Pub Date : 2024-02-14DOI: 10.1093/jcag/gwad061.053
V. Chabot, D. Lévesque, F. Boisvert, N. Rivard
Abstract Background Shp-2 gene polymorphisms are associated with greater susceptibility to ulcerative colitis. How Shp-2 contributes to disease susceptibility is however unclear. Intestinal epithelial cell (IEC)-specific deletion of Shp-2 results in severe colitis in mice (Shp-2IEC-KO). We found important alterations in microbiota composition, namely increased Enterobacteria of the Proteobacteria phylum and decreased Firmicutes levels, that preceded clinical signs of inflammation. Antibiotherapy or epithelial KO of Myd88 inhibits colitis in Shp-2IEC-KO mice. Notably, feces from Shp-2IEC-iKO mice display much more LPS-like bioactivity than do feces from controls (unpublished data). These observations support a role for TLR4/Myd88-bacterial recognition in initiation of colitis in Shp-2IEC-KO mice. Aims The aim of the present study was to identify the molecular mechanisms by which Shp-2 may regulate TLR4 signaling in IEC. Methods 1) The regulation of Shp-2 phosphorylation was analysed in IEC-6 cells stimulated or not with 10 ug/ml of LPS, a TLR4 ligand. 2) We mapped the Shp-2-dependent interactome in LPS-stimulated IEC-6 cells by an APEX2 proximity assay used in combination with mass spectrometry (MS) analysis. Cells stably expressing APEX2-tagged Shp-2 were generated. Addition of doxycycline results in expression of “physiological” levels of Shp-2;APEX2 construct. Proximity biotinylation labeling of Shp-2 by APEX2 was performed after 10 min stimulation with LPS and labeled candidates were analyzed by MS. Results 1) Upon stimulation of IEC-6 cells with LPS, Shp-2 protein is rapidly phosphorylated (Y542, Y580) and potentially activated. This increased phosphorylation is abolished by pretreatment with N-acetyl cystein, a commonly used antioxydant. 2) Using Prostar R package, the three replicates of MS data were filtered for the minimum quantification of 66,66% of each protein in at least one condition. They were normalized within conditions using VSN normalization, then the Partially Observed Values (POV) and the Missing in Entire Column (MEC) values were imputed respectively with SLSA and DetQuantile (Quantile 1%, Factor 0,2). A differential analysis between the LPS and non-treated conditions identified 334 proteins enriched with a FC of ± ≥2,5 with a p-value inferior then 0,05. Among the top Shp-2 interactors, we found Tak1 (ampersand:003E3,5X change) and Tab1 (ampersand:003E3,0X change), two proteins involved in NF-kB signaling. Decreased interaction with the TLR effectors Myd88 (ampersand:003C2,5X change) and Irak1 (ampersand:003C3,2X change) was also noted after LPS treatment. Conclusions These data suggest for the first time that Shp-2 may regulate NF-kB signaling downstream of TLR4 in IEC. Thus, SHP-2 may contribute to the maintenance of mucosal tolerance to microbiota in the colon. Funding Agencies CIHR
{"title":"A53 MOLECULAR MECHANISMS FOR A ROLE OF SHP-2 IN TLR4 SIGNALING IN INTESTINAL EPITHELIAL CELLS","authors":"V. Chabot, D. Lévesque, F. Boisvert, N. Rivard","doi":"10.1093/jcag/gwad061.053","DOIUrl":"https://doi.org/10.1093/jcag/gwad061.053","url":null,"abstract":"Abstract Background Shp-2 gene polymorphisms are associated with greater susceptibility to ulcerative colitis. How Shp-2 contributes to disease susceptibility is however unclear. Intestinal epithelial cell (IEC)-specific deletion of Shp-2 results in severe colitis in mice (Shp-2IEC-KO). We found important alterations in microbiota composition, namely increased Enterobacteria of the Proteobacteria phylum and decreased Firmicutes levels, that preceded clinical signs of inflammation. Antibiotherapy or epithelial KO of Myd88 inhibits colitis in Shp-2IEC-KO mice. Notably, feces from Shp-2IEC-iKO mice display much more LPS-like bioactivity than do feces from controls (unpublished data). These observations support a role for TLR4/Myd88-bacterial recognition in initiation of colitis in Shp-2IEC-KO mice. Aims The aim of the present study was to identify the molecular mechanisms by which Shp-2 may regulate TLR4 signaling in IEC. Methods 1) The regulation of Shp-2 phosphorylation was analysed in IEC-6 cells stimulated or not with 10 ug/ml of LPS, a TLR4 ligand. 2) We mapped the Shp-2-dependent interactome in LPS-stimulated IEC-6 cells by an APEX2 proximity assay used in combination with mass spectrometry (MS) analysis. Cells stably expressing APEX2-tagged Shp-2 were generated. Addition of doxycycline results in expression of “physiological” levels of Shp-2;APEX2 construct. Proximity biotinylation labeling of Shp-2 by APEX2 was performed after 10 min stimulation with LPS and labeled candidates were analyzed by MS. Results 1) Upon stimulation of IEC-6 cells with LPS, Shp-2 protein is rapidly phosphorylated (Y542, Y580) and potentially activated. This increased phosphorylation is abolished by pretreatment with N-acetyl cystein, a commonly used antioxydant. 2) Using Prostar R package, the three replicates of MS data were filtered for the minimum quantification of 66,66% of each protein in at least one condition. They were normalized within conditions using VSN normalization, then the Partially Observed Values (POV) and the Missing in Entire Column (MEC) values were imputed respectively with SLSA and DetQuantile (Quantile 1%, Factor 0,2). A differential analysis between the LPS and non-treated conditions identified 334 proteins enriched with a FC of ± ≥2,5 with a p-value inferior then 0,05. Among the top Shp-2 interactors, we found Tak1 (ampersand:003E3,5X change) and Tab1 (ampersand:003E3,0X change), two proteins involved in NF-kB signaling. Decreased interaction with the TLR effectors Myd88 (ampersand:003C2,5X change) and Irak1 (ampersand:003C3,2X change) was also noted after LPS treatment. Conclusions These data suggest for the first time that Shp-2 may regulate NF-kB signaling downstream of TLR4 in IEC. Thus, SHP-2 may contribute to the maintenance of mucosal tolerance to microbiota in the colon. Funding Agencies CIHR","PeriodicalId":508018,"journal":{"name":"Journal of the Canadian Association of Gastroenterology","volume":"619 ","pages":"34 - 35"},"PeriodicalIF":0.0,"publicationDate":"2024-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139837058","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-14DOI: 10.1093/jcag/gwad061.130
S Gupta, K. Pawlak, J. De Rezende-Neto, G. May, J. Mosko, N. Calo
Abstract Background A 26-year-old male sustained significant traumatic thoracoabdominal injuries following a gunshot. He underwent several laparotomies, small bowel resections, an extended left hemicolectomy with end-colostomy formation, and a flap to close the abdomen. He subsequently developed a high-output enterocutaneous fistula (ECF) and loss of colostomy output. CT imaging confirmed an ECF from the ileum to the anterior abdominal wall and a severe ileal stricture distal to the fistula. Aims In the context of his complex surgical abdomen and proximity of the ECF to the abdominal flap, surgical re-intervention was deemed high-risk. He was placed on total parenteral nutrition and referred for endoscopic management. Methods Under fluoroscopic guidance, we injected methylene blue & contrast dye from the skin side of the ECF. A dilated segment of small bowel was filled, with no downstream passage of contrast (Fig 1A). Retrograde ileoscopy was performed with an Olympus pediatric colonoscope via the patient’s colostomy. 90 cm from the ileocecal valve (ICV), we encountered a benign enteric stenosis that could not be traversed. Contrast was injected, with fluoroscopy revealing a 10 cm long tortuous stenosis (Fig 1B), extending to the previously filled loop of small bowel. Given the length and characterof the stricture, endoscopic balloon dilation and enteral stenting were technically infeasible. Results We proceeded to retrograde endoscopic ultrasound (EUS)-guided entero-enterostomy creation. With the aid of a guidewire, and under endoscopic, fluoroscopic and endosonographic guidance, a linear echoendoscope was advanced into the ileum via the colostomy, cecum and ICV. 50 cm from the ICV, we identified an adjacent dilated loop of small bowel (Fig. 1C). Water was instilled through the ECF, with the endosonographic view demonstrating filling, thus indicating this location to be upstream from the ECF. A 19-gauge needle was punctured through, with subsequent aspiration of methylene blue (Fig. 1D). We then created an EUS-guided entero-enterostomy using a 15mm lumen-apposing metal stent (Hot-AXIOS; Boston Scientific, Massachusetts, USA; Fig. 1E). Passage of methylene blue & contrast through the stent confirmed accurate deployment (Fig. 1F&G). With both the ECF & stricture bypassed, the patient’s colostomy output returned and ECF output diminished. Conclusions Electrocautery-enhanced lumen apposition with metal stenting is well established. It can facilitate the formation of an anchored anastomosis across non-adherent luminal structures in a single-step fashion. Herein, we have reported a novel application of this technique in the management of a complex post-surgical trauma patient with a high-output ECF and deep enteric stenosis. Figure 1: Retrograde EUS-guided entero-enterostomy Funding Agencies None
{"title":"A130 RETROGRADE ENDOSCOPIC ULTRASOUND-GUIDED ENTERO-ENTEROSTOMY USING A LUMEN-APPOSING METAL STENT FOR THE MANAGEMENT OF A HIGH-OUTPUT ENTEROCUTANEOUS FISTULA AND ILEAL STRICTURE IN A COMPLEX SURGICAL ABDOMEN","authors":"S Gupta, K. Pawlak, J. De Rezende-Neto, G. May, J. Mosko, N. Calo","doi":"10.1093/jcag/gwad061.130","DOIUrl":"https://doi.org/10.1093/jcag/gwad061.130","url":null,"abstract":"Abstract Background A 26-year-old male sustained significant traumatic thoracoabdominal injuries following a gunshot. He underwent several laparotomies, small bowel resections, an extended left hemicolectomy with end-colostomy formation, and a flap to close the abdomen. He subsequently developed a high-output enterocutaneous fistula (ECF) and loss of colostomy output. CT imaging confirmed an ECF from the ileum to the anterior abdominal wall and a severe ileal stricture distal to the fistula. Aims In the context of his complex surgical abdomen and proximity of the ECF to the abdominal flap, surgical re-intervention was deemed high-risk. He was placed on total parenteral nutrition and referred for endoscopic management. Methods Under fluoroscopic guidance, we injected methylene blue & contrast dye from the skin side of the ECF. A dilated segment of small bowel was filled, with no downstream passage of contrast (Fig 1A). Retrograde ileoscopy was performed with an Olympus pediatric colonoscope via the patient’s colostomy. 90 cm from the ileocecal valve (ICV), we encountered a benign enteric stenosis that could not be traversed. Contrast was injected, with fluoroscopy revealing a 10 cm long tortuous stenosis (Fig 1B), extending to the previously filled loop of small bowel. Given the length and characterof the stricture, endoscopic balloon dilation and enteral stenting were technically infeasible. Results We proceeded to retrograde endoscopic ultrasound (EUS)-guided entero-enterostomy creation. With the aid of a guidewire, and under endoscopic, fluoroscopic and endosonographic guidance, a linear echoendoscope was advanced into the ileum via the colostomy, cecum and ICV. 50 cm from the ICV, we identified an adjacent dilated loop of small bowel (Fig. 1C). Water was instilled through the ECF, with the endosonographic view demonstrating filling, thus indicating this location to be upstream from the ECF. A 19-gauge needle was punctured through, with subsequent aspiration of methylene blue (Fig. 1D). We then created an EUS-guided entero-enterostomy using a 15mm lumen-apposing metal stent (Hot-AXIOS; Boston Scientific, Massachusetts, USA; Fig. 1E). Passage of methylene blue & contrast through the stent confirmed accurate deployment (Fig. 1F&G). With both the ECF & stricture bypassed, the patient’s colostomy output returned and ECF output diminished. Conclusions Electrocautery-enhanced lumen apposition with metal stenting is well established. It can facilitate the formation of an anchored anastomosis across non-adherent luminal structures in a single-step fashion. Herein, we have reported a novel application of this technique in the management of a complex post-surgical trauma patient with a high-output ECF and deep enteric stenosis. Figure 1: Retrograde EUS-guided entero-enterostomy Funding Agencies None","PeriodicalId":508018,"journal":{"name":"Journal of the Canadian Association of Gastroenterology","volume":"39 4","pages":"98 - 99"},"PeriodicalIF":0.0,"publicationDate":"2024-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139837112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-14DOI: 10.1093/jcag/gwad061.074
A. Binaqail, V. Morinville, V Nguyen
Abstract Background The etiopathogenesis of microscopic colitis may reflect an immunological reaction in genetically predisposed individuals exposed to an external stimulus causing gut microbiota disruption. Numerous factors such as smoking, autoimmune diseases, and medications have been linked to this condition in adults. Steroids may be required as therapy. Pediatric cases of microscopic colitis have only rarely been reported. Aims Case report. Methods Retrospective single chart review and literature review of microscopic colitis in children. Results A 17-year-old female newly diagnosed with major depression disorder following intentional acetaminophen intoxication was started on sertraline, a selective serotonin reuptake inhibitor (SSRI). Within 2 months from initiation, she began to have non bloody watery diarrhea and had a 5 kg weight loss over a 1-month period . Her laboratory workup only revealed a hypochromic, microcytic anemia. Due to severity of symptoms and reluctance of treating team to discontinue sertraline, she underwent an esophagogastroduodenoscopy and ileo-colonoscopy, both showing grossly normal mucosa. Histological assessment of the colon demonstrated increased intraepithelial lymphocytes, up to 50-60 lymphocytes/100 enterocytes (normal ≤ 20 lymphocytes/100 enterocytes), with associated reactive superficial epithelial changes including goblet cell and mucin depletion, compatible with lymphocytic colitis (Figure1). Sertraline was weaned off, and gastrointestinal symptoms resolved completely. A repeat sigmoidoscopy 5 months later confirmed complete normalization of the histology. Conclusions Microscopic Colitis encompasses two disorders, lymphocytic colitis and collagenous colitis, in which the endoscopic appearance is unremarkable, but histological changes are diagnostic. The clinical manifestations of both are similar and typically include chronic non bloody watery diarrhea, weight loss and abdominal pain. Certain medications have been implicated in causing lymphocytic colitis, including SSRIs. SSRIs historically have not been frequently prescribed in pediatrics, but their use has increased in recent years. The complete resolution of symptoms and histology, without the need for any medical therapy, strongly supports that this lymphocytic colitis was caused by sertraline. The association of lymphocytic colitis with sertraline is not well-known among pediatric practitioners: neither the pediatrician nor psychiatrist in our case were aware of such a possibility. This case highlights that medication adverse events, even if rare, should always be considered when chronology is supportive, and at times, simple discontinuation of the drug is sufficient to completely resolve the issue. Funding Agencies None
{"title":"A74 A RARE CASE OF ANTIDEPRESSANT-INDUCED LYMPHOCYTIC COLITIS IN A TEENAGER","authors":"A. Binaqail, V. Morinville, V Nguyen","doi":"10.1093/jcag/gwad061.074","DOIUrl":"https://doi.org/10.1093/jcag/gwad061.074","url":null,"abstract":"Abstract Background The etiopathogenesis of microscopic colitis may reflect an immunological reaction in genetically predisposed individuals exposed to an external stimulus causing gut microbiota disruption. Numerous factors such as smoking, autoimmune diseases, and medications have been linked to this condition in adults. Steroids may be required as therapy. Pediatric cases of microscopic colitis have only rarely been reported. Aims Case report. Methods Retrospective single chart review and literature review of microscopic colitis in children. Results A 17-year-old female newly diagnosed with major depression disorder following intentional acetaminophen intoxication was started on sertraline, a selective serotonin reuptake inhibitor (SSRI). Within 2 months from initiation, she began to have non bloody watery diarrhea and had a 5 kg weight loss over a 1-month period . Her laboratory workup only revealed a hypochromic, microcytic anemia. Due to severity of symptoms and reluctance of treating team to discontinue sertraline, she underwent an esophagogastroduodenoscopy and ileo-colonoscopy, both showing grossly normal mucosa. Histological assessment of the colon demonstrated increased intraepithelial lymphocytes, up to 50-60 lymphocytes/100 enterocytes (normal ≤ 20 lymphocytes/100 enterocytes), with associated reactive superficial epithelial changes including goblet cell and mucin depletion, compatible with lymphocytic colitis (Figure1). Sertraline was weaned off, and gastrointestinal symptoms resolved completely. A repeat sigmoidoscopy 5 months later confirmed complete normalization of the histology. Conclusions Microscopic Colitis encompasses two disorders, lymphocytic colitis and collagenous colitis, in which the endoscopic appearance is unremarkable, but histological changes are diagnostic. The clinical manifestations of both are similar and typically include chronic non bloody watery diarrhea, weight loss and abdominal pain. Certain medications have been implicated in causing lymphocytic colitis, including SSRIs. SSRIs historically have not been frequently prescribed in pediatrics, but their use has increased in recent years. The complete resolution of symptoms and histology, without the need for any medical therapy, strongly supports that this lymphocytic colitis was caused by sertraline. The association of lymphocytic colitis with sertraline is not well-known among pediatric practitioners: neither the pediatrician nor psychiatrist in our case were aware of such a possibility. This case highlights that medication adverse events, even if rare, should always be considered when chronology is supportive, and at times, simple discontinuation of the drug is sufficient to completely resolve the issue. Funding Agencies None","PeriodicalId":508018,"journal":{"name":"Journal of the Canadian Association of Gastroenterology","volume":"20 8","pages":"51 - 51"},"PeriodicalIF":0.0,"publicationDate":"2024-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139837132","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-14DOI: 10.1093/jcag/gwad061.139
K Patel, D. Yang, T. Krahn, S. Wesilenko, B. Halloran, S. Zepeda-Gomez
Abstract Background Esophagogastroduodenoscopy (EGD) is recommended for initial endoscopic evaluation of patients with suspected upper gastrointestinal bleeding (UGIB). When this is negative, the standard recommendation is to perform a colonoscopy, despite low diagnostic yield of less than 5%. In these patients, the question remains as to whether small bowel investigations would be of higher yield prior to colonoscopy. Aims To compare the diagnostic yield between early video capsule endoscopy (VCE) versus colonoscopy after a negative EGD in patients with suspected UGIB. Methods This is preliminary data from a prospective randomized control trial (RCT) of adult patients with suspected UGIB (melena and hemoglobin drop of more than 20 g/L within 48 hours of admission). Patients at a single centre were enrolled prior to initial EGD; those with negative EGD were included and randomized to either colonoscopy (next day) or early VCE (immediately after EGD). Patients with a confirmed source of bleeding in their group required no further testing, but those without underwent further testing with the alternative (VCE or colonoscopy). We evaluated patient outcomes, including bleeding localization time, hospitalization duration, procedure count, complications and rebleeding rates. Results A total of 19 adult patients have been enrolled, of which 12 had negative EGD and were randomized to either VCE or colonoscopy, with six patients in each arm (Figure 1). In the VCE group, 100% (6/6) of patients had bleeding sources detected by early VCE, with 50% (3/6) of them undergoing endoscopic treatment. In the colonoscopy group, only one patient had a positive finding (1/6), the rest underwent subsequent VCE. The VCE identified the bleeding source in 80% (4/5) of patients with negative colonoscopy. Patient are outlined in Table 1. Conclusions Based on our preliminary data, the diagnostic yield of early and subsequent VCE was higher when compared to colonoscopy after initial negative EGD in patients with suspected UGIB. Table 1. Summary of findings and patient outcomes OUTCOMES Early VCE Arm Colonoscopy Arm All participants Bleeding localized after first test, % (n) 100 (6/6) 17 (1/6) 58 (7/12) Average time to localization of bleed (days) ± standard deviation 5.33 ±2.46 6 ±2.31 5.67 ±1.62 Average length of hospital stay (days) ± standard deviation 5.33 ±0.97 5.17 ±1.55 5.25 ±0.874 Average number of procedures 2.67 3.17 2.92 Etiology of bleeding -Actively bleeding AVMs in small bowel – 33% (2/6) -Non-bleeding AVMs – 50% (3/6) -Active bleeding in right colon – 17% (1/6) -Clean based longitudinal ulcer in transverse colon – 17% (1/6) Funding Agencies Medtronic Canada (Brampton, ON, CA) will provide the video capsule in the treatment group. This is the only equipment funding required in this study.
{"title":"A139 EARLY VIDEO CAPSULE ENDOSCOPY VERSUS COLONOSCOPY FOLLOWING NEGATIVE ESOPHAGOGASTRODUDENOSCOPY IN PATIENTS WITH SUSPECTED UPPER GASTROINTESTINAL BLEEDING: PRELIMINARY DATA FROM A RANDOMIZED CONTROLLED TRIAL","authors":"K Patel, D. Yang, T. Krahn, S. Wesilenko, B. Halloran, S. Zepeda-Gomez","doi":"10.1093/jcag/gwad061.139","DOIUrl":"https://doi.org/10.1093/jcag/gwad061.139","url":null,"abstract":"Abstract Background Esophagogastroduodenoscopy (EGD) is recommended for initial endoscopic evaluation of patients with suspected upper gastrointestinal bleeding (UGIB). When this is negative, the standard recommendation is to perform a colonoscopy, despite low diagnostic yield of less than 5%. In these patients, the question remains as to whether small bowel investigations would be of higher yield prior to colonoscopy. Aims To compare the diagnostic yield between early video capsule endoscopy (VCE) versus colonoscopy after a negative EGD in patients with suspected UGIB. Methods This is preliminary data from a prospective randomized control trial (RCT) of adult patients with suspected UGIB (melena and hemoglobin drop of more than 20 g/L within 48 hours of admission). Patients at a single centre were enrolled prior to initial EGD; those with negative EGD were included and randomized to either colonoscopy (next day) or early VCE (immediately after EGD). Patients with a confirmed source of bleeding in their group required no further testing, but those without underwent further testing with the alternative (VCE or colonoscopy). We evaluated patient outcomes, including bleeding localization time, hospitalization duration, procedure count, complications and rebleeding rates. Results A total of 19 adult patients have been enrolled, of which 12 had negative EGD and were randomized to either VCE or colonoscopy, with six patients in each arm (Figure 1). In the VCE group, 100% (6/6) of patients had bleeding sources detected by early VCE, with 50% (3/6) of them undergoing endoscopic treatment. In the colonoscopy group, only one patient had a positive finding (1/6), the rest underwent subsequent VCE. The VCE identified the bleeding source in 80% (4/5) of patients with negative colonoscopy. Patient are outlined in Table 1. Conclusions Based on our preliminary data, the diagnostic yield of early and subsequent VCE was higher when compared to colonoscopy after initial negative EGD in patients with suspected UGIB. Table 1. Summary of findings and patient outcomes OUTCOMES Early VCE Arm Colonoscopy Arm All participants Bleeding localized after first test, % (n) 100 (6/6) 17 (1/6) 58 (7/12) Average time to localization of bleed (days) ± standard deviation 5.33 ±2.46 6 ±2.31 5.67 ±1.62 Average length of hospital stay (days) ± standard deviation 5.33 ±0.97 5.17 ±1.55 5.25 ±0.874 Average number of procedures 2.67 3.17 2.92 Etiology of bleeding -Actively bleeding AVMs in small bowel – 33% (2/6) -Non-bleeding AVMs – 50% (3/6) -Active bleeding in right colon – 17% (1/6) -Clean based longitudinal ulcer in transverse colon – 17% (1/6) Funding Agencies Medtronic Canada (Brampton, ON, CA) will provide the video capsule in the treatment group. This is the only equipment funding required in this study.","PeriodicalId":508018,"journal":{"name":"Journal of the Canadian Association of Gastroenterology","volume":"394 1","pages":"106 - 107"},"PeriodicalIF":0.0,"publicationDate":"2024-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139837162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-14DOI: 10.1093/jcag/gwad061.033
R. D. Fitzpatrick, J. R. Noone, R. A. Cartwright, D. M. Gatti, T. Brosschot, J. M. Lane, M. Zafarullah, I. Kroker Kimber, L. Reynolds
Abstract Background During inflammatory bowel disease (IBD) both the number of intestinal eosinophils and susceptibility to enteric bacterial infections can drastically increase. It is unknown, however, whether eosinophils recruited to the tissues lining the gastrointestinal (GI) tract during severe disease help to control pathogenic bacterial colonization or whether their presence promotes bacterial infection. No studies to date have examined the role of eosinophils during an acute bacterial infection in the small intestine. Aims Our research aims to uncover the role of eosinophils during an enteric Salmonella infection in mice and we hypothesize that eosinophils undergo phenotypic changes in the presence of Salmonella and aid in the clearance of this enteric bacterial pathogen. Methods To assess how the presence of Salmonella impacts the frequency and phenotype of eosinophils we performed flow cytometry on eosinophils isolated from mice 3-days post-oral infection with Salmonella enterica serovar Typhimurium and compared these findings to naïve BALB/c controls. To determine if eosinophils are essential for controlling Salmonella infection we quantified levels of Salmonella colonization along the GI tract, liver and spleen of wild-type and eosinophil-deficient (ΔdblGATA) littermate mice by plating homogenized tissues on LB agar. Results Following an oral Salmonella infection we found higher frequencies of eosinophils in the gut-draining mesenteric lymph nodes compared to uninfected mice. Intestinal lamina propria-resident eosinophils in the small intestine and colon displayed altered phenotypes following infection in an intestinal-region specific manner: during infection, in the small intestine eosinophils increased their expression of MHCII, and in the colon eosinophils displayed elevated granularity. When wild-type and ΔdblGATA mice were pre-treated with the antibiotic streptomycin 1-day prior to infection to confer robust Salmonella burdens in the small intestine we found a significant reduction in Salmonella colonization in the ileum of the small intestine in ΔdblGATA mice compared to their wild-type littermates. These data suggest eosinophils have a role in promoting colonization by this enteric bacterial pathogen. Conclusions Our data contribute to the growing evidence that microbes can influence the phenotype of intestinal eosinophils and demonstrate that the influence of and requirements for eosinophils during bacterial infection is highly context-dependent. We found that eosinophils are not essential for controlling an acute enteric Salmonella infection and instead they promote Salmonella colonization in the small intestine. Funding Agencies CIHRTRIANGLE
{"title":"A33 EOSINOPHILS PROMOTE SALMONELLA TYPHIMURIUM COLONIZATION IN THE MURINE SMALL INTESTINE","authors":"R. D. Fitzpatrick, J. R. Noone, R. A. Cartwright, D. M. Gatti, T. Brosschot, J. M. Lane, M. Zafarullah, I. Kroker Kimber, L. Reynolds","doi":"10.1093/jcag/gwad061.033","DOIUrl":"https://doi.org/10.1093/jcag/gwad061.033","url":null,"abstract":"Abstract Background During inflammatory bowel disease (IBD) both the number of intestinal eosinophils and susceptibility to enteric bacterial infections can drastically increase. It is unknown, however, whether eosinophils recruited to the tissues lining the gastrointestinal (GI) tract during severe disease help to control pathogenic bacterial colonization or whether their presence promotes bacterial infection. No studies to date have examined the role of eosinophils during an acute bacterial infection in the small intestine. Aims Our research aims to uncover the role of eosinophils during an enteric Salmonella infection in mice and we hypothesize that eosinophils undergo phenotypic changes in the presence of Salmonella and aid in the clearance of this enteric bacterial pathogen. Methods To assess how the presence of Salmonella impacts the frequency and phenotype of eosinophils we performed flow cytometry on eosinophils isolated from mice 3-days post-oral infection with Salmonella enterica serovar Typhimurium and compared these findings to naïve BALB/c controls. To determine if eosinophils are essential for controlling Salmonella infection we quantified levels of Salmonella colonization along the GI tract, liver and spleen of wild-type and eosinophil-deficient (ΔdblGATA) littermate mice by plating homogenized tissues on LB agar. Results Following an oral Salmonella infection we found higher frequencies of eosinophils in the gut-draining mesenteric lymph nodes compared to uninfected mice. Intestinal lamina propria-resident eosinophils in the small intestine and colon displayed altered phenotypes following infection in an intestinal-region specific manner: during infection, in the small intestine eosinophils increased their expression of MHCII, and in the colon eosinophils displayed elevated granularity. When wild-type and ΔdblGATA mice were pre-treated with the antibiotic streptomycin 1-day prior to infection to confer robust Salmonella burdens in the small intestine we found a significant reduction in Salmonella colonization in the ileum of the small intestine in ΔdblGATA mice compared to their wild-type littermates. These data suggest eosinophils have a role in promoting colonization by this enteric bacterial pathogen. Conclusions Our data contribute to the growing evidence that microbes can influence the phenotype of intestinal eosinophils and demonstrate that the influence of and requirements for eosinophils during bacterial infection is highly context-dependent. We found that eosinophils are not essential for controlling an acute enteric Salmonella infection and instead they promote Salmonella colonization in the small intestine. Funding Agencies CIHRTRIANGLE","PeriodicalId":508018,"journal":{"name":"Journal of the Canadian Association of Gastroenterology","volume":"44 2","pages":"18 - 18"},"PeriodicalIF":0.0,"publicationDate":"2024-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139837196","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-14DOI: 10.1093/jcag/gwad061.285
M. Dahiya, H. Bedi, A. Fetz, E. Yoshida, H. Ko, B. Salh, D. Chahal
Abstract Background Primary sclerosing cholangitis (PSC) results in progressive inflammation and fibrosis of bile ducts causing chronic cholestasis. PSC is associated with an increased risk of malignancy [hepatobiliary and colorectal cancers (CRC)] compared to the general population, in addition to an increased risk of developing end-stage liver disease, often requiring liver transplantation at a relatively young age. The increased risk of adverse outcomes confers an increased risk of premature death of patients with PSC. PSC is commonly associated with IBD, particularly ulcerative colitis (UC), which in itself carries a higher rate of CRC. A study of the impact of PSC with IBD on development of cancer and survival outcomes is imperative. Aims To compare the risk of cancer, liver transplantation, and mortality in PSC-IBD versus isolated PSC. Methods Retrospective data from PSC patients from two hospital sites in Vancouver, British Columbia was analyzed to compare the relative risk of death, transplantation, and malignancy in PSC-IBD versus isolated PSC. Results 169 patients with PSC were included in the analysis [mean age of diagnosis of PSC 37 (SD 16.92) years, 41.4% (70) female]. Out of the 169 patients with PSC, 102 had IBD [29.4% (30) with Crohn’s Disease (CD); 70.6% (72) with UC]. The mean age of IBD diagnosis was 28.96 (SD 14.46) years. Death occurred in 31 [64.5% (20) with IBD; RR 1.19, 95% CI 0.61-2.32, p=0.60] patients, 35 [57.1% (20) with IBD; RR 0.88, 95% CI 0.48-1.59, p=0.66] patients developed cancer, and 33 [66.7% (22) with IBD; RR 1.31, 95% CI 0.68-2.52, p=0.41] patients required liver transplantation. The cause of death was malignancy in 15 [53.3% (8) with IBD] patients, liver failure in 5 [80% (4) with IBD] patients, sepsis in 2 [100% (2) with IBD] patients, and unknown cause of death in 9 [77.7% (7) with IBD] patients. For malignancy types, 16 [68.75% (11) with IBD] patients had cholangiocarcinoma (CCA), 4 [50% (2) with IBD] had CRC, 2 [50% (1) with IBD] had gallbladder cancer, 1 [0% (0) with IBD] had pancreatic cancer, 1 [0% (0) with IBD] had esophageal cancer, and 11 [54.5% (6) with IBD] had other malignancies not involving the hepatobiliary or gastrointestinal system. Of the patients who died due to malignancy, 73.3% (11) had CCA. Conclusions Although we do not observe any statistically significant difference in risk of cancer, transplantation, or all-cause mortality in patients with PSC-IBD when compared to isolated PSC, we do observe that 59% of all-included patients experienced one or more adverse outcome. It is important for clinicians to recognize the high rates of adverse outcomes in PSC-IBD and isolated PSC patients, potentially warranting earlier or more frequent screening for outcomes such as malignancy and liver dysfunction. Funding Agencies None
{"title":"A285 COMPARISON OF ADVERSE OUTCOMES IN PATIENTS WITH COMBINED INFLAMMATORY BOWEL DISEASE AND PRIMARY SCLEROSING CHOLANGITIS VERSUS ISOLATED PRIMARY SCLEROSING CHOLANGITIS","authors":"M. Dahiya, H. Bedi, A. Fetz, E. Yoshida, H. Ko, B. Salh, D. Chahal","doi":"10.1093/jcag/gwad061.285","DOIUrl":"https://doi.org/10.1093/jcag/gwad061.285","url":null,"abstract":"Abstract Background Primary sclerosing cholangitis (PSC) results in progressive inflammation and fibrosis of bile ducts causing chronic cholestasis. PSC is associated with an increased risk of malignancy [hepatobiliary and colorectal cancers (CRC)] compared to the general population, in addition to an increased risk of developing end-stage liver disease, often requiring liver transplantation at a relatively young age. The increased risk of adverse outcomes confers an increased risk of premature death of patients with PSC. PSC is commonly associated with IBD, particularly ulcerative colitis (UC), which in itself carries a higher rate of CRC. A study of the impact of PSC with IBD on development of cancer and survival outcomes is imperative. Aims To compare the risk of cancer, liver transplantation, and mortality in PSC-IBD versus isolated PSC. Methods Retrospective data from PSC patients from two hospital sites in Vancouver, British Columbia was analyzed to compare the relative risk of death, transplantation, and malignancy in PSC-IBD versus isolated PSC. Results 169 patients with PSC were included in the analysis [mean age of diagnosis of PSC 37 (SD 16.92) years, 41.4% (70) female]. Out of the 169 patients with PSC, 102 had IBD [29.4% (30) with Crohn’s Disease (CD); 70.6% (72) with UC]. The mean age of IBD diagnosis was 28.96 (SD 14.46) years. Death occurred in 31 [64.5% (20) with IBD; RR 1.19, 95% CI 0.61-2.32, p=0.60] patients, 35 [57.1% (20) with IBD; RR 0.88, 95% CI 0.48-1.59, p=0.66] patients developed cancer, and 33 [66.7% (22) with IBD; RR 1.31, 95% CI 0.68-2.52, p=0.41] patients required liver transplantation. The cause of death was malignancy in 15 [53.3% (8) with IBD] patients, liver failure in 5 [80% (4) with IBD] patients, sepsis in 2 [100% (2) with IBD] patients, and unknown cause of death in 9 [77.7% (7) with IBD] patients. For malignancy types, 16 [68.75% (11) with IBD] patients had cholangiocarcinoma (CCA), 4 [50% (2) with IBD] had CRC, 2 [50% (1) with IBD] had gallbladder cancer, 1 [0% (0) with IBD] had pancreatic cancer, 1 [0% (0) with IBD] had esophageal cancer, and 11 [54.5% (6) with IBD] had other malignancies not involving the hepatobiliary or gastrointestinal system. Of the patients who died due to malignancy, 73.3% (11) had CCA. Conclusions Although we do not observe any statistically significant difference in risk of cancer, transplantation, or all-cause mortality in patients with PSC-IBD when compared to isolated PSC, we do observe that 59% of all-included patients experienced one or more adverse outcome. It is important for clinicians to recognize the high rates of adverse outcomes in PSC-IBD and isolated PSC patients, potentially warranting earlier or more frequent screening for outcomes such as malignancy and liver dysfunction. Funding Agencies None","PeriodicalId":508018,"journal":{"name":"Journal of the Canadian Association of Gastroenterology","volume":"6 3","pages":"230 - 230"},"PeriodicalIF":0.0,"publicationDate":"2024-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139837336","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-14DOI: 10.1093/jcag/gwad061.030
D. Tsang, C. Maisonneuve, A. Ayyaz, E. Foerster, M. Nissan, L. Baerg, D. Trcka, C. Streutker, J. L. Wrana, S. Girardin, D. Philpott
Abstract Background Inflammatory bowel disease is characterized by chronic inflammation of the gastrointestinal tract, resulting in recurrent injury to the intestinal epithelium. Restitution of the small intestinal epithelium is a coordinated response that involves the dedifferentiation of epithelial cell lineages, proliferation of Lgr5+ intestinal stem cells, and fetal-like stem cell reversion. While gut microbiota are critical mediators of intestinal inflammation, their impact on epithelial restitution remains unclear. Aims We aim to identify the how microbes regulate small intestinal epithelial restitution following damage. Our hypothesis is that gut microbiota accelerate restitution through pattern recognition receptor-driven signals following fetal-like stem cell reversion. Methods Irradiation (IR, 12Gγ) was used to induce a synchronized small intestinal epithelial restitution response in mice. Intestinal restitution kinetics were assessed transcriptionally (scRNA-Seq, qPCR) and histologically. Small intestinal organoids were used to assess epithelial restitution kinetics in vitro. Results ScRNA-Seq of small intestinal epithelial cells following IR from germ-free mice (GF), and specific pathogen-free mice (SPF) mice revealed that microbiota induced greater expression of fetal-like stem cell reversion markers, Ly6a and Clu, and greater expression of the proliferation marker, Pcna. These results were supported histologically as irradiated SPF mice observed an increase in fetal-like stem cells marked by Ly6a and Clu and an increase BrdU+ proliferating cells. ScRNA-seq and in situ hybridization highlighted that fetal-like intestinal stem cells upregulate expression of Nod2, a bacterial pattern recognition receptor. Using intestinal organoids to assess the function of Nod2, we observed that muramyl dipeptide driven Nod2-signlaing potentiates an interferon gene signature following IFNγ and TNFα co-stimulation. Further supporting the role for Nod2 in intestinal restitution, intestinal epithelium specific Nod2KO mice decreased BrdU+ proliferating cells post-IR compared to littermate controls. Conclusions Microbiota promote small intestinal restitution following IR through Nod2-signaling in fetal-like intestinal stem cells. Funding Agencies CIHR
{"title":"A30 MICROBIOTA AND NOD2 REGULATE SMALL INTESTINAL RESTITUTION THROUGH FETAL-LIKE INTESTINAL STEM CELLS","authors":"D. Tsang, C. Maisonneuve, A. Ayyaz, E. Foerster, M. Nissan, L. Baerg, D. Trcka, C. Streutker, J. L. Wrana, S. Girardin, D. Philpott","doi":"10.1093/jcag/gwad061.030","DOIUrl":"https://doi.org/10.1093/jcag/gwad061.030","url":null,"abstract":"Abstract Background Inflammatory bowel disease is characterized by chronic inflammation of the gastrointestinal tract, resulting in recurrent injury to the intestinal epithelium. Restitution of the small intestinal epithelium is a coordinated response that involves the dedifferentiation of epithelial cell lineages, proliferation of Lgr5+ intestinal stem cells, and fetal-like stem cell reversion. While gut microbiota are critical mediators of intestinal inflammation, their impact on epithelial restitution remains unclear. Aims We aim to identify the how microbes regulate small intestinal epithelial restitution following damage. Our hypothesis is that gut microbiota accelerate restitution through pattern recognition receptor-driven signals following fetal-like stem cell reversion. Methods Irradiation (IR, 12Gγ) was used to induce a synchronized small intestinal epithelial restitution response in mice. Intestinal restitution kinetics were assessed transcriptionally (scRNA-Seq, qPCR) and histologically. Small intestinal organoids were used to assess epithelial restitution kinetics in vitro. Results ScRNA-Seq of small intestinal epithelial cells following IR from germ-free mice (GF), and specific pathogen-free mice (SPF) mice revealed that microbiota induced greater expression of fetal-like stem cell reversion markers, Ly6a and Clu, and greater expression of the proliferation marker, Pcna. These results were supported histologically as irradiated SPF mice observed an increase in fetal-like stem cells marked by Ly6a and Clu and an increase BrdU+ proliferating cells. ScRNA-seq and in situ hybridization highlighted that fetal-like intestinal stem cells upregulate expression of Nod2, a bacterial pattern recognition receptor. Using intestinal organoids to assess the function of Nod2, we observed that muramyl dipeptide driven Nod2-signlaing potentiates an interferon gene signature following IFNγ and TNFα co-stimulation. Further supporting the role for Nod2 in intestinal restitution, intestinal epithelium specific Nod2KO mice decreased BrdU+ proliferating cells post-IR compared to littermate controls. Conclusions Microbiota promote small intestinal restitution following IR through Nod2-signaling in fetal-like intestinal stem cells. Funding Agencies CIHR","PeriodicalId":508018,"journal":{"name":"Journal of the Canadian Association of Gastroenterology","volume":"98 1","pages":"16 - 17"},"PeriodicalIF":0.0,"publicationDate":"2024-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139837396","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-14DOI: 10.1093/jcag/gwad061.065
J Sung, A. Gregorieff, S. Gruenheid
Abstract Background Gastric cancer is one of the leading causes of cancer-related deaths and its prevalence has been associated with infection by Helicobacter pylori. H. pylori persistence leads to chronic inflammation, which results in the elimination of acid-secreting parietal cells and the appearance of abnormal mucus-producing cells at the base of the gastric glands, known as spasmolytic polypeptide/trefoil factor 2-expressing metaplasia (SPEM) cells. The processes driving these alterations in epithelial cell fate during H. pylori infection and their function in regeneration of the gastric epithelium remain unclear. Previous work done in our lab have demonstrated that Hippo signalling, more specifically the transcriptional effectors yes-associated protein 1 (YAP) and transcription coactivator with PDZ-binding motif (TAZ), plays an essential role in controlling cell fate during gastric tissue regeneration in a chemical injury model. In the same model, loss of YAP/TAZ resulted in chronic immune cell infiltration in corpus glands, suggesting an immunomodulatory role for YAP and TAZ. Aims The objectives of this project is to characterize the immunomodulatory function of YAP/TAZ in an in vivo model of acute injury as well as an in vivo model of H. pylori infection. Methods Acute injury is induced by high-dose tamoxifen treatment in conditional knock-out (cKO) mice with YAP/TAZ deleted throughout the gastric epithelium. Subsequent immunophenotyping experiments such as flow cytometry and multiplex analysis are performed to characterize the role played by YAP/TAZ in regulating the immune response. For a more biologically relevant model, cKO mice are also infected with H. pylori, and similar immunophenotyping analyses are performed. Results Preliminary results showed that the loss of YAP/TAZ resulted in differential type II response as well as chronic B cell infiltration upon tissue injury. Conclusions This project aims to provide important insights on immune-epithelial cell interactions important for tissue regeneration and tumorigenesis as well as host-pathogen interactions implicated in H. pylori persistence. Funding Agencies CIHRFRQS
{"title":"A65 THE YAP-PER: CAN YAP/TAZ MEDIATE EPITHELIAL-IMMUNE CROSSTALK DURING PYLORIC METAPLASIA?","authors":"J Sung, A. Gregorieff, S. Gruenheid","doi":"10.1093/jcag/gwad061.065","DOIUrl":"https://doi.org/10.1093/jcag/gwad061.065","url":null,"abstract":"Abstract Background Gastric cancer is one of the leading causes of cancer-related deaths and its prevalence has been associated with infection by Helicobacter pylori. H. pylori persistence leads to chronic inflammation, which results in the elimination of acid-secreting parietal cells and the appearance of abnormal mucus-producing cells at the base of the gastric glands, known as spasmolytic polypeptide/trefoil factor 2-expressing metaplasia (SPEM) cells. The processes driving these alterations in epithelial cell fate during H. pylori infection and their function in regeneration of the gastric epithelium remain unclear. Previous work done in our lab have demonstrated that Hippo signalling, more specifically the transcriptional effectors yes-associated protein 1 (YAP) and transcription coactivator with PDZ-binding motif (TAZ), plays an essential role in controlling cell fate during gastric tissue regeneration in a chemical injury model. In the same model, loss of YAP/TAZ resulted in chronic immune cell infiltration in corpus glands, suggesting an immunomodulatory role for YAP and TAZ. Aims The objectives of this project is to characterize the immunomodulatory function of YAP/TAZ in an in vivo model of acute injury as well as an in vivo model of H. pylori infection. Methods Acute injury is induced by high-dose tamoxifen treatment in conditional knock-out (cKO) mice with YAP/TAZ deleted throughout the gastric epithelium. Subsequent immunophenotyping experiments such as flow cytometry and multiplex analysis are performed to characterize the role played by YAP/TAZ in regulating the immune response. For a more biologically relevant model, cKO mice are also infected with H. pylori, and similar immunophenotyping analyses are performed. Results Preliminary results showed that the loss of YAP/TAZ resulted in differential type II response as well as chronic B cell infiltration upon tissue injury. Conclusions This project aims to provide important insights on immune-epithelial cell interactions important for tissue regeneration and tumorigenesis as well as host-pathogen interactions implicated in H. pylori persistence. Funding Agencies CIHRFRQS","PeriodicalId":508018,"journal":{"name":"Journal of the Canadian Association of Gastroenterology","volume":"120 ","pages":"43 - 44"},"PeriodicalIF":0.0,"publicationDate":"2024-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139837476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-14DOI: 10.1093/jcag/gwad061.304
C H Tsai, G. Malik, S. Congly
Abstract Background Chronic hepatitis C virus (HCV) infection negatively impacts quality and quantity of life. With the onset of direct-acting antivirals (DAAs), cure rates of HCV have increased to over 95%. Despite these advancements, chronic HCV infection continues to pose a substantial health and financial burden and without drug coverage, treatment of HCV with these DAAs is unaffordable. In the United States, Medicare Part D is a voluntary drug coverage plan predominantly for individuals covered by Medicare (typically over 65 years old) which can facilitate access to these DAAs. Aims This study aims to analyze the shifts in HCV treatment and spending in the USA from 2012 to 2021 for Medicare Part D and assess the impact of generic drugs on overall expenditure. Methods A retrospective cross-sectional study was conducted using publicly available Centers for Medicare and Medicaid Services (CMS) Medicare D drug spending data from 2012 to 2021. The total expenditure and utilization of HCV drugs was calculated, and average spending per beneficiary was utilized to estimate potential cost savings if generic DAAs were employed. Results The study revealed a decline in HCV claims and beneficiaries over 65 since 2015 with a peak of 134,752 beneficiaries decreasing to 35,735 in 2021. Accordingly, spending was the highest in 2015 (8.8 billion USD) and subsequently trended downwards to 1.5 billion in 2021. Over the ten-year period, the USA spent a total of 33.1 billion USD on HCV treatment. Harvoni accounted for 53% of the spending, followed by Sovaldi (17%) and Epclusa (14%). Generic drug utilization slowly increased with the introduction of generics in 2019 with 6.4% of beneficiaries treated with generic DAAs in 2019, rising to 15.3% in 2020 and 14.8% in 2021. If all prescriptions of Harvoni and Epclusa were substituted by ledipasvir/sofosbuvir and sofosbuvir/velpatasvir, respectively, there is a potential $2.7 billion cost reduction. This translates to a potential 47.3% reduction in HCV treatment expenditures from 2019 to 2021. Conclusions The decreasing number of beneficiaries for HCV treatment among people over the age of 65 suggests a decreasing HCV prevalence in this age group. This reflects the success of DAA treatment and low reinfection rates. However, the underutilization of generic DAAs despite their lower cost highlights a missed opportunity for substantial savings. This study emphasizes the importance of policy negotiations to ensure optimal resource management, advocating for a shift towards generic drug usage to alleviate the financial burden associated with HCV treatment. Trends in total spending on DAAs for HCV and number of beneficiaries within Medicare Part D from 2012 to 2021. Annual percent changes in expenditure are shown within the data bars. Funding Agencies None
{"title":"A304 EXPLORING HEPATITIS C TREATMENT COST TRENDS OVER A DECADE: A CROSS-SECTIONAL ANALYSIS WITHIN MEDICARE PART D (2012-2021)","authors":"C H Tsai, G. Malik, S. Congly","doi":"10.1093/jcag/gwad061.304","DOIUrl":"https://doi.org/10.1093/jcag/gwad061.304","url":null,"abstract":"Abstract Background Chronic hepatitis C virus (HCV) infection negatively impacts quality and quantity of life. With the onset of direct-acting antivirals (DAAs), cure rates of HCV have increased to over 95%. Despite these advancements, chronic HCV infection continues to pose a substantial health and financial burden and without drug coverage, treatment of HCV with these DAAs is unaffordable. In the United States, Medicare Part D is a voluntary drug coverage plan predominantly for individuals covered by Medicare (typically over 65 years old) which can facilitate access to these DAAs. Aims This study aims to analyze the shifts in HCV treatment and spending in the USA from 2012 to 2021 for Medicare Part D and assess the impact of generic drugs on overall expenditure. Methods A retrospective cross-sectional study was conducted using publicly available Centers for Medicare and Medicaid Services (CMS) Medicare D drug spending data from 2012 to 2021. The total expenditure and utilization of HCV drugs was calculated, and average spending per beneficiary was utilized to estimate potential cost savings if generic DAAs were employed. Results The study revealed a decline in HCV claims and beneficiaries over 65 since 2015 with a peak of 134,752 beneficiaries decreasing to 35,735 in 2021. Accordingly, spending was the highest in 2015 (8.8 billion USD) and subsequently trended downwards to 1.5 billion in 2021. Over the ten-year period, the USA spent a total of 33.1 billion USD on HCV treatment. Harvoni accounted for 53% of the spending, followed by Sovaldi (17%) and Epclusa (14%). Generic drug utilization slowly increased with the introduction of generics in 2019 with 6.4% of beneficiaries treated with generic DAAs in 2019, rising to 15.3% in 2020 and 14.8% in 2021. If all prescriptions of Harvoni and Epclusa were substituted by ledipasvir/sofosbuvir and sofosbuvir/velpatasvir, respectively, there is a potential $2.7 billion cost reduction. This translates to a potential 47.3% reduction in HCV treatment expenditures from 2019 to 2021. Conclusions The decreasing number of beneficiaries for HCV treatment among people over the age of 65 suggests a decreasing HCV prevalence in this age group. This reflects the success of DAA treatment and low reinfection rates. However, the underutilization of generic DAAs despite their lower cost highlights a missed opportunity for substantial savings. This study emphasizes the importance of policy negotiations to ensure optimal resource management, advocating for a shift towards generic drug usage to alleviate the financial burden associated with HCV treatment. Trends in total spending on DAAs for HCV and number of beneficiaries within Medicare Part D from 2012 to 2021. Annual percent changes in expenditure are shown within the data bars. Funding Agencies None","PeriodicalId":508018,"journal":{"name":"Journal of the Canadian Association of Gastroenterology","volume":"4 5","pages":"247 - 248"},"PeriodicalIF":0.0,"publicationDate":"2024-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139837632","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-14DOI: 10.1093/jcag/gwad061.032
E. R. Cobo, G. Blyth, F. Fiorani, P. Lahiri, A. Herik, A. Dufour, K. Chadee
Abstract Background Colonic goblet cells by secreting Muc2 mucin and specific proteins is critical for physically entrapping and expelling invading enteropathogens. Thus, is not surprising that Muc2-/- littermates exhibit increased susceptibility to attaching/effacing Citrobacter rodentium colonization. The colonic epithelium also secretes small cathelicidin peptide, which potentially interacts intimately with goblet cells and was presumed to accumulate within the sterile inner mucus layer as a simple antimicrobial peptide defense. Aims To determine the effects of cathelicidin on mucin secretion in goblet cells during C. rodentium-induced colitis and the impact on the mucus barrier defense. Methods We used cathelicidin-deficient (Camp-/-) mice, mouse colonoids and human colonic LS174T like-goblet epithelial cells to elucidate the mechanisms by which cathelicidin regulates goblet cell secretions. Results Camp -/- littermates infected with C. rodentium displayed increased fecal shedding and epithelial colonization. Camp-/- littermates at the peak of C. rodentium infection (7 dpi) showed a deficient mucin layer with fewer Alcian blue/PAS filled goblet cells and a reduction in fucose (UEA-1+) and N-acetylglucosamine (WGA+) glycoproteins. By transmission electron microscopy (TEM), goblet cells in Camp-/- colons were swollen and retained a large number of mucus granules during C. rodentium infection. C. rodentium infected Camp-/- littermates showed impaired reactive oxygen species (ROS) production and a transcriptomic profiling associated with decreased ROS biosynthesis and an increase in ROS negative regulators. In mucin producing LS174T colonic epithelial cells, human cathelicidin LL-37 promptly induced the secretion of goblet cell-associated TFF3 and RELMβ, via a ROS-dependent mechanism. Conclusions These findings revealed that mice lacking cathelicidin (Camp-/-) were more susceptible to C. rodentium colonization caused by defective goblet cell mucus and mucin-associated protein secretion via a ROS-dependent mechanism. Importantly, cathelicidin regulated mucus secretion revealing a non microbicidal action of this peptide with homeostatic properties on the colonic mucus barrier, critical in excluding luminal microbiota away from the epithelia to clear bacterial infections and restore gut homeostasis. Funding Agencies NSERC
{"title":"A32 CATHELICIDIN REGULATES GOBLET CELL MUCUS SECRETION DURING CITROBACTER RODENTIUM-INDUCED COLITIS","authors":"E. R. Cobo, G. Blyth, F. Fiorani, P. Lahiri, A. Herik, A. Dufour, K. Chadee","doi":"10.1093/jcag/gwad061.032","DOIUrl":"https://doi.org/10.1093/jcag/gwad061.032","url":null,"abstract":"Abstract Background Colonic goblet cells by secreting Muc2 mucin and specific proteins is critical for physically entrapping and expelling invading enteropathogens. Thus, is not surprising that Muc2-/- littermates exhibit increased susceptibility to attaching/effacing Citrobacter rodentium colonization. The colonic epithelium also secretes small cathelicidin peptide, which potentially interacts intimately with goblet cells and was presumed to accumulate within the sterile inner mucus layer as a simple antimicrobial peptide defense. Aims To determine the effects of cathelicidin on mucin secretion in goblet cells during C. rodentium-induced colitis and the impact on the mucus barrier defense. Methods We used cathelicidin-deficient (Camp-/-) mice, mouse colonoids and human colonic LS174T like-goblet epithelial cells to elucidate the mechanisms by which cathelicidin regulates goblet cell secretions. Results Camp -/- littermates infected with C. rodentium displayed increased fecal shedding and epithelial colonization. Camp-/- littermates at the peak of C. rodentium infection (7 dpi) showed a deficient mucin layer with fewer Alcian blue/PAS filled goblet cells and a reduction in fucose (UEA-1+) and N-acetylglucosamine (WGA+) glycoproteins. By transmission electron microscopy (TEM), goblet cells in Camp-/- colons were swollen and retained a large number of mucus granules during C. rodentium infection. C. rodentium infected Camp-/- littermates showed impaired reactive oxygen species (ROS) production and a transcriptomic profiling associated with decreased ROS biosynthesis and an increase in ROS negative regulators. In mucin producing LS174T colonic epithelial cells, human cathelicidin LL-37 promptly induced the secretion of goblet cell-associated TFF3 and RELMβ, via a ROS-dependent mechanism. Conclusions These findings revealed that mice lacking cathelicidin (Camp-/-) were more susceptible to C. rodentium colonization caused by defective goblet cell mucus and mucin-associated protein secretion via a ROS-dependent mechanism. Importantly, cathelicidin regulated mucus secretion revealing a non microbicidal action of this peptide with homeostatic properties on the colonic mucus barrier, critical in excluding luminal microbiota away from the epithelia to clear bacterial infections and restore gut homeostasis. Funding Agencies NSERC","PeriodicalId":508018,"journal":{"name":"Journal of the Canadian Association of Gastroenterology","volume":"98 ","pages":"17 - 18"},"PeriodicalIF":0.0,"publicationDate":"2024-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139837634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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