Pancreatic Enzyme Use Reduces Pancreatitis Frequency in Children With Acute Recurrent or Chronic Pancreatitis: A Report From INSPPIRE.

INTRODUCTION: Among children who suffer from acute recurrent pancreatitis (ARP) or chronic pancreatitis (CP), acute pancreatitis (AP) episodes are painful, often require hospitalization, and contribute to disease complications and progression. Despite this recognition, there are currently no interventions to prevent AP episodes. In this retrospective cohort study, we assessed the impact of pancreatic enzyme therapy (PERT) use on clinical outcomes among children with pancreatic-sufficient ARP or CP. METHODS: Children with pancreatic-sufficient ARP or CP in the INSPPIRE-2 cohort were included. Clinical outcomes were compared for those receiving vs not receiving PERT, as well as frequency of AP before and after PERT. Logistic regression was used to study the association between development of AP episodes after starting PERT and response predictors. RESULTS: Among 356 pancreatic-sufficient participants, 270 (76%) had ARP, and 60 (17%) received PERT. Among those on PERT, 42% did not have a subsequent AP episode, during a mean 2.1 years of follow-up. Children with a SPINK1 mutation ( P = 0.005) and those with ARP (compared with CP, P = 0.008) were less likely to have an AP episode after starting PERT. After initiation of PERT, the mean AP annual incidence rate decreased from 3.14 down to 0.71 ( P < 0.001). DISCUSSION: In a retrospective analysis, use of PERT was associated with a reduction in the incidence rate of AP among children with pancreatic-sufficient ARP or CP. These results support the need for a clinical trial to evaluate the efficacy of PERT to improve clinical outcomes among children with ARP or CP.

Longitudinal Quality of Life and Glycemic Outcomes of Total Pancreatectomy With Islet Autotransplantation in Children With Chronic Pancreatitis Followed in a Pediatric Multidisciplinary Pancreas Clinic.

BACKGROUND: Total pancreatectomy with islet autotransplantation (TPIAT) is a potentially curative treatment for patients with chronic pancreatitis (CP) refractory to medical and endoscopic therapies. Patients often receive the initial follow-up medical care at the surgery-performing center, but then may follow up closer to where they live. We sought to describe the characteristics and outcomes of pediatric patients who underwent TPIAT at a national surgical referral center and were subsequently followed at our regional subspecialty center, the Children's Hospital Colorado. METHODS: We performed a retrospective analysis of baseline and outcomes data for the 10 pediatric patients who underwent TPIAT from 2007 to 2020 and received follow-up care at our institution. RESULTS: All patients had a diagnosis of CP, and nine of 10 patients had an identified underlying genetic risk factor. Insulin usage was common immediately following TPIAT, but at 1 year of follow-up, five of nine patients (55.6%) were insulin-independent and nine of nine had an HbA1c below 6.5%. For the four patients on insulin 1 year after TPIAT, total daily insulin dose ranged from 0.06 to 0.71 units/kg/day. All patients who underwent mixed meal tolerance testing had a robust peak C-peptide response at 1 year. There were significant improvements in nausea, school/work absences, narcotic dependence, and pancreas-related hospital admissions 1 year after TPIAT. CONCLUSIONS: Patients followed at our center had long-term improvements with low-insulin usage, detectable C-peptide, and improved pancreatitis-related outcomes after TPIAT. Pediatric patients who undergo TPIAT can be successfully co-managed in conjunction with the original surgery-performing center.

A National Survey of the Training and Practice Patterns of Practicing Pediatric Advanced Endoscopists in the United States.

BACKGROUND AND AIMS: Pediatric advanced endoscopy consists primarily of endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic ultrasound (EUS) and is becoming more common in pediatrics. This study aims to characterize the current landscape of pediatric advanced endoscopy training and practice by directly surveying independently practicing pediatric advanced endoscopists (PAEs). We also aim to ascertain expert opinion on competency in pediatric ERCP and EUS. METHODS: A 66-question REDCap survey and a 73-question Qualtrics survey were distributed to members of the ERCP Special Interest Group of North American Society of Pediatric Gastroenterology, Hepatology, and Nutrition. Respondents currently performing ERCP or EUS independently in children were included. Statistical analysis was performed using Mann-Whitney U test. RESULTS: Of 41 PAEs surveyed, 38 (92.7%) responded and 27 independent practitioners were included. Thirteen respondents performed EUS. PAEs who completed an advanced endoscopy fellowship (AEF) were more comfortable performing American Society for Gastrointestinal Endoscopy grade 3 or grade 4 ERCPs ( P < 0.0008) and felt more prepared to practice EUS independently than other trainees. Expert opinion of PAEs felt a threshold of 200 procedures was needed to attain competency in either ERCP or EUS. Pediatric duodenoscope exposure improved comfort in performing ERCP in children <10 kg ( P = 0.009). CONCLUSIONS: Training of pediatric gastroenterologists in ERCP and EUS are highly variable, though the skills attained are similar. AEF-trained specialists reported greater training volumes and felt more prepared to practice independently than those who did not. Competency thresholds determined by expert PAEs for ERCP and EUS agree with American Society for Gastrointestinal Endoscopy guidelines for adult advanced endoscopy trainees.

Pediatric Drug-Associated Pancreatitis Reveals Concomitant Risk Factors and Poor Reliability of Causality Scoring: Report From INSPPIRE.

OBJECTIVES: Drug-associated acute pancreatitis (DAP) studies typically focus on single acute pancreatitis (AP) cases. We aimed to analyze the (1) characteristics, (2) co-risk factors, and (3) reliability of the Naranjo scoring system for DAP using INSPPIRE-2 (the INternational Study group of Pediatric Pancreatitis: In search for a cuRE-2) cohort study of acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP) in children. METHODS: Data were obtained from ARP group with ≥1 episode of DAP and CP group with medication exposure ± DAP. Physicians could report multiple risk factors. Pancreatitis associated with Medication (Med) (ARP+CP) was compared to Non-Medication cases, and ARP-Med vs CP-Med groups. Naranjo score was calculated for each DAP episode. RESULTS: Of 726 children, 392 had ARP and 334 had CP; 51 children (39 ARP and 12 CP) had ≥1 AP associated with a medication; 61% had ≥1 AP without concurrent medication exposure. The Med group had other risk factors present (where tested): 10 of 35 (28.6%) genetic, 1 of 48 (2.1%) autoimmune pancreatitis, 13 of 51 (25.5%) immune-mediated conditions, 11 of 50 (22.0%) obstructive/anatomic, and 28 of 51 (54.9%) systemic risk factors. In Med group, 24 of 51 (47%) had involvement of >1 medication, simultaneously or over different AP episodes. There were 20 ARP and 4 CP cases in "probable" category and 19 ARP and 7 CP in "possible" category by Naranjo scores. CONCLUSIONS: Medications were involved in 51 of 726 (7%) of ARP or CP patients in INSPPIRE-2 cohort; other pancreatitis risk factors were present in most, suggesting a potential additive role of different risks. The Naranjo scoring system failed to identify any cases as "definitive," raising questions about its reliability for DAP.

Ketorolac Is Safe and Associated With Lower Rate of Post-Endoscopic Retrograde Cholangiopancreatography Pancreatitis in Children With Pancreatic Duct Manipulation.

OBJECTIVES: Use of non-steroidal anti-inflammatory drugs (NSAIDs) for post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) prevention in pediatrics is not well studied. Because of difficulty in accurately dosing indomethacin suppositories in pediatric patients, our center has used intravenous ketorolac for PEP prevention and present data on its safety and associated PEP rates. METHODS: Prospective monitoring of PEP for all patients who underwent ERCP at a pediatric tertiary care center from July 2010 to June 2018. Retrospective review of patient and procedural factors and severity of PEP. Routine use of ketorolac for PEP prevention began in 2014. RESULTS: Two hundred and ninety-eight ERCPs were analyzed. One hundred and sixty-six patients received intraprocedural ketorolac and 132 did not. One patient had post-ERCP bleeding and bleeding rates were not significantly different between ketorolac and non-ketorolac groups (0.6% vs 0%, P = 1). Overall rates of PEP were not significantly different between the ketorolac and no ketorolac group (9% vs 13%, P = 0.29); however, for high-risk pediatric patients with injection of contrast into and/or cannulation of the pancreatic duct, the rates of PEP were significantly lower for patients who received ketorolac (11% vs 25%, P = 0.035). CONCLUSIONS: Pediatric patients undergoing ERCP with manipulation of the pancreatic duct are high risk for PEP, and ketorolac was associated with a lower rate of PEP in these patients. Ketorolac was well tolerated without a higher rate of bleeding after ERCP. These results are the first to provide evidence showing an association with intraprocedural NSAID use and lower rates of PEP in select pediatric patients.

Chemistry of Simple Organic Peroxy Radicals under Atmospheric through Combustion Conditions: Role of Temperature, Pressure, and NOx Level.

Organic peroxy radicals (RO2) are key intermediates in the oxidation of organic compounds in both combustion systems and the atmosphere. While many studies have focused on reactions of RO2 in specific applications, spanning a relatively limited range of reaction conditions, the generalized behavior of RO2 radicals across the full range of reaction conditions (temperatures, pressures, and NO levels) has, to our knowledge, never been explored. In this work, two simple model systems, n-propyl peroxy radical and γ-isobutanol peroxy radical, are used to evaluate RO2 fate using pressure-dependent kinetics. The fate of these radicals was modeled based on literature data over 250-1250 K, 0.01-100 bar, and 1 ppt to 100 ppm of NO, which spans the typical range of atmospheric and combustion conditions. Covering this entire range provides a broad overview of the reactivity of these species under both atmospheric and combustion conditions, as well as under conditions intermediate to the two. A particular focus is on the importance of reactions that were traditionally considered to occur in only one of the two sets of conditions: RO2 unimolecular isomerization reactions (long known to occur in combustion systems but only recently appreciated in atmospheric systems) and RO2 bimolecular reactions of RO2 with NO (thought to occur mainly in atmospheric systems and rarely considered in combustion chemistry).

Results of duodenoscope culture and quarantine after manufacturer-recommended cleaning process.

BACKGROUND AND AIMS: Outbreaks of infections transmitted by duodenoscopes have prompted changes to duodenoscope cleaning protocols. However, little is known about effectiveness of clinical cleaning practices. We present culture data after duodenoscope manufacturer-recommended high-level disinfection (HLD) and quarantine. METHODS: Our institution adopted a combination of manufacturer-recommended cleaning with the Centers for Disease Control and Prevention-recommended culture and quarantine in 2015. Duodenoscopes (models TJF-Q180V, TJF-160, and PJF-160; Olympus, Center Valley, Penn, USA) underwent HLD according to the manufacturer's reprocessing manual protocols after use. Two culture specimens were then obtained using a sterile brush from the distal tip, including elevator mechanism, and by flushing sterile water through the working channel. Duodenoscopes were quarantined until cultures resulted. Positive cultures were defined as >10 colony-forming units (CFUs) of low-concern organisms or any CFUs of high-concern organisms according to Centers for Disease Control and Prevention recommendations. If either culture specimen was positive, the process was repeated until cultures were negative. Data were collected from December 2015 to July 2018. RESULTS: There were 140 instances of duodenoscope cleaning with 280 specimens. Twenty-eight of 234 (12%) initial culture specimens (18% of cultured duodenoscopes) were positive. Five of 36 (14%) second cultures were positive. Two of 8 (25%) third cultures were positive. Ninety-eight percent of organisms cultured were gram positive. In 8 instances both culture methods (brushing and flush) were positive; otherwise, only 1 method was positive. In 11 instances (8%) duodenoscopes were removed from quarantine before final culture results. No patient had infections related to ERCP. CONCLUSIONS: Eighteen percent of duodenoscopes had a positive culture after initial HLD. Only 3% were gram-negative bacteria. Repeated HLD was 86% and 75% effective at eliminating initial and repeat positive cultures, respectively. Initial HLD per manufacturer recommendations is not always effective at eliminating bacterial contamination. Additional steps are necessary to decrease risks of duodenoscope-transmitted infections.

Pressure-dependent kinetics of peroxy radicals formed in isobutanol combustion.

Bio-derived isobutanol has been approved as a gasoline additive in the US, but our understanding of its combustion chemistry still has significant uncertainties. Detailed quantum calculations could improve model accuracy leading to better estimation of isobutanol's combustion properties and its environmental impacts. This work examines 47 molecules and 38 reactions involved in the first oxygen addition to isobutanol's three alkyl radicals located α, ß, and γ to the hydroxide. Quantum calculations are mostly done at CCSD(T)-F12/cc-pVTZ-F12//B3LYP/CBSB7, with 1-D hindered rotor corrections obtained at B3LYP/6-31G(d). The resulting potential energy surfaces are the most comprehensive isobutanol peroxy networks published to date. Canonical transition state theory and a 1-D microcanonical master equation are used to derive high-pressure-limit and pressure-dependent rate coefficients, respectively. At all conditions studied, the recombination of γ-isobutanol radical with O2 forms HO2 + isobutanal. The recombination of ß-isobutanol radical with O2 forms a stabilized hydroperoxy alkyl radical below 400 K, water + an alkoxy radical at higher temperatures, and HO2 + an alkene above 1200 K. The recombination of ß-isobutanol radical with O2 results in a mixture of products between 700-1100 K, forming acetone + formaldehyde + OH at lower temperatures and forming HO2 + alkenes at higher temperatures. The barrier heights, high-pressure-limit rates, and pressure-dependent kinetics generally agree with the results from previous quantum chemistry calculations. Six reaction rates in this work deviate by over three orders of magnitude from kinetics in detailed models of isobutanol combustion, suggesting the rates calculated here can help improve modeling of isobutanol combustion and its environmental fate.

Comparative Analysis of Adverse Events After Esophageal Balloon and Bougie Dilations in Children.

BACKGROUND: Pneumatic balloon and bougie dilation are widely used methods for pediatric esophageal dilation. There are no studies directly comparing the safety of these techniques in pediatric patients. This study compared adverse events (AEs) of balloon and bougie dilation in children at a single institution. METHODS: AEs were identified by means of a prospective clinical registry of all procedure related AEs from 2012 to 2015 at a single institution. Identified AEs underwent retrospective review of procedural and clinical details. The category of each AE was recorded and severity was assigned using a 5-point scoring system. AEs were compared between balloon and bougie dilation for different severities. RESULTS: There were 105 patients who underwent 246 dilation sessions. Balloon dilation was performed more commonly (n = 190, 77%) as compared to Maloney dilators (n = 56, 23%). Patients with balloon dilation were younger (3.0 vs 14.5 years, P = 0.0001) and more likely to have strictures from caustic ingestion (42% vs 2%, P < 0.0001) or surgical anastomoses (34% vs 5% P < 0.0001). Bougie dilation was used more commonly in patients with eosinophilic esophagitis (77% vs 7%, P < 0.0001)). In multivariate analysis, each year of increasing age was associated with a 12% increase in any AEs (P = 0.015), but no difference in clinically significant AEs (grade 2 or higher) was identified between dilation methods. CONCLUSIONS: Bougie and balloon dilation did not have significant differences in AE rates, but the patient populations differed between the 2 methods. The dilation method should depend on stricture characteristics and endoscopist expertise with each method.

Modeling of aromatics formation in fuel-rich methane oxy-combustion with an automatically generated pressure-dependent mechanism.

With the rise in production of natural gas, there is increased interest in homogeneous partial oxidation (POX) to convert methane to syngas (CO + H2), ethene (C2H4) and acetylene (C2H2). In POX, polycyclic aromatic hydrocarbons (PAH) are important undesired byproducts. To improve the productivity of such POX processes, it is necessary to have an accurate chemical mechanism for methane-rich combustion including PAH. A new mechanism was created to capture the chemistry from C0 to C12, incorporating new information derived from recent quantum chemistry calculations, with help from the Reaction Mechanism Generator (RMG) software. For better estimation of kinetics and thermochemistry of aromatic species, including reactions through carbene intermediates, new reaction families and additional data from quantum chemistry calculations were added to RMG-database. Many of the rate coefficients in the new mechanism are significantly pressure-dependent at POX conditions. The new mechanism was validated against electron-ionization molecular beam mass spectrometry (EI-MBMS) data from a high-temperature flow reactor reported by Kohler et al. In this work quantification of additional species from those experiments is reported including phenylacetylene (C8H6), indene (C9H8), naphthalene (C10H8) and acenaphthylene (C12H8) at many temperatures for several feed compositions. Comparison of the experimental species concentration data and the new kinetic model is satisfactory; the new mechanism is generally more accurate than other published mechanisms. Moreover, because the new mechanism is composed of elementary chemical reaction steps instead of global fitted kinetics, pathway analysis of species could be investigated step-by-step to understand PAH formation. For methane-rich combustion, the most important routes to key aromatics are propargyl recombination for benzene, reactions of the propargyl radical with the phenyl radical for indene, and hydrogen abstraction acetylene addition (HACA) for naphthalene.

Correct Symmetry Treatment for X + X Reactions Prevents Large Errors in Predicted Isotope Enrichment.

Confusion over how to account for symmetry numbers when reactants are identical can cause significant errors in isotopic studies. An extraneous factor of 2 in the reaction symmetry number, as proposed in the literature, violates reaction equilibrium and causes huge enrichment errors in isotopic analysis. In actuality, no extra symmetry factor is needed with identical reactants.

Impact of fellow training level on adverse events and operative time for common pediatric GI endoscopic procedures.

BACKGROUND AND AIMS: Previous studies on pediatric endoscopic training have not examined in detail if adverse events (AEs) are affected by the fellow's training level. We aimed to determine whether trainee presence and educational level increase AEs or operative time (OT) for pediatric intestinal endoscopy. METHODS: This was a prospective observational study of AEs for all endoscopic procedures and retrospective analysis of OT (time of endoscope insertion until removal) for a sample of specified procedures at a tertiary children's hospital. AEs were categorized by severity grades: 1, home management; 2, outpatient evaluation; 3, hospitalization and/or repeat endoscopy; 4, surgery and/or intensive care unit admission; and 5, death. RESULTS: A total of 15,886 procedures (6257 with trainee) including 1627 therapeutic procedures (733 with trainee) were analyzed for AEs. Four hundred thirteen total AEs (2.60%) and 213 AEs grade 2 to 4 (1.34%) were identified. Fellow presence at any training level did not increase AE rates for any procedures. Median OT for 3762 EGDs decreased from 17 to 11 minutes from the first quarter to the fourth quarter of first-year fellowship and then remained stable. EGDs without fellows were shorter (9 minutes, P < .0001) compared with any training level. Median times of 1291 colonoscopies with EGD decreased from 55 to 51 to 47 minutes for fellows in the first half, second half of first-year fellowship, and second and third year, respectively. Attendings alone were faster (37 minutes, P < .0001). CONCLUSIONS: Current pediatric endoscopic training for is safe regardless of fellow training level. Trainee efficiency improves during and after fellowship.

Use of Fully Covered Self-expanding Metal Biliary Stents in Pediatrics: A Case Series.

OBJECTIVES: Endoscopic retrograde cholangiopancreatography is used to manage biliary pathology in pediatric patients. Plastic biliary stents have been used in this population for obstructive lesions and bile leaks; however, they are sometimes not effective due to migration, occlusion, or ineffective sealing. Fully covered self-expanding metal stents (FCSEMS) have larger diameters making them more suitable for some situations. Their use in pediatrics has, however, not been defined. The aim of the present study is to describe our experience with FCSEMS at our institution. METHODS: We present a series of all patients who underwent FCSEMS placement at Children's Hospital Colorado including 3 adolescents and 1 young adult with complex medical needs. RESULTS: Patient age range was 12 to 24 years and the weight ranged between 36 and 75 kg. All patients underwent previous endoscopic retrograde cholangiopancreatography and 1 or more rounds of plastic stenting without adequate clinical response before consideration of FCSEMS placement. Indications included recalcitrant biliary anastomotic stricture after liver transplant, persistent bile leak after needle perforation, recurrent obstructive choledocholithiasis after cholecystectomy, and malignant biliary stricture. Sizes of FCSEMS depended on patient bile duct size and biliary pathology. Dwell time was 6 to 8 weeks. Three patients had resolution of biliary pathology after FCSEMS therapy. One patient had distal migration of FCSEMS necessitating repeat stenting. There were no adverse events from FCSEMS placement or removal. CONCLUSIONS: FCSEMS therapy should be considered in appropriate pediatric patients when plastic biliary stents are not effective. Further studies are needed to evaluate the safety and efficacy of FCSEMS in the pediatric age group.

Clinical Implications of Pediatric Colonic Eosinophilia.

OBJECTIVE: Pediatric colonic eosinophilia represents a confounding finding with a wide differential. It is often difficult to determine which children may progress to inflammatory bowel disease (IBD), which have an eosinophilic colitis (EC), and which may have no underlying pathology. There is little guidance for the practitioner on the approach to these patients. To define the clinical presentations of colonic eosinophilia and identify factors which may aid in diagnosis we reviewed patients with colonic eosinophilia and the clinicopathologic factors associated with their diagnoses. METHODS: An 8-year retrospective chart review of children whose histopathology identified colonic eosinophilia (N = 72) compared to controls with normal biopsies (N = 35). RESULTS: Patients with colonic eosinophilia had increased eosinophils/high-power field compared to controls (P < 0.001) and had 3 clinical phenotypes. Thirty-six percent had an inflammatory phenotype with elevated erythrocyte sedimentation rate (P < .0001), chronic inflammation on colonic biopsies (P < 0.001), and were diagnosed as having IBD. Thirty-seven percent were diagnosed as having EC, associated with male sex (P < 0.005) and peripheral eosinophilia (P = 0.041). Twenty-one percent had no significant colonic pathology. Forty-three percent of patients had >1 colonoscopy and 68% of these had change from initial diagnoses. CONCLUSIONS: There are 3 main phenotypes of children with colonic eosinophilia. Signs of chronic systemic inflammation raise suspicion for IBD. Peripheral eosinophilia and male sex are associated with EC. A significant percent of children with colonic eosinophilia do not have colonic disease. Eosinophils/high-power field is not reliable to differentiate etiologies. Repeat colonoscopies may be required to reach final diagnoses.