The Ca 2+ release channel ryanodine receptor 2 (RyR2) is required for excitation-contraction coupling in the heart and is also present in the brain. Mutations in RyR2 have been linked to exercise-induced sudden cardiac death (catecholaminergic polymorphic ventricular tachycardia [CPVT]). CPVT-associated RyR2 mutations result in "leaky" RyR2 channels due to the decreased binding of the calstabin2 (FKBP12.6) subunit, which stabilizes the closed state of the channel. We found that mice heterozygous for the R2474S mutation in Ryr2 (Ryr2-R2474S mice) exhibited spontaneous generalized tonic-clonic seizures (which occurred in the absence of cardiac arrhythmias), exercise-induced ventricular arrhythmias, and sudden cardiac death. Treatment with a novel RyR2-specific compound (S107) that enhances the binding of calstabin2 to the mutant Ryr2-R2474S channel inhibited the channel leak and prevented cardiac arrhythmias and raised the seizure threshold. Thus, CPVT-associated mutant leaky Ryr2-R2474S channels in the brain can cause seizures in mice, independent of cardiac arrhythmias. Based on these data, we propose that CPVT is a combined neurocardiac disorder in which leaky RyR2 channels in the brain cause epilepsy, and the same leaky channels in the heart cause exerciseinduced sudden cardiac death. IntroductionPharmacological seizure models have implicated abnormalities in intracellular Ca 2+ cycling of inhibitory interneurons and/or astrocytes as a mechanism of seizure generation (1, 2), and the inositol 1,4,5-trisphosphate receptor (IP3R), an intracellular calcium release channel on the ER, has been associated with seizures in mice (3). However, a causal relationship between defective intracellular calcium release channels and seizures has not been reported. Calcium stored within the ER contributes to neuronal signaling and is controlled by intracellular Ca 2+ release channels, in particular ryanodine receptors (RyRs) (4-6) and IP3Rs (7,8). To explore the underlying mechanism for seizures in CPVT we generated mice that harbor a missense mutation (RyR2-R2474S) that has been linked to exercise-induced cardiac arrhythmias in humans (9-12).More than 50 distinct RYR2 mutations have been linked to catecholaminergic polymorphic ventricular tachycardia (CPVT), an arrhythmogenic cardiomyopathy (13-15). CPVT patients experience syncope and sudden cardiac death (SCD) from the toddler to adult ages, and by 35 years age the mortality is up to 50% (13,16,17).

Background and Study Aims: Endoscopic ultrasound-directed transgastric ERCP (EDGE) is an alternative to enteroscopy- and laparoscopy-assisted ERCP in patients with Roux-en-Y gastric bypass anatomy. Although short-term results are promising, the long-term outcomes are not known. Aims of this study were 1) to determine rates of long-term adverse events (AEs) after EDGE, with a focus on rates of persistent gastrogastric or jejunogastric fistula; 2) identify predictors of persistent fistula; 3) assess outcomes of endoscopic closure when persistent fistula is encountered. Patients and Methods: This was a multicenter, retrospective study involving 13 centers between 1/2014 and 3/2019. AEs were defined according to ASGE lexicon. Persistent fistula was defined as upper GI series or EGD showing evidence of fistula. Results: A total of 178 patients (mean age 58 years, 79% F) underwent EDGE. Technical success was achieved in 98% of cases (175/178) with a mean procedure time of 92 min. Periprocedural AEs occurred in 28 patients (15.7%; mild 10.1%, moderate 3.3%, severe 2.2%). The 4 severe adverse events were managed laparoscopically. Persistent fistula was diagnosed in 10% of those sent for objective testing (9/90). Following identification of fistula, 5/9 patients underwent endoscopic closure procedures, which were successful in all cases. Conclusions: The EDGE procedure is associated with high clinical success rates, and an acceptable risk profile. Persistent fistula after lumen apposing stent removal are uncommon, but objective testing is recommended to identify their presence. When persistent fistula are identified, endoscopic treatment is warranted, and should be successful in closing the fistula.

Background and study aims Indications for accessing the duodenum, and/or excluded stomach in Roux-en-Y gastric bypass (RYGB) patients extend beyond diagnosis and treatment of pancreaticobiliary maladies. Given the high technical and clinical success of EUS-directed transgastric ERCP (EDGE) in RYGB anatomy, we adopted this transgastric (anterograde) approach to evaluate and treat luminal and extraluminal pathology in and around the excluded gut in RYGB patients. EUS-directed transgastric intervention (“EDGI”), other than ERCP, is the terminology we have chosen to describe this heterogenous group of transgastric diagnostic and/or interventional endoscopic procedures (transgastric interventions) performed via a lumen-apposing mental stent (LAMS) in select patients with RYGB. Patients and methods A multicenter (n = 4), retrospective study of RYGB patients with suspected luminal or extraluminal pathology, in or around the duodenum and/or excluded stomach, underwent EDGI using LAMS between December 2015 and January 2019. Results A total of 14 patients (78.6 % women; mean age, 55.7 + 12.4 years) underwent EDGI via LAMS. Technical and clinical success rates of EDGI were 100 %. The most common transgastric interventions were diagnostic EUS of extraluminal pathology (n = 6, 42.7 %) and endoscopic biopsy of gastroduodenal luminal abnormalities (n = 5, 35.7 %). Two moderate-severity adverse events due to LAMS maldeployment occurred during EUS-JG creation (14.3 %), and each instance was successfully rescued with a bridging stent. Conclusions A variety of gastroduodenal luminal and extraluminal disorders in RYGB patients can be effectively diagnosed and managed using EDGI via LAMS.

Backgrounds Endoscopic ultrasound (EUS)-guided placement of lumen-apposing metal stents (LAMSs) has gained popularity for the treatment of pancreatic walled-off necrosis (WON). We compared the 20-mm and 15-mm LAMSs for the treatment of symptomatic WON in terms of clinical success and adverse events. Methods We conducted a retrospective, case-matched study of 306 adults at 22 tertiary centers from 04/2014 to 10/2018. A total of 102 patients with symptomatic WON who underwent drainage with 20-mm LAMS (cases) and 204 patients who underwent drainage with 15-mm LAMS (controls) were matched by age, sex, and drainage approach. Conditional logistic regression analysis was performed to compare clinical success (resolution of WON on follow-up imaging without reintervention) and adverse events (according to American Society for Gastrointestinal Endoscopy criteria). Results Clinical success was achieved in 92.2 % of patients with 20-mm LAMS and 91.7 % of patients with 15-mm LAMS (odds ratio 0.92; P = 0.91). Patients with 20-mm LAMS underwent fewer direct endoscopic necrosectomy (DEN) sessions (mean 1.3 vs. 2.1; P < 0.001), despite having larger WON collections (transverse axis 118.2 vs. 101.9 mm, P = 0.003; anteroposterior axis 95.9 vs. 80.1 mm, P = 0.01). There was no difference in overall adverse events (21.6 % vs. 15.2 %; P = 0.72) and bleeding events (4.9 % vs. 3.4 %; P = 0.54) between the 20-mm and 15-mm LAMS groups, respectively. Conclusions The 20-mm LAMS showed comparable clinical success and safety profile to the 15-mm LAMS, with the need for fewer DEN sessions for WON resolution.

Lumen-apposing metal stents (LAMS) use in gastrointestinal endoscopy has been on the rise for various indications for the last few years. Currently, LAMS is a well-established treatment for post-pancreatitis peri-pancreatic fluid collections and walled-off necrosis (WON), but it is still not a standard of care in the treatment of post-surgical fluid collections (PSFC). Most of the earlier studies for treatment of PSFC utilized double pigtail plastic stents (DPS). We present a series of 3 cases where LAMS was successfully used for PSFC drainage. The cases include a patient with perigastric abscess after Whipple’s procedure, a case of peri-pancreatic collection after distal pancreatectomy, and a patient with peri-pancreatic fluid collection after right partial hepatectomy and splenectomy due to lacerations from a motor vehicle accident.