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Background: Acute pancreatitis (AP) increases the risk of diabetes mellitus (DM). Our aim was to identify clinical, laboratory and imaging predictors of preDM/DM in youth post index AP., Methods: This was a prospective cohort study of patients ≤21 years-old with an index admission for AP and follow up at 3 and/or 12 months. Clinical laboratory values, imaging findings, admission course, and plasma chemokine and cytokine measures collected at index admission were tested for association with preDM/DM development. A multivariable regression model was used to predict preDM/DM., Results: Among 187 enrolled participants, 137 (73 %) and 144 (77 %) underwent DM screening at 3 and 12 months respectively, and 137 (73 %) had imaging available. PreDM/DM occurred in 22/137 (16 %; preDM n = 21, DM n = 1) at 3 months and 23/144 (16 %; preDM n = 18, DM n = 5) participants at 12 months. Univariate associations with preDM/DM at 12 months included: severe AP (SAP) (52 % preDM/DM vs. 17 % no DM; p = 0.0008), median [IQR] IL-6 (910 pg/ml [618-3438] vs. 196 pg/ml [71-480], p < 0.05) and CRP (4.16 mg/L [1.67-10.7] vs. 1.55 mg/L [0.4-3.68], p = 0.1) at time of AP attack. The optimal multivariable model to predict preDM/DM included with clinical variables was severe acute pancreatitis (SAP), c reactive protein (CRP), interleukin-6 (IL-6), and age [AUC = 0.80; (0.70, 0.88)]. Including imaging markers, the ideal model included SAP, CRP, IL-6, subcutaneous fat area, age and presence of autoimmune disease with an AUC [0.82 (0.71, 0.90)]., Conclusions: Development of preDM/DM following an index AP episode can be predicted by baseline AP severity, baseline CRP, IL-6 levels, and subcutaneous fat area., Competing Interests: Conflicts of interest G Ginzburg has no declarations of interest. Y Zhang has no declarations of interest. NK Abu Ata has no declarations of interest. PR Farrell has no declarations of interest. V Garlapally has no declarations of interest. N Kotha has no declarations of interest. T Thompson has no declarations of interest. DS Vitale has no declarations of interest. AT Trout has consulted for GE Healthcare; has Research support from GE Healthcare, Siemens Healthineers, and Perspectum Inc. No support was received for the current work. M Abu-El-Haija has no declarations of interest., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Pediatric acute pancreatitis (AP) is associated with significant morbidity. Therefore, improved understanding of children who will develop severe AP is critical. Adult studies have reported AP associated gut dysbiosis, but pediatric studies are lacking., Aims: Assess stool microbial taxonomic and functional profiles of children with first attack of AP compared to those of healthy controls (HC), and between mild and severe AP METHODS: Children under 21 years hospitalized at a tertiary center (n = 30) with first AP attack were recruited including HC (n = 34) from same region. Shotgun metagenomic sequencing was performed on extracted DNA., Results: Demographics were similar between AP and HC. Alpha diversity (-0.68 ± 0.13, p-value < 0.001), and beta-diversity (R 2 =0.13, p-value < 0.001) differed, in children with AP compared to HC. Species including R.gnavus, V.parvula, E.faecalis, C.innocuum were enriched in AP. MetaCyc pathways involved in amino acid metabolism and fatty acid beta-oxidation were enriched in AP. Beta-diversity (R 2 =0.06, p-value = 0.02) differed for severe AP compared to mild AP with enrichment in E.faecalis and C.citroniae., Conclusions: Gut dysbiosis occurs in pediatric AP and is associated with AP severity. A multicenter study confirming these findings could pave way for interventional trials manipulating the gut microbiome to mitigate AP severity., Competing Interests: Conflict of interest None., (Copyright © 2023 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: Toll-like receptor 4 (TLR4) has been suggested as one of the forefront cross-communicators between the intestinal bacteria and the host to regulate inflammatory signals and energy homeostasis. High-fat diet-induced inflammation is mediated by changes in gut microbiota and requires a functional TLR-4, the deficiency of which renders mice resistant to diet-induced obesity and its associated metabolic dysfunction. Furthermore, gut microbiota was suggested to play a key role in the beneficial effects of Roux-en-Y gastric bypass (RYGB), a commonly performed bariatric procedure., Objectives: To explore whether TLR4, myeloid differentiation factor 8 (MyD88; 1 of its key downstream signaling regulators) and gut microbiota play an integrative role in RYGB-induced metabolic outcomes., Setting: Animal- based study., Method: We performed RYGB in TLR4 and MyD88 knock-out (KO) mice and used fecal microbiota transplant (FMT) from RYGB-operated animals to these genetic mouse models to address our questions., Results: We demonstrate that RYGB reduces TLR4 expression explicitly in the small and large intestine of C57Blc/6J mice. We also show that TLR4 KO mice have an attenuated glucoregulatory response to RYGB. In addition, we reveal that MyD88 KO mice fail to respond to all RYGB-induced metabolic effects. Finally, fecal microbiota transplant from RYGB-operated mice into TLR4 KO and MyD88 KO naïve recipients fails to induce a metabolic phenotype similar to that of the donors, as it does in wild-type recipients., Conclusion: TLR4 and MyD88 are required for RYGB-induced metabolic response that is likely mediated by gut microbiome., (Published by Elsevier Inc.)

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.)

Background: Blue Rubber Bleb Nevus Syndrome (BRBNS) is a rare, severe, sporadically occurring disorder characterized by multiple venous malformations., Aims: To present and analyze a case series of pediatric patients with BRBNS and to describe diagnostic approaches and management options applied., Patients and Methods: Multicenter, retrospective study, evaluating the diagnosis and management of children with BRBNS., Results: Eighteen patients diagnosed with BRBNS were included. Cutaneous venous malformations were observed in 78% and gastrointestinal venous malformations in 89%. Lesions were also found in other organs including muscles, joints, central nervous system, eyes, parotid gland, spine, kidneys and lungs. Gastrointestinal lesions were more common in the small intestine than in stomach or colon. The management varied significantly among centers. Endoscopic therapy and surgical therapy alone failed to prevent recurrence of lesions. In younger children and in patients with musculoskeletal or other organ involvement, sirolimus was used with 100% success rate in our series (5 patients treated) although poor compliance with subtherapeutic sirolimus trough levels led to recurrence in a minority., Conclusions: Considering the multi-organ involvement in BRBNS, diagnosis and management requires a multidisciplinary approach. The treatment includes conservative, medical, endoscopic and surgical options. Prospective multicenter studies are needed to identify the optimal management of this rare condition., (Copyright © 2019 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

For children with Cystic Fibrosis (CF) suffering from acute recurrent pancreatitis (ARP), abdominal pain can be severe, difficult to treat, impair their quality of life, affect participation at school, and can lead to chronic opioid dependence. Total pancreatectomy with islet autotransplantation (TPIAT) is an uncommon treatment that is reserved for refractory cases of ARP. We present a case of a 4 year old female with pancreatic-sufficient CF, refractory ARP, frequent hospital admissions for abdominal pain, and continued growth failure despite gastrostomy tube and parenteral nutrition. One year after successful TPIAT, the patient is insulin-independent, growing well, and has not been re-hospitalized for abdominal pain. To our knowledge, this is the youngest patient with CF to undergo TPIAT for debilitating ARP. With CFTR modulators restoring some pancreatic function, CF clinicians should have increased vigilance for the development of ARP., (Copyright © 2019. Published by Elsevier B.V.)

Total pancreatectomy with islet autotransplantation (TPIAT) is used to treat debilitating chronic pancreatitis (CP) and acute recurrent pancreatitis (ARP) that has failed medical and endoscopic therapy. We performed a retrospective review of TPIAT patients at a free-standing children's hospital to evaluate perioperative outcomes. Twenty patients (median age 13, 65% female) underwent TPIAT (2015 through 2017). Of the 20 patients, 95% had CP and 1 patient (5%) had ARP alone. Seventy-five percent of the patients had a pancreatitis-associated genetic mutation; 40% had pancreas divisum. The median surgical time was 757 (IQR 657 to 835) minutes. Median islet equivalents per kg of body weight (IEQ/kg) were 6404 (IQR 5018 to 7554). At 90 days postoperatively vs preoperatively, significantly fewer patients were receiving parenteral nutrition (0% vs 25%, P = .006) and opioids (45% vs 75%, P = .01). Short Form 36-Item Health Survey (SF-36) physical health module scores and total scores improved (34.0 preoperatively vs 54.6 at 90 days, P = .008, and 47.1 vs 65.3, P = .007, respectively); SF-10 physical health scores also improved (13.4 vs 33.1, P = .02). Insulin requirement decreased from 0.5 unit/kg/day to 0.4 unit/kg/day between discharge and 90 days (P = .02). TPIAT is an effective option when debilitating disease persists despite maximal medical and endoscopic therapy. Opioid, parenteral nutrition, and exogenous insulin use can successfully be weaned within 90 days after TPIAT, with gains in health-related quality of life., (© 2018 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Pancreatic disease has onset in utero in humans with cystic fibrosis (CF), and progresses over time to complete destruction of the organ. The exact mechanisms leading to pancreatic damage in CF are incompletely understood. Inflammatory cells are present in the pancreas of newborn pigs with CF (CF pigs) and humans, which suggests that inflammation may have a role in the destructive process. We wondered whether tissue inflammation and genes associated with inflammatory pathways were increased in the pancreas of fetal CF pigs [83 to 90 days gestation (normal pig gestation is ~114 days)] and newborn pigs. Compared with fetal pigs without CF (non-CF pigs), in fetal CF pigs, the pancreas exhibited patchy inflammation and acinar atrophy, with progression in distribution and severity in neonatal CF pigs. Large-scale transcript profiling revealed that the pancreas in fetal and newborn CF pigs exhibited significantly increased expression of proinflammatory, complement cascade, and profibrotic genes when compared with fetal and newborn non-CF pigs. Acinar cells exhibited increased apoptosis in the pancreas of fetal and newborn CF pigs. α-Smooth muscle actin and transforming growth factor β1 were increased in both fetal and newborn CF pig pancreas, suggesting activation of profibrotic pathways. Cell proliferation and mucous cell metaplasia were detected in newborn, but not fetal, CF pigs, indicating that they were not an initiator of pathogenesis but a response. Proinflammatory, complement cascade, proapoptotic, and profibrotic pathways are activated in CF pig pancreas, and likely contribute to the destructive process., (Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)