RESULTS: Ninety-eight participants with FIC1 (n = 26), BSEP (n = 53, including 8 with biallelic truncating mutations [severe] and 10 with p.E297G or p.D482G [mild]), or MDR3 (n = 19, including four monoallelic) deficiency were analyzed. Thirty-five had a surgical interruption of the enterohepatic circulation (sEHC), including 10 who underwent liver transplant (LT) after sEHC. Onset of symptoms occurred by age 2 years in most with FIC1 and BSEP deficiency, but was later and more variable for MDR3. Pruritus was nearly universal in FIC1 and BSEP deficiency. In participants with native liver, failure to thrive was common in FIC1 deficiency, high ALT was common in BSEP deficiency, and thrombocytopenia was common in MDR3 deficiency. sEHC was successful after more than 1 year in 7 of 19 participants with FIC1 and BSEP deficiency. History of LT was most common in BSEP deficiency. Of 102 mutations identified, 43 were not previously reported. CONCLUSIONS: In this cohort, BSEP deficiency appears to be correlated with a more severe disease course. Genotype-phenotype correlations in these diseases are not straightforward and will require the study of larger cohorts.

Dietary Exposures and Intake Doses to Bisphenol A and Triclosan in 188 Duplicate-Single Solid Food Items Consumed by US Adults.

Few data exist on bisphenol A (BPA) or triclosan (TCS) residue levels in foods consumed by adults in everyday settings. In a further analysis of study data, the objectives were to determine BPA and TCS residue concentrations in duplicate-single solid food items consumed by adults and to estimate dietary exposure and intake doses per food item. A convenience sample of 50 adults was recruited in North Carolina (2009-2011). Participants completed 24 h food diaries and collected 24 h duplicate-diet solid food samples consumed on days 1 and 2 during sampling weeks 1, 2, and 6. A total of 188 of the collected 776 duplicate-diet solid food samples contained a single, solid food item. BPA and TCS residue levels were quantified in the 188 food items using GC-MS. BPA and TCS were detected in 37% and 58% of these food items, respectively. BPA concentrations were highest in a cheese and tomato sandwich (104 ng/g), whereas the highest TCS concentrations were in a burrito (22.1 ng/g). These chemicals co-occurred in 20% of the samples (maximum = 54.7 ng/g). Maximum dietary intake doses were 429 ng/kg/day for BPA in a vegetable soup with tortilla sample and 72.0 ng/kg/day for TCS in a burrito sample.

Exposure to Triclosan and Bisphenol Analogues B, F, P, S and Z in Repeated Duplicate-Diet Solid Food Samples of Adults.

Triclosan (TCS) and bisphenol analogues are used in a variety of consumer goods. Few data exist on the temporal exposures of adults to these phenolic compounds in their everyday diets. The objectives were to determine the levels of TCS and five bisphenol analogues (BPB, BPF, BPP, BPS, and BPZ) in duplicate-diet solid food (DDSF) samples of adults and to estimate maximum dietary exposures and intake doses per phenol. Fifty adults collected 776 DDSF samples over a six-week monitoring period in North Carolina in 2009-2011. The levels of the target phenols were concurrently quantified in the DDSF samples using gas chromatography/mass spectrometry. TCS (59%), BPS (32%), and BPZ (28%) were most often detected in the samples. BPB, BPF, and BPP were all detected in <16% of the samples. In addition, 82% of the total samples contained at least one target phenol. The highest measured concentration of 394 ng/g occurred for TCS in the food samples. The adults' maximum 24-h dietary intake doses per phenol ranged from 17.5 ng/kg/day (BPB) to 1600 ng/kg/day (TCS). An oral reference dose (300,000 ng/kg/day) is currently available for only TCS, and the adult's maximum dietary intake dose was well below a level of concern.

Biologic Mesh Underlay in Thoracoscopic Primary Repair of Congenital Diaphragmatic Hernia Confers Reduced Recurrence in Neonates: A Preliminary Report.

Purpose: The purpose of this study was to determine if utilization of biologic mesh underlay during thoracoscopic congenital diaphragmatic hernia (CDH) primary repair (PR) results in reduced 5-year hernia recurrence rates. Methods: A retrospective review was completed for all primarily repaired CDH utilizing a thoracoscopic approach from January 1, 2003 to June 31, 2013. Patients were included in the study cohort if they had a thoracoscopic PR of their CDH without any mesh reinforcement or with biologic mesh underlay. Charts were then reviewed for no less than 5 years postoperatively for reports of clinical and/or radiographic hernia recurrence. The cumulative annual hernia recurrence as well as other demographic factors were analyzed. Results: Within the study period, 46 patients were identified that met study criteria. Three patients were lost to follow-up. Fifteen of the remaining patients (15/43: 34.9%) had a biologic underlay. Within the cohort, seven recurrences were noted within 5 years of the index procedure (7/43; 16.7%). Four recurrences occurred within the first postoperative year, and all occurred by the third postoperative year. One recurrence was in a patient with a biologic underlay at 4 months after repair. This was a clinically/radiographically silent 4 mm defect and noted at laparoscopy for another indication (1/15: 6.6%). The remainder occurred in primarily repaired patients without mesh reinforcement (6/28: 21.4%). Conclusions: Thoracoscopic PR of CDH can be successfully performed in select patients. The use of a biologic mesh underlay in this subset of patients appears to confer reduced hernia recurrence.

Parent reported long-term quality of life outcomes in children after congenital diaphragmatic hernia repair.

PURPOSE: The aim of this study was to determine long-term outcomes for congenital diaphragmatic hernia (CDH) patients including quality of life (QoL), symptom burden, reoperation rates, and health status. METHODS: A chart review and phone QoL survey were performed for patients who underwent CDH repair between 2007 and 2014 at a tertiary free-standing children's hospital. Comprehensive outcomes were collected including subsequent operations and health status. Associations with QoL were tested using Wilcoxon Rank-Sum tests and Pearson correlation coefficients. RESULTS: Of 102 CDH patients identified, 46 (45.1%) patient guardians agreed to participate with mean patient age of 5.8 (SD, 2.2) years at time of follow-up. Median PedsQLTM and PedsQLTM Gastrointestinal scores were 91.8 (IQR, 84.8-95.8) and 95.8 (IQR, 93.0-98.2), out of 100. Thoracoscopic repair was associated with higher PedsQLTM scores while defects with an intrathoracic stomach were associated with increased gas and bloating. No difference in QoL was found when comparing defect side, patch vs primary repair, prenatal diagnosis, extracorporeal membrane oxygenation, or recurrence. Older age weakly correlated with worse school functioning and heartburn. CONCLUSION: Children with CDH have reassuring QoL scores. Given the correlation between older age and poor school function, longer follow-up of patients with CDH may be warranted. LEVEL OF EVIDENCE: III (Retrospective comparative study).

Primary versus secondary anastomosis in intestinal atresia.

PURPOSE: Neonates with intestinal atresia (IA) undergo either primary anastomosis (PA) or ostomy creation with secondary anastomosis (SA). Our purpose was to compare outcomes for PA and SA and to assess factors influencing procedure selection. METHODS: We conducted a retrospective cohort study of neonates with IA between 2009 and 2015. Patient characteristics, operative details, and outcomes were collected. Surgeon-level preferences (defined as performing >50% PA or SA) were assessed using logistic regression. RESULTS: Of 92 IA patients, 70 (76.1%) underwent PA and 22 (23.9%) underwent SA. Neonates with PA had shorter hospitalizations (27 days vs. 95 days, p < 0.001), shorter total parenteral nutrition duration (19 days vs. 74.5 days, p < 0.001), and fewer readmissions (33.3% vs. 63.2%, p = 0.024). On multivariable regression analysis, higher Apgar scores (Odds Ratio (OR) 4.16, 95% Confidence Interval (CI) 1.20-14.29) and uncomplicated atresia (OR 3.97, 95% CI 1.37-11.48) were associated with PA. At the surgeon-level, utilization of PA varied from 43.5% to 100%. Surgeon preference is not influenced by the demographic, presentation, or surgical findings of this patient population. CONCLUSIONS: PA has better outcomes than SA. Though procedural selection is influenced by the clinical status of the neonate, however surgeon preference plays a significant role in this clinical decision. LEVEL OF EVIDENCE: Level III Treatment Study.

Retroperitoneal paraganglioma in a patient with Fontan: The hypoxia connection.

Paragangliomas are rare neuroendocrine tumors where hypoxia-inducible factor plays a critical role in tumorigenesis. It has been suggested that patients with congenital heart disease, in particular, may have cellular environment and relative hypoxia favorable to the development of these neuroendocrine tumors. Here, we present a case of an 11-year-old child with hypoplastic left heart syndrome previously palliated with Fontan procedure, diagnosed with paraganglioma on surveillance imaging. We present the clinical course, intervention, and outcome as well as review the possible contributory mechanisms. As we continue to improve long-term survival for single ventricle patients, awareness of these tumors during surveillance may be warranted as timely intervention may lead to cure.

Thoracoscopic Repair of Congenital Diaphragmatic Hernia After Extracorporeal Membrane Oxygenation: Feasibility and Outcomes.

INTRODUCTION: Thoracoscopic repair of congenital diaphragmatic hernia (CDH) has been associated with faster recovery, earlier extubation, and decreased morbidity. Nevertheless, thoracoscopic repair is rarely attempted in the post-extracorporeal membrane oxygenation (ECMO) patient. Commonly cited reasons for not attempting thoracoscopy include concerns that the patients' respiratory status is too tenuous to tolerate insufflation pressures or that presumed defect size is so large that it precludes thoracoscopic repair. Our purpose is to review our experience with post-ECMO thoracoscopic CDH repair and evaluate the success of this approach. METHODS: We performed retrospective analysis of attempted thoracoscopic CDH repairs after ECMO decannulation at our institution from 2001 to 2015. Primary outcome was rate of conversion. Secondary outcomes were intraoperative end-tidal CO2, time to extubation, and rate of recurrence. RESULTS: We identified 21 post-ECMO patients in whom thoracoscopic CDH repair was attempted. Thoracoscopic repair was successfully completed in 28%. No patients had reported intolerance to insufflation at 3-7 mmHg. Average end-tidal CO2 at 15 operative minutes was 36.9 mmHg in the thoracoscopic group versus 50.7 mmHg in the open group and at 60 minutes was 34.25 mmHg versus 45.6 mmHg, respectively. One patient in the thoracoscopic group died and 1 experienced a large pneumothorax. In the converted group there was one clinically significant pneumothorax and three pleural effusions. Survivors after thoracoscopy were extubated an average of 5.6 ± 2.6 days after surgery versus 19.4 ± 10 days in the converted group (P < .05). Recurrence rates at last follow-up were equal between the two groups at 20%. CONCLUSIONS: Thoracoscopic CDH repair is both safe and feasible after ECMO with no increase in operative morbidity or mortality. Insufflation pressures of 3-7 mmHg are well tolerated without undue increase in end-tidal CO2. When compared to conversion cases, thoracoscopic repair is associated with significantly decreased time to extubation with no difference in recurrence.