bluuebunny/crossref_metadata_2025 huggingface dataset:
A195 IL-13 DRIVES CROHN’S DISEASE ASSOCIATED-INTESTINAL FIBROSIS IN SHIP DEFICIENT MICE
Authors: Safari K , Menzies S C , Sly L M
Published: February 2024

Background

Crohn’s disease (CD) is an immune-mediated disease characterized by chronic, relapsing and remitting, or progressive inflammation of the digestive tract. One in 3 people with CD will develop intestinal fibrosis requiring surgery within 10 years of diagnosis. Biological therapy is effective at reducing inflammation in CD and early and aggressive treatment with biologics will reduce the incidence of fibrosis. However, in children, for whom a step-up approach to therapy is used, and populations that are refractory to biological therapy; fibrosis remains a serious concern. Treatments are urgently needed as currently there are no treatments that target intestinal fibrosis directly in CD.

Mice deficient in the Src homology 2 domain-containing inositolpolyphosphate 5’-phosphatase (SHIP-/-) develop spontaneous CD-like ileal inflammation and fibrosis. Fibrosis is dependent on PI3Kp110δ activity. IL-4 and IL-13 lead to downstream activation of PI3Kp110δ. Recent work in our lab has shown through pharmacological inhibition that the development of fibrosis in SHIP-/- mice is dependenet on IL-13 signaling, but not IL-4.

Aims

Aim 1: To determine whether genetic ablation of IL-13 prevents ileal fibrosis in SHIP-/- mice

Aim 2: To determine the cellular source of IL-13 in the distal ileum of SHIP-/- mice

Aim 3: To determine the cellular source of IL-13 in the distal ileum of individuals with CD

Methods

SHIP-/- mice were crossed with IL-13 deficient mice (IL13-/-) to generate SHIP+/+IL13+/+, SHIP+/+IL13-/-, SHIP-/-IL13+/+, and SHIP-/-IL13-/- mice. Measurements of ileal fibrosis included gross and histopathology, muscle thickening, and collagen accumulation (Masson’s trichrome staining for fibrosis). Single cell RNA sequencing (snRNA-seq) was performed on the distal ileum of SHIP-/- mice to determine the cellular source of IL-13. Previously published scRNA-seq data were analyzed to determine the cellular source of IL-13 in individuals with CD.

Results

Genetic ablation of IL-13 in SHIP-/- mice (SHIP-/-IL13-/-) reduced the development of ileal fibrosis. Analysis of single cell RNA sequencing data (scRNA seq) has revealed mast cells as the cellular source of IL-13 in the distal ileum of people with CD.

Conclusions

Mast cell derived IL-13 may be driving the development of intestinal fibrosis in CD. Our data suggest that an antibody-based biologic targeting IL-13 may be an effective strategy to prevent fibrosis in people with Crohn’s Disease.

Funding Agencies

CAG, CIHR
A198 RELATIONSHIP BETWEEN HEPATIC GENE EXPRESSION AND MICROBIOME ACCORDING TO DISEASE SEVERITY IN OBESE PATIENTS WITH NON-ALCOHOLIC FATTY LIVER DISEASE
Authors: Ghorbani Y , Schwenger K , Teterina A , Liu Y , Lou W , Fischer S , Jackson T , Okrainec A , Allard J P
Published: February 2024

Background

Non-alcoholic fatty liver disease (NAFLD) ranges from steatosis to inflammation (steatohepatitis; NASH), fibrosis and cirrhosis. Development and progression of NAFLD/NASH is attributed to factors such as obesity and metabolic syndrome as well as intestinal microbiome (IM) but research is limited on the relationship between IM and hepatic gene expression.

Aims

Our objective was to assess in obese patients;1) the transcriptome signature of NAFLD and fibrosis and; 2) determine the relationship between the identified genes and IM.

Methods

Biochemical and anthropometric measurements as well fecal samples for IM shotgun metagenomic sequencing were collected in those with obesity undergoing bariatric surgery. Liver histology was assessed using Brunt scoring system and hepatic transcriptome was assessed using RNA-Seq. Differences in biochemical data and IM were determined using Kruskal-Wallis test followed by Wilcoxon ranked sum test. Differentially expressed genes (DEGs) in the liver were determined using DESeq2 package in R and had |log2 foldchange| ≥1 with adjusted p-value ampersand:003C0.05. Spearman correlation coefficients was used to evaluate the association between significant DEGs and significant bacteria and adjusted using Benjamini-Hochberg.

Results

93 patients had both transcriptome and IM data. Of those, 27 had normal liver obese (NLO) and 66 had NAFLD (including 31 NASH). In those with NAFLD, 19 had no fibrosis (F0) and 47 had presence of fibrosis (F1-F4). We found 71 significantly different DEGs (e.g. PPP1R3G ) in NASH vs NLO and 12 (e.g. THBS2 and GLI2) in NAFLD with presence of fibrosis vs no fibrosis. Those with NASH generally had higher Escherichia coli, Blautia hansenii and lower Alistipees putredinis. Those with NAFLD and fibrosis had increased E. coli and reduced Eubacterium ventriosum and A. putredinis. In the preliminary analysis of NASH vs NLO, B. hansenii negatively correlated with glucose homeostasis-related PPP1R3G. In those with NAFLD, A. putredinis correlated negatively with THBS2 (i.e. Thrombospondin-2) and, in patients with NAFLD and fibrosis, E. coli correlated positively with GLI2 (related to activation of hepatic stellate cells).

Conclusions

DEGs were associated with specific bacteria in NASH or fibrosis. Next steps include analyzing the microbial metagenomic pathways as well as metabolites and determine the relationship between the IM, hepatic transcriptome and metabolites according to disease severity.

Funding Agencies

CIHRAmerican College of Gastroenterology Bridge Award, BBDC Tamarack Graduate Award in Diabetes Research
A208 ENDOSCOPIC SUBMUCOSAL DISSECTION (ESD) FOR BARRETT’S NEOPLASIA: CLINICAL OUTCOMES AND MID-TERM FOLLOW-UP AT A CANADIAN TERTIARY REFERRAL CENTER
Authors: Fujiyoshi Y , Khalaf K , Natalia C , Mosko J , May G , Teshima C
Published: February 2024

Background

Endoscopic submucosal dissection (ESD) is an established technique for resecting early gastrointestinal neoplastic lesions. However, for Barrett’s neoplasia treatment, piecemeal EMR has been the standard approach, leaving the efficacy of ESD for Barrett’s neoplasia unclear.

Aims

To assess the outcomes of Barrett’s neoplasia treated with ESD at a tertiary center in Canada.

Methods

This is a single center, retrospective study. All patients aged over 18 who underwent ESD for Barrett’s neoplasia at St. Michael’s Hospital between December 2017 and August 2023 were included. Primary outcomes were En-bloc, R0, curative resection, and recurrence rates, while secondary outcomes focused on the adverse event rate.

Results

Of the 72 patients studied (mean age 67.7 years; 90% male), 31.9% (23/72) were SSBE and 68.1% (49/72) were LSBE. The mean±SD lesion size was 4.5±3.4 cm, with circumferential occupancy at 53.4±23.9 %. Paris classifications were as follows: 0-Is: 8 (11.1%), 0-IIa: 26 (36.1%), 0-IIb: 9 (12.5%), 0-IIc: 6 (8.3%), 0-IIa+IIc: 13 (18.6%), 0-IIa+Is: 10 (13.9%). The mean operation time stood at 144.4 (75.3) minutes. Adverse events comprised deep mural injury (4.1%) and delayed bleeding (2.8%). Pathology findings showed high-grade dysplasia in 6.9% and adenocarcinoma in 93.1%, further differentiated as: well-differentiated (55%), moderately differentiated (33%), and poorly differentiated (12%). The invasion depth was intramucosal in 76%, SM1 in 6%, and SM2-SM3 in 18%. Lympho-vascular invasion was present in 22%. En-bloc, R0, and curative resection rates were 96% (69/72), 82% (59/72), and 64% (46/72), respectively. Of the curative resection patients, 42 have completed follow-up EGD, with 11.9% (5/42) showing persistent dysplasia at first follow-up. These were treated by either EMR (4 cases) or ESD (1 case), leading to a 100% (42/42) complete remission of dysplasia (CRD) rate with median follow-up time of 127 (68-190) days. After achieving CRD, local recurrence was found in 2.4% (1/42) with a median follow-up time of 289 (136-524) days. This recurrence post-CRD was successfully treated with EMR, regaining CRD.

Conclusions

Our study showcases the Canadian experience of using ESD for Barrett’s neoplasia at a large single tertiary referral center. Given the challenging demarcation lines in Barrett’s neoplasia and the frequent presence of metachronous lesions, even with curative resection, 11.9% showed persistent lesions during the first follow-up. However, these lesions were treatable endoscopically, with 100% eventually achieving CRD. Although there was a 2.4% recurrence rate post-CRD, this too could be managed endoscopically. Overall, the mid-term outcomes of treating Barrett’s neoplasia with ESD are promising.

Funding Agencies

None
A209 ESOPHAGEAL EPIDERMOID METAPLASIA: ADVOCATING FOR A PRIMARY ENDOSCOPIC SUBMUCOSAL DISSECTION APPROACH
Authors: Gilhotra R , Zarrin A , Jiang S X , Xiong W , Shahidi N
Published: February 2024

Background

Esophageal epidermoid metaplasia (EM), or leukoplakia, is a rare finding on endoscopy; typically seen incidentally as a white plaque and histologically characterized by orthokeratosis. The link between EM and squamous neoplasia has been identified. There is no consensus on the management of EM.

Aims

To present a case of circumferential esophageal EM managed with endoscopic submucosal dissection (ESD).

Methods

Case report and review of the literature

Results

A 56-year-old female with a known history of EM was referred for consideration of ESD due to dysplastic progression confirmed on histopathology. Previous attempts at eradication included argon plasma coagulation and staged band mucosectomy. Fully circumferential ESD was performed over a 100mm segment in the mid esophagus using the double tunnel technique. Histopathology revealed multifocal low-grade squamous intraepithelial neoplasia within epidermoid metaplasia with negative margins.

Conclusions

Esophageal epidermoid metaplasia may increase the risk of squamous cell carcinoma. There are no consensus recommendations regarding its management with previous described strategies including surveillance and eradication with radiofrequency ablation and band mucosectomy. ESD for epidermoid metaplasia has not been described; however, given the overall efficacy, efficiency, safety and now widespread availability of this technique a primary ESD approach should be considered.

Funding Agencies

None
A227 EXPLORING THE ROLE OF MICROBIAL AND GENETIC FACTORS IN DEFINING THE INTESTINAL IMMUNE SYSTEM USING A HUMANIZED GNOTOBIOTIC MOUSE MODEL
Authors: Bayer G , Tsankov B K , Samman B , Foerster E , Winsor N , Visser G V , Hakim S , Allen-Vercoe E , Philpott D
Published: February 2024

Background

Studies of the gut microbial ecosystem and its role in disease are often complicated by the intricate network of interactions between its microbial members and the host. Therefore, mouse models in which the microbiota diversity can be strictly controlled, and the functional potential be easily assessed, are needed.

Aims

Establishing a taxonomically and functionally diverse human gnotobiotic microbiota that recapitulates many microbe-host interactions of the complex human microbiome. To validate the effects of the defined bacterial gut community on the host, we will assess host physiology, intestinal immunity and the response to inflammatory stimuli.

Methods

Germ-free (GF) mice were inoculated with a defined bacterial community isolated from the stool of a healthy human donor. Stability of colonization across multiple generations and spatial organization of the bacterial community in the intestine were assessed using 16S rRNA gene sequencing and species-specific quantitative PCR. Immune cells were isolated from the colonic lamina propria and characterized by flow cytometry.

Results

Inoculated GF mice were reproducibly colonized with 8 bacterial species, collectively termed Human Defined Community 1 (HDC1). The HDC1 is vertically transmitted from mothers to offspring and the relative abundances remain stable in the colony over an extended period in a gnotobiotic isolator. We observed spatial stratification of the HDC1 microbiota between the small intestine and colon or cecum. HDC1 mice form a colonic inner mucus layer comparable in thickness to SPF mice suggesting physiological spatial organization of the bacterial community over the cross-sectional axis of the colon. Characterization of colonic lamina propria immune cells in HDC1 mice revealed myeloid and lymphoid cell abundances closely resembling those of mice harboring a complex microbiota (specific pathogen-free [SPF] mice), including normal macrophage and dendritic cell counts and normal proportions of CD4+ cells (regulatory T, Th1 and Th17 cells). Finally, we showed that HDC1 mice can be transplanted with human gut commensals and Crohn's disease (CD)-associated bacteria, demonstrating the tractability of this human defined microbiota.

Conclusions

In summary, HDC1 gnotobiotic mice are stably colonized with a human defined bacterial community and harbor an intestinal innate and adaptive immune system similar to SPF mice. Therefore, HDC1 mice represent a reliable and tractable tool for host-microbe interaction studies. Ultimately, we will employ the HDC1 model to decipher the role of Nod2 – the strongest genetic risk factor for CD development – in shaping both the microbiota and host immunity.

Funding Agencies

CIHROGS
A229 DRUG PERSISTENCE WITH THERAPY OF ADALIMUMAB BIOSIMILAR, IDACIO, IN INFLAMMATORY BOWEL DISEASES
Authors: Cheung S , Kudaeva F , Heidari P , Truong D
Published: February 2024

Background

For post marketed medicine, drug persistence could be used as an indication for effectiveness and safety in routine clinical care over time. Non-adherence and non-persistence to treatment are associated with disease flares and may lead to disease progression among patients with inflammatory bowel diseases (IBD) in real-life.

Aims

The aim of this analysis was to explore drug persistence with an adalimumab biosimilar, Idacio, in IBD patients using the data collected by Fresenius Kabi patient support program (KabiCare) in Canada.

Methods

Patients with IBD enrolled in KabiCare and received at least one dose of adalimumab biosimilar, Idacio, were followed up from February 2021 to September 2023 in Canada. Medication initiation date and stop date, disease types (Crohn’s disease [CD], and ulcerative colitis [UC]) and patient treatment (categorized by naïve to biologic,or switched from other biologics) were recorded in the database. The stop date was the date when KabiCare was informed that medication was discontinued. The patients continuing medication were censored at the maximal follow-up date of analysis, September 12, 2022. Log-rank tests were used for KM (Kaplan-Meier) plot comparison to examine if there were differences in medication adherence between CD and UC, and between naïve group vs. switch group by disease.

Results

The study sample consisted of 1049 patients: 830 (79.1%) had CD, and 338 (32.2%) were in naïve group. KabiCare followed patients with CD for a median time of 512 days (interquartile range: 285-673 days; maximum: 895 days), and followed patients with UC for a median time of 492 days (interquartile range: 183-672 days; maximum: 925 days). At 800 days after starting the medicine, the drug persistence probability was similar for patients with CD and UC (At day-800: 76.6% vs. 67.6%, p=0.07). Among patients with CD, the drug persistence probability was higher in the switch group compared to naïve group (At day-800: 78.9% vs. 71.7%, p=0.0028). Among patients with UC, the drug persistence probably was similar in the switch group compared to naïve group (At day-800: 78.4% vs. 62.3%, p=0.34).

Conclusions

The drug persistence of adalimumab biosimilar, Idacio, was over 76% in patients with CD and over 67% in patients with UC 800 day after therapy initiation. Compared to patients in the naïve group, patients in the switch group were more likely to stay on adalimumab therapy.

Funding Agencies

None
A241 CORRELATION BETWEEN PLASMA IGA LEVEL AND BIOLOGICAL THERAPY IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE
Authors: Lee B , Hsu J , Tsai T
Published: February 2024

Background

IgA is the predominant antibody class secreted by intestinal immune cells. However, the level of plasma IgA in Inflammatory Bowel Disease (IBD) patients under medical treatment remains unknown. Therefore, our study aimed to investigate the relationship between plasma IgA concentration in IBD patients under biological therapy.

Aims

To assess the correlation between plasma IgA level in IBD patients under biological therapy.

Methods

We collected data from outpatient clinics at our hospital, including 12 IBD patients, comprising 4 patients with Crohn's disease (CD) and 8 patients with Ulcerative Colitis (UC). Data was collected between 2020 and 2023. We measured plasma IgA concentrations both before initiating biologic therapy and at the 14th week of biological treatment (4 under Adalimumab and 8 under Vedolizumab). Additionally, we compared baseline plasma IgA levels between 24 IBD patients (7 CD and 17 UC) and 24 healthy individuals. Student T test was used for statistical analyze.

Results

The average baseline plasma IgA level was significantly higher in IBD patients (2134±187.2 ug/ml, mean ± standard error) when compared to healthy individuals (1346± 114.8 ug/ml, p=0.0008). In the view of CD and UC, the baseline plasma IgA level was 2179±439.4 ug/ml and 2116±203.1 ug/ml, respectively. Baseline plasma IgA level also showed statistical significantly higher in CD and UC compared to healthy individuals (p=0.0063, p=0.0005, respectively), and without difference between UC and CD patients (p=0.8824) (Figure 1A).

Furthermore, we investigated the impact of biological therapy on plasma IgA levels in IBD patients, finding a significant decrease in plasma IgA levels after biological therapy (2182±254.7 ug/ml to 1824±135.5 ug/ml, p=0.0181). Similar trend was noted in UC patients under biological therapy with borderline statistical significant (2141± 307.7ug/ml to1809±173.3ug/ml, p=0.0561), but not found in CD patients (2265±518.3 ug/ml to 1855±247.5 ug/ml, p= 0.1333)(Figure 1B).

Conclusions

We found that baseline plasma IgA level was higher in IBD patients compared to healthy individuals. Besides, plasma IgA level decreased after biological therapy in IBD patients, especially in UC patients. These findings suggest that plasma IgA level may be a potential biomarker for IBD patients.

Funding Agencies

None
A251 GUT-SPECIFIC DOWNREGULATION OF INTERFERON-LAMBDA RESPONSES OCCURS IN INFLAMMATORY BOWEL DISEASES
Authors: Ogungbola O , Mahmood R , Ouyang J , Vu V , Nguyen N , Liu X , Bittorf K , Lamb S , El-Matary W , Bernstein C , Wine E , Tyrrell L D , Armstrong H K , Santer D
Published: February 2024

Background

Inflammatory bowel diseases (IBD) affect 1:140 Canadians, resulting in significant inflammation and gut damage. Unlike type I and II interferons (IFNs), the most recently discovered IFNs, interferon-lambdas (IFN-λs), uniquely downregulate gut inflammation and promote gut healing in mouse models. However, it remains unknown if the important anti-inflammatory IFN-λ signaling pathways induced downstream of the IFN-λR1/IL-10RB heterodimeric receptor are altered in IBD.

Aims

To compare intestinal and peripheral IFN-λR levels and responses in people with active or remission IBD and those without IBD. We hypothesized that intestinal IFN-λR1 levels and downstream activities are decreased in people living with IBD, which could contribute to IBD pathology (gut inflammation and mucosal damage).

Methods

During routine colonoscopy, uninflamed biopsy samples were obtained from the terminal ileum and sigmoid colon. IFN-λR1 levels were quantified in intestinal biopsy and blood samples from persons with or without IBD (n=12 adults and n=12 pediatric) by immunohistochemistry and flow cytometry. Fresh intestinal biopsies were also cultured ex vivo for 24 hr in media +/- IFN-λ3 and gene expression was quantified by RT-qPCR.

Results

In IBD gut tissues, a significant decrease in IFN-λR1+ cells was more prominent in IBD patients with active disease (pampersand:003C0.01, 30-50% reduction). The decrease was more prominent in IBD patients with active disease. Consequently, there was a significantly lower IFN-λ-driven upregulation of genes such as IFIT1 and MX1 in IBD as compared to non-IBD tissues (pampersand:003C0.05, 4-7-fold reduction). Interestingly, IFN-λR1 levels were not decreased in peripheral blood immune cells, indicating the dysregulation of IFN-λR responses is likely gut-specific.

Conclusions

Our findings demonstrate that people living with IBD have dysregulated IFN-λ responses in the gut which could lead to the lower induction of key anti-inflammatory pathways. This work supports the further study of mechanisms regulating the IFN-λ system to develop strategies to restore and promote IFN-λ responses as a novel potential future IBD therapy.

Funding Agencies

University of Manitoba, Weston Family Foundation, The Children's Hospital Research Institute of Manitoba.
A253 BEHAVIOUR CHANGE CONSIDERATIONS TO IMPROVE PHYSICAL ACTIVITY PARTICIPATION AMONG INDIVIDUALS WITH QUIESCENT AND MILDLY ACTIVE IBD – A QUALITATIVE STUDY
Authors: Oketola B , Webber S , Singh H , Kredentser M , Reynolds K , Restall G
Published: February 2024

NOT PUBLISHED AT AUTHOR’S REQUEST

Please acknowledge all funding agencies listed below

Funding Agencies

CAGPfizer
A254 CANAGLIFLOZIN EXACERBATES CHEMICALLY INDUCED COLITIS WHEN COMBINED WITH A HIGH SUGAR DIET
Authors: Madsen K , Omeltchenko T , Hotte N , Thiesen A , Villaflor B , Cheng C
Published: February 2024

Background

Consumption of high-sugar diets exacerbates inflammation and hinders the healing process in animal models of acute colitis. Canagliflozin (CANA) is a sodium glucose cotransporter-2 (SGLT2) inhibitor primarily used for the management of type 2 diabetes and cardiovascular disease. CANA has demonstrated the ability to suppress human T cell and macrophage effector function and to improve inflammation in rat colitis models. Based on these findings, we hypothesized that CANA would mitigate the deleterious effects of a high sugar diet in a DSS colitis model through its effects on immune effector cells.

Aims

The aim of this study was to examine the effects of a high sugar diet and CANA administration on colonic inflammation in an animal model of acute colitis.

Methods

Adult wild-type male and female 129/SvEv mice were placed on standard chow or a high-sugar diet (HSD) containing 50% sucrose (AIN76A) ± CANA (10mg/kg) gavaged daily (n=4-6 for each group). Following three days on the respective diet, mice received 1.8-2% dextran sodium sulfate (DSS) in their drinking water for 5 days, followed by water alone for 4 days. Disease Activity Index (DAI) was computed daily based on changes in animal weight, stool consistency, and blood in stool. Colonic tissues were evaluated for histological changes, weight-to-length ratio, and cytokine levels using the MesoScale discovery platform.

Results

Mice on the HSD had increased severity of colitis compared with chow fed mice as evidenced by enhanced DAI, increased weight loss, and increased levels of colonic TNFα (pampersand:003C0.02). Response to CANA treatment was both sex and diet dependent. Contrary to our hypothesis, CANA treatment increased severity of colitis in male mice on the HSD as evidenced by increased DAI and delayed healing with increased enterocyte injury and increased levels of lamina propria neutrophils and lymphocytes. CANA treatment did not exacerbate disease severity in females on the HSD but did delay healing as evidenced by increased lamina propria neutrophils and lymphocytes and worse enterocyte injury. These effects were not observed in mice that were fed standard chow diets with CANA.

Conclusions

A high-sugar diet significantly exacerbates chemically induced colitis and delays healing. This effect is intensified when combined with CANA, especially in male mice. These findings indicate that effects of SGLT2 inhibitors on colonic inflammation can be modulated by both dietary intake and sex.

Funding Agencies

CCC
A260 ADVANCING INFLAMMATORY BOWEL DISEASE DIAGNOSIS THROUGH STOOL PROTEOMIC SIGNATURES OBTAINED VIA DIA-MASS SPECTROMETRY AND MACHINE LEARNING
Authors: Shajari E , Gagné D , Malick M , Brunet M , Delisle M , Boisvert F , Beaulieu J
Published: February 2024

Background

Resembling symptoms between flare-up Inflammatory bowel disease (IBD) and other gastrointestinal diseases and conditions, make the initial diagnosis and accurate treatment of this disease challenging. Currently, the most common clinical methods used for diagnosing and monitoring IBD are colonoscopy and biopsy, which are invasive and uncomfortable procedures, and the fecal calprotectin test, which is not sufficiently accurate. Therefore, it is necessary to develop an alternative method.

Aims

In this study, our aim was to develop a robust predictive model for a noninvasive and accurate test to distinguish active IBD from non-IBD controls.

Methods

A total of 120 samples were collected, with 78 samples separated for retrospective analysis and model training, while 42 samples were set aside for prospective validation. We employed SWATH mass spectrometry for the identification and quantification of the stool proteome. The obtained data underwent multiple stages, including data preprocessing, feature selection, model training, and performance evaluation. We optimized data processing procedures through advanced bioinformatics, selecting an appropriate pipeline that included data normalization, batch effect correction, and missing value imputation. Subsequently, we assessed various machine learning algorithms to determine the most effective classifier for predicting IBD based on the selected proteins.

Results

After data preprocessing, we identified 48 differentially abundant proteins (DAPs). To eliminate redundant proteins, we employed Correlation-based Feature Selection (CFS), resulting in selecting 7 proteins. To identify the most suitable predictive model for our dataset, we assessed five popular machine learning methods: Support Vector Machines (SVM), Random Forests, Logistic Regression, k-nearest neighbors (KNN), and Naive Bayes. Among these, SVM exhibited the highest performance. Finally, we evaluated the model's performance by applying the selected algorithm to 42 prospective blind samples. The results revealed a sensitivity of 96% and a specificity of 76%, highlighting its strength and effectiveness.

Conclusions

In conclusion, this study offers a proof of concept for the application of SWATH for precise IBD diagnosis using stool proteomics and showcases the effectiveness of our data processing and machine learning approach. Additionally, it highlights the potential of this method for classifying Crohn's Disease (CD) vs. Ulcerative Colitis (UC) and distinguishing active IBD from remission.

Workflow of study

Funding Agencies

CIHRCrohn's and Colitis Canada , Studentship from CRMUS,
A272 EFFECTS OF EMPAGLIFLOZIN ON CHEMICALLY INDUCED COLITIS IN A MOUSE MODEL ARE MODULATED BY SEX AND DIETARY INTERACTIONS
Authors: Madsen K , Villaflor B , Hotte N , Thiesen A , Cheng C , Omeltchenko T
Published: February 2024

Background

High sugar diets have been shown to dramatically increase disease severity in mouse models of colitis. Empagliflozin (EMPA) is a highly selective sodium glucose cotransporter-2 (SGLT2) inhibitor that is used therapeutically as an antihyperglycemic agent in the management of type 2 diabetes. In human trials EMPA treatment exerts potent anti-inflammatory effects independently of glycemic control. Further, we have previously demonstrated in a genetic mouse model of colitis that EMPA treatment was highly effective in improving colonic inflammation. Based on these findings, we hypothesized that EMPA treatment may also be effective in mitigating disease severity in chemically induced colitis in mice fed a high sugar diet.

Aims

The aim of this study was to examine the effects of treatment with EMPA on chemically induced colitis in mice fed a high sugar diet

Methods

At 6-8 weeks of age, wild-type 129/SvEv mice were placed on chow (CH) or high sugar diet (HS) (50% sucrose: AIN76A) ± EMPA (10mg/kg). After two days on the diet, mice were administered dextran sodium sulfate (DSS) for 5 days in drinking water followed by water alone for 2 days (n=4-6 mice for all groups). Disease activity index (DAI) was calculated daily from animal weight change, stool consistency, and stool hemoccult. As a measurement of degree of healing, colonic tissues were evaluated at day 9 for histological changes, weight-to-length ratio, and cytokine levels by ELISA. As a measure of EMPA functionality, urinary and blood glucose levels were measured.

Results

Mice on the HS diet demonstrated increased susceptibility to colitis compared with chow fed mice with increased colonic levels of IL-1β, weight loss, and DAI. Significant interactions between sex and diet were seen in responses to EMPA treatment. EMPA treatment did not alter severity of colitis but did significantly delay healing in male mice on both the HS and chow diets as evidenced by increased DAI and increased enterocyte injury with increased levels of lamina propria neutrophils and lymphocytes. EMPA treatment did not increase disease severity in females on either diet. No differences were seen in colonic TNFα, IL-10, IL-12p70, or IL-22 between any of the groups. Urinary glucose levels were elevated in mice receiving EMPA and significantly higher in males compared with females (pampersand:003C0.05). EMPA treatment did not alter fasting blood glucose levels.

Conclusions

A high sugar diet strongly exacerbates disease severity in a sex-dependent manner in a chemically induced model of colitis. Further, contrary to our hypothesis, EMPA treatment did not improve colitis in females and worsened disease in males suggesting that the documented anti-inflammatory effects of EMPA may be condition dependent.

Funding Agencies

CCC
A273 A PILOT PROSPECITVE, MULTI-CENTRE, RANDOMIZED CONTROLLED TRIAL COMPARING FECAL MICROBIOTA TRANSPLANTATION (FMT) TO PLACEBO AT INDUCING REMISSION IN MILD TO MODERATE CROHN'S DISEASE
Authors: Wong K , Kao D , Jijon H , Franz R , Narula N , Peerani F , Turbide C , Kroeker K , Moayyedi P , Madsen K
Published: February 2024

Background

FMT has shown promise at inducing remission in ulcerative colitis. The effect of FMT on inducing remission in Crohn’s disease however remains unknown.

Aims

To evaluate the efficacy of FMT at inducing remission in mild-to-moderate Crohn’s disease

Methods

This double-blind, randomized, trial conducted at 3 Canadian academic centers (Edmonton, Hamilton and Calgary) randomized. Adult patients with mild-to-moderate Crohn’s disease with modified Harvey Bradshaw Index (mHBI) score of ampersand:003E5 and at least one objective measure of inflammation (CRP ≥ 8mg/L or fecal calprotectin (FCP) ≥ 250 ug/g) on stable dosing of concomitant therapy were assigned to FMT or placebo. First assigned treatment was by colonoscopy followed by 20 [DK1] capsules weekly for 7 weeks. Endoscopic severity (SES-CD) was assessed at baseline during colonoscopic delivery of assigned treatment and at week 8 by a blinded central reader using video recording. The primary endpoint was the proportion of patients in both clinical (mHBI ampersand:003C 5) and endoscopic remission (SES-CD ≤ 5) at week 8. Responders (reduction of HBI ≥ 3 or HBI ≤ 5 and reduction of CRP or FCP by ≥ 10%) in FMT group were eligible to continue with open-label FMT capsule every 2 weeks. Non-responders in the placebo group were permitted to restart the trial at week 0 with open-label FMT. Secondary outcomes included patient reported outcomes and safety outcomes.

Results

Between July 2017 to Jun 2021, 28 were randomized (16 to FMT and 12 to placebo). The study team voluntarily suspended the trial twice due to Health Canada safety warnings regarding potential transmission of multi-drug resistant organisms and SARS-CoV-2 through FMT. At week 8, 0% (0/16) of patients in the FMT group versus 8.3% (1/12) in the placebo group reached the primary endpoint of combined clinical and endoscopic remission. Of the 50% (8/16) in the FMT group who achieved a clinical response and continued on open-label FMT every 2 weeks, 12.5% (1/8) achieved the primary endpoint. Of the 7 non-responders in the placebo group who restarted the trial at week 0 and received open-label FMT, 28.6% (2/7) achieved primary endpoint at week 8 on open-label FMT. No death or hospitalization were observed. The study was terminated early at the recommendation of the Data Safety Monitoring Board.

Conclusions

FMT was not effective at inducing remission in Crohn’s disease using the FMT regimen in this study. However, this study was limited by a small sample size and recruitment barrier during the COVID pandemic. Future studies may consider other strategies to potentially enhance treatment response, including antibiotic pre-treatment, optimized donor-recipient pairing, and concomitant anti-inflammatory diet.

Funding Agencies

CIHR
A278 ACCEPTABILITY, FEASIBILITY, AND IMPACT OF THE MYGUT DIGITAL HEALTH PLATFORM IN THE MONITORING AND MANAGEMENT OF INFLAMMATORY BOWEL DISEASE
Authors: Zhen J , Simoneau M , Sharma P , Germain P , Marshall J , Afif W , Narula N
Published: February 2024

Background

Inflammatory bowel disease (IBD) is a chronic gastrointestinal disorder that has been associated with depression, anxiety, and decreased quality of life. With new technological advancements, digital health monitoring platforms offer a promising avenue to integrate self-management strategies into the care of patients with IBD.

Aims

This study aimed to investigate patients’ acceptability to implementing the MyGut IBD health monitoring platform into their care, evaluate whether its use leads to better quality of life/improved health outcomes, and determine the feasibility of its long-term use.

Methods

We conducted a multi-centre, single-arm trial at McMaster University and McGill University, among their affiliated hospitals, from September 2020 to September 2023. Patients with IBD were recruited in gastroenterology clinics and asked to install the MyGut application onto their mobile devices. Various metrics such as willingness to use the application, patient satisfaction, symptom control/quality of life scores (measured through the short inflammatory bowel disease questionnaire (SIBDQ)), resource utilization, and feasibility statements were collected throughout the study. Patients exhibiting abnormal SIBDQ scores were identified for follow-up. After one year, patient outcome metrics were compared to baseline values.

Results

Out of the 84 patients initially enrolled, 58 patients (69%) continued until study completion at one-year. At recruitment, all 84 patients (100%) were willing to use the MyGut application after a brief tutorial and 72.6% (61/84) had already been using technology for health-related purposes. There was a significant improvement in SIBDQ scores after one year of MyGut use (median = 57.5, IQR 50.25–62) when compared to baseline (median = 54.5, IQR 47.25–58.75) (p = 0.01). However, only 42.9% of patients (21/49) were willing to continue using the application after one year, a significant decrease compared to the 71.9% (41/57) who were willing to continue after two months (p = 0.002). No differences were observed in patient satisfaction measures (p = 0.42 to 1) or number of ER visits/hospitalizations (p = 0.78) before and after one year of MyGut use.

Conclusions

Overall, IBD is a condition that often necessitates frequent medical follow-up and may benefit from proactive symptom management strategies. This study demonstrates that patients with IBD are very willing to integrate digital health monitoring platforms into their care and these may subsequently lead to improved symptom control and enhanced quality of life. Future studies should aim to investigate the subset of patients that would benefit most from these health interventions, and as illustrated, continued efforts must be made to optimize the acceptability/feasibility of its long-term use.

Funding Agencies

CCC
A300 ADVANCED HEPATIC ECHINOCOCCOSIS: A CASE REPORT
Authors: Quan S Y , Wells M
Published: February 2024

Background

Alveolar echinococcosis (AE) is a rare and potentially fatal disease caused by the parasite echinococcus multilocularis (EM). Humans are intermediate hosts who become infected through contact with definitive hosts (foxes, wolves, coyotes, dogs and cats) and ingestion of contaminated food and water. AE primarily affects the liver but has the potential for local or metastatic spread. It has a clinical latency time of 5-15 years and resembles a malignancy in appearance and growth, posing a challenge in diagnosis and management. Treatment includes benzimidazole therapy and surgical resection, however, removal of the entire parasitic mass is not always possible.

Aims

Present a case of hepatic AE involving the gallbladder, biliary tree, and spleen.

Methods

Case report.

Results

A 49-year-old farmer was admitted to a Saskatchewan hospital for a 2-week history of abdominal pain, jaundice, and progressive weight loss. Computed tomography (CT) of the abdomen and pelvis showed a necrotic mass in the gallbladder compromising the liver, splenic lesions and involvement of the biliary tree. The patient was given a preliminary diagnosis of metastatic cholangiocarcinoma and underwent a gallbladder biopsy which returned as echinococcus, confirmed with two liver biopsies and a positive EM nucleic acid test. He was then diagnosed with advanced hepatic AE with metastasis to the gallbladder, biliary tree, and spleen. The patient required a long-term hepatic drain and developed a hepatocutaneous fistula. While surgery is curative, his disease was too extensive for resection. He was started on Albendazole and received into our care for a liver transplant assessment 10 months later. Currently, there is limited literature on liver transplantation in advanced AE as it may not be curative. Additionally, subsequent immunosuppression may expedite residual parasite growth leading to aggressive disease recurrence. In this case, liver transplant would also require a splenectomy and excision of the hepatocutaneous fistula for complete parasite removal. Repeat CT of the abdomen and pelvis at thirteen months after the patient's initial hospitalization did not show disease progression. Given his stability on Albendazole, the added surgical complexity, and possibility of aggressive disease recurrence post liver-transplant, the multidisciplinary committee decided against liver transplant at this time. He continues to do well on Albendazole 15 months after initial presentation.

Conclusions

The reported mortality rate of AE is ampersand:003E 90% within 10-15 years of diagnosis if untreated or inadequately treated. This case highlights the complexities in management of advanced hepatic AE and the importance of early diagnosis and treatment with radical surgery. Although not curative, benzimidazole therapy is effective in slowing disease progression in unresectable cases. Further studies are needed to assess the role of liver transplantation in advanced hepatic AE.

Funding Agencies

None
A310 CANADIAN GASTROENTEROLOGY RESIDENT ATTITUDES TOWARDS TREATING PATIENTS WITH DISORDERS OF GUT BRAIN INTERACTION
Authors: Rodrigues D , Parker C H , Salim M , Liu L W
Published: February 2024

Background

Disorders of gut brain interaction (DGBI) are common in the Canadian population. Studies show DGBI represent 30% of new referrals to gastroenterology (GI) clinics. Despite this, evidence suggests that gastroenterologists experience challenges in providing care for these patients, with a recent study from the United States indicating that this discomfort may begin early in residency training.

Aims

Our aim was to determine Canadian GI resident attitudes towards treating patients with DGBI, with a focus on determining underlying causes and solutions for potential negative attitudes.

Methods

Gastroenterology residents participating in accredited adult GI training programs in Canada were invited to participate in an online 30-item survey. This was based on similar studies in the adjacent field of chronic pain and administered using RedCap. Recruitment occurred through email invites distributed to residency program directors and QR code links presented at national GI resident meetings over one year.

Results

In total, 42 residents participated in the survey. Most residents reported frequent exposure to DGBI. Although most residents felt confident at diagnosing DGBI, only few felt confident in managing them. The majority reported less enjoyment and personal reward at managing DGBI than other gastrointestinal diseases, finding them frustrating to treat and expressing concern regarding the uncertainty of the diagnosis and low likelihood of successful management. Residents believed that challenges in the treatment stemmed from the following: inadequate training, uncertainty regarding the severity of symptoms that were reported, co-existing psychiatric issues, a lack of clarity on therapy and inadequate time. Residents reported that senior residents and staff both expressed negative opinions about caring for those with DGBI, and felt that displeasure for managing patients with DGBI was pervasive in the GI community. Importantly, the majority of trainees believed it was important to formally learn about the physiological underpinnings of DGBI as well as their diagnosis and management. Furthermore, understanding the impact of DGBI on a patient’s quality of life was thought to be important.

Conclusions

This national survey demonstrates that Canadian GI trainees are less confident and less interested in providing care for those with DGBI due to a variety of factors including inadequate training and a potential hidden curriculum. Residents believe in the importance of education in this field. The results of this study will be used to develop educational experiences to ultimately improve the care of those with DGBI.

Funding Agencies

None
A311 EFFICACY OF PANCREATIC CANCER SCREENING IN HIGH RISK INDIVIDUALS
Authors: Harjot B , Cheng D , Buttar J , Lam E , Telford J J
Published: February 2024

Background

Pancreatic cancer (PC) is the 11th most prevalent cancer in Canada with about 6900 new cases in 2021. Due to late diagnosis, it is the 4th largest cause of cancer related mortality in Canada. Despite advances in diagnosis and treatment over the past decade, the 5-year survival remains ampersand:003C10%, making pancreatic cancer one of the most lethal malignancies worldwide. However, if detected early, the 5-year survival increases to 80%. The incidence of pancreatic cancer remains low. Therefore, the International Cancer of the Pancreas Screening (CAPS) consortium do not recommend screening everyone. Selective screening in high-risk individuals may be effective in early detection and treatment of pancreatic cancer.

Aims

1. To determine the characteristics of patients undergoing PC screening at a single tertiary care center in Vancouver.

2. To determine the frequency of disease progression and outcomes in patients diagnosed with high-risk lesions during screening.

Methods

Retrospective chart review was performed for patients who were screened between January 1, 2005 to June 30, 2023. As per consensus from the CAPS Consortium, patients with at least 2 close relatives with PC, and those with predisposing genetic mutations screened using endoscopic ultrasound (EUS) and/or magnetic resonance imaging (MRI) were included in the study. Clinical data, such as age, tobacco use, genetic risk, endoscopic findings, and outcomes, such as disease progression, were collected. Statistical analysis was performed using Rstudio and Microsoft Excel.

Results

73 patients were included, with 42 included due to pathogenic germline mutations, and 31 with familial pancreatic cancer. Most were female (52, 71.2%). Median age in the study was 54 years (range 24-74 years) at initial screening. 66 patients (90.4%) received an EUS and 7 patients (9.6%) received MRI for initial screening. At the time of initial screening. 74.6% of patients had a normal pancreas. 6 patients (8.2%) were found to have neoplastic lesions, e.g. ampulloma, neuroendocrine tumour or adenocarcinoma at initial screening and referred for surgery. In the median follow up time of 67.9 months (range 0-168.1 months), 6 patients were noted to have disease progression, 4 of which had increase in cyst size without any other worrisome features. 2 patients had progression to malignancy. 1 of those patients received chemotherapy and surgical resection and remains alive; the other patient was lost of follow up due to geographical move.

Conclusions

Pancreatic cancer screening in high risk individuals is effective in early detection and treatment. Given lower incidence of pancreatic cancer, we likely need additional patient enrolment to observe a significant improvement in patient outcomes.

Funding Agencies

None
Organizational Culture: Structure and Evolution
Authors: Gradstein Mark
Published: February 2024

We present a model of the formation and evolution of organizational culture and its effect on performance. The analysis reveals circumstances under which, because of cultural externalities, excessive polarization or, alternatively, homogeneity may result, indicating inter alia an important role for the performance of managing cultural diversity in organizations. The exhibited framework can be useful in dissecting how different aspects of cultural diversity and the nature of management–workers’ interactions affect organizational functioning (JEL D02, D23, M54, Z13).
Accumulation of circulating myeloid-derived suppressor cell subsets: predicting poor clinical efficacy and prognosis through T cell suppression in non-Hodgkin's lymphoma
Authors: Pu Lian-Fang , Li Man-Man , Feng Xiang-Jiang , Zhang Tun , Hu Lin-Hui , Zheng Hui-Min , Charwudzi Alice , Ding Yang-Yang , Liu Jun , Liu Ze-Lin , Xiong Shu-Dao
Published: February 2024

Myeloid-derived suppressor cells (MDSCs) are implicated in the regulation of immune responses closely associated with poor clinical outcomes in cancer. However, the MDSC subtypes in non-Hodgkin's lymphoma (NHL) have not been systematically investigated. So, we investigated the percentage of MDSC subsets in 78 newly diagnosed NHL patients by flow cytometry. The results showed that all MDSC subsets increased in NHL patients compared with healthy donors. Notably, MDSCs, monocytic MDSCs, and CD14 + CD66b + MDSCs significantly increased in NHL patients compared with those with lymphadenitis donors. polymorphonuclear MDSCs (PMN-MDSCs), early-stage MDSCs (e-MDSCs), and the International Prognostic Index were independent risk factors for poor clinical efficacy and were involved in constructing the nomogram for predicting clinical efficacy. Progression-free survival (PFS) was significantly shorter in patients with high level of MDSC subsets, and PMN-MDSCs emerged as an independent prognostic factor for PFS. PMN-MDSCs, e-MDSCs, and the International Prognostic Index were involved in constructing the nomogram for predicting PFS. Patients with a higher percentage of MDSCs, PMN-MDSCs, e-MDSCs, and CD14 + CD66b + MDSCs experienced a shorter overall survival compared with those with lower percentages. In addition, research on mechanisms found that T cell function was suppressed and mediated by the expansion of MDSCs via involving arginase-1 and interleukin-10 in vitro and in vivo. In conclusion, our study demonstrates that the increased circulating MDSC subsets predict poor clinical efficacy and prognosis in NHL, potentially involving T cell suppression through MDSC subset expansion. These findings indicate the potential of MDSC subsets as comprehensive diagnostic, prognostic biomarkers, and therapeutic targets for NHL.