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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., (Copyright © 2024 by The American College of Gastroenterology.)

Objective: To determine if mild-moderate hypertriglyceridemia (HTG) is associated with increased development of chronic pancreatitis (CP) or pancreatitis-associated complications in children with acute recurrent or CP., Study Design: Longitudinal data from the INternational Study group of Pediatric Pancreatitis: In search for a cuRE-2 (INSPPIRE-2) cohort of children with acute recurrent or CP (n = 559) were analyzed. Subjects were divided into normal triglycerides (<150 mg/dL; 1.7 mmol/L), any HTG (≥150 mg/dL; ≥1.7 mmol/L), mild-moderate HTG (150-499 mg/dL; 1.7-5.6 mmol/L), moderate HTG (500-999 mg/dL; 5.6-11.3 mmol/L), and severe HTG groups (≥1000 mg/dL; ≥11.3 mmol/L), based on highest serum triglyceride value. Laboratory, imaging, pancreatitis and hospital events, complications, and quality of life data were analyzed., Results: In children with acute recurrent or CP and HTG, there was no increase in the number of pancreatitis attacks per person-years, nor an increase in CP prevalence. However, HTG severity was associated with increased pancreatic inflammation, pancreatic cysts, pain, hospital days, number of hospitalizations, intensive care, and missed school days., Conclusions: Mild-moderate HTG in children with acute recurrent or CP was not associated with increased pancreatitis frequency, nor increased development of CP, but was associated with increased pancreatitis complications and disease burden. As a treatable condition, treatment of mild-moderate HTG may be considered to reduce pancreatitis-associated complications and medical burden in children with acute recurrent or CP., Competing Interests: Declaration of Competing Interest Z.M.S. is currently an employee of 4D Molecular Therapeutics Inc and a consultant for BridgeBio Pharma and Renexxion. M.A.H. is the president of CAPER, a board member of CAPER, and a board member of the National Pancreas Foundation. T.G. received a research grant from Vertex Pharmaceuticals, and she is a consultant for Cystic Fibrosis Foundation (CFF). C.Y.O. is a consultant for and has received research grant from Vertex Pharmaceuticals. E.R.P. is a consultant for BridgeBio and Ultragenyx. S.J.S. is a consultant for UpToDate, Nestle, Abbvie, Renexxion, and the CFF. A.J.F. is a consultant for Takeda and AbbVie, CFF, and is a member of the CAPER board. V.D.M. is an Associate Editor for JPGN Reports. D.M.T. is an Associate Editor for JPGN. M.W. is a consultant for and has received research grants from Vertex Pharmaceuticals. M.E.L. receives royalties from Millipore Inc and UpToDate and consults for CFF. A.U. is a consultant for CFF and Abbvie Inc. The other authors declare no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

In vitro models of autoimmunity are constrained by an inability to culture affected epithelium alongside the complex tissue-resident immune microenvironment. Coeliac disease (CeD) is an autoimmune disease in which dietary gluten-derived peptides bind to the major histocompatibility complex (MHC) class II human leukocyte antigen molecules (HLA)-DQ2 or HLA-DQ8 to initiate immune-mediated duodenal mucosal injury 1-4 . Here, we generated air-liquid interface (ALI) duodenal organoids from intact fragments of endoscopic biopsies that preserve epithelium alongside native mesenchyme and tissue-resident immune cells as a unit without requiring reconstitution. The immune diversity of ALI organoids spanned T cells, B and plasma cells, natural killer (NK) cells and myeloid cells, with extensive T-cell and B-cell receptor repertoires. HLA-DQ2.5-restricted gluten peptides selectively instigated epithelial destruction in HLA-DQ2.5-expressing organoids derived from CeD patients, and this was antagonized by blocking MHC-II or NKG2C/D. Gluten epitopes stimulated a CeD organoid immune network response in lymphoid and myeloid subsets alongside anti-transglutaminase 2 (TG2) autoantibody production. Functional studies in CeD organoids revealed that interleukin-7 (IL-7) is a gluten-inducible pathogenic modulator that regulates CD8 + T-cell NKG2C/D expression and is necessary and sufficient for epithelial destruction. Furthermore, endogenous IL-7 was markedly upregulated in patient biopsies from active CeD compared with remission disease from gluten-free diets, predominantly in lamina propria mesenchyme. By preserving the epithelium alongside diverse immune populations, this human in vitro CeD model recapitulates gluten-dependent pathology, enables mechanistic investigation and establishes a proof of principle for the organoid modelling of autoimmunity., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Duodenal bicarbonate secretion is critical to epithelial protection, as well as nutrient digestion and absorption, and is impaired in cystic fibrosis (CF). We examined if linaclotide, typically used to treat constipation, may also stimulate duodenal bicarbonate secretion. Bicarbonate secretion was measured in vivo and in vitro using mouse and human duodenum (biopsies and enteroids). Ion transporter localization was identified with confocal microscopy, and de novo analysis of human duodenal single-cell RNA sequencing (scRNA-Seq) data sets was performed. Linaclotide increased bicarbonate secretion in mouse and human duodenum in the absence of cystic fibrosis transmembrane conductance regulator (CFTR) expression (Cftr-knockout mice) or function (CFTRinh-172). Na+/H+ exchanger 3 inhibition contributed to a portion of this response. Linaclotide-stimulated bicarbonate secretion was eliminated by down-regulated in adenoma (DRA, SLC26A3) inhibition during loss of CFTR activity. ScRNA-Seq identified that 70% of villus cells expressed SLC26A3, but not CFTR, mRNA. Loss of CFTR activity and linaclotide increased apical brush border expression of DRA in non-CF and CF differentiated enteroids. These data provide further insights into the action of linaclotide and how DRA may compensate for loss of CFTR in regulating luminal pH. Linaclotide may be a useful therapy for CF individuals with impaired bicarbonate secretion.

Cystic fibrosis (CF) may cause a spectrum of hepatobiliary complications, including portal hypertension, multilobular cirrhosis, and liver failure. Current guidelines on the detection and monitoring of hepatobiliary complications in CF were published in 1999. The CF Foundation assembled a committee to evaluate research advances and formulate revised guidelines for CF-associated liver disease. A committee of hepatologists, gastroenterologists, pulmonologists, pharmacists, nurses, dietitians, individuals with CF, and the parents of a child with CF devised "population, intervention, comparison, and outcome" questions regarding hepatobiliary disease in CF. PubMed literature searches were performed for each population, intervention, comparison, and outcome question. Recommendations were voted on with 80% agreement required to approve a recommendation. Public comment on initial recommendations was solicited prior to the formulation of final recommendations. Thirty-one population, intervention, comparison, and outcome questions were assembled, 6401 manuscripts were title screened for relevance, with 1053 manuscripts undergoing detailed full-text review. Seven recommendations were approved for screening, 13 for monitoring of existing disease, and 14 for treatment of CF-associated hepatobiliary involvement or advanced liver disease. One recommendation on liver biopsy did not meet the 80% threshold. One recommendation on screening ultrasound was revised and re-voted on. Through a multidisciplinary committee and public engagement, we have assembled updated recommendations and guidance on screening, monitoring, and treatment of CF-associated hepatobiliary involvement and advanced liver disease. While research gaps remain, we anticipate that these recommendations will lead to improvements in CF outcomes through earlier detection and increased evidence-based approaches to monitoring and treatment., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background/objectives: Bone health of children with acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP) is not well studied., Methods: This retrospective study was performed at three sites and included data from INSPPIRE-2., Results: Of the 87 children in the study: 46 had ARP (53%), 41 had CP (47%). Mean age was 13.6 ± 3.9 years at last DXA scan. The prevalence of low height-for-age (Z-score < -2) (13%, 10/78) and low bone mineral density (BMD) adjusted for height (Z-score < -2) (6.4%, 5/78) were higher than a healthy reference sample (2.5%, p < 0.0001 and p = 0.03, respectively)., Conclusion: Children with ARP or CP have lower height and BMD than healthy peers. Attention to deficits in growth and bone mineral accrual in children with pancreatic disease is warranted., (Copyright © 2023 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Introduction: Pancreatitis in inflammatory bowel disease has been attributed to peripancreatic intestinal disease and/or drug-induced pancreatic toxicity. We used large cohort analyses to define inflammatory bowel disease and pancreatitis temporal co-occurrence with a detailed descriptive analysis to gain greater insight into the pathophysiological relationship between these 2 diseases., Methods: Truven Health MarketScan private insurance claims from 141,017,841 patients (younger than 65 years) and 7,457,709 patients from 4 academic hospitals were analyzed. We calculated the prevalence of Crohn's disease or ulcerative colitis (UC) with acute pancreatitis or chronic pancreatitis (CP) and performed temporal and descriptive analyses., Results: Of 516,724 patients with inflammatory bowel disease, 12,109 individuals (2.3%) had pancreatitis. Acute pancreatitis (AP) was 2-6x more prevalent than CP. In adults, AP occurred equally among Crohn's disease and UC (1.8%-2.2% vs 1.6%-2.1%, respectively), whereas in children, AP was more frequent in UC (2.3%-3.4% vs 1.5%-1.8%, respectively). The highest proportion of pancreatitis (21.7%-44.7%) was at/near the time of inflammatory bowel disease diagnosis. Of them, 22.1%-39.3% were on steroids during pancreatitis. Individuals with CP or recurrent pancreatitis hospitalizations had increased risk of a future inflammatory bowel disease diagnosis (odds ratio = 1.52 or 1.72, respectively)., Discussion: Pancreatitis in inflammatory bowel disease may not simply be a drug adverse event but may also involve local and/or systemic processes that negatively affect the pancreas. Our analysis of pancreatitis before, during, and after inflammatory bowel disease diagnosis suggests a bidirectional pathophysiologic relationship between inflammatory bowel disease and pancreatitis, with potentially more complexity than previously appreciated., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

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., Competing Interests: Dr Lowe is on the Board of Directors of the National Pancreas Association and receives royalties from Millipore Inc and UpToDate. Dr Gonska received a research grant from Vertex Pharmaceuticals, and she is a consultant for Cystic Fibrosis Foundation (CFF). Dr Uc is a member of American Board of Pediatrics, Subboard of Pediatric Gastroenterology, Associate Editor of Pancreatology , and consultant for CFF. Dr Schwarzenberg is a consultant for UpToDate, Nestle, AbbVie, and the CFF, and she has a grant from Gilead. Dr Troendle is an Associate Editor for JPGN . Dr Morinville is an Associate Editor for JPGN Reports . The remaining authors report no conflicts of interest., (Copyright © 2023 by European Society for European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Although it was described previously for estrogen (E 2 ) regulation of intestinal epithelial Cl - and HCO 3 - secretion in sex difference, almost nothing is known about the roles of estrogen receptor (ER) subtypes in regulating E 2 -modulated epithelial ion transports and epithelial restitution. Here, we aimed to investigate ERα and ERβ subtypes in the regulation of E 2 -modulated colonic epithelial HCO 3 - and Cl - secretion and epithelial restitution. Through physiological and biochemical studies, in combination of genetic knockdown, we showed that ERα attenuated female colonic Cl - secretion but promoted Ca 2+ -dependent HCO 3 - secretion via store-operated calcium entry (SOCE) mechanism in mice. However, ERβ attenuated HCO 3 - secretion by inhibiting Ca 2+ via the SOCE and inhibiting cAMP via protein kinases. Moreover, ERα but not ERβ promoted epithelial cell restitution via SOCE/Ca 2+ signaling. ERα also enhanced cyclin D1, proliferating cell nuclear antigen, and β-catenin expression in normal human colonic epithelial cells. All ERα-mediated biological effects could be attenuated by its selective antagonist and genetic knockdown. Finally, both ERα and ERβ were expressed in human colonic epithelial cells and mouse colonic tissues. We therefore conclude that E 2 modulates complex colonic epithelial HCO 3 - and Cl - secretion via ER subtype-dependent mechanisms and that ERα is specifically responsible for colonic epithelial regeneration. This study provides novel insights into the molecular mechanisms of how ERα and ERβ subtypes orchestrate functional homeostasis of normal colonic epithelial cells., Competing Interests: Conflicts of interest The authors declare no conflicts of interest with the content of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

See Bonus NeoBriefs videos and downloadable teaching slides Gastrointestinal complications of cystic fibrosis (CF) are often the earliest manifestations of disease and contribute to significant morbidity and mortality. Early diagnosis of CF is paramount, as early intervention has been associated with improved long-term pulmonary and nutritional outcomes. In this review, we describe common gastrointestinal, pancreatic, hepatic, and nutritional manifestations of CF in neonates to aid clinicians in diagnosing and managing the earliest gastrointestinal manifestations of CF. Furthermore, we discuss how the use of CFTR-targeted therapies by pregnant and/or breastfeeding persons may affect CF diagnosis in newborns and their potential impact on halting or reversing CF disease progression., (Copyright © 2023 by the American Academy of Pediatrics.)

Multiciliated cell loss is a hallmark of airway epithelial remodeling in chronic inflammatory airway diseases including cystic fibrosis (CF), asthma, and chronic obstructive pulmonary disease. It disrupts mucociliary clearance, which fuels disease progression. Effective clearance requires an optimal proportion of multiciliated and secretory cells. This is controlled by Notch signaling such that between two adjacent cells the one that activates Notch becomes a secretory cell and the one that avoids Notch activation becomes a multiciliated cell. Consequently, blocking Notch by a small molecule inhibitor of the γ-secretase enzyme that cleaves the Notch receptor for signal activation directs differentiation toward the multiciliated lineage. Thus, γ-secretase inhibitor (GSI) treatment may alleviate multiciliated cell loss in lung disease. Here, we demonstrate the therapeutic restoration of multiciliated cells by the GSI LY450139 (semagacestat). LY450139 increased multiciliated cell numbers in a dose-dependent manner in healthy primary human nasal epithelial cells (HNECs) during differentiation and in mature cultures, but not when applied during early epithelialization of progenitors. LY450139 did not impact stem cell proliferation. Basal and apical administration were equally effective. In healthy adult mice, LY450139 increased multiciliated cell numbers without detectible toxicity. LY450139 also increased multiciliated cells and decreased excess mucus secretory cells in CF HNECs and IL-13 remodeled healthy HNECs. LY450139 normalized multiciliated cell numbers in CF HNECs without interfering with the activity of CFTR modulator compounds. In summary, we demonstrate that GSI administration is a promising therapeutic to restore multiciliated cells and potentially improve epithelial function in a wide range of chronic lung diseases. NEW & NOTEWORTHY Our findings show that low-dose, short-term topical or systemic γ-secretase inhibitor treatment may lead to restoration of multiciliated cells without toxicity and potentially improve epithelial function in a wide range of chronic lung diseases.

Previous wireless motility capsule (WMC) studies demonstrated decreased small intestinal pH in people with CF (PwCF) however the data is lacking on the colonic pH profile. We re-analyzed previously published WMC data to determine colonic pH/bicarbonate concentration and single cell RNA sequencing (sc-RNAseq) to examine the normal expression of acid-base transporters in the colon/rectum.CF patients showed significantly lower pH and bicarbonate concentration values, particularly in the distal rectosigmoid region. There was no difference in colonic motility parameters between CF and non-CF subjects. SLC26A3 is highly expressed bicarbonate transporter in the colon and rectum, more so than CFTR. While dysmotility can alter intraluminal pH, observed changes likely originate from alterations in intestinal ion transport rather than colonic dysmotility. SLC26A3 is abundantly expressed in the human colon and rectum and may be a therapeutic target for restoration of bicarbonate transport. These findings may help better understand the gastrointestinal symptoms in PwCF., Competing Interests: Declaration of Competing Interest All authors report no conflict of interest related to this study., (Copyright © 2022 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

The cystic fibrosis (CF) transmembrane conductance regulator corrector/potentiator combinations lumacaftor/ivacaftor and elexacaftor/tezacaftor/ivacaftor improve sweat chloride, pulmonary function, and nutrition. Yet it is unclear whether they may also impact the progression of liver fibrosis, which is a substantial source of morbidity and mortality for patients with CF. We conducted a retrospective, single-center analysis of children and adolescents with CF treated with lumacaftor/ivacaftor and/or elexacaftor/tezacaftor/ivacaftor therapy, focusing on alterations in liver function tests and fibrosis indices using previously-established thresholds that corresponded with increased liver elastography. In pairwise comparisons of before and during treatment timepoints, we found that those with CF-associated liver involvement experienced significant decreases in gamma-glutamyl transferase, aspartate aminotransferase-to-platelet index, and gamma-glutamyl transferase-to-platelet ratio while on lumacaftor/ivacaftor. These differences were not observed in patients treated with elexacaftor/tezacaftor/ivacaftor, nor were they observed in patients without underlying CF-associated liver disease. These results provide the first evidence that lumacaftor/ivacaftor may improve liver fibrosis in children and adolescents with CF and suggest it may be beneficial in the treatment of CF-associated liver disease., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Objectives: The objective of this study is to investigate risk factors and disease burden in pediatric acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP)., Methods: Data were obtained from INternational Study group of Pediatric Pancreatitis: In search for a cuRE-2 (INSPPIRE-2), the largest multi-center prospective cohort study in pediatric patients with ARP or CP., Results: Of 689 children, 365 had ARP (53%), 324 had CP (47%). CP was more commonly associated with female sex, younger age at first acute pancreatitis (AP) attack, Asian race, family history of CP, lower BMI%, genetic and obstructive factors, PRSS1 mutations and pancreas divisum. CFTR mutations, toxic-metabolic factors, medication use, hypertriglyceridemia, Crohn disease were more common in children with ARP. Constant or frequent abdominal pain, emergency room (ER) visits, hospitalizations, medical, endoscopic or surgical therapies were significantly more common in CP, episodic pain in ARP. A total of 33.1% of children with CP had exocrine pancreatic insufficiency (EPI), 8.7% had diabetes mellitus. Compared to boys, girls were more likely to report pain impacting socialization and school, medical therapies, cholecystectomy, but no increased opioid use. There was no difference in race, ethnicity, age at first AP episode, age at CP diagnosis, duration of disease, risk factors, prevalence of EPI or diabetes between boys and girls. Multivariate analysis revealed that family history of CP, constant pain, obstructive risk factors were predictors of CP., Conclusions: Children with family history of CP, constant pain, or obstructive risk factors should raise suspicion for CP., Competing Interests: M.E.L. is on the Board of Directors of the National Pancreas Association and receives royalties from Millipore Inc and UpToDate. T.G. received a research grant from Vertex Pharmaceuticals, and she is a consultant for Cystic Fibrosis Foundation (CFF). A.U. is a member of American Board of Pediatrics, Subboard of Pediatric Gastroenterology, Associate Editor of Pancreatology, and consultant for CFF. S.J.S. is a consultant for UpToDate, Nestle, Abbvie, and the Cystic Fibrosis Foundation, and she has a grant from Gilead. V.D.M. is an Associate Editor for JPGN Reports. The remaining authors report no conflicts of interest., (Copyright © 2022 by European Society for European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Purpose: Cystic fibrosis (CF) is not well-characterized in Asians, potentially resulting in delayed diagnosis and poor prognosis. We characterized CF in Asian subgroups to address these disparities., Methods: De-identified ethnicity and CFTR variant data were obtained from the United States, United Kingdom, and Canadian CF registries. We measured the prevalence of CF, CFTR variant allele frequencies, effectiveness of screening panels, and eligibility for modulator therapies., Results: The prevalence of CF was 1 in 74,982 people (Canada) to 1 in 13,340 people (United Kingdom) for South Asians and 1 in 256,541 (Canada) to 1 in 52,563 (United Kingdom) for other Asians, suggesting 26,000 to 146,000 patients with CF in South Asia. p.(F508del) variant was markedly less frequent in Asians than in non-Hispanic Whites. Splicing and nonsense variants occurred at high allelic frequencies in Asians, resulting in 41% to 49% of South Asians and 21% to 39% of other Asians being ineligible for CFTR modulator therapies. Hologic/EU2v1 panels failed to identify 37% to 47% of South Asian and 23% to 46% of other Asian patients with CF., Conclusions: Among Asians, CF appears to be more common in South Asians. A significant CF population may exist in South Asia. CFTR variants in South and other Asians markedly differ from non-Hispanic Whites causing inequities in newborn screening, diagnosis, and treatment. New strategies are necessary to mitigate these health care disparities., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Introduction: Cystic fibrosis transmembrane conductance regulator (CFTR)-mediated chloride and bicarbonate secretion is integral to the pancreas' ability to produce the alkaline pancreatic juice required for proper activation of enzymes for digestion. Disruption in this process increases the risk for pancreatitis., Areas Covered: Using original basic and clinical research, as well as clinical case reports and recent reviews indexed in PubMed, we discuss why patients with CFTR dysfunction are at risk for pancreatitis. We also discuss diagnostic modalities for assessing CFTR function, as well as new therapeutic advancements and the impact these are having on pancreatic function, pancreatitis in particular., Expert Opinion: CFTR-related pancreatitis occurs in the presence of monallelic or biallelic mutations and/or from toxin-mediated channel disruption. Research-based CFTR diagnostics have been expanded, yet all current methods rely on measuring CFTR chloride transport in non-pancreatic cells/tissue. Newer CFTR-directed therapies ('CFTR modulators') are both improving pancreatitis (pancreatic-sufficient CF patients) and increasing the risk for pancreatitis (previously pancreatic-insufficient CF patients). Our experiences with these drugs are enlightening us on how CFTR modulation can affect pancreatitis risk across a wide spectrum of pancreatic disease, and represents an opportunity for therapeutic relief from pancreatitis in those without CF, but who suffer from CFTR-related pancreatitis.

Although capsaicin has been studied extensively as an activator of the transient receptor potential vanilloid cation channel subtype 1 (TRPV1) channels in sensory neurons, little is known about its TRPV1-independent actions in gastrointestinal health and disease. Here, we aimed to investigate the pharmacological actions of capsaicin as a food additive and medication on intestinal ion transporters in mouse models of ulcerative colitis (UC). The short-circuit current (I sc ) of the intestine from WT, TRPV1-, and TRPV4-KO mice were measured in Ussing chambers, and Ca 2+ imaging was performed on small intestinal epithelial cells. We also performed Western blots, immunohistochemistry, and immunofluorescence on intestinal epithelial cells and on intestinal tissues following UC induction with dextran sodium sulfate. We found that capsaicin did not affect basal intestinal I sc but significantly inhibited carbachol- and caffeine-induced intestinal I sc in WT mice. Capsaicin similarly inhibited the intestinal I sc in TRPV1 KO mice, but this inhibition was absent in TRPV4 KO mice. We also determined that Ca 2+ influx via TRPV4 was required for cholinergic signaling-mediated intestinal anion secretion, which was inhibited by capsaicin. Moreover, the glucose-induced jejunal I sc via Na + /glucose cotransporter was suppressed by TRPV4 activation, which could be relieved by capsaicin. Capsaicin also stimulated ouabain- and amiloride-sensitive colonic I sc . Finally, we found that dietary capsaicin ameliorated the UC phenotype, suppressed hyperaction of TRPV4 channels, and rescued the reduced ouabain- and amiloride-sensitive I sc . We therefore conclude that capsaicin inhibits intestinal Cl - secretion and promotes Na + absorption predominantly by blocking TRPV4 channels to exert its beneficial anti-colitic action., Competing Interests: Conflicts of interests The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Abdominal pain, emergency department visits, and hospitalizations impact lives of children with acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP). Data on health-related quality of life (HRQOL) in this population, however, remains limited. We aimed to evaluate HRQOL in children with ARP or CP; and test biopsychosocial risk factors associated with low HRQOL., Methods: Data were acquired from the INternational Study Group of Pediatric Pancreatitis: In search for a cuRE registry. Baseline demographic and clinical questionnaires, the Child Health Questionnaire (measures HRQOL) and Child Behavior Checklist (measures emotional and behavioral functioning) were completed at enrollment., Results: The sample included 368 children (54.3% girls, mean age = 12.7years, standard deviation [SD] = 3.3); 65.2% had ARP and 34.8% with CP. Low physical HRQOL (M = 38.5, SD = 16.0) was demonstrated while psychosocial HRQOL (M = 49.5, SD = 10.2) was in the normative range. Multivariate regression analysis revealed that clinical levels of emotional and behavioral problems (B = -10.28, P  < 0.001), episodic and constant abdominal pain (B = 04.66, P = 0.03; B = -13.25, P < 0.001) were associated with low physical HRQOL, after accounting for ARP/CP status, age, sex, exocrine, and endocrine disease (F [9, 271] = 8.34, P < 0.001). Borderline and clinical levels of emotional and behavioral problems (B = -10.18, P < 0.001; B = -15.98, P < 0.001), and constant pain (B = -4.46, P < 0.001) were associated with low psychosocial HRQOL (F [9, 271] = 17.18, P < 0.001)., Conclusions: Findings highlight the importance of assessing HRQOL and treating pain and psychosocial problems in this vulnerable group of children., Competing Interests: M.L. is on the Board of Directors of the National Pancreas Association; receives royalties from Millipore Inc and UpToDate. T.G. received a research grant from Vertex Pharmaceuticals and she is a consultant for Cystic Fibrosis Foundation. M.B. is a consultant for AbbVie Inc and ARIEL Precision Medicine. C.Y.O. is a consultant for Vertex Pharmaceuticals. A.U. is a member of American Board of Pediatrics, Subboard of Pediatric Gastroenterology and a consultant for Cystic Fibrosis Foundation. The other authors declare no conflicts of interest., (Copyright © 2022 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Objectives: Chronic pancreatitis (CP) is rare in childhood but impactful because of its high disease burden. There is limited literature regarding the management of CP in children, specifically about the various surgical approaches. Herein, we summarize the current pediatric and adult literature and provide recommendations for the surgical management of CP in children., Methods: The literature review was performed to include the scope of the problem, indications for operation, conventional surgical options as well as total pancreatectomy with islet autotransplantation, and outcomes following operations for CP., Results: Surgery is indicated for children with debilitating CP who have failed maximal medical and endoscopic interventions. Surgical management must be tailored to the patient's unique needs, considering the anatomy and morphology of their disease. A conventional surgical approach (eg, drainage operation, partial resection, combination drainage-resection) may be considered in the presence of significant and uniform pancreatic duct dilation or an inflammatory head mass. Total pancreatectomy with islet autotransplantation is the best surgical option in patients with small duct disease. The presence of genetic risk factors often portends a suboptimal outcome following a conventional operation., Conclusions: The morphology of disease and the presence of genetic risk factors must be considered while determining the optimal surgical approach for children with CP. Surgical outcomes for CP are variable and depend on the type of intervention. A multidisciplinary team approach is needed to assure that the best possible operation is selected for each patient, their recovery is optimized, and their immediate and long-term postoperative needs are well-met., (Copyright © 2022 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Objectives: The aim of this article is to provide guidance to centers and organizations on the personnel (both physician and nonphysician) needed to create and sustain an optimal team, along with potential alternatives, to provide care to children with acute recurrent pancreatitis and chronic pancreatitis., Methods: This document was developed in collaboration with the North American Society of Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) Pancreas Committee and the National Pancreas Foundation (NPF) after several meetings., Results: This document highlights both physician and nonphysician personnel needed to provide multidisciplinary care to children with pancreatitis per the recommendation of the NASPGHAN Pancreas Committee members in year 2021 and added to the currently published NPF criteria. We summarize how the NPF criteria would fit with the recently published pediatric pancreatitis society articles from the NASPGHAN., Conclusions: It is important to manage children with acute recurrent pancreatitis and chronic pancreatitis in a multidisciplinary setting. There is need to study the impact of these personnel on the outcomes of children with pancreatitis., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Cystic fibrosis (CF) is a monogenic disease caused by impaired production and/or function of the CF transmembrane conductance regulator (CFTR) protein. Although we have previously shown correction of the most common pathogenic mutation, there are many other pathogenic mutations throughout the CF gene. An autologous airway stem cell therapy in which the CFTR cDNA is precisely inserted into the CFTR locus may enable the development of a durable cure for almost all CF patients, irrespective of the causal mutation. Here, we use CRISPR-Cas9 and two adeno-associated viruses (AAVs) carrying the two halves of the CFTR cDNA to sequentially insert the full CFTR cDNA along with a truncated CD19 (tCD19) enrichment tag in upper airway basal stem cells (UABCs) and human bronchial epithelial cells (HBECs). The modified cells were enriched to obtain 60%-80% tCD19 + UABCs and HBECs from 11 different CF donors with a variety of mutations. Differentiated epithelial monolayers cultured at air-liquid interface showed restored CFTR function that was >70% of the CFTR function in non-CF controls. Thus, our study enables the development of a therapy for almost all CF patients, including patients who cannot be treated using recently approved modulator therapies., Competing Interests: Declaration of interests M.H.P. has equity and serves on the Scientific Advisory Board of CRISPR Therapeutics and Graphite Bio. J.V.N. is a consultant with COOK Medical, which manufactures the pSIS graft. Neither company had any input on the design, execution, interpretation, or publication of the work in this manuscript., (Copyright © 2021 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

Objectives: It is unknown to what extent coronavirus 2019 (COVID-19) may co-occur with acute pancreatitis (AP) in children and how their clinical course may differ from children with AP alone., Methods: An online survey was sent to pediatric gastroenterologists to report on COVID-19 and AP cases from December 11, 2020, to February 26, 2021., Results: From 72 respondents (20 countries, 5 continents), 22 cases of positive COVID-19 infection and AP were reported. Patients were predominantly White or Hispanic/Latinx (73%), female (68%), and adolescents (68%). For 86% of patients, this was their first episode of AP. Sixty-eight percent of positive COVID-19 tests were polymerase chain reaction based. There was significant morbidity; 60% required intensive care, 45% had multiorgan involvement, and 24% developed shock. Eleven percent had pancreatic necrosis. Abnormal clotting and systemic inflammatory laboratories were common (31%-92% and 93%, respectively). Median length of symptomatic pancreatitis recovery was 1.8× longer than AP without COVID-19., Conclusions: Coronavirus 2019 infection and AP co-occur primarily in children without a prior history of pancreatitis. Given the increased need for intensive care, multiorgan involvement, and potentially higher risk for pancreatic necrosis, pediatric providers should have a high level of suspicion for AP in children with COVID-19 infection., Competing Interests: This study did not directly receive any funding support, but the authors are supported by the National Institutes of Health–National Institute of Diabetes and Digestive and Kidney Diseases (K08DK124684 to Z.M.S., K23DK118190 to M.A.E.H.), Cystic Fibrosis Foundation (SELLER16L0, SELLER19GE0, and SELLER20A0-KB), and Stanford Maternal Child Health Research Institute (Z.M.S.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding sources, nor did funding sources influence its content. The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Complications from liver cirrhosis are a leading cause of death in children with cystic fibrosis. Identifying children at risk for developing liver cirrhosis and halting its progression are critical to reducing liver-associated mortality., Objective: Quantitative US imaging, such as shear-wave elastography (SWE), might improve the detection of liver fibrosis in children with cystic fibrosis (CF) over gray-scale US alone. We incorporated SWE in our pediatric CF liver disease screening program and evaluated its performance using magnetic resonance (MR) elastography., Materials and Methods: Ninety-four children and adolescents with CF underwent 178 SWE exams, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT) and platelet measurements. Of these, 27 children underwent 34 MR elastography exams. We evaluated SWE performance using 6-MHz and 9-MHZ point SWE, and 9-MHz two-dimensional (2-D) SWE., Results: The 6-MHz point SWE was the only method that correlated with MR elastography (r=0.52; 95% confidence interval [CI] 0.20-0.74; P=0.003). SWE of 1.45 m/s distinguished normal from abnormal MR elastography (79% sensitivity, 100% specificity, 100% positive predictive value [PPV], 55% negative predictive value [NPV], area under the receiver operating characteristic [AUROC] curve 0.94). SWE of 1.84 m/s separated mild-moderate (3.00-4.77 kPa) from severe (>4.77 kPa) MR elastography (88% sensitivity, 86% specificity, 78% PPV, 93% NPV, AUROC 0.79). Elevations of AST, ALT, GGT and thrombocytopenia were associated with higher SWE. AST-to-platelet ratio index of 0.42, fibrosis-4 of 0.29, and GGT-to-platelet ratio of 1.43 all had >95% NPV for SWE >1.84 m/s., Conclusion: Given its correlation with MR elastography, SWE might be a clinically useful predictor of liver fibrosis. We identified imaging criteria delineating the use of SWE to identify increased liver stiffness in children with CF. With multicenter validation, these data might be used to improve the detection and monitoring of liver fibrosis in children with CF.

Acute pancreatitis (AP) is associated with significant morbidity and mortality, and it substantially contributes to the healthcare burden of gastrointestinal disease and quality of life in children and adults. AP across the lifespan is characterized by similarities and differences in epidemiology, diagnostic modality, etiologies, management, adverse events, long-term outcomes, and areas in greatest need of research. In this review, we touch on each of these shared and distinctive features of AP in children and adults, with an emphasis on recent advances in the conceptualization and management of AP.

Abstract: Endoscopic pancreatic function testing (ePFT) is one of the few ways to directly diagnose exocrine pancreatic insufficiency, and considerable confusion regarding indications, utility, and interpretation of the test remains. This position paper of the Pancreas Committee of the North American Society of Pediatric Gastroenterology, Hepatology and Nutrition reviews the history and indications for ePFT in children. We compare various methods in current practice and determine their strengths and limitations, and based on data from children and adults we provide guidance on a protocol on how to perform ePFT in children. Lastly, we pose areas in need of further research relating to ePFT in children., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Purpose of Review: The pancreas is highly affected in cystic fibrosis, with complications occurring early in childhood. This review highlights recent research in exocrine pancreatic function in the era of cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies and discusses how these are affecting pancreatitis and exocrine pancreatic insufficiency (EPI) in children. Additionally, new research into exocrine--endocrine interactions sheds light on how CFTR dysfunction in ductal cells may affect beta cells., Recent Findings: Ivacaftor has disproved the hypothesis that EPI in children with cystic fibrosis is irreversible. Improvements in pancreatic function have increased pancreatitis episodes in some children and reduced them in others. Imaging advances are providing complementary methods for exocrine pancreatic function testing. New research into the interplay between the exocrine and endocrine components of the pancreas are elucidating the intertwined and complex relationship between the exocrine and endocrine pancreas., Summary: Pancreatic complications contribute to the morbidity and mortality of children with cystic fibrosis. Increasing use of highly effective CFTR modulators will not only abrogate these but will also advance our understanding of pancreatic pathophysiology in cystic fibrosis. New frontiers into pancreatic gene therapy and exocrine--endocrine research will help provide new therapeutic opportunities for pancreatitis, EPI, and diabetes in cystic fibrosis.

Cystic fibrosis (CF) is a monogenic disorder caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. Mortality in CF patients is mostly due to respiratory sequelae. Challenges with gene delivery have limited attempts to treat CF using in vivo gene therapy, and low correction levels have hindered ex vivo gene therapy efforts. We have used Cas9 and adeno-associated virus 6 to correct the ΔF508 mutation in readily accessible upper-airway basal stem cells (UABCs) obtained from CF patients. On average, we achieved 30%-50% allelic correction in UABCs and bronchial epithelial cells (HBECs) from 10 CF patients and observed 20%-50% CFTR function relative to non-CF controls in differentiated epithelia. Furthermore, we successfully embedded the corrected UABCs on an FDA-approved porcine small intestinal submucosal membrane (pSIS), and they retained differentiation capacity. This study supports further development of genetically corrected autologous airway stem cell transplant as a treatment for CF., Competing Interests: Declaration of Interests M.H.P. has equity and serves on the scientific advisory board of CRISPR Therapeutics. J.V.N. is a consultant with COOK Medical, which manufactures the pSIS graft. Neither company had any input on the design, execution, interpretation, or publication of the work in this manuscript., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: Abdominal pain is common and is associated with high disease burden and health care costs in pediatric acute recurrent and chronic pancreatitis (ARP/CP). Despite the strong central component of pain in ARP/CP and the efficacy of psychological therapies for other centralized pain syndromes, no studies have evaluated psychological pain interventions in children with ARP/CP. The current trial seeks to 1) evaluate the efficacy of a psychological pain intervention for pediatric ARP/CP, and 2) examine baseline patient-specific genetic, clinical, and psychosocial characteristics that may predict or moderate treatment response., Methods: This single-blinded randomized placebo-controlled multicenter trial aims to enroll 260 youth (ages 10-18) with ARP/CP and their parents from twenty-one INSPPIRE (INternational Study Group of Pediatric Pancreatitis: In search for a cuRE) centers. Participants will be randomly assigned to either a web-based cognitive behavioral pain management intervention (Web-based Management of Adolescent Pain Chronic Pancreatitis; WebMAP; N = 130) or to a web-based pain education program (WebED; N = 130). Assessments will be completed at baseline (T1), immediately after completion of the intervention (T2) and at 6 months post-intervention (T3). The primary study outcome is abdominal pain severity. Secondary outcomes include pain-related disability, pain interference, health-related quality of life, emotional distress, impact of pain, opioid use, and healthcare utilization., Conclusions: This is the first clinical trial to evaluate the efficacy of a psychological pain intervention for children with CP for reduction of abdominal pain and improvement of health-related quality of life. Findings will inform delivery of web-based pain management and potentially identify patient-specific biological and psychosocial factors associated with favorable response to therapy. Clinical Trial Registration #: NCT03707431., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: Liver nodularity occurs across the spectrum of cystic fibrosis liver disease (CFLD), from regenerative nodules to cirrhosis, and can occur without liver enzyme abnormalities. Our aims were to determine if incorporating abdominal ultrasound (US) with annual laboratory testing improves the detection of CFLD and establish CF-specific thresholds for liver screening labs., Methods: CF patients at least 6 years old who were exocrine pancreatic-insufficient had an US with Doppler and shear wave elastography. Patients were divided into Normal, Echogenic, or Nodular groups, based on US findings. Results were compared with aspartate aminotransferase (AST), alanine aminotransferase (ALT), platelets, AST to platelet ratio index (APRI), Fibrosis 4 (FIB-4), and gamma-glutamyl transferase (GGT) to platelet ratio (GPR). Receiver operator curve, sensitivity, specificity, positive predictive value, negative predictive value, and optimal cut-off with Youden Index were calculated., Results: From 82 patients, incorporation of US identified more nodular livers than using labs alone. The Nodular group had significantly greater median AST (44), ALT (48), GGT (46), APRI (0.619), FIB-4 (0.286), GPR (1.431). Optimal cut-offs to detect liver nodularity in CF were AST >33, ALT >45, GGT >21, Platelets <230, APRI >0.367, FIB-4 >0.222, GPR >0.682. Using GGT, APRI, and GPR, we generated an algorithm to direct the use of US in CFLD screening., Conclusions: Using modified serum lab thresholds, addition of liver fibrosis indices, and/or abdominal US can increase detection of liver nodularity in CF. A combination of GGT, GPR, and APRI can help direct which CF children should undergo US evaluation. These tools may improve earlier identification of fibrosis and/or cirrhosis in CF patients.

Approximately 5%-10% of patients with cystic fibrosis (CF) will develop advanced liver disease with portal hypertension, representing the third leading cause of death among patients with CF. Cystic fibrosis with advanced liver disease and portal hypertension (CFLD) represents the most significant risk to patient mortality, second only to pulmonary or lung transplant complications in patients with CF. Currently, there is no medical therapy to treat or reverse CFLD. Liver transplantation (LT) in patients with CFLD with portal hypertension confers a significant survival advantage over those who do not receive LT, although the timing in which to optimize this benefit is unclear. Despite the value and efficacy of LT in selected patients with CFLD, established clinical criteria outlining indications and timing for LT as well as disease-specific transplant considerations are notably absent. The goal of this comprehensive and multidisciplinary report is to present recommendations on the unique CF-specific pre- and post-LT management issues clinicians should consider and will face., (Copyright © 2019 by the American Association for the Study of Liver Diseases.)

Background: Depression frequently co-occurs in patients with inflammatory bowel disease [IBD] and is a driver in health care costs and use., Aim: This study examined the associations between depression and total health care costs, emergency department [ED] visits, computed tomography [CT] during ED/inpatient visits, and IBD-related surgery among IBD patients., Methods: Our sample included 331772 IBD patients from a national administrative claims database [Truven Health MarketScan® Database]. Gamma and Poisson regression analyses assessed differences related to depression, controlling for key variables., Results: Approximately 16% of the IBD cohort was classified as having depression. Depression was associated with a $17,706 (95% confidence interval [CI] [$16,892, 18,521]) increase in mean annual IBD-related health care costs and an increased incidence of ED visits (adjusted incidence rate ratio [aIRR] of 1.5; 95% CI [1.5, 1.6]). Among patients who had one or more ED/inpatient visits, depression was associated with an increased probability of receiving repeated CT [one to four scans, adjusted odds ratio [aOR] of 1.6; 95% CI [1.5, 1.7]; five or more scans, aOR of 4.6; 95% CI [2.9, 7.3]) and increased odds of undergoing an IBD-related surgery (aOR of 1.2; 95% CI [1.1, 1.2]). Secondary analysis with a paediatric subsample revealed that approximately 12% of this cohort was classified as having depression, and depression was associated with increased costs and incidence rates of ED visits and CT, but not of IBD-related surgery., Conclusions: Quantifiable differences in health care costs and patterns of use exist among patients with IBD and depression. Integration of mental health services within IBD care may improve overall health outcomes and costs of care.

We created the INternational Study Group of Pediatric Pancreatitis: In Search for a CuRE (INSPPIRE 2) cohort to study the risk factors, natural history, and outcomes of pediatric acute recurrent pancreatitis and chronic pancreatitis (CP). Patient and physician questionnaires collect information on demographics, clinical history, family and social history, and disease outcomes. Health-related quality of life, depression, and anxiety are measured using validated questionnaires. Information entered on paper questionnaires is transferred into a database managed by Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer's Coordinating and Data Management Center. Biosamples are collected for DNA isolation and analysis of most common pancreatitis-associated genes.Twenty-two sites (18 in the United States, 2 in Canada, and 1 each in Israel and Australia) are participating in the INSPPIRE 2 study. These sites have enrolled 211 subjects into the INSPPIRE 2 database toward our goal to recruit more than 800 patients in 2 years. The INSPPIRE 2 cohort study is an extension of the INSPPIRE cohort study with a larger and more diverse patient population. Our goals have expanded to include evaluating risk factors for CP, its sequelae, and psychosocial factors associated with pediatric acute recurrent pancreatitis and CP.

High-quality and well-annotated biorepositories are needed to better understand the pathophysiology and biologic mechanisms of chronic pancreatitis (CP) and its consequences. We report a methodology for the development of a robust standard operating procedure (SOP) for a biorepository based on the experience of the clinical centers within the consortium to study Chronic Pancreatitis, Diabetes and Pancreas Cancer Clinical Centers (CPDPC), supported by the National Cancer Institute and the National Institute for Diabetes and Digestive and Kidney Diseases as a unique multidisciplinary model to study CP, diabetes, and pancreatic cancer in both children and adults. Standard operating procedures from the CPDPC centers were evaluated and consolidated. The literature was reviewed for standard biorepository operating procedures that facilitated downstream molecular analysis. The existing literature on biobanking practices was harmonized with the SOPs from the clinical centers to produce a biorepository for pancreatic research. This article reports the methods and basic principles behind the creation of SOPs to develop a biorepository for the CPDPC. These will serve as a guide for investigators developing biorepositories in pancreas research. Rigorous and meticulous adherence to standardized biospecimen collection will facilitate investigations to better understand the pathophysiology and biologic mechanisms of CP, diabetes, and pancreatic cancer.

Background: Opioids are commonly prescribed for relief in inflammatory bowel disease (IBD). Emerging evidence suggests that adolescents and young adults are a vulnerable population at particular risk of becoming chronic opioid users and experiencing adverse effects., Objectives: This study evaluates trends in the prevalence and persistence of chronic opioid therapy in adolescents and young adults with IBD in the United States., Method: A longitudinal retrospective cohort analysis was conducted with the Truven MarketScan Database from 2007 to 2015. Study subjects were 15-29 years old with ≥2 IBD diagnoses (Crohn's: 555/K50; ulcerative colitis: 556/K51). Opioid therapy was identified with prescription claims within the Truven therapeutic class 60: opioid agonists. Persistence of opioid use was evaluated by survival analysis for patients who remained in the database for at least 3 years following index chronic opioid therapy use., Results: In a cohort containing 93,668 patients, 18.2% received chronic opioid therapy. The annual prevalence of chronic opioid therapy increased from 9.3% in 2007 to 10.8% in 2015 (P < 0.01), peaking at 12.2% in 2011. Opioid prescriptions per patient per year were stable (approximately 5). Post hoc Poisson regression analyses demonstrated that the number of opioid pills dispensed per year increased with age and was higher among males. Among the 2503 patients receiving chronic opioid therapy and followed longitudinally, 30.5% were maintained on chronic opioid therapy for 2 years, and 5.3% for all 4 years., Conclusion: Sustained chronic opioid use in adolescents and young adults with IBD is increasingly common, underscoring the need for screening and intervention for this vulnerable population.

Background & Aims: Epidemiologic analyses of acute pancreatitis (AP) and chronic pancreatitis (CP) provide insight into causes and strategies for prevention and affect allocation of resources to its study and treatment. We sought to determine current and accurate incidences of AP and CP, along with the prevalence of CP, in children and adults in the United States., Methods: We collected data from the Truven MarketScan Research Databases of commercial inpatient and outpatient insurance claims in the United States from 2007 through 2014 (patients 0-64 years old). We calculated the incidences of AP and CP and prevalence of CP based on International Classification of Diseases, 9th Revision diagnosis codes. Children were defined as 18 years or younger and adults as 19 to 64 years old., Results: The incidence of pediatric AP was stable from 2007 through 2014, remaining at 12.3/100,000 persons in 2014. Meanwhile, the incidence for adult AP decreased from 123.7/100,000 persons in 2007 to 111.2/100,000 persons in 2014. The incidence of CP decreased over time in children (2.2/100,000 persons in 2007 to 1.9/100,000 persons in 2014) and adults (31.7/100,000 persons in 2007 to 24.7/100,000 persons in 2014). The prevalences of pediatric and adult CP were 5.8/100,000 persons and 91.9/100,000 persons, respectively, in 2014. Incidences of AP and CP increased with age. We found little change in incidence during the first decade of life but linear increases starting in the second decade., Conclusions: We performed a comprehensive epidemiologic analysis of privately insured, non-elderly adults and children with AP and CP in the United States. Changes in gallstone formation, smoking, and alcohol consumption, along with advances in pancreatitis management, may be responsible for the stabilization and even decrease in the incidences of AP and CP., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Real-world data quantifying the costs of increasing use of biologics in inflammatory bowel disease (IBD) are unknown., Aim: To determine the outpatient IBD drug utilization trends, relative market share, and costs in the USA during a 9-year period., Methods: The Truven MarketScan ® Database was analysed for patients with Crohn's disease (CD) and ulcerative colitis (UC) during 2007-2015. National drug codes were used to identify prescription drugs; Healthcare Common Procedure Coding System J-codes were used to capture biologic out-patient infusions. Proportion of drug usage, relative market share and per-member per-year (PMPY) costs were analysed for biologics, immunomodulators, 5-ASAs and corticosteroids., Results: In 415 405 patients (188 842 CD; 195 183 UC; 31 380 indeterminate colitis; 54.67% female), utilization trends show a consistent rise in the market share of biologics during the 9-year study period. The proportion of patients using biologics increased from 21.8% to 43.8% for CD and 5.1%-16.2% for UC. This contrasts a small decrease in immunomodulator and 5-ASA use for CD and relative constancy of other classes including corticosteroids-only use as primary IBD medication from 2007 to 2015. The average biologic-taking patient accounted for $25 275 PMPY in 2007 and $36 051 PMPY in 2015. The average paediatric biologic-taking patient accounted for $23 616 PMPY in 2007 and $41 109 PMPY in 2015. In all patients, the share of costs for biologics increased from 72.9% in 2007 to 85.7% in 2015 (81.7% in 2007 to 94.9% in 2015 in paediatrics)., Conclusion: The vast majority of costs allocated to out-patient IBD medications in the USA is attributed to increasing use of biologic therapies despite the relative minority of biologic-taking patients., (© 2017 John Wiley & Sons Ltd.)

Background: Although the incidence of acute pancreatitis (AP) in children is increasing, management recommendations rely on adult published guidelines. Pediatric-specific recommendations are needed., Methods: The North American Society for Pediatric Gastroenterology, Hepatology and Nutrition Pancreas committee performed a MEDLINE review using several preselected key terms relating to management considerations in adult and pediatric AP. The literature was summarized, quality of evidence reviewed, and statements of recommendations developed. The authorship met to discuss the evidence, statements, and voted on recommendations. A consensus of at least 75% was required to approve a recommendation., Results: The diagnosis of pediatric AP should follow the published INternational Study Group of Pediatric Pancreatitis: In Search for a CuRE definitions (by meeting at least 2 out of 3 criteria: (1) abdominal pain compatible with AP, (2) serum amylase and/or lipase values ≥3 times upper limits of normal, (3) imaging findings consistent with AP). Adequate fluid resuscitation with crystalloid appears key especially within the first 24 hours. Analgesia may include opioid medications when opioid-sparing measures are inadequate. Pulmonary, cardiovascular, and renal status should be closely monitored particularly within the first 48 hours. Enteral nutrition should be started as early as tolerated, whether through oral, gastric, or jejunal route. Little evidence supports the use of prophylactic antibiotics, antioxidants, probiotics, and protease inhibitors. Esophago-gastro-duodenoscopy, endoscopic retrograde cholangiopancreatography, and endoscopic ultrasonography have limited roles in diagnosis and management. Children should be carefully followed for development of early or late complications and recurrent attacks of AP., Conclusions: This clinical report represents the first English-language recommendations for the management of pediatric AP. Future aims should include prospective multicenter pediatric studies to further validate these recommendations and optimize care for children with AP.

Background: Airway mucociliary clearance (MCC) is an important defense mechanism against pulmonary infections and is compromised in cystic fibrosis (CF). Cl- and HCO3- epithelial transport are integral to MCC. During pulmonary infections prostaglandin E2 (PGE2) production is abundant., Aim: To determine the effect of PGE2 on airway Cl- and HCO3- secretion and MCC in normal and CF airways., Methods: We examined PGE2 stimulated MCC, Cl- and HCO3- secretion using ferret trachea, human bronchial epithelial cell cultures (CFBE41o- with wildtype CFTR (CFBE41 WT) or homozygous F508del CFTR (CFBE41 CF) and human normal bronchial submucosal gland cell line (Calu-3) in Ussing chambers with or without pH-stat., Results: PGE2 stimulated MCC in a dose-dependent manner and was partially impaired by CFTRinh-172. PGE2-stimulated Cl- current in ferret trachea was partially inhibited by CFTRinh-172, with niflumic acid eliminating the residual current. CFBE41 WT cell monolayers produced a robust Cl- and HCO3- secretory response to PGE2, both of which were completely inhibited by CFTRinh-172. CFBE41 CF cells exhibited no response to PGE2. In Calu-3 cells, PGE2 stimulated Cl- and HCO3- secretion. Cl- secretion was partially inhibited by CFTRinh-172, with additional inhibition by niflumic acid. HCO3- secretion was completely inhibited by CFTRinh-172., Conclusions: PGE2 stimulates bronchotracheal MCC and this response is decreased in CF. In CF airway, PGE2-stimulated Cl- and HCO3- conductance is impaired and may contribute to decreased MCC. There remains a CFTR-independent Cl- current in submucosal glands, which if exploited, could represent a means of improving airway Cl- secretion and MCC in CF.

Cystic fibrosis (CF), the most common autosomal recessive lethal disease in Caucasians, causes chronic pulmonary disease and can lead to cor pulmonale with right ventricular dysfunction. The presence of the cystic fibrosis transmembrane conductance regulator (CFTR) in cardiac myocardia has prompted debate regarding possible defective ion channel-induced cardiomyopathy. Clinical heart disease in CF is considered rare and is restricted to case reports. It has been unclear if this is due to the lack of physiological importance of CFTR in the heart, the relatively short lifespan of those with CF, or a technical inability to detect subclinical disease. Extensive echocardiographic investigations have yielded contradictory results, leading to the dogma that left ventricular defects in CF occur secondary to lung disease. In this review, we consider why studies examining heart function in CF have not provided clarity on this topic. We then focus on data from new echocardiographic and magnetic resonance imaging technology, which are providing greater insight into cardiac function in CF and demonstrating that, in addition to secondary effects from pulmonary disease, there may be an intrinsic primary defect in the CF heart. With advancing lifespans and activity levels, understanding the risk of cardiac disease is vital to minimizing morbidity in adults with CF., (Copyright © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: CFTR is expressed in cardiac myocytes. In mice, lack of CFTR alters cardiomyocyte contraction and Ca2+ signaling, and decreases cardiac reserve. We undertook a pilot study evaluating left ventricular (LV) function in CF patients using strain and strain rate echocardiography., Methods: Echocardiography with tissue Doppler and strain and strain rate imaging were performed in 8 CF adults following pulmonary function tests. Results were compared to literature values obtained in healthy subjects., Results: All CF individuals had normal LV ejection fractions. In contrast, 50% of men and 100% of women with CF had decreased LV systolic strain. Strain rates were significantly decreased in 100% of CF individuals. RV function was normal and LV function did not correlate with lung function., Conclusions: Strain and strain rate echocardiography identified LV systolic abnormalities in CF individuals not detected by conventional echocardiography. We propose that this echocardiography modality may identify subclinical cardiac dysfunction in CF., (Copyright © 2015 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: Left ventricular (LV) abnormalities have been reported in cystic fibrosis (CF); however, it remains unclear if loss of cystic fibrosis transmembrane conductance regulator (CFTR) function causes heart defects independent of lung disease., Methods: Using gut-corrected F508del CFTR mutant mice (ΔF508), which do not develop human lung disease, we examined in vivo heart and aortic function via 2D transthoracic echocardiography and LV catheterization., Results: ΔF508 mouse hearts showed LV concentric remodeling along with enhanced inotropy (increased +dP/dt, fractional shortening, decreased isovolumetric contraction time) and greater lusitropy (-dP/dt, Tau). Aortas displayed increased stiffness and altered diastolic flow. β-adrenergic stimulation revealed diminished cardiac reserve (attenuated +dP/dt,-dP/dt, LV pressure)., Conclusions: In a mouse model of CF, CFTR mutation leads to LV remodeling with alteration of cardiac and aortic functions in the absence of lung disease. As CF patients live longer, more active lives, their risk for cardiovascular disease should be considered., (Copyright © 2012 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)