bluuebunny/crossref_metadata_2025 huggingface dataset:
A16 ESOPHAGEAL ORGANOID PROLIFERATION AND DIFFERENTIATION ARE ALTERED BY LOSS OF MSH2
Authors: Rolland M , Gonneaud A , Jean D , Giroux V
Published: February 2022

Background

The stratified epithelium of the esophagus includes Krt15+ basal stem cells that display self-renewing and regenerative capacity, and multipotency. However, the mechanisms that specifically control their functions remain unknown. Interestingly, RNA sequencing and GSEA revealed an enrichment of a gene set associated with DNA repair in Krt15+ cells vs Krt15- cells. We also observed that Msh2 (DNA mismatch repair pathway) is the most significantly upregulated gene in Krt15+ stem cells.

Aims

To determine the effect of Msh2 loss on self-renewal and differentiation of esophageal organoids.

Methods

Esophageal epithelial cells were isolated from a wild-type mouse. Using flow cytometry, esophageal Krt15+ (GFP+) and Krt15- (GFP-) cells were sorted from Krt15-CrePR1 (R26mT/mG) mice. All cell populations were grown as organoids and Msh2 was depleted using a CRISPR/Cas9 approach. Impact of Msh2 loss on self-renewal and differentiation in esophageal epithelial organoids was evaluated through organoid formation assays, WST-1 proliferation assays and histological analysis.

Results

At baseline, organoids depleted for Msh2 formed more poorly differentiated and less well-differentiated organoids than controls. Lower expression of differentiation gene Krt13 was also observed in Msh2-depleted organoids, confirming an altered differentiation pattern. Furthermore, these organoids showed a higher organoid formation rate and proliferation by WST-1 assay, suggesting that self-renewal capacity and viability are increased when Msh2 is depleted. Interestingly, following radiation, organoids depleted for Msh2 showed higher residual levels of p-H2AX (DNA damage marker), suggesting that their capacity to cope with DNA damages is altered. As mentioned above, we previously reported that Msh2 is the most upregulated gene in Krt15+ vs Krt15- cells. Therefore, to determine if Msh2 role is distinct in both populations, we depleted Msh2 in Krt15+ and Krt15- cells-derived organoids. Interestingly, our preliminary results suggest that Msh2 deletion led to increased p-H2AX and decreased Krt13 levels in Krt15+ organoids but not in Krt15- organoids.

Conclusions

Our results show that Msh2 is potentially a key contributor of esophageal stemness in homeostatic and injured conditions.

Funding Agencies

CIHRCanada Research Chair
A25 CRITICAL APPRAISAL OF GI ENDOSCOPY CLINICAL PRACTICE GUIDELINES DURING THE COVID-19 PANDEMIC
Authors: Tham D , Gimpaya N , Gholami R , Pattni C , Seleq S , Bansal R , Fujiyoshi M A , Ramkissoon A , Lisondra J , Ariaratnam J , Scaffidi M , Khan R , Grover S
Published: February 2022

Background

Clinical Practice Guidelines (CPGs) are integral during a pandemic, offering guidance to clinicians through uncertainty. Existing literature has established that the need for rapid publication of CPGs during previous infectious disease outbreaks resulted in less rigorous guidelines. CPGs were rapidly developed since the onset of the pandemic in December 2019, providing guidance in gastrointestinal (GI) endoscopy, an area where COVID-19 may pose risk of transmission.

Aims

To evaluate the quality of GI endoscopy guidelines developed during the COVID-19 pandemic and to compare these with (a) endoscopy CPGs developed prior to the pandemic; (b) CPGs for other endoscopic topics unrelated to COVID-19; and, (c) non-endoscopic CPGs published during the pandemic.

Methods

We systematically searched Medline, Embase and Scopus for CPGs published by GI societies from January 1, 2018 to December 31, 2020. A grey literature search was conducted. Two authors screened full-texts. In this interim analysis, CPGs were grouped based on publication year: before 2020, or 2020. Endoscopy CPGs published in 2020 were categorized as COVID or non-COVID related. Two authors independently assessed the CPGs using the AGREE II tool, consisting of six domains for evaluating guidelines. A domain score of 60 was set as a threshold to indicate good quality.

Results

There were 70 endoscopy guidelines and 27 CPGs focused on other GI topics. The mean overall scores were 69% (±12%) for endoscopy CPGs published before 2020 (n=28), and 51% (±23%) for CPGs published in 2020 (n=42). For individual AGREE II domains, mean scores for pre-2020 CPGs ranged from 33.11 (±17.39) in Applicability to 81.55 (±10.37) in Clarity of Presentation. For CPGs published during COVID-19, mean domain scores ranged from 34.18 (±10.52) in Applicability to 75.26 (±13.85) in Clarity of Presentation. 21 of 42 CPGs published in 2020 were related to COVID. Mean overall scores were 35% (±20%) for COVID-related CPGs and 67% (±13%) for non-COVID-19 CPGs. For COVID-19 CPGs, scores ranged from 27.88 (±20.31) in Rigour of Development to 69.58 (±10.81) in Scope and Purpose. For non-COVID CPGs, the scores ranged from 37.30 (±8.93) in Applicability to 84.52 (±5.93) in Clarity of Presentation.

Conclusions

The difference in overall scores between COVID-19 endoscopy CPGs and non-COVID endoscopy CPGs may suggest that the urgency to disseminate COVID-19 information decreased CPG quality or completeness of reporting. This interim analysis is limited by the lack of distinction between peer-reviewed CPGs and non-peer reviewed recommendations. Given the importance of CPGs in clinical decision making, it is important to ensure that the rapid development of guidelines does not compromise quality and rigour.

Funding Agencies

None
A31 OUTCOMES OF PATIENTS UNDERGOING REPEAT VIDEOCAPSULE ENDOSCOPY (VCE) PRESENTING WITH OBSCURE GASTROINTESTINAL BLEEDING (OGIB)
Authors: Krahn T , Suliman M I , Halloran B , Wasilenko S , Zepeda-Gomez S
Published: February 2022

Background

Videocapsule Endoscopy (VCE) as well as balloon-assisted enteroscopy (BAE) are useful tools in the diagnosis and management of obscure gastrointestinal bleeding (OGIB). There is limited data assessing the diagnostic yield of VCE in subjects with OGIB according to different subtypes: 1) obscure overt 2) inactive overt and 3) active overt.

Aims

We evaluated the diagnostic yield and outcomes of patients undergoing a second VCE in OGIB.

Methods

This is a retrospective analysis of all patients who underwent more than one VCE completed at the University of Alberta from January 1, 2015 to August 31, 2021. Demographic and background information was collected including previous endoscopy results, cross-sectional imaging, and subsequent interventions. Patient data was analyzed according to subtype of OGIB at presentation.

Results

During the study period, there were 59 subjects who met inclusion criteria. The indication for VCE was recurrent iron deficiency anemia (IDA), active OGIB, and/or inactive OGIB in 38 subjects. The median time to VCE after initial endoscopic evaluation was 61 days. Median age of cases was 61.5 years and 49% were female.

Initial VCE had clinically significant positive findings in 68% of cases (Table 1). The diagnostic yield was 75%, 56% and 74% in active OGIB, inactive OGIB, and IDA, respectively. Active bleeding or fresh blood was present in 33% of VCEs for active OGIB compared to 11% of inactive OGIB and 13% of subjects with IDA.

At second VCE investigation, there were positive findings in 42% of cases. Findings on second VCE differed from initial VCE in 17 of 38 cases. Findings that changed clinical management were found in 76% of patients after first and second VCE.

BAEs were performed in 20 subjects after VCE, with therapeutics applied in 75%. The most common findings were arteriovenous malformations (AVMs) (65%) and erosions/ulcers (15%).

Conclusions

The diagnostic yield of VCE is high in appropriately selected patients and did not significantly differ in patients with IDA, active, and inactive OGIB. Serial VCE is appropriate for the investigation of suspected recurrent small bowel bleeding when initial workup is nondiagnostic.

Funding Agencies

None
A37 EFFICACY AND SAFETY OF RISANKIZUMAB AS MAINTENANCE THERAPY IN PATIENTS WITH CROHN’S DISEASE: 52 WEEK RESULTS FROM THE PHASE 3 FORTIFY STUDY
Authors: Panaccione R , Ferrante M , Feagan B G , Sandborn W , Panes J , Peyrin-Biroulet L , Colombel J , Schreiber S , Dubinsky M , Baert F , Hisamatsu T , Neimark E , Huang B , Liao X , Song A , Berg S , Duan W , Pang Y , Pivorunas V , Kligys K , Wallace K , D’Haens G
Published: February 2022

Background

Risankizumab (RZB), an anti-IL-23 p19 inhibitor, was well-tolerated and superior to placebo (PBO) in inducing clinical remission and endoscopic response in patients (pts) with moderate-to-severe Crohn’s disease (CD) in two phase 3 studies at 12 weeks.

Aims

FORTIFY (NCT03105102), was a 52-week (wk) phase 3 double-blind, re-randomized responder withdrawal study that evaluated the efficacy and safety of continuing RZB as subcutaneous (SC) maintenance therapy versus withdrawal to placebo in pts achieving induction response to RZB

Methods

Week 12 IV RZB responders were re-randomized 1:1:1 to: RZB SC 360mg (N=141), RZB 180mg (N=157), or PBO (withdrawal from IV RZB; N=164) every 8wks for 52wks. Co-primary endpoints were clinical remission (per CD Activity Index [CDAI] (US); or stool frequency/abdominal pain score [SF/APS] (OUS) and endoscopic response at wk52. Other clinical and endoscopic endpoints, inflammatory biomarkers, RZB serum levels, and safety were assessed over time.

Results

Rates of clinical remission (CDAI, SF/APS) and clinical response were similar for RZB and PBO groups through wk24, with rates lower for PBO thereafter. At wk52, clinical remission (CDAI, SF/APS) and endoscopic response rates were significantly higher with RZB 360mg than PBO ( P<0.01); RZB 180mg was superior to PBO for clinical remission per CDAI and endoscopic response ( P<0.01). Endoscopic remission and deep remission rates increased over time with 360mg, remained steady with 180mg, and decreased with PBO. Mean fecal calprotectin (FCP) and C-reactive protein (CRP) levels decreased with SC RZB, but increased with PBO, over 52wks. Exposure-adjusted event rates (per 100 pts-years) of serious adverse event (AE) were generally similar among groups (360mg, 21.0 E/100PY and 180mg, 19.5 E/100PY vs PBO, 19.3 E/100PY), as were AEs leading to drug discontinuation (4.8 E/100PY and 2.4 E/100PY vs 3.7 E/100PY), and serious infections (6.0 E/100PY and 3.0 E/100PY vs 5.0 E/100PY).

Conclusions

In pts with moderate-to-severe CD, a robust pharmacodynamic effect on the IL-23 pathway after 12wks RZB IV induction was maintained with RZB SC maintenance therapy. The durability of RZB was demonstrated with high rates of efficacy over the 52-wk study. RZB was superior to PBO for achieving clinical remission and endoscopic response at wk52. Results for the more stringent endpoints (endoscopic remission\deep remission) and persistent improvements in inflammatory biomarkers are consistent with a dose response relationship. Continued RZB SC maintenance treatment was generally safe and well-tolerated.

Funding Agencies

AbbVie
A39 TARGETING IL-4 TO TREAT CROHN’S DISEASE ASSOCIATED INTESTINAL FIBROSIS IN SHIP DEFICIENT MICE
Authors: Safari K , Menzies S , Jung H , Sly L M
Published: February 2022

Background

Crohn’s disease (CD) is an immune-mediated disease characterized by chronic, relapsing, or progressive inflammation along the gastrointestinal tract. One in 3 people with CD will develop intestinal fibrosis requiring surgery within 10 years of diagnosis. Biological therapy is very effective at reducing inflammation in CD; however, biologics do not reduce the incidence of fibrosis or surgery in people with CD, suggesting that a distinct mechanism(s) may exist that drives intestinal fibrosis. Treatments for intestinal fibrosis are urgently needed as currently, no treatment exists that target intestinal fibrosis directly.

Mice deficient in the Src homology 2 domain-containing inositolphosphate 5’-phosphatase (SHIP-/-) develop spontaneous CD-like ileal inflammation and fibrosis. Fibrosis is dependent on PI3Kp110δ activation, which leads to induction of the enzyme arginase I (argI). Genetic ablation or pharmacologic inhibition of PI3Kp110δ or inhibition of arginase activity blocked the development of intestinal fibrosis in SHIP-/- mice. Both IL-4 and IL-13 can activate PI3Kp110δ but intestinal pathology in SHIP-/- mice is characterized by high levels of IL-4. Thus, we hypothesize that SHIP-/- mice develop CD-like intestinal fibrosis due to increased IL-4 signalling.

Aims

Aim 1: To determine whether genetic ablation of IL-4 prevents ileal fibrosis in SHIP-/- mice

Aim 2

To determine whether inhibition of IL-4 activity can block or reverse ileal fibrosis in SHIP-/- mice

Methods

SHIP-/- mice were crossed with mice deficient in IL-4 (IL-4-/-) to generate wild type, SHIP+/+IL-4-/- SHIP-/-IL-4+/+, and SHIP-/-IL4-/- mice. Fibrosis was assessed in mice at 8 weeks of age. SHIP-/- mice (8-week-old) were treated with an anti-IL-4 antibody, IgG isotype control or PBS (injection control), for 2 weeks. Ileal fibrosis was assessed in SHIP-/- mice and compared to mice treated with anti-IL-4 antibody or controls. Measurements of ileal fibrosis include muscle thickening, and collagen accumulation by Masson’s trichrome staining.

Results

SHIP-/-IL4-/- mice do not have less ileal fibrosis than their SHIP-/- littermates. Inhibition of IL-4 signalling in SHIP-/- mice did not reduce ileal fibrosis.

Conclusions

Blocking IL-4 is not sufficient to block the development of ileal fibrosis in SHIP-/- mice. In future experiments, we will examine whether blocking IL-13, alone or in combination with IL-4, can ameliorate the development of intestinal fibrosis in SHIP-/- mice.

Funding Agencies

CIHR
A41 THE ROLE OF PGC-1α IN MURINE BONE MARROW DENDRITIC CELLS
Authors: Jaleel S , Lopes F
Published: February 2022

Background

The intestinal immune system tolerates food antigens and the commensal microbiota to prevent chronic inflammation. Inflammatory bowel diseases (IBD) such as ulcerative colitis and Crohn’s disease, are characterized by the loss of tolerance towards the microbiota, leading to inflammation, which is characterized by the high production of cytokines such as TNF and the influx of macrophages and neutrophils to the gut. Tolerance is driven by tolerogenic dendritic cells (tolDCs). Currently, there is no cure for IBD and while available treatments may reduce symptoms, there are no pharmacological therapies that specifically seek to rescue tolerance. Inducing tolDCs in patients with IBD may be a promising therapy since it is a way to directly target the main cause of the disease. tolDCs have been defined by down-regulating TNF (pro-inflammatory cytokine), producing IL-10 (anti-inflammatory cytokine), and active oxidative phosphorylation (OXPHOS) in the mitochondria.

Aims

Given the tolDC characteristic of active OXPHOS, the objective of our project was to evaluate the role of PGC-1α, a major mediator of mitochondria biogenesis, in generating toDCs using murine bone marrow-derived dendritic cells (BMDC). Our hypothesis is that tolDCs would be (1) generated by pharmacological activation of PGC-1α by ZLN005, and (2) constrained by inhibition of PGC-1α by SR18292.

Methods

We treated BMDC cultures with ZLN005 (PGC-1α activator) or SR18292 (PGC-1α inhibitor), and LPS. We characterized the effect of PGC-1α manipulation on the metabolism of BMDCs by metabolomics and Seahorse XF Cell Mito Stress Test. In addition, we evaluated features of tolDCs, such as gene expression by qPCR, and cytokine production by ELISA.

Results

We observed that activation of PGC-1α altered the metabolic profile of BMDC, and upregulates genes known to be expressed in tolDCs. However, this transcriptional upregulation was lost after LPS stimulation and did not alter TNF or IL-10 levels in BMDCs. PGC-1α inhibition, on other hand, decreased features of tolDCs, such as metabolic profile, transcriptional activation, and the levels of LPS-induced IL-10. Our data suggest that PGC-1α activation with ZLN005 does not increase the generation of tolDCs in vitro. However, inhibition of PGC-1α with SR18292 constrains tolDCs generation.

Conclusions

PGC-1α is important for the development of tolDCs in murine dendritic cells.

Funding Agencies

NSERC and FRQNT
A42 HETEROGENEITY IN EFFICACY AND SAFETY ENDPOINTS FOR PEDIATRIC CLINICAL TRIALS IN INFLAMMATORY BOWEL DISEASE: A NEED FOR HARMONIZATION
Authors: Crowley E , Turner D , Ma C , Nguyen T , McKay H , Schneider R , Silverberg A , Muise A , Feagan B , Griffiths A , Jairath V
Published: February 2022

NOT PUBLISHED AT AUTHOR’S REQUEST

Funding Agencies: None
A47 MICROBIAL FUNCTIONS AS BIOMARKERS OF PRO-INFLAMMATORY RESPONSE TO SELECT DIETARY FIBERS IN IBD
Authors: Armstrong H , Bording-Jorgensen M , Valcheva R , Zhang Z , Jovel J , Petrova A , Carroll M W , Huynh H Q , Dieleman L A , Wine E
Published: February 2022

Background

Dietary fibers are not digested in the bowel; they are fermented by microbes, typically promoting gut health. However, IBD patients experience sensitivity to consumption of fibers. Our previous findings offered the first mechanistic evidence demonstrating that unfermented dietary β-fructans (inulin and FOS) can induce pro-inflammatory cytokines in a subset of pediatric IBD colonic biopsies cultured ex vivo, and in the SYNERGY-1 (β-fructan) clinical study of adult remission UC patients. Incubating FOS with whole-microbiota intestinal washes from non-IBD or remission IBD patients improved fermentation and reduced pro-inflammatory responses, but not from patients with active disease. Fibre-induced immune responses correlated with microbe functions, luminal metabolites, and fibre avoidance.

Aims

Here we aimed to expand on our findings and define the role of microbial functions in mediating host response to β-fructans.

Methods

Colonic biopsies cultured ex vivo and cell lines in vitro were incubated with FOS (5g/L), or fermentation supernatants (24hr anaerobic fermentation). Immune responses (cytokine secretion [ELISA/MSD] and expression [qPCR]) were assessed. Taxonomic classification of microbial fermentation cultures was conducted with Kraken2 and metabolic profiling by HUMAnN2. HPLC and gas chromatography volatile fatty acid (CG-VFA) analysis were used to identify concentrations of remaining fibre and SCFAs following anaerobic fermentation.

Results

7 microbial enzymes were identified to be predictive of cytokine (IL-1β, IL23, IL-5, IL-8, MIP-1α) secretion in ex vivo colonic biopsies from pediatric Crohn disease (CD; n=38), ulcerative colitis (UC; n=20), and non-IBD (n=21) patients, in response to β-fructans; their use as biomarkers of response was determined in patient stool from the SYNERGY-1 clinical study cohort. Fermentation of FOS by whole-microbe intestinal washes from only non-IBD or remission IBD patients reduced cytokine secretion, and our findings demonstrate that this was due to a combination of reduction of β-fructan present and production of a precise combination of anti-inflammatory SCFAs.

Conclusions

Our findings suggest that intolerance and avoidance of fibers in select IBD patients is associated with the inability to ferment these fibers, mediated by altered microbial functions (enzymes), leading to worsened inflammation. Data indicate that gut microbial function, not composition, predicts patient pro-inflammatory response to β-fructans, supporting our hypothesis that overall community function impacts fibre fermentation and affects associated pro-inflammatory effects. Our work highlights select disease state scenarios in which administration of fermentable fibers should be avoided and tailored dietary interventions considered.

Funding Agencies

CIHRWeston Foundation, Mitacs
A53 A NOVEL PH-SENSITIVE OPIOID ANALOGUE PROVIDES SUSTAINED ANALGESIA DURING COLONIC INFLAMMATION AND LACKS COMMON SIDE EFFECTS
Authors: Degro C E , Jiménez-Vargas N N , Tsang Q K , Yu Y , Stein C , Bunnett N W , Lomax A E , Reed D E , Vanner S
Published: February 2022

Background

Opioids provide effective pain relief during flares of inflammatory bowel disease but are limited by serious side effects. We showed that acute administration of a novel pH-sensitive opioid agonist, NFEPP, had potent analgesic effects in inflamed acidified colonic tissues without opioid typical side effects. However, the effects of repeated application of NFEPP during the course of an acute flare of colonic inflammation are unknown.

Aims

To assess the analgesic and side effect profile resulting from repeated NFEPP applications during the course of acute colitis.

Methods

Acute colitis in C57BL/6 mice was induced via 2.5% dextran sulfate sodium dissolved in drinking water for 5 days. Mice were then randomly group assigned to either vehicle, fentanyl or NFEPP. Drugs and vehicle were administered sc. BID for 5 days (0.4 mg/kg), with a final injection on Day 6 (Day 1–6). Visceral nociception was evaluated by performing visceromotor responses (VMRs) to colorectal distension at different time points during colitis. Side effects were assessed using 1) a combination of oral contrast-enhanced abdominal CT-scans (before/after treatment) and defecation assessments to analyze gastrointestinal transit and isometric tension recordings to evaluate colon motility 2) pulse oximeter measurements to reveal cardiorespiratory effects. Inflammation was assessed by histological scoring, myeloperoxidase activity assay and tissue pH measurement of colon samples.

Results

NFEPP decreased VMRs to colorectal distension over the entire period of acute DSS colitis (Day 6: 40.54%, p<0.001, reduction compared to baseline). However, strongest VMR inhibition was observed at Day 3 (66.7%, p<0.05), concordant with the peak of inflammation (MPO: 3.5 U/mg tissue, p<0.001; tissue Damage-Score: 3.0, p<0.001; tissue pH: ΔpH= -0.28, p=0.001, all compared to healthy control). Treatment with NFEPP did not delay gastrointestinal transit (GIT, p=0.37, compared to baseline) nor fecal output (p=0.45, compared to vehicle) whereas fentanyl decreased transit (GIT: p<0.05; fecal output: p<0.05). Colonic contractile responses evoked by electrical field stimulation were reduced in fentanyl treated mice compared to NFEPP (10 Hz: p<0.05). Fentanyl significantly reduced oxygen saturation (15 min: 85% SpO2, p<0.01) and caused a sustained reduction in heart rate at Day 2 (60 min: Δ BPM -91.8 from baseline, p=0.001) whereas NFEPP did not affect oxygen saturation (p=0.95) and revealed minor, transient effects on heart rate (15 min: Δ BPM -75.6, p<0.01) which recovered after 60 min.

Conclusions

Prolonged NFEPP administration effectively inhibits visceral nociception during acute colitis in a preclinical mouse model without altering gastrointestinal transit, colon motility and oxygen saturation.

Funding Agencies

CCC
A55 INTERLEUKIN-10 ELICITS CYTOPROTECTION VIA MITOCHONDRIAL SIGNAL TRANSDUCER AND ACTIVATORS OF TRANSCRIPTION 3 (MTSTAT3) TO PREVENT BACTERIAL PATHOBIONT EVOKED MITOCHONDRIAL FRAGMENTATION IN GUT EPITHELIA
Authors: NavaneethaKrishnan S , Wang A , Mckay D M
Published: February 2022

Background

Aberrant mitochondrial function is increasingly reported in inflammatory bowel disease (IBD). We recently reported that the IBD-associated pathobiont, adherent-invasive E. coli (AIEC) (strain LF82)-evoked epithelial mitochondrial fragmentation and mitochondrial depolarization. Remarkably, the transcription factor, signal transducer and activator of transcription (STAT)-3, can migrate to mitochondria (mtSTAT3) to regulate functions such as reactive oxygen species and ATP production. This non-canonical activity is dependent on STAT3 phosphorylation at serine727. IL-10 is an important regulator of enteric homeostasis that signals via STAT-3, however whether IL-10 affects mitochondrial dynamics is unknown.

Aims

To determine (1) if IL-10 preserves mitochondrial function in E. coli-LF82-infected epithelia through mtSTAT3, and if so, (2) to identify the mechanism by which mtSTAT3 restores mitochondrial functions.

Methods

The human colon-derived T84 epithelial cells or human organoids were exposed to E. coli LF82 (108 cfu/ml, 4h) ± co-treatment or an 18h pre-treatment with IL-10 (10 ng/ml). The effect of IL-10 on bacterial growth and its invasion of T84 cells were assessed by growth curve analysis and bacterial internalisation assays. We assessed mitochondrial network morphology using mito-tracker red and confocal microscopy, mitochondrial membrane potential with the fluorescent-dye TMRE and flow cytometry and fluorescence microscopy, and oxygen consumption rate (OCR) and ATP levels. STAT3 phosphorylation was analysed in whole cell protein extracts by western blot. Pharmacological inhibitors of JAK and Erk1/2 were used to examine the pathway of mtSTAT3 activation.

Results

IL-10 affected neither E. coli-LF82 growth nor invasion of T84 epithelia, but substantially reduced the AIEC-induced mitochondrial fragmentation in T84 cells and organoids. IL-10 preservation of the mitochondrial network was accompanied by increased mitochondrial membrane potential, OCR, and ATP levels in E. coli-LF82 infected T84 cells. IL-10 + E. coli-LF82-treated epithelia displayed increased phospho-S727 STAT3 that was reduced by inhibition of Erk1/2 but not JAK activity.

Conclusions

Mitochondria are a potential drug target in IBD, and the E. coli-LF82 pathobiont can be added to a growing list of microbial pathogens that evoke epithelial mitochondrial dysfunction. We have uncovered that IL-10 can stabilize mitochondrial function in E. coli-LF82 infected cells, possibly through mtSTAT-3. Our results underscore the role of IL-10/STAT3 signaling in preserving mitochondrial functions that could result in mitochondria-targeted therapeutics in IBD and other bacteria-driven enteropathies.

Funding Agencies

CIHRAIHS
A62 PROTEASE-ACTIVATED RECEPTOR-2 ACTIVATION ENHANCES EPITHELIAL WOUND HEALING THROUGH SRC PATHWAY-DEPENDENT CELL MIGRATION
Authors: Lucena Périco L , MacNaughton W
Published: February 2022

Background

Protease-activated receptors (PARs) and their activating enzymes play a role in inflammatory bowel disease (IBD) pathogenesis, but the specific roles of PAR2 in disease initiation and progression remain unclear. Interestingly, PAR2 activation has both pro-proliferative and pro-migratory effects and could be involved with restoration of the epithelial barrier following injury. We previously showed that the PAR2 activation increase the epithelial wound healing through ERK, PI3K and JNK pathways. However, the role of Src kinase, which is also activated by PAR2, is not known.

Aims

We hypothesized that PAR-2 activation induces a wound healing response in intestinal epithelial cells through Src activity.

Methods

Circular wounds were made in T84 colonic epithelial cells monolayers. Wounded monolayers were treated with the PAR2 activating peptide, 2-furoyl-LIGRLO (2fLI, 5 μM), or the inactive control reverse-sequence peptide, 2-furoyl-OLRGIL (2fO, 5 μM), and live cell imaging was used to record wound closure over a 12 or 24-hr period. The specificity of PAR2 was assessed with a PAR2 inhibitor (GB88). Proliferation and cytotoxicity were measured using EdU and TUNEL assays. The mechanism of action was evaluated using inhibitors of FAK (PF57328 and FAK14) and Src (PP2) and western blot (WB) was used to confirm the protein levels [p-FAK (Y397; Y576/577) and p-Src (Y416)]. For immunofluorescence, images of E-cadherin and F-actin or p-FAK were taken to capture the entire wound border and surrounding cells.

Results

PAR2 activation by 2fLI promoted wound closure compared to 2fO or vehicle control at the 12 and 24 hr timepoints ( p<0.05). PAR2’s ability to enhance wound closure was blocked with the PAR2 inhibitor, GB88 ( p<0.01). PAR2 activation had no effect on proliferation at the wound-edge and did not cause apoptosis, but enhanced lamellipodia/filopodia formation ( p<0.001), indicating that PAR2 might program the cells toward a migratory phenotype rather than a proliferative phenotype. When we investigated the mechanisms of action, PAR2 activation did not induce focal adhesion kinase (FAK) expression in T84 cells and inhibition of FAK by selective inhibitors (PF573288 and FAK14) did not alter PAR2-induced wound healing. The immunofluorescence for p-FAK (Y397) and WB (Y937 and Y576/577) confirmed these results. However, the Src tyrosine kinase inhibitor (PP2, p<0.0001) inhibited PAR2-induced wound healing. PAR2 activation increased Src phosphorylation (Y416, p<0.05).

Conclusions

PAR2 activation drives wound healing in part via Src tyrosine kinase activity, but independently of FAK activity. These findings provide a further mechanism whereby PAR2 can participate in the resolution of intestinal wounds in gastrointestinal inflammatory diseases.

Funding Agencies

CAG, CIHR
A65 PREDICTING TRANSITION SUCCESS IN YOUNG ADULTS WITH INFLAMMATORY BOWEL DISEASE: PRELIMINARY RESULTS
Authors: Bihari A , Goodman K , Wine E , Kroeker K
Published: February 2022

Background

Patients diagnosed with inflammatory bowel disease (IBD) in childhood present more often with extensive disease, are more likely to be admitted to hospital and are less adherent with clinic appointments. Due to these risks, a smooth, uninterrupted transition from pediatric to adult care should be a priority. We have conducted interviews with providers, patients, and parents about their opinions on indicators of successful transition. Themes of successful transition that emerged included independence in seeking care and disease management. Characterizing successful transition based on stakeholder input makes it possible to monitor its achievement and identify its determinants.

Aims

This study aims to: 1) describe the frequency of success indicators in transitioned patients and 2) identify predictors associated with success indicators. We hypothesize that patients with more experience in pediatric care (e.g., younger age at diagnosis or on biologics) are more likely to achieve success.

Methods

We conducted a retrospective medical chart review to obtain data on patients who transitioned to adult care between January, 2014 - September, 2019 at the University of Alberta. We abstracted potential predictors, including social and disease factors, at first adult appointment which had notes on pediatric history. We chose available success indicators related to two themes: independence in seeking care (e.g., attending appointments, communicating for oneself) and disease management (e.g., lab work frequency and medication adherence). We abstracted selected success indicators within a two-year period from first appointment in adult care. We used Poisson and logistic regression to estimate incidence rate ratios (IR) and odds ratios (OR) for the association of potential predictors with success indicators.

Results

We reviewed medical charts of 99 patients. At first adult appointment, the median age at diagnosis was 14.5 years old (IQR: 13.2 – 15.9) and 57.6% of patients were on biologic agents. Within two years, 42.4% of patients required a change to a different therapy, 22.2% had at least two instances where a parent called on their behalf, and 16.2% had notes of medication nonadherence in adult care. Regression analysis (Table 1) estimated that patients who lived > 100km from clinic had a lab work incidence rate in the first year that was two-thirds that of patients who lived closer. Strong predictors of non-adherence in adult care included chart notes on pediatric medication non-adherence (OR~12) and, inversely, taking biologics (OR=0.34).

Conclusions

These results identified factors that could be used to identify patients likely to have poor outcomes following transition to adult care. These are preliminary results; we plan to analyze a total of 350 medical charts.

Funding Agencies

None
A73 CANADIAN INFLAMMATORY BOWEL DISEASE MOBILE APPS: CURRENT LANDSCAPE AND NEEDS
Authors: Chiew B A , Raman M , Tandon P , Panaccione R , Taylor L
Published: February 2022

Background

Evidence-based digital health applications (apps) offering comprehensive lifestyle therapies for inflammatory bowel disease (IBD) patients are limited in Canada.

Aims

The aims of this study were to explore the Canadian IBD digital app landscape and review preliminary data from a recently launched digital app for IBD, LyfeMD. (www.lyfemd.ca).

Methods

“IBD”, “Inflammatory bowel disease”, “UC”, “Ulcerative colitis”, “Crohns” and “Crohn’s disease (CD)” were searched by one team member (BC) on the App Store. Apps were included if they offered any type of lifestyle therapy, including education. The mobile application rating system (MARS) was used to evaluate each app and is a validated tool used to assess the quality of mobile health apps. For the LyfeMD app, 35 IBD users completed a baseline assessment survey to identify: 1) physical activity, sitting, and screen time, and; 2) stress, sleep, depression and anxiety. Eleven participants completed in-depth user experience evaluations after 4 weeks. Survey scores were calculated using published scoring protocols and descriptive data were prepared.

Results

The LyfeMD and My IBD Care app scored highest on the MARS with a total score of 4.8/5. Of the other eight apps identified, scores ranged from 2.4 to 4.6 (overall mean=4.0). LyfeMD differentiated itself from other apps by providing lifestyle programs to improve nutrition, physical activity and mental health. Of the LyfeMD users, 74% had CD (median Harvey Bradshaw index=3.1, IQR=1.1–4.8) and 26% had ulcerative colitis (median partial mayo score=1.0, 0.5–6.0), 60% had a BMI ≥25 kg/m2, 57% were meeting 150 minute/week activity guidelines, 49% had high sitting time, 100% had high screen time, 69% had a moderate to high level of stress, 100% experienced sleep problems, 69% reported depression, and 49% reported anxiety. Eleven people completed the detailed user experience evaluations. They reported the app helped them identify behaviour changes to improve overall wellness; most often what they eat (64%), overall well-being (64%) and physical activity (46%).

Conclusions

Two IBD apps available in Canada had a high MARS rating, however only the LyfeMD app offered comprehensive lifestyle therapies. The growing literature supports benefit for lifestyle therapies in IBD, and the LyfeMD app may be effective to identify areas amenable to lifestyle modification.

Funding Agencies

Ascend, Alberta Innovates
A74 SURVEILLANCE IMAGING FOLLOWING COMPLETELY RESECTED GASTROENTEROPANCREATIC NEUROENDOCRINE TUMORS: A SINGLE CENTER AUDIT OF LOCAL PRACTICE PATTERNS
Authors: Iannuzzi J , Yeo C , Sawhnry S , Pasieka J , Parkins V , Ruether D , Chan D , Albalawi Z , Lithgow K
Published: February 2022

Background

Neuroendocrine tumours (NET) are a heterogenous group of neoplasms that secrete peptides and neuroamines. For patients with potentially malignant gastroenteropancreatic (GEP) NET, surgical resection represents the only curative option. GEP NETs are characterized by long periods of disease-free survival and time-to-recurrence following surgical resection. Clinical guidelines recommend surveillance with cross sectional imaging, either CT or MRI, for at least 10 years.

Aims

The purpose of this study was to characterize local practice patterns of imaging surveillance (modality, frequency, and duration of follow-up) and how this compares to guideline recommendations.

Methods

We retrospectively reviewed clinical and imaging records from patients diagnosed with well-differentiated GEP NET at our center from January 2005 to July 2020 inclusive. Eligible cases were identified by a data analyst from the Alberta Cancer Board with each case being manually screened for eligibility. Exclusion criteria included patients with metastatic disease at presentation, G1 appendiceal NET < 1 cm, R0 G1 T1 rectal NET, and insulinoma. Location of primary NET, modality of surveillance imaging, date of test and duration of follow-up collected. The mean number of surveillance scans per person and per person-year follow-up based on the location of the primary NET were calculated.

Results

A total of 387 cases were initially retrieved with 62 eligible cases identified. The mean length of follow-up was 71 months (range 8 to 147). The mean number of surveillance scans was 7 (range 2 to 14) and the mean number of surveillance scans per person year was 1.1. Frequency of surveillance scans per year of follow-up did not differ based on the location of the primary tumor (p=0.966). Imaging modalities included cross sectional imaging (MRI and contrast enhanced CT) and nuclear medicine imaging (octreotide, MIBG, F-18 FDG-PET, and Gallium-68 DOTATATE PET CT). Most commonly, cross-sectional imaging was performed with CT or MRI representing 38% (n=166) and 39% (n=170) of all surveillance respectively. Nuclear medicine imaging was used in 15% (n=61) of surveillance scans and 3% used combined cross-sectional and nuclear medicine. Amongst cases with resection date >10 years (n=8) mean length of follow-up was 119 months (9.9 years).

Conclusions

Frequency and modality of imaging at our center is generally in accordance with current clinical guidelines, though the role of nuclear medicine imaging in this setting has not been established. CT and MRI were utilized equally during surveillance. The burden of these modalities in terms of radiation exposure and cost warrants further evaluation.

Funding Agencies

None
A89 PERCEPTIONS OF NON-TECHNICAL SKILLS IN GASTROINTESTINAL ENDOSCOPY: A THEMATIC ANALYSIS OF FOUR FOCUS GROUPS
Authors: Scaffidi M , Gimpaya N , Pattni C , Genis S , Khan R , Li J , Bansal R , Grover S
Published: February 2022

Background

Nontechnical skills (NTS), which involve an individual’s cognitive, attitudinal, and social skills that supplement task expertise, are an essential component in the practice of gastrointestinal endoscopy. There is a growing body of literature that highlights the association between these skills and patient outcomes. To date, however, these skills have not been adequately defined within the context of gastrointestinal endoscopy.

Aims

To define the domain and corresponding characteristics of NTS in GI endoscopy.

Methods

We conducted a qualitative study at a tertiary-care academic center in Toronto, Ontario. Specifically, we held four focus groups with physician endoscopists, nurses who work in an endoscopy unit, and patients who have had previous endoscopies, in order to ascertain their input on the role of NTS in gastrointestinal endoscopy. The three groups were interviewed independently and there was one focus group of both physicians and nurses that was used for validation of our initial thematic framework. Data from the focus groups was collected using a combination of field notes and discussion transcriptions. Three authors independently generated codes from these data. Using these codes, a thematic network analysis was used to identify emerging themes. The primary outcome of this study was the development of a cohesive thematic network of NTS in endoscopy, including their characteristics and examples.

Results

The four focus groups included a total of 34 participants, including 15 physician endoscopists, 15 nurses, and 4 patients. Using thematic network analysis, we identified six dimensions of NTS using the first three focus groups: communication; professionalism; teamwork; leadership; decision-making; and situational awareness. Additional topics related to the practice and evaluation of NTS were identified. In particular, there is a degree of subjectivity in the appraisal of NTS due to the nuances among individual practice, aside from egregious errors of NTS (e.g. unprofessional behaviours). The use of video recordings was suggested as a way to capture signs of good NTS, such as appropriate levels of calmness during procedures and attention to patient comfort. Finally, patient involvement can be useful for evaluating communication and professionalism based on patient comprehension and the nature of the therapeutic relationship.

Conclusions

Our findings provide the first cohesive framework of NTS in gastrointestinal endoscopy that is anchored in real world experiences with relevant stakeholders – physicians, nurses, and patients. Future research should consolidate these findings into an assessment tool for NTS in order to evaluate and provide feedback to endoscopists who are both in training and in practice.

Funding Agencies

CAG
A99 PHARMACEUTICAL INDUSTRY FUNDING TO GASTROINTESTINAL PATIENT ADVOCACY ORGANIZATIONS
Authors: Verma Y , Bansal R , Gimpaya N , Scaffidi M , Khan R , Grover S
Published: February 2022

Background

Patient advocacy organizations (PAOs) are not-for-profit organizations that aim to support families and individuals afflicted by illnesses. PAOs play a significant role in guiding health policy, providing education to patients, lobbying, and supporting research. Previous studies have demonstrated that PAOs may receive financial payments from pharmaceutical and medical device manufacturers. This may create a risk of conflict of interest.

Aims

To assess the prevalence and transparency of financial donations from industry to gastrointestinal patient advocacy groups based in the United States (US).

Methods

We conducted a cross-sectional study to determine the prevalence of industry donations to PAOs. Data was extracted from the Kaiser Health News (KHN) Database, a database that tracked payments from pharmaceutical companies to PAOs in 2015. After an initial list of 1215 PAOs was obtained from the database, authors extracted the annual revenues, websites and mission statements for each PAO. Authors individually screened each organization’s mission statement and website to determine whether their primary scope of focus included gastroenterology. A final list of 11 PAOs with annual revenues surpassing $500,000 USD was included for descriptive analysis. From this list, the annual reports and websites of each group were reviewed to determine the extent of transparency of PAOs disclosing financial relationships with industry sponsors. The primary outcome of our study was the total amount of funding that each PAO received from pharmaceutical companies. The secondary outcome was the self-reported amount of funding stated on each PAO’s website and annual report.

Results

From our analysis of 11 PAOs, 9 (81%) organizations received payments from pharmaceutical companies. The median dollar value of donations received was $31,052 USD (IQR=$25 to $302,550). The total dollar value of donations received was $4,059,433 USD. Across the 9 PAOs that received donations, 5 (56%) organizations disclosed a financial relationship with a pharmaceutical company on their website and 2 (22%) disclosed the value of industry donations within a range. No group specified an exact amount of funding received.

Conclusions

Our results demonstrate that a majority of US based gastrointestinal PAOs receive funding from pharmaceutical companies. Furthermore, our results show that many PAOs that receive industry funding do not disclose this amount on their website or annual reports. Given their role in providing patient centered support, it is important for PAOs to disclose financial relationships with industry so as to not produce a conflict of interest.

Funding Agencies

None
A102 INDICATION FOR ENDOSCOPIC RETROGRADE CHOLANGIOPANCREATOGRAPHY AND ASSOCIATION WITH HEMORRHAGE: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Parvizian M K , Zhang M , Edwards M , Bhoey P , Hookey L , Rodrigues D
Published: February 2022

Background

Hemorrhage is a complication associated with up to 2% of cases of Endoscopic Retrograde Cholangiopancreatography (ERCP), most commonly following sphincterotomy. Studies investigating risk factors associated with hemorrhage, such as ERCP indication, have been conflicting.

Aims

We performed a systematic review and meta-analysis to determine the association between the indication for ERCP and ERCP-associated hemorrhage.

Methods

A systematic search of MEDLINE, EMBASE, and CENTRAL was done from inception until September 2021 for studies reporting on factors associated with ERCP-associated hemorrhage (both immediate and delayed) in adults. Exclusion criteria included: pediatric patients, no outcome of interest, did not investigate hemorrhage risk factors, inappropriate study design (basic science, reviews, and case reports/series), or if no English text was available. A DerSimonian and Laird random-effects meta-analysis was performed to generate pooled Odds Ratios (OR) with 95% Confidence Intervals (CIs) for each procedural indication in relation to hemorrhage.

Results

952 records were identified of which 17 were included in our quantitative analysis. Common indications included acute cholangitis, choledocholithiasis, Sphincter of Oddi dysfunction (SOD), acute pancreatitis, chronic pancreatitis, and malignancy-associated duct obstruction. Rates of hemorrhage varied in the included studies (median 2.2%; IQR 1.7–6.9). Sphincterotomy rates also differed in the included studies (median 100%; IQR 71.1–100). Five studies did not report on antiplatelet or anticoagulant use with the remaining reporting varying rates of antiplatelet (median 8.3%; IQR 0–26.5) and anticoagulant (median 0.8%; IQR 0–2.25) use. Hemorrhage was significantly associated with acute cholangitis (OR 2.48; 95% CI 1.62–3.78) and choledocholithiasis (OR 1.76; 95% CI 1.06–2.94) but not SOD (OR 1.38; 95% CI 0.74–2.58), malignancy (OR 0.68; 95% CI 0.29–1.59), acute pancreatitis (OR 1.08; 95% CI 0.30–3.82), or chronic pancreatitis (OR 0.56; 95% CI 0.16–1.99).

Conclusions

Acute cholangitis and choledocholithiasis were associated with increased hemorrhage, whereas SOD, malignancy, acute pancreatitis, and chronic pancreatitis were not. Providers should consider procedural indication when counselling patients on hemorrhage risk in ERCP.

Funding Agencies

None